JP2010501626A - Bifeprunox dose to treat schizophrenia - Google Patents

Abstract

The present disclosure relates to daily doses of bifeprunox for the treatment of patients with schizophrenia. Such a dose is effectively used in a method of treating schizophrenia comprising administering to a patient a pharmaceutical composition comprising an effective amount of at least one bifeprunox compound, Among other effects, it results in reduced side effects associated with schizophrenia treatment such as no weight gain, improved non-fasting triglyceride levels and / or total cholesterol levels. The treatment effect is, for example, a decrease in the PANSS total score in the patient and an increase in time to exacerbation of schizophrenia and improvement of psychotic symptoms.
[Selection figure] None

Description

  The present invention provides a daily dose of bifeprunox for the treatment of patients with schizophrenia, treatment of patients with stable schizophrenia and patients with acute exacerbation of schizophrenia with bifeprunox. And to a pharmaceutical composition comprising a dose of at least one bifeprunox compound.

  Schizophrenia is a mental disorder that interferes with life-long daily life characterized by severe and variable symptoms, including positive and negative symptoms, cognitive impairment and depression. The course of the disease can be divided into four main phases: pre-onset, acute, stable / maintained and late course. Early onset refers to symptoms that occur before the onset of positive symptoms. During the acute phase patients experience overt positive symptoms such as delusions and hallucinations. The stability / maintenance phase can be divided into two subphases. The first 5-10 years of the disease are often characterized by numerous exacerbations of positive symptoms, with more stable periods interspersed between acute episodes. This sub-phase is followed by a plateau period characterized by stabilization of symptoms and a decrease in the number of exacerbations. An important treatment goal during the maintenance phase is to facilitate the return of the patient to the community and to establish a long-term maintenance plan. In the late stages of the disease, positive symptoms tend to decrease with age, and many patients with long-term disability regain some social and professional ability, however, the effects of long-term dysfunction are rare It will not be overcome.

  Further symptoms, including the maintenance of schizophrenia and the late stages, include prevention of recurrence; maintenance of cognitive function; weight gain, prevention of hyperglycemia and dyslipidemia; and improvement of quality of life You continue to face numerous issues such as the need for improvement and long-term control of psychotic symptoms. Furthermore, positive symptoms can be more resistant to treatment with each subsequent episode. Consistent with this concept, 85% to 90% of patients with schizophrenia experience clinical exacerbations. Furthermore, at least half of patients given antipsychotics do not adhere to the prescribed treatment regimen and are therefore at risk of recurrence. Thus, despite an eager effort to improve treatment, the majority of patients with schizophrenia have severe disability; often relapse and may require hospitalization.

  The compounds currently used to treat schizophrenia are associated with several undesirable side effects. These side effects include weight gain, hyperprolactinemia, elevated triglyceride levels, metabolic syndrome (markers: diabetes, hyperlipidemia, hypertension and obesity), prolonged QTc interval, glucose abnormalities and manifestations of extrapyramidal symptoms Is included. For example, an extended QTc interval, ie, a corrected QT interval in the electrocardiogram, can lead to problematic heart rhythms or cardiac arrhythmias. Similarly, the weight gain observed with conventional atypical antipsychotics such as risperidone and olanzapine is associated with an increased risk of cardiovascular disease and diabetes.

  Further, schizophrenia treatment with drugs can be over a long period of time. As such, these undesirable side effects affect patients on a daily basis as well as contributing to their long-term health. These side effects can also lead to non-compliance with the patient's treatment regimen. Even when treatment is limited and / or over a short period of time, side effects affect the patient's willingness to comply with the treatment regimen.

  Accordingly, there is a need for methods to prevent and / or reduce these undesirable side effects and to maintain, reduce and / or improve baseline symptoms in patients undergoing schizophrenia treatment.

  Treating a schizophrenic patient with a dose of at least one bifeprunox compound, in particular comprising a daily dose of 20-30 mg (pharmaceutical composition) is one or more of these side effects and The inventors have found that it is possible to reduce and / or prevent one or more symptoms of schizophrenia. In an embodiment of the invention, the dose is administered once daily. Particular dose embodiments are the 20 mg dose and the 30 mg dose. Particularly preferred is a daily dose of 20 mg.

  The favorable effects of this treatment include reduction of total positive and negative symptom rating scale (PANSS) score in patients, maintenance of body weight, maintenance and / or improvement of triglyceride and / or total cholesterol levels, especially chronic stable schizophrenia Maintaining clinical stability of schizophrenia in patients with illness (treatment effect is, for example, increased time to exacerbation), improvement of one or more psychotic symptoms, or baseline measurement prior to administration This includes, but is not limited to, maintenance and / or reduction of extrapyramidal signs and symptoms (EPS) profiles. Another favorable effect is a reduction in the occurrence of hyperglycemia and / or one or more diabetes-related adverse events.

  In aspects of the invention, bifeprunox is used for long-term treatment of patients with schizophrenia, particularly at daily doses of 20-30 mg. The term “long-term treatment” refers to treatment for at least 3 months or at least 6 months, for example.

  The aspects disclosed herein provide some general overview of the various aspects of the disclosure, but do not limit the scope of the disclosure in any way.

  Bifeprunox compounds are described in US Pat. No. 6,225,312 and US Pat. No. 7,030,241, the contents of which are incorporated herein by reference. The hydrochloride salt of this compound (7- [4-([1,1′-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone (Bifeprunox) is described in WO 97/36893 and Monomethanesulfonate is described and claimed in WO 02/066449. In the second of these patent publications, N, N, N-bis (2-ethanol) -m-phenylbenzylamine The direct formation of monomethane sulfonate by the reaction between the reactive mesylate ester of and 7-amino-2 (3H) -benzoxazolone is disclosed.Stable polymorph of bifeprunox monomethane sulfonate is disclosed Disclosed and claimed in WO 2005/016898 and also encompassed by the term “bifeprunox compound”. Is given bifeprunox N- oxide. Bifeprunox N- oxides, it is disclosed in WO2007 / 023 141 and as claimed.

  Bifeprunox compounds are indicated for the treatment of CNS (Central Nervous System) disorders including schizophrenia, other psychotic disorders (especially psychosis) and Parkinson's disease. In the framework of the present invention, the dosage strength (or dose) is expressed in an amount corresponding to bifeprunox base. As used herein, the term “bifeprunox base” has the following formula:

7- [4-([1,1′-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone (INN bifeprunox) having the formula

  As used herein, the term “bifeprunox compound” refers to the active compound 7- [4-([1,1′-biphenyl] -3-ylmethyl) -1-piperazinyl] -2 (3H) -benzoxazolone, The N-oxide and pharmaceutically acceptable salts, solvates and hydrates thereof. When N-oxide is used as the bifeprunox compound, the amount in milligrams is the same amount that one skilled in the art would choose for a bifeprunox compound without oxide. In addition, pharmaceutically acceptable salts of bifeprunox or its N-oxide can be prepared using standard methods well known in the art, for example, converting a compound of the present invention to a suitable acid, such as an inorganic acid. Alternatively, it can be obtained by mixing with an organic acid.

  The present disclosure maintains and reduces symptoms associated with the treatment of schizophrenia by administering to a patient in need thereof a pharmaceutical composition comprising a dose of at least one bifeprunox compound. And / or relates to the use of bifeprunox in the treatment of schizophrenia to improve. For example, the pharmaceutical composition comprises at least one bifeprunox compound in an amount between 5 mg and 40 mg, such as 10 mg to 40 mg or even eg 20 mg to 30 mg of bifeprunox compound. In one embodiment, bifeprunox is used in the treatment of patients with schizophrenia who have weight problems or are prone to weight problems.

  Aspects of the invention relate to a daily dose of bifeprunox for the treatment of patients with schizophrenia, wherein the dose is 20-30 mg of at least one bifeprunox compound. In particular, the dose is useful for maintaining clinical stability in patients with stable schizophrenia and more particularly chronic stable schizophrenia. The embodiments are a 20 mg dose and a 30 mg dose, respectively.

  In a further aspect, the invention relates to a daily dose of bifeprunox for the treatment of patients with acute exacerbation schizophrenia, wherein the dose is 20-30 mg of at least one bifeprunox compound. The embodiment is a 20 mg dose and a 30 mg dose, respectively, used in the treatment with favorable side effects.

  Aspects of the invention provide for the treatment of patients with psychosis and mood disorders (especially with schizophrenia) in which bifeprunox (ie, at least one bifeprunox compound) is administered in combination with the mood stabilizer lithium Bifeprunox for use in and a kit for said use.

  A further aspect of the invention is the use of in the treatment of patients with CNS disorders (especially with schizophrenia), wherein at least one bifeprunox compound is administered in combination with an antidepressant (especially SSRI, especially paroxetine). For bifeprunox and a kit for the use.

  Further aspects of the invention include CYP2C9 inhibitors (eg fluconazole), CYP3A4 inhibitors (eg ketoconazole and carbamazepine), CYP2D6 inhibitors (eg paroxetine) and H2-antagonists (eg famotidine) and bifeprunox, respectively. (A method for) and a kit for the treatment.

  In an embodiment of the present disclosure, the at least one bifeprunox compound comprises bifeprunox mesylate. Preferably, the at least one bifeprunox compound is bifeprunox mesylate. The bifeprunox mesylate can be selected from α, γ or δ crystal polymorphic forms and mixtures thereof. For example, the at least one bifeprunox compound comprises at least one polymorphic form selected from α and γ polymorphic forms.

  The crystalline polymorphic form of bifeprunox alpha mesylate according to the present disclosure is defined by at least physicochemical parameters as disclosed in WO2005 / 016898.

  In another aspect, the disclosure provides at least about 50 weight percent (wt.%), At least about 60 wt. %, At least about 70 wt. %, At least about 80 wt. %, At least about 90 wt. % Or at least about 95 wt. % Bifeprunox mesylate is a polymorphic alpha form of bifeprunox mesylate. In another embodiment, the pharmaceutical composition is substantially devoid of any gamma or delta polymorphic form of bifeprunox mesylate. In another aspect, the bifeprunox mesylate provided by this disclosure is 10 wt. %, 5 wt. %, 2.5 wt. Less than% gamma or delta polymorphic form of bifeprunox mesylate. In another embodiment, at least about 99 wt. % Bifeprunox mesylate is the polymorphic alpha form.

  The production of polymorph form α can be carried out according to the method described in WO2005 / 016898.

  At least one bifeprunox compound of the present disclosure can be formulated into a dosage form in which the active agent is present in solid form by methods known in the art. Examples of such dosage forms are tablets (optionally coated), capsules, granular aerosols, suppositories and suspensions. Such dosage forms can be made by mixing at least one bifeprunox compound with an inert pharmaceutically acceptable excipient and carrier.

The pharmaceutical composition of the present disclosure can comprise at least one pharmaceutical excipient. Non-limiting examples of suitable excipients include suspending agents (eg, gums, xanthan, cellulose derivatives and sugars), humectants (eg, sorbitol), solubilizers (eg, ethanol, water, PEG and propylene glycol) ), Surfactants (eg, sodium lauryl sulfate, Span, Tween and cetylpyridine), preservatives, antioxidants (eg, parabens and vitamins E and C), anti-caking agents (anti- caking agents), coating agents, chelating agents (eg EDTA), stabilizers, antimicrobial agents, antifungal or antibacterial agents (eg parabens, chlorobutanol, phenol, sorbic acid), isotonic agents (eg sugars, chlorides) Sodium), thickeners (eg methylcellulose), perfumes (eg , Chocolate, salmantin (thalmantin)
), Aspartame, stable other flavors in root beer or watermelon or pH 7-9), antifoaming agents (e.g., simethicone, Mylicon ^(R)), disintegrants, flow aids (flow aid), lubricants, additives, Colorants, diluents, wetting agents, preservatives, carriers, binders (eg, hydroxypropylmethylcellulose, polyvinylpyrrolidone, other cellulosic materials and starches), diluents (eg, lactose and other sugars, starches, second Calcium phosphates and cellulosic materials), disintegrants (eg starch polymers and cellulosic materials), glidants and water-insoluble or water-soluble lubricants or smoothing agents.

  One illustrative dosage form includes lactose monohydrate, microcrystalline cellulose, starch, as well as a milled and screened dose of active substance (bifeprunox as described herein). It comprises sodium glycolate (eg type A), sodium stearyl fumarate and optionally colloidal anhydrous silica. In one embodiment, the lactose is present in an amount of about 20% to about 90%, about 70% to about 90%, or about 75% to about 85% by weight, based on the total weight of the tablet core. . Microcrystalline cellulose is present in an amount of about 5% to about 90%, about 10% to about 15%, or about 11% to about 12% by weight, based on the total weight of the tablet core. Sodium starch glycolate (eg, Type A) is about 0.1% to about 2.5%, about 0.3% to about 0.7% or about 0.00% by weight based on the total weight of the tablet core. Present in an amount of 5% by weight. Sodium stearyl fumarate is present in an amount of about 0.1% to about 1.5%, about 0.6% to about 1.3% or about 1.0% by weight based on the total weight of the tablet core. Exists. Colloidal anhydrous silica may optionally be added to the formulation to improve the flow characteristics of the powder. If desired, colloidal anhydrous silica is typically present in an amount from about 0.05% to about 0.5% or about 0.4% by weight, based on the total weight of the tablet core. The amount of optional coating is from about 2.0% to about 5.0%, from about 3.0% to about 4.0% or about 3.5% by weight based on the total weight of the tablet core. is there.

  In at least one embodiment, a pharmaceutical composition comprising at least one bifeprunox compound of the present disclosure can be administered to a patient in need thereof, such as a human patient.

  The present disclosure also reduces PANSS total score in patients, maintains weight, maintains and / or improves triglyceride and / or total cholesterol levels, maintains clinical stability of schizophrenia It also relates to, but is not limited to, improving one or more psychotic symptoms or maintaining an EPS profile similar to baseline measurements prior to administration. The present disclosure also relates to a method of reducing the occurrence of hyperglycemia and / or diabetes related adverse events. These methods are illustrated in the following clinical examples provided below.

  US patent application Ser. Nos. 10 / 920,361, 10 / 920,386 and 11 / 354,652 are hereby incorporated by reference in their entirety. It is understood that all data herein are approximate and subject to normal measurement errors due to, for example, the equipment used and other parameters affecting peak position and peak intensity. Unless otherwise specifically defined or otherwise required by context, the term “about” generally means ± 5% of the recited value as used herein.

Panel 34 Shows the PANSS positive score (FAS, LOCF). Panel 35 Shows the PANSS negative score (FAS, LOCF). Panel 36 Shows the PANSS total psychopathology score (FAS, LOCF). Panel 42 Shows the percentage of patients with a reduction of at least 25% of the PANSS total score (FAS, LOCF). Panel 432 shows the percentage of patients with a CGI-I score of 2 or less (FAS, LOCF).

  The following examples are only intended to further illustrate the present disclosure in more detail, and therefore these examples are in no way considered to limit the scope of the present disclosure.

Example 1. Efficacy of bifeprunox in the treatment of schizophrenia A 6-week, randomized, double-blind, placebo-controlled and risperidone reference study to evaluate the efficacy and safety of a fixed dose of bifeprunox in the treatment of schizophrenia Using. A total of 599 patients were randomized.

  Treatment began with a simple blind placebo induction period of at least 3 days, followed by bifeprunox titration from 0.25 mg to 30 mg / day or 40 mg / day for bifeprunox treated patients. Risperidone-treated patients were titrated from 2 mg to 6 mg daily over a 3 day period and maintained at 6 mg / day for the remainder of the treatment period.

  To measure the change in PANSS total score from baseline to endpoint, rating scale assessments were performed weekly except week 5. Other assessments include: PANSS positive symptom subscale score, PANSS negative symptom subscale score, PANSS total psychopathology subscale score, BPRS total score, BPRS psychosis score, CGI-S score, CGI-I score, PANSS total score Responder rates based and the Calgary Depression Scale for Schizophrenia (CDSS) for schizophrenia were included.

  For safety and tolerability measurements, physical examinations, body weight, waist circumference, vital signs, 12-lead electrocardiogram (ECG), clinical laboratory evaluation (hematology, biochemistry, urinalysis, prolactin, IGF-1, IGFBP -3, specific laboratory evaluation of thyroid function), the need for anticholinergic treatment during the double-blind treatment period, concomitant drug use, adverse event monitoring and normal movement assessments are included It was.

  The 20 mg bifeprunox treatment group showed a statistically significant difference from placebo for the primary endpoint of change from baseline to endpoint in the PANSS total score. The mean change (standard deviation) from baseline to endpoint in the PANSS total score was -13.5 (20.1) for the 30 mg bifeprunox group and -10.3 (20.5) for the 40 mg bifeprunox group. ), -7.7 (19.2) for the placebo group and -19.7 (19.3) for the risperidone group.

  The 30 mg bifeprunox group showed significant differences from placebo for CGI-S score, PANSS negative symptom subscale score and PANSS positive symptom subscale score. Notable differences are also seen in the 30 mg bifeprunox for changes from baseline to endpoint in PANSS Total Psychiatric Subscale Score, BPRS Total Score, BPRS Psychiatric Cluster Score, PANSS Responder Rate and CGI-I Responder Rate Recognized between group and placebo. In this study, a PANSS responder refers to a patient whose PANSS total score has decreased by more than 20% from baseline to endpoint. A CGI-I responder refers to patients who are classified as “significantly improved” or “moderately improved” on the CGI overall improvement rating scale at the endpoint.

The 40 mg bifeprunox group had a PANSS positive symptom subscale score and BPRS
The change in the psychotic cluster score was markedly different from placebo.

  There was a decrease in body weight in the bifeprunox treatment group as opposed to an increase in the placebo and risperidone treatment groups.

  The bifeprunox group has a lower incidence of N → H shifts in triglycerides, VLDL and LDL and a higher incidence of N → L shifts in total cholesterol and VLDL compared to placebo and risperidone groups Had.

Example 2 Clinical study on bifeprunox in the treatment of schizophrenia Example 2a-Clinical study 1
Objective : The primary objective of this clinical study was to use the change from baseline to endpoint of the positive and negative symptom scale (PANSS) total score as the primary outcome measure scale at 5 mg, 10 mg, or 20 mg bifeprunox. It was to see if the 6 week treatment was superior to the placebo treatment in adult patients with schizophrenia. Secondary objectives included: PANSS positive symptom subscale score, PANSS negative symptom subscale score, PANSS comprehensive psychopathology subscale, PANSS-derived simplified psychiatric symptom scale (BPRS) total score, PANSS-derived BPRS psychosis, In treating schizophrenia using the responder rate and the CGI-I responder rate based on the clinical overall impression disease severity score (CGI-S), clinical overall impression improvement score (CGI-I), and PANSS total score It was to evaluate the efficacy of bifeprunox. Physical findings, body weight, vital signs (including pulse rate and systolic blood pressure (BP) —both 5 minutes after lying down and 2 minutes after standing), as well as oral temperature ), 12-lead electrocardiogram (ECG), safety assessment including hematology, biochemistry and urinalysis, need for anticholinergic treatment during double-blind treatment, concomitant drug use, adverse event monitoring, As well as assessing the safety and tolerability of bifeprunox using the assessment of abnormal movements, including the Simpson-Angus Rating Scale (SAS), Burns Acathisia Rating Scale (BAS), and Abnormal Involuntary Movement Rating Scale (AIMS) That was also the purpose of this study.

Methodology : This was a randomized, double-blind, fixed-dose placebo-controlled risperidone reference parallel group multicenter study in adult patients with schizophrenia. There were five treatment groups in this study. Treatment groups were as follows: bifeprunox 5 mg, bifeprunox 10 mg, bifeprunox 20 mg, risperidone 6 mg and placebo. Study drug was administered once daily. After baseline measurements were taken, the drop period started. Patients treated with bifeprunox were on a standardized titration schedule (1 day: 0.125 mg, 2 days: 0.25 mg, 3 days: 0.5 mg, 4 days: 1.0 mg, 5 days: 2.0 mg, 6 days: 5 1.0 mg, 7 days: 10.0 mg, 8 days: 20 mg) to 5 mg, 10 mg or 20 mg. Upon reaching the specified dose, the patient was maintained at that dose for the remainder of the 6 week treatment period. Risperidone-treated patients were titrated to 6 mg over 3 days using a once daily regimen (1 day: 2 mg, 2 days: 4 mg, 3 days: 6 mg).

Number of patients (planned, screened, randomized and analyzed) : A total of 575 patients with schizophrenia were planned to be included in the study. A total of 836 patients were screened at 40 centers and a total of 589 patients (5 mg bifeprunox: 115 patients; 10 mg bifeprunox: 120 patients; 20 mg bifeprunox: 115 patients; Placebo: 119 patients; risperidone: 120 patients) were randomly sampled at 37 centers.

Test product, dose and mode of administration : Bifeprunox tablets, total daily dose of 0.125 mg to 20 mg, administered orally using a once daily dosing regimen.

Reference treatment, dose and mode of administration : Placebo and risperidone, 2 mg to 6 mg, administered orally using a once daily dosing regimen.

Efficacy results : 20 mg bifeprunox dose reduces both positive and negative symptoms of schizophrenia compared to placebo as shown by statistically significant comparisons from analysis of PANSS total and subscale scores As well as reducing total psychopathology. Patients in the 20 mg bifeprunox group had 5.8 points greater improvement from baseline in the PANSS total score compared to placebo patients. Lower doses of bifeprunox were not effective. The 10 mg dose of bifeprunox did not show a statistically greater improvement for any efficacy endpoint. The 5 mg dose showed greater improvement with respect to several secondary efficacy measures compared to placebo, but did not show any advantage over placebo for the primary efficacy endpoint (PANSS total score). Risperidone 6 mg was used as an active reference in this study and showed a clear separation from the placebo group. In general, the magnitude of improvement seen in the 20 mg bifeprunox group was less than that seen in the risperidone group for most efficacy endpoints.

Safety results : The proportion of patients with adverse events (TEAE) that occurred under at least one treatment was similar across treatment groups: 89% in the 5 mg bifeprunox group (102 patients), 10 mg bifepuru 87% in the Knox group (104 patients), 83% in the 20 mg bifeprunox group (95 patients), 85% in the placebo group (101 patients), and 89% in the risperidone group (107 patients) ). Overall, from 349 patients treated with bifeprunox, the most frequently reported TEAEs were headache, dyspepsia, insomnia, nausea, vomiting NOS, constipation and agitation. TEAEs with a higher incidence ( > 5% difference) in the 20 mg bifeprunox group (N = 114 patients) compared to the placebo group (N = 119 patients) have constipation, dyspepsia and Vomiting NOS was included. Related TEAEs with a higher incidence ( > 5% difference) in the 20 mg bifeprunox group compared to placebo were constipation, vomiting NOS and headache NOS. The proportion of patients with at least one serious TEAE was lowest in the 20 mg bifeprunox group (11 patients, 10%), followed by the placebo group (15 patients, 13%). For the remaining groups, the proportion of patients with at least one serious TEAE was between 16% and 18%. The incidence of TEAEs considered severe was similar between the 20 mg bifeprunox group and the placebo group for all TEAEs (<5% difference). There was no dose-dependent trend in the bifeprunox group in the overall incidence observed for any event, the incidence of related TEAEs or the incidence of severe TEAEs.

The total number of patients with at least one SAE was higher in the active treatment group compared to the placebo group (9%) (bifeprunox group: 12-15%, risperidone group: 16%). The most commonly reported SAE ( > 5% in any treatment group) was exacerbated psychosis and exacerbated schizophrenia NOS. There was a slightly higher incidence of exacerbated schizophrenia NOS in the 20 mg bifeprunox group (8 patients, 7%) compared to placebo and risperidone (5 patients, 4% each). Suicide attempts are for 1 patient in the 10 mg bifeprunox group (<1%), 2 patients in the 20 mg bifeprunox group (2%), 0 patients in the placebo group and 0 patients in the risperidone group Reported. Serious adverse events of suicidal ideation were reported for 1 patient each (<1%) in the 10 mg bifeprunox and risperidone groups (1 additional patient in the 20 mg bifeprunox group was not Experienced severe adverse events). No trend for a dose-dependent increase in the incidence of any SAE was observed for the bifeprunox group. Bifeprunox was safe and well tolerated at all dose levels. The total number of patients with at least one AE leading to withdrawal was similar between treatment groups (5 mg bifeprunox: 13 patients, 11%; 10 mg bifeprunox: 17 patients, 14%; 20 mg bifeprunox: 11 patients, 10%; placebo: 15 patients, 13%; risperidone: 17 patients, 14%). The most common AEs (reported by> 2% of patients in any treatment group) leading to withdrawal were agitation, exacerbated psychosis and exacerbated schizophrenia NOS. There were no treatment group differences in the incidence of AEs leading to study drug discontinuation between the 20 mg bifeprunox group and the placebo group. There was no trend for a dose-dependent increase in the incidence of AEs leading to withdrawal in the bifeprunox group. Evaluation of laboratory tests, vital signs, ECG and physical findings did not raise any unexpected safety concerns. Bifeprunox patients showed a decrease in prolactin compared to the placebo group. Mild weight loss was observed in the bifeprunox group, but not in the placebo or risperidone groups.

  There was no significant difference between treatment groups in changes from baseline to endpoint in BAS, SAS or AIMS scores. The use of anticholinergics for patients treated with bifeprunox was similar to that of patients with placebo and was less than in patients with risperidone.

Conclusion : One conclusion of the study is that a 20 mg dose of bifeprunox given once daily for 6 weeks was effective in reducing both positive and negative symptoms of schizophrenia. Overall, all doses of bifeprunox were safe and well tolerated by schizophrenic patients. There was no safety / tolerance dose-response relationship.

Example 2b-Clinical Study 2
Primary objective : 6 weeks at a fixed dose of bifeprunox (30 mg / day or 40 mg / day) using changes from baseline to endpoint of the positive and negative symptom scale (PANSS) total score as the primary outcome To determine whether treatment can show superior efficacy compared to placebo in adult patients with schizophrenia.

Secondary objectives : PANSS positive symptom subscale score, PANSS negative symptom subscale score, PANSS comprehensive psychopathology subscale, PANSS-derived simplified psychiatric symptom scale (BPRS) total score, PANSS-derived BPRS psychosis score, Using the Clinical Overall Impression Disease Severity Score (CGI-S), Clinical Overall Impression Improvement Score (CGI-I), Responder Rate Based on PANSS Total Score, Schizophrenia Calgary Depression Rating Scale (CDSS) and Patient Satisfaction To assess the efficacy of bifeprunox in treating schizophrenia. Bifeprunox pharmacokinetic (PK) data in patients with schizophrenia is also evaluated and presented in a separate report (along with data from Study S1540303). Physical findings, body weight, waist circumference, vital signs (pulse rate and systolic / minimum blood pressure [BP] —both 5 minutes after lying down and 2 minutes after standing, as well as oral temperature), 12-lead electrocardiogram (ECG), clinical examination Evaluation (hematology, biochemistry, urinalysis, prolactin, specific test evaluation for IGF-1, IGFBP-3 and thyroid function), need for anticholinergic treatment during double-blind treatment period, concomitant medications Bifeprunox with use, adverse event (AE) monitoring, and evaluation of abnormal movements, including the Simpson-Angus Rating Scale (SAS), Burns Acathisia Rating Scale (BAS) and Abnormal Involuntary Movement Rating Scale (AIMS) Assess the safety and tolerability of

Methodology : This was a Phase III 6-week randomized, double-blind, placebo-controlled risperidone-referenced parallel multicenter study of bifeprunox efficacy, tolerability and safety in adult patients with schizophrenia. Patients who completed this study had the option of continuing over time. The treatment groups were: bifeprunox 30 mg / day, bifeprunox 40 mg / day, risperidone 6 mg / day and placebo. After completing at least 3 days of a single blind placebo induction period, bifeprunox-treated patients were titrated from 0.25 mg to 30 mg / day or 40 mg / day according to a standardized titration scheme over a period of 8 days. Upon reaching the specified dose, the patient was maintained at that dose for the remainder of the 6 week treatment period. Risperidone-treated patients were titrated from 2 mg to 6 mg daily for a period of 3 days and then maintained at 6 mg / day for the remainder of the treatment period. Rating scale assessments of efficacy and abnormal movement disorders were performed every week except week 5. Safety assessments were performed at screening, during treatment and at the end of the study. Patient satisfaction with study drugs was assessed at 6 weeks. Blood samples were obtained at 2, 4 and 6 weeks for measurement of bifeprunox in plasma. Blood samples were also obtained at screening / baseline, 3 and 6 weeks for clinical laboratory evaluation.

Number of patients (planned, approved, randomized and analyzed) : A total of 576 patients with schizophrenia were planned to be included in the study. Of the 783 screened patients, a total of 599 patients were randomized (30 mg bifeprunox: 148 patients, 40 mg bifeprunox: 148 patients, placebo: 149 patients; risperidone: 154 Human patient).

Main criteria for diagnosis and inclusion : Male or female patients aged 18-75 with schizophrenia (according to DSM-IV-TR criteria). The patient must have a total PANSS score between 70-120; at least two of the four PANSS items (concept integration failure, hallucinatory behavior, suspicion, unnatural thought content) Must have a score > 4; and the score on CGI-S must be at least 4.

Reference treatment, dose and mode of administration : placebo and risperidone, 6 mg, administered orally once daily.

Efficacy results : The 30 mg bifeprunox treatment group was given placebo for the primary endpoint of change from baseline to endpoint in the PANSS total score (LOCF) based on the Hochberg corrected p-value (corrected p = 0.020). The statistically significant difference was shown. The 40 mg bifeprunox treatment group was not significantly different from the placebo group for the primary efficacy endpoint (corrected p = 0.156). The mean change from baseline to endpoint (SD) in the PANSS total score was -13.5 (20.1) for the 30 mg bifeprunox group, -10.3 (20.5) for the 40 mg bifeprunox group, -7.7 (19.2) for the placebo group and -19.7 (19.3) for the risperidone group. Treatment effect values (for mean change from baseline at endpoint [LOCF]) corresponding to the difference between bifeprunox and placebo are: -5.9 for the 30 mg bifeprunox group, and 40 mg bifeprunox It was -3.2 for the group. No statistically significant difference based on the planned step-down method was seen in the change from baseline to endpoint of CGI-S for the 30 mg bifeprunox treatment group compared to placebo. Therefore, the difference between the placebo and 30 mg bifeprunox groups for changes from baseline to endpoint in the PANSS negative symptom and PANSS positive symptom subscale scores was calculated using the step-down method for statistical significance compared to placebo. Was not evaluated. The 30 mg bifeprunox group has a CGI-S score (nominal p = 0.028), a PANSS negative symptom subscale score (nominal p = 0.027), and a PANSS positive symptom subscale score (nominal p = 0.0). 010) was markedly different from placebo.

  Notable differences are PANSS total psychopathology subscale score (p = 0.025), BPRS total score (p = 0.199), BPRS psychosis cluster score (p = 0.002), PANSS (30%) responder rate A change from baseline to endpoint was observed between the 30 mg bifeprunox group and placebo in (p = 0.019) and CGI-I responder rate (p = 0.039). No significant differences in endpoints were observed between the 30 mg bifeprunox group and placebo for patient satisfaction (p = 0.051), CGI improvement score or CDSS score. For the 40 mg bifeprunox group, no statistically significant difference from placebo was found for the primary efficacy parameters. A significant difference from placebo was the 40 mg bifeprunox group for both secondary efficacy parameters except for the PANSS positive symptom subscale score (p = 0.020) and the BPRS psychosis cluster score (p = 0.031). It was not recognized.

Safety results : The proportion of patients with at least one TEAE was similar in the bifeprunox dose group (74% -76%) and higher than the placebo group (64%) but in the risperidone group (78% ) Was slightly lower than in AEs expressed under treatment with a higher incidence ( > 5% difference) in the bifeprunox group compared to the placebo group included nausea, vomiting, constipation, dyspepsia, diarrhea and dizziness. Differences between the bifeprunox treatment groups were generally not observed in the incidence of individual TEAEs in the bifeprunox group. Among the TEAEs that occur in at least 5% of patients in any treatment group have a higher incidence ( > 2% difference) in the 40 mg bifeprunox group compared to the 30 mg bifeprunox group, nausea, Vomiting, toothache, loss of appetite, inability to sit still, dizziness, headache and insomnia were included. In contrast, dry mouth, hypersalivation, decreased appetite, sedation, somnolence, anxiety and vaginitis are higher in the 30 mg bifeprunox group ( > 2% difference) than in the 40 mg bifeprunox group Happened in. The incidence of severe TEAEs was generally low ( < 1) except for TEAEs with psychotic disorders ( < 6%) and schizophrenia (3% each in the bifeprunox and placebo groups and 2% in the risperidone group). % Incidence). The incidence of severe TEAEs was generally similar across treatment groups, and there was no difference between the bifeprunox treatment groups in the incidence of severe TEAEs for any event. Certain interesting TEAEs were defined before database lock and included events related to suicide, attempted suicide, sexual dysfunction, syncope, vasovagal seizures and orthostatic hypotension. A total of 76 patients (13%) reported at least one specific interesting TEAE during the study. The proportion of patients with at least one specific interesting TEAE was higher in the bifeprunox and risperidone treatment groups (12% to 16%) compared to the placebo group (6%). The majority of certain interesting TEAEs occurred in < 1% of patients in any treatment group. Vertigo was most commonly reported and occurred at a slightly higher incidence in the bifeprunox treatment group compared to the other two groups.

A total of 60 patients (10%) experienced 81 SAEs (including death). Most SAEs occurred in < 1% of patients. Exceptions were psychotic disorders ( < 5%) and schizophrenia (3% in each of the four treatment groups). The incidence of SAE was similar between the bifeprunox group and placebo. There was no significant difference between treatment groups on the abnormal movement rating scale (BAS, SAS or AIMS score). The use of anticholinergics for patients treated with bifeprunox was similar to that of patients treated with placebo. Overall, there were no clinically significant changes in laboratory parameters, physical findings or ECG readings with bifeprunox. The bifeprunox group had a lower incidence of N → H shift in triglycerides, VLDL and LDL and a higher incidence of N → L shift in total cholesterol and VLDL compared to placebo and risperidone groups. The incidence of markedly abnormal total cholesterol levels was similar across treatment groups (1% -2%). Significantly abnormal triglyceride levels were reported by slightly fewer patients in the 40 mg bifeprunox group compared to the other groups. Slightly greater incidence of N → H shift of triiodine thyronine in the 30 mg bifeprunox and risperidone groups (6% each) compared to the placebo (4%) and 40 mg bifeprunox (5%) groups and placebo (2 %) And risperidone (<1%) groups had a slightly greater incidence of N → L shift of TSH in 30 mg bifeprunox (4%) and 40 mg bifeprunox (5%). There was a slightly similar decrease in body weight in the bifeprunox treatment group as opposed to an increase in the placebo and risperidone treatment groups. The incidence of significantly abnormal weight loss was slightly higher in both bifeprunox treatment groups compared to the placebo and risperidone groups, while the incidence of significantly abnormal weight gain was relative to the bifeprunox and placebo groups. It was higher in the risperidone treatment group.

Conclusion : One conclusion of this study is that a 30 mg dose of bifeprunox given once daily for 6 weeks alleviates symptoms of schizophrenia as indicated by a statistically significant comparison from the analysis of the PANSS total score It was effective in. Patients in the 30 mg bifeprunox group had a 5.9 point greater improvement from baseline to endpoint in the PANSS total score compared to placebo patients based on LOCF data. The statistically significant difference observed between the active control drug, risperidone and placebo for primary and secondary efficacy parameters indicates that this is an effective study.

  The 30 mg bifeprunox treatment group shows significant differences from placebo for changes from baseline to endpoint in the three key secondary efficacy endpoints, CGI-S, PANSS negative and positive symptom subscale scores (Based on nominal p-value); No statistical significance was obtained for these three key secondary efficacy endpoints based on the step-down method. A notable difference was 30 mg bifeprunox at the endpoint for most of the other secondary efficacy parameters (change from baseline to endpoint in the PANSS total psychopathology subscale score, BPRS total score and BPRS psychosis cluster score). Recognized between group and placebo. A significant difference between the 30 mg bifeprunox dose and placebo was also shown at the endpoints for PANSS and CGI-I responder rates. The 40 mg bifeprunox treatment group showed no statistically significant difference from placebo for primary efficacy parameters. There were no significant differences between the 40 mg bifeprunox and placebo groups for any of the secondary efficacy parameters except for the PANSS positive symptom subscale and the BPRS cluster score. Overall, the 30 mg and 40 mg doses of bifeprunox were safe and were well tolerated by schizophrenic patients.

Example 2c: Clinical study 3
Primary objective : 6 weeks at a fixed dose of bifeprunox (20 mg / day or 30 mg / day) using changes from baseline to endpoint in the positive and negative symptom scale (PANSS) total score as the primary outcome To determine whether treatment can show superior efficacy compared to placebo in adult patients with schizophrenia.

Secondary objectives : PANSS positive symptom subscale score, PANSS negative symptom subscale score, PANSS comprehensive psychopathology subscale, PANSS-derived simplified psychiatric symptom scale (BPRS) total score, PANSS-derived BPRS psychosis score, Clinical General Impression Disease Severity Score (CGI-S), Clinical General Impression Improvement Score (CGI-I), CGI-I Responder Rate, PANSS Responder Rate Based on PANSS Total Score, Calgary Depression Rating Scale (CDSS) for Schizophrenia ) And patient satisfaction to assess the efficacy of bifeprunox in treating schizophrenia. Physical findings, body weight, waist circumference, vital signs (pulse rate and systolic blood pressure [BP] and oral temperature), 12-lead electrocardiogram (ECG), laboratory tests (hematology, fasting insulin levels, fasting glucose, fasting) Specific chemistry evaluation of biochemistry, urinalysis, prolactin, IGF-1, IGFBP-3 and thyroid function) including lipid profile, need for anticholinergic treatment during double-blind treatment, use of concomitant medications Of bifeprunox using adverse event (AE) monitoring, and assessment of abnormal movements, including the Simpson-Angus Rating Scale (SAS), Burns Acathisia Rating Scale (BAS) and Abnormal Involuntary Movement Rating Scale (AIMS) Assess safety and tolerability.

Methodology : This was a phase III 6-week randomized, double-blind, placebo-controlled, olanzapine-referenced, parallel, multicenter study of bifeprunox efficacy, tolerability and safety in adult patients with schizophrenia. There were four treatment groups in this study, approximately 144 patients per treatment group. Treatment groups were: bifeprunox 20 mg / day, bifeprunox 30 mg / day, olanzapine 15 mg / day and placebo. After completing a simple blind placebo induction period of at least 3 days, bifeprunox-treated patients were titrated from 0.25 mg to 20 mg / day or 30 mg / day according to a standardized titration scheme over a period of 7 or 8 days, respectively. Upon reaching the specified dose, the patient was maintained at that dose for the remainder of the 6 week treatment period. Olanzapine-treated patients began dosing at 10 mg / day over the first 7-day period and then maintained at 15 mg / day for the remainder of the treatment period. The patient was admitted after confirmation of study eligibility (if not already an inpatient) until at least 10 days after baseline starting from the Screening Visit. The patient could be hospitalized for longer than 10 days if deemed medically necessary by the researcher. Rating scale assessments of efficacy and abnormal movement disorders were performed every week except week 5. Safety assessments were performed at screening, during treatment and at the end of the study. Patient satisfaction with study drugs was assessed at 6 weeks. Whole blood samples were obtained at 2, 4 and 6 weeks for measurement of bifeprunox in plasma.

Number of patients (planned, approved, randomized and analyzed) : A total of 576 patients with schizophrenia were planned to be included in the study. A total of 814 patients were screened at 32 centers and a total of 604 patients (20 mg bifeprunox: 154 patients, 30 mg bifeprunox: 150 patients; placebo: 150 patients; olanzapine: 150 (Patients) were randomly sampled at 32 institutions.

Main criteria for diagnosis and inclusion : Male or female patients aged 18-75 with schizophrenia (according to DSM-IV-TR criteria). The patient must have a total PANSS score between 70-120; at least two of the four PANSS items (concept integration failure, hallucinatory behavior, suspicion, unnatural thought content) Must have a score > 4; the score on the CGI-S must be at least 4.

Test product, dose and mode of administration : Bifeprunox tablets, total daily dose 20 mg or 30 mg (one 20 mg tablet and one 10 mg tablet), administered orally using a once daily dosing regimen.

Reference treatment, dose and mode of administration : Placebo and olanzapine, 5 mg and 15 mg, administered orally using a once daily dosing regimen.

Efficacy results : Both the 20 mg and 30 mg treatment groups showed improvement over baseline at the endpoint, but showed no efficacy when compared to the placebo group with respect to primary and key secondary efficacy parameters. However, the 20 mg bifeprunox group showed a marked improvement over the placebo group in terms of changes from baseline to endpoint in the secondary efficacy parameter, CGI improvement score (nominal p = 0.027). In yet another secondary efficacy parameter, the difference between the 20 mg bifeprunox group and the approached placebo group is significant for the PANSS-20% responder rate (p = 0.061). However, these occurrences of significant and near-significant differences between secondary efficacy parameters do not exceed what is expected to happen by chance, ie 5% of treatment comparisons. In all other secondary and key secondary parameters, none of the bifeprunox treatment groups showed significant improvement over the placebo group for any efficacy endpoint. A 15 mg dose of olanzapine was used as an activity control in this study. The difference in PANSS total score between olanzapine and placebo was analyzed according to sensitivity analysis. These results indicated that olanzapine was significantly different from placebo (p <0.001). In general, the magnitude of improvement seen in the bifeprunox dose group was higher than that seen in the placebo group, but was lower than that seen in the olanzapine group for most efficacy endpoints.

Safety results : The proportion of patients with adverse events (TEAE) that occurred under at least one treatment was highest in the 20 mg bifeprunox group (126 patients, 82%), followed by 30 mg bifeprunox ( 115 patients, 77%), olanzapine (110 patients, 73%), and placebo (107 patients, 72%). Overall, from 304 patients treated with bifeprunox, the most frequently reported TEAEs were headache, nausea, vomiting, dyspepsia and insomnia. TEAEs with a higher incidence ( > 5% difference) in the bifeprunox group compared to the placebo group included nausea, vomiting and constipation. In general, no clear dose-dependent increase in the incidence of individual TEAEs was observed in the bifeprunox group. TEAEs with a slightly higher incidence ( > 2% difference) in the 30 mg bifeprunox group compared to the 20 mg bifeprunox group included fatigue, dizziness and sedation. The proportion of patients with at least one serious TEAE was similar in the bifeprunox and placebo groups (9% -12%) and slightly lower in the olanzapine treatment group (6%). There was no evidence of a dose-dependent increase in the incidence of serious TEAEs in the bifeprunox group for any event. Certain interesting TEAEs were defined prior to database lock and included the following events: suicide, attempted suicide, sexual dysfunction, syncope, vasovagal seizures and orthostatic hypotension. A total of 58 patients (10%) reported at least one specific interesting TEAE during the study. The total number of patients with at least one specific interesting TEAE was compared to the placebo (11 patients, 7%) or olanzapine (10 patients, 7%) group with the bifeprunox treatment group (30 mg bifepul). Knox; 20 patients, 13%; 20 mg bifeprunox; 17 patients, 11%). The majority of certain interesting TEAEs occurred in < 1% of patients in any treatment group. The most commonly reported TEEA of interest is dizziness, which had a slightly higher incidence in the bifeprunox treatment group compared to the other two groups (30 mg bifeprunox: 15 patients 10%; 20 mg bifeprunox: 13 patients, 8%; placebo: 9 patients, 6%; olanzapine: 8 patients, 5%). Other particularly interesting TEAEs that occur in at least two patients in the treatment group include vasovagal syncope (30 mg bifeprunox: 2 patients) and orthostatic hypotension (30 mg bifeprunox: 3 Patient) was included.

The proportion of patients with at least one SAE was the lowest in the olanzapine treatment group (6 patients, 4%), followed by the bifeprunox group (20 mg: 15 patients, 10%; 30 mg: 12 The highest incidence of SAE was found in the placebo group (20 patients, 13%). The most commonly reported SAEs were psychotic disorders (4% overall) and schizophrenia (2% overall). The incidence of these SAEs was similar or lower in the bifeprunox group compared to the placebo group. Two patients in the 30 mg bifeprunox group had SAE of vasovagal syncope compared to 0 patients in the other treatment group. Apart from this possible exception, there was no other significant indication of a dose-dependent increase in the incidence of any other SAE seen for the bifeprunox group. The percentage of patients who discontinued study medication due to AEs was highest in the placebo group (11%), followed by the bifeprunox group (8% each) and the olanzapine treatment group (6%). The proportion of patients with at least one AE leading to study termination is greatest in the placebo group (12%), with comparable proportions of 20 mg bifeprunox (8%), 30 mg bifeprunox (7%) and In the olanzapine (6%) treatment group had at least one AE leading to study termination. The most common AEs (reported by > 2% of patients in any treatment group) leading to study drug discontinuation were psychotic disorders and schizophrenia. There was no clear trend of dose-dependent increase in the incidence of AEs leading to study drug discontinuation in the bifeprunox group. Examination, vital signs and evaluation of ECG results did not raise any unexpected safety concerns. Patients in the bifeprunox group showed a decrease in prolactin compared to patients in the placebo and olanzapine groups. The incidence of significantly abnormal weight loss was similar between the bifeprunox and placebo groups (5% -6%) and low in the olanzapine treatment group (<1%). The incidence of markedly abnormal increases in body weight was similar in the bifeprunox and placebo groups (1% to 3%) and much higher in the olanzapine group (19%). There was no significant difference between treatment groups in changes from baseline to endpoint in BAS, SAS or AIMS scores. The use of anticholinergics for patients treated with bifeprunox was similar to that of patients with placebo.

Description and Conclusion : This is a 6-week randomized, double-blind, fixed-dose placebo control of the efficacy, tolerability and safety of bifeprunox with olanzapine activity reference in the treatment of 604 patients with schizophrenia It was a parallel group multicenter study. The study was conducted at 32 institutions in the United States (26), Colombia (3) and India (5).

  This was an effective study evidenced by results showing statistically significant differences between the active control olanzapine and placebo treatments for the primary efficacy parameters.

  Both the 20 mg and 30 mg treatment groups showed improvement over baseline at the endpoint, but showed no efficacy when compared to the placebo group with respect to primary and key secondary efficacy parameters. However, the 20 mg bifeprunox group showed a marked improvement over the placebo group in terms of changes from baseline to endpoint in the secondary efficacy parameter, CGI improvement score (nominal p = 0.027). In yet another secondary efficacy parameter, the difference between the 20 mg bifeprunox group and the approached placebo group is significant for the PANSS-20% responder rate (p = 0.061). However, these occurrences of significant and near-significant differences between secondary efficacy parameters do not exceed what is expected to happen by chance, ie 5% of treatment comparisons. In all other secondary and key secondary parameters, none of the bifeprunox treatment groups showed significant improvement over the placebo group for any efficacy endpoint.

  A 15 mg dose of olanzapine was used as an activity reference in this study. In general, the magnitude of improvement seen in the bifeprunox dose group was higher than that seen in the placebo group, but was lower than that seen in the olanzapine group for most efficacy endpoints.

  In contrast, in the large study in Clinical Study 1, the 20 mg bifeprunox dose was higher in schizophrenia compared to placebo as indicated by statistically significant comparisons from the analysis of the PANSS total and subscale scores. It was effective in reducing both positive and negative symptoms and reducing overall psychopathology. In this study, using an observed values analysis of changes in PANSS total score from baseline to 6 weeks, the results were 20 mg bifeprunox (−24.42 [15.6]), 30 mg bifeprunox. (−24.56 [17.02]) and olanzapine (−29.11 [16.88]) groups are more similar, however, the placebo group also has similar results (−22.29 [19.14]. ])showed that. This indicates that patients who remained in the study for 6 weeks responded well to their treatment regimen.

  Bifeprunox was well tolerated at both dose levels. The withdrawal rate due to adverse events was lower in the bifeprunox group compared to the placebo group. Adverse events that occur more frequently in bifeprunox-treated patients than in placebo patients were primarily gastrointestinal and of mild to moderate severity. Only 2 patients discontinued study drug due to gastrointestinal AE (in 20 mg bifeprunox group) (1 patient discontinued due to nausea and 1 patient discontinued due to nausea and vomiting) did). The proportion of patients with at least one SAE was lower in the bifeprunox group (7% -8%) compared to the placebo group (13%). The most commonly reported SAEs were psychotic disorders (4% overall) and schizophrenia (1% overall). The incidence of these SAEs was similar or lower in the bifeprunox group compared to the placebo group. Two patients in the 30 mg bifeprunox group had SAE of vasovagal syncope compared to 0 patients in the other treatment group. Apart from this possible exception, there was no other significant indication of a dose-dependent increase in the incidence of any other SAE for the bifeprunox group. Examination, vital signs and evaluation of ECG results did not raise any unexpected safety concerns. Bifeprunox was found in previous studies and was associated with a decrease in prolactin consistent with that expected based on the drug's partial dopamine agonist profile, and was not associated with any AE. In contrast, increased prolactin was observed in the placebo and olanzapine groups. A slight decrease in average body weight was observed in the bifeprunox group, while an increase in body weight was observed in the olanzapine group. The incidence of significantly abnormal weight loss was comparable between the bifeprunox and placebo groups (5% -6%) and low in the olanzapine treatment group (1%). The incidence of markedly abnormal increases in body weight was similar in the bifeprunox and placebo groups (1% -3%) and much higher in the olanzapine (19%) group. These results are consistent with those observed in other bifeprunox studies, and weight gain is considered a problem for atypical antipsychotics and may be associated with increased risk of cardiovascular disease and diabetes It is worth noting.

  There were no significant differences between treatment groups with respect to the abnormal movement rating scale (BAS, SAS or AIMS score). The use of anticholinergics for patients treated with bifeprunox was similar to that of patients with placebo. The incidence of extrapyramidal disorders was low in all groups (bifeprunox group: <1% to 3%; olanzapine: 1%; placebo: 3%). The 20 mg and 30 mg doses of bifeprunox did not show a statistically significantly greater improvement compared to placebo for most efficacy endpoints. A better CGI improvement score was seen in the 20 mg (but not 30 mg) bifeprunox group compared to the placebo group.

  Nausea, vomiting and constipation were more prominent AEs versus placebo. Overall, the 20 mg and 30 mg doses of bifeprunox were safe and were well tolerated by patients with schizophrenia.

Example 2d-Clinical Study 4
Primary objective : To determine whether 6-month bifeprunox treatment is superior to placebo treatment in patients with chronic schizophrenia, using time from random sampling to exacerbation as the primary outcome measure.

Secondary objective : Are acute effects better than placebo treatment after 6 weeks of bifeprunox treatment using changes from baseline in the positive and negative syndrome rating scale (PANSS) total score as outcome measures? Check to see if.

Other secondary objectives : To assess the long-term safety and tolerability of bifeprunox against placebo.

Methodology : This study was a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled, fixed-dose study. The study consisted of a 3-6 day induction period without the use of antipsychotics, after which patients were treated with a fixed dose of bifeprunox (20 mg / day (BX20) or 30 mg / day (BX30)) or placebo (PBO). Randomized for a 6-month double-blind procedure. Patients assigned to the BX group were titrated from 0.25 mg / day over 7 days (BX20) or 8 days (BX30) and then continued at these doses for the remainder of the study. Efficacy assessments were performed at baseline (excluding CGI-I), at 1, 2, 4, 6 and 9 weeks and at 3, 4, 5 and 6 months. Safety assessments were performed at screening, during treatment, and at the end of the study. At predetermined time points, blood samples were obtained for drug concentration analysis of BX and its major metabolites (3'- and 4'-sulfate conjugates of BX) and pharmacoeconomic evaluation was performed.

Number of patients planned and analyzed : There were a total of 495 patients planned to participate: 165 in each treatment group.

Diagnosis and main inclusion criteria : PANSS total score > 60 and CGI-S score > 4 (moderate) at screening and baseline; PANSS items P7 (hostility) and G8 (noncooperative) at screening and baseline Have a score < 4 (moderate); be between 18 and 65 years old (including extremum); be inpatient, partially hospitalized, or tracked in day care program within 90 days A primary diagnosis of schizophrenia according to the DSM-IV-TR criteria for more than 2 years who were outpatient; and had no antipsychotic modification within 1 month prior to screening prior to screening Patient having.

Study product, dose and dosage form, batch number : bifeprunox-gradual increase to 20 or 30 mg once daily over 7 (20 mg) or 8 days (30 mg); encapsulated tablet, oral.

Reference treatment, dosage and dosage form : placebo-encapsulated tablets, oral.

Efficacy results : The primary efficacy variable was time to exacerbation and the analysis was based on FAS. The primary efficacy analysis dismissed the hypothesis of equal time to exacerbation of schizophrenia in the three treatment groups (Cox model, p = 0.008). Subsequent comparisons between each of the BX groups and the PBO group showed that patients in the BX group had a statistically significantly longer period of progression to schizophrenia than patients in the PBO group (BX20: p = 0.008 and BX30: p = 0.006). The proportion of patients exacerbated was 59% in the PBO group, 41% in the BX20 group, and 38% in the BX30 group. The Cox proportional hazard model gives an approximate hazard ratio of 0.66 (BX20) and 0.65 (BX30) compared to PBO; that is, the risk of exacerbation is greater than for patients in the BX20 or BX30 groups About 1.5 times higher for patients in the PBO group. Bifeprunox was also statistically significantly superior to PBO in analyzing time to exacerbation based on PPS. Since the majority of patients in PPS participated in the majority of the study, the results were very close to the results of the main analysis for both the estimated hazard ratio and the p-value obtained. This explains the robustness of the main efficacy analysis conclusions. The secondary efficacy variable was the PANSS total score at 6 weeks. The corrected mean change from baseline to 6 weeks (BX20: -4.0; BX30: -2.7) in the PANSS total score (FAS, LOCF) for each BX group is PBO according to Hochberg's step-up method. It was statistically significantly greater than that of the group (1.1) (BX20: p = 0.002; BX30: p = 0.177).

  The same general pattern is seen for progression over time in the PANSS total score, PANSS positive and total psychopathology subscale score, BPRS total score and BPRS psychosis cluster score (all FAS, LOCF): First (6 or 9 weeks) The average score decreased, and then they stabilized in both BX groups, while in the PBO group, the average score decreased to 2 or 4 weeks, after which the score steadily increased. For each of these variables, treatment with BX (any dose) was treated with PBO after 6 or 9 weeks by pairwise comparison of each of the PBO and BX groups for FAS using LOCF (ANCOVA). More generally, it was shown to be statistically significantly better.

  The average PANSS negative subscale score (FAS, LOCF) decreased in both BX groups up to 6 weeks, after which the score stabilized. In the PBO group, the score decreased until 4 weeks, after which the score tended to increase. In the per-visit LOCF analysis of mean PANSS negative subscale scores (FAS, ANCOVA), treatment with both BX doses was performed at all time points except 2 and 4 weeks for the BX30 group. It was statistically significantly better than that of PBO.

  For all treatment groups, the average CDSS total score (FAS, LOCF) initially decreased (baseline to 2 weeks), after which the score remained stable (both BX groups) or increased over time. (PBO group). There was no statistically significant difference between any of the BX groups and the PBO group at any time point in the LOCF analysis (FAS, ANCOVA) by visit of mean CDSS total score. This result should be seen in the context of low baseline CDSS scores, reflecting low levels of depression symptoms.

  Mean CGI-S score (FAS, LOCF) decreased to 6 weeks in both BX groups, after which the score stabilized. In the PBO group, the average CGI-S score decreased until 4 weeks, after which the score tended to increase. LOC group was statistically significantly better than PBO group at 3, 4, 5 and 6 months for BX20 and 5 and 6 months for BX30 in the visit-by-hoc LOCF analysis of mean CGI-S scores (FAS, ANCOVA) It was.

  Mean CGI-I score (FAS, LOCF) decreased to 6 weeks in both BX groups, after which the score stabilized. In the PBO group, the score decreased only slightly until 2 weeks, after which the score steadily increased. In the LOCF analysis per visit for mean CGI-I scores (FAS, ANCOVA), both BX doses were statistically significantly better than PBO after 6 weeks.

For a small number of patients (PBO: 25 patients; BX20: 32 patients; BX30: 36 patients) who mainly met the criteria for negative symptoms, in the PANSS total score (all groups) and PANSS positive subordinates The corrected mean change from baseline in the scale scores (PBO and BX20) generally followed the same pattern and was within the same range as that of the entire population. In contrast, the corrected mean change from baseline in the PANSS positive subscale score of patients treated with BX30 followed the same pattern over time as the entire population, but the change was greater. The corrected mean change from baseline in the PANSS negative subscale score (all groups) followed the same pattern over time as the entire population; however, the average change was generally twice as large in this population compared to the total population . In the visit-by-visit LOCF analysis (ANCOVA) of the PANSS total score, PANSS positive subscale score, and PANSS negative subscale score, BX20 was not statistically significantly different from PBO at any time point. BX30 is statistically significantly better than PBO in the PANSS total score after 6 weeks and in the PANSS positive subscale score after 2 weeks, whereas BX30 is statistically better than PBO in the PANSS negative subscale score after 2 weeks. It was not significantly different.

  PANSS total score, PANSS positive subscale score, PANSS negative subordinate score for a small number of patients (PBO: 18 patients; BX20: 15 patients; BX30: 22 patients) who mainly met the criteria for symptoms of depression Scale scores and CDSS total scores followed an overall pattern generally similar to that of the entire population. This is probably due to the low level of depressive symptoms present in a small number of patients and baselines in the per-visit LOCF analysis (ANCOVA) of PANSS total score, PANSS positive subscale score, PANSS negative subscale score and CDSS total subscale score There was no statistically significant difference between any of the BX groups and the PBO group at any time point in the subpopulation.

  The proportion of patients with a PANSS total score (FAS, LOCF) reduction of at least 25% in the BX20 group was statistically significantly greater than that in the PBO group after 9 weeks, while the proportion of responders in the BX30 group was 5 months Was statistically significantly greater than in the PBO group only.

A small percentage (0-8%) of patients (regardless of treatment) had a decrease in PANSS total score > 35%, > 45% or > 55%. There was no trend between or within treatment groups regarding the distribution in the proportion of patients with a particular decrease.

The proportion of patients with CGI-I score < 2 (FAS, LOCF) at 6 weeks and 6 months was higher than in the PBO group (6 weeks: 11%; 6 months: 9%) (6 weeks: BX20 17 BX30 19%; 6 months: BX20 22%; BX30 20%). The difference between the BX and PBO groups was statistically significant after 9 weeks (BX20) and after 9 weeks (BX30) except for 3 months (p <0.05).

  Calculated mean total cholesterol and mean LDL decreased from baseline to 6 months in all groups regardless of treatment and fasting / non-fasting conditions (except for non-fasting PBO patients). Calculated mean VLDL and triglycerides decreased from baseline to 6 months in all groups regardless of treatment and fasting / non-fasting conditions (except for non-fasting BX30 patients). Mean HDL increased from baseline to 6 months in all groups regardless of treatment and fasting / non-fasting conditions. Corrected mean HDL cholesterol levels increased from baseline to 6 months in all three treatment groups regardless of fasting / non-fasting conditions (PBO: 0.04 / 0.06 (fasting / non-fasting) ); BX20: 0.07 / 0.08; BX30: 0.07 / 0.08 mmol / L). There was no statistically significant difference between any of the BX groups and the PBO group.

Corrected mean triglyceride values decreased from baseline to 6 months in all three treatment groups regardless of fasting / non-fasting conditions (PBO: -0.06 / -0.22 (fasting / non-fasting) BX20: -0.16 / -0.21; BX30: -0.37 / -0.03 mmol / L). There was no statistically significant difference between any of the BX groups (except BX30 (fasting)) and the PBO group.

  Corrected mean fasting glucose values increased from baseline to 6 months in all three treatment groups (PBO: 0.10; BX20: 0.13; BX30: 0.09 mmol / L), and any of the BX groups There was no statistically significant difference between the heel and the PBO group.

  The corrected mean body weight change (APTS, OC, ANCOVA) from baseline to 6 months was -0.8 kg in the PBO group, -0.3 kg in the BX20 group, and -0.5 kg in the BX30 group. The corrected mean weight loss in the BX20 and BX30 groups was not statistically significantly different from that in the PBO group.

  In all treatment groups, patients who also had nausea and / or vomiting had greater weight loss (PBO: -0.6 vs. -1.9 kg; BX20: -1.0 vs. -1.9 kg; BX30) : -1.1 vs. -2.3 kg), patients lost weight whether they had nausea and / or vomiting.

  There was no treatment effect of BX (any dose) on the condition of patients with metabolic syndrome during the study. About 75% (range: 70% -80%) patients had no metabolic syndrome at baseline or at the end of the study. There were no statistically significant treatment differences in the status of patients with metabolic syndrome.

  There were no clinically relevant changes within treatment groups or differences between treatment groups in laboratory values, vital signs, metabolic syndrome or ECG parameters.

Conclusion : One conclusion of this study is that both doses of bifeprunox (20 mg / day and 30 mg / day) were statistically significantly better than placebo and prevented exacerbation of schizophrenia. For patients with chronic stable schizophrenia, baseline symptoms were significantly better maintained with BX (both doses) than with PBO either after 6 weeks of treatment or after long-term treatment. A comparison of the safety profiles of bifeprunox and placebo showed a higher incidence of adverse events associated with gastrointestinal and dizziness in the bifeprunox group versus the placebo group. The incidence of nausea and vomiting and abnormal movements leading to withdrawal from the study was higher in the BX30 group than in the BX20 group. A favorable metabolic profile (based on weight change, blood lipids and presence / absence of metabolic syndrome) was found for bifeprunox.

Results PANSS total score associated with clinical studies 1-4
Clinical study 1 : The mean change from baseline to endpoint (SD) in the PANSS total score was −9.7 (17.5) for the bifeprunox 5 mg group and −5. For the bifeprunox 10 mg group. 0 (18.3), -11.3 (17.0) for the bifeprunox 20 mg group, -5.3 (16.3) for the placebo group, and -15.7 (14.9) for the risperidone group. there were. Treatment effect values corresponding to the difference between baseline bifeprunox and placebo mean change at endpoint (LOCF) were -4.1, 0.6 and-for the bifeprunox 5 mg, 10 mg and 20 mg groups, respectively. 5.8. From pairwise comparisons, a statistically significant decrease in endpoint (LOCF) was seen for the 20 mg bifeprunox group versus placebo (p value corrected for multiple comparisons, p = 0.031). No significant treatment group differences were seen for the 5 mg bifeprunox and 10 mg bifeprunox treatment groups compared to placebo, respectively.

Clinical Study 2 : The mean change from baseline to endpoint (SD) in the PANSS total score was -13.5 (20.1) for the 30 mg bifeprunox group and -10.3 (20 for the 40 mg bifeprunox group). .5), -7.7 (19.2) for the placebo group, and -19.7 (19.3) for the risperidone group (as shown in the table below). Treatment effect values (for mean change from baseline at endpoint [LOCF]) corresponding to the difference between bifeprunox and placebo are: -5.9 for the 30 mg bifeprunox group, and 40 mg bifeprunox It was -3.2 for the group. A statistically significant treatment group difference was seen for the 30 mg bifeprunox treatment group compared to placebo at the endpoint based on the Hochberg corrected p value (p = 0.020). Differences between the 30 mg bifeprunox and placebo treatment groups were also observed from 2 to 4 weeks from the nominal p-value (p < 0.004 for each of 2 to 4 weeks). Furthermore, the treatment effect was consistently increased over the 6 week study (range of effects: -5.6 at 2 weeks and -6.3 at 4 weeks; Table 3.0.1). A statistically significant difference between the 40 mg bifeprunox group and the placebo group was not evident at the endpoint based on the Hochberg corrected p-value.

Clinical study 3 : The mean change from baseline to endpoint (SD) in the PANSS total score was −13.8 (19.9) for the 20 mg bifeprunox group and −13.1 (20 for the 30 mg bifeprunox group). .2), -10.7 (19.4) for the placebo group and -22.0 (18.2) for the olanzapine group (Table 15). Treatment effect values (for mean change from baseline at endpoint [LOCF]) corresponding to the difference between bifeprunox and placebo are: -3.5 for the 20 mg bifeprunox group, and 30 mg bifeprunox It was -2.2 for the group. No statistically significant treatment group differences were seen for the 20 mg or 30 mg bifeprunox treatment groups compared to the placebo group based on Hochberg corrected p-value. Similarly, there was no significant difference between the placebo group and either of the two bifeprunox dose groups at any other time points (1-4 weeks) during the study. When data were analyzed only for patients with the same reviewer for each visit, the difference in mean change from baseline to endpoint (SD) in the PANSS total score (LOCF) was similar to that seen in the primary analysis . The difference in PANSS total score between olanzapine and placebo was analyzed according to sensitivity analysis. These results indicated that olanzapine was significantly different from placebo (p <0.001).

Clinical Study 4 : The mean change in PANSS total score for each BX group from baseline to 6 weeks (BX20: -4.0 and BX30: -2.7) is greater than that of the PBO (1.1) group It was statistically significantly larger (BX20: p = 0.002; BX30: p = 0.177).

PANSS positive
Clinical Study 1 : The following table presents the mean PANSS positive subscale score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The treatment effect values (bifeprunox-placebo) at the endpoint LOCF were -1.1, 0.7, and -1.5 for the bifeprunox 5 mg, 10 mg, and 20 mg groups, respectively. A statistically significantly greater decrease in endpoint (LOCF) (uncorrected p = 0.037) was seen in the PANSS positive subscale score for comparison of treatment effect estimates for the bifeprunox 20 mg group and placebo.

  For observational analysis of changes from baseline, a trend similar to the PANSS total score was seen in changes from baseline in the PANSS positive subscale score in the bifeprunox treatment group over time. Paired comparisons between bifeprunox and placebo groups were not statistically significant.

Clinical Study 2 : The following table presents the PANSS positive symptom subscale score at baseline for the ITT population and changes from baseline by visit using LOCF. The mean change from baseline to endpoint (SD) in the PANSS positive symptom subscale score was −4.5 (6.6) for the 30 mg bifeprunox group and −4.2 (6. 9) -2.5 (6.0) for the placebo group and -7.2 (6.6) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -1.9 for the 30 mg bifeprunox group and -1.7 for the 40 mg bifeprunox group. SEP1 did not yield significant results and therefore SEP2 and SEP3 were not evaluated (see section 7.4.1.1). However, a significant difference between the bifeprunox 30 mg treatment group and placebo was noted at the endpoint (nominal p = 0.01). A significant difference between the 30 mg bifeprunox and placebo treatment groups was also observed from 2 weeks to 4 weeks (p < 0.006).

Similarly, a significant difference between the bifeprunox 40 mg treatment group and placebo was observed at the endpoint (p = 0.020). Differences to placebo were also observed from 1 to 3 weeks (p < 0.013).

Clinical Study 3 : The following table presents the PANSS positive symptom subscale score at baseline for the ITT population and changes from baseline by visit using LOCF. The mean change (SD) from baseline to endpoint in the PANSS positive symptom subscale score was -4.3 (6.1) for the 20 mg bifeprunox group and -4.2 (6.2. For the 30 mg bifeprunox group). 8) -3.5 (6.2) for the placebo group and -7.0 (5.8) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -1.1 for the 20 mg bifeprunox group and -0.7 for the 30 mg bifeprunox group. The difference in nominal p-value ( < 0.05) is the difference between the placebo group and the bifeprunox dose group at 6 weeks / endpoint or at any other time point under study (1-4 weeks). It was not recognized between.

Clinical study 4 : Mean PANSS positive subscale score (FAS, LOCF) decreased over time in both BX groups up to 9 weeks, after which the score increased only slightly. In the PBO group, the average PANSS total score decreased to 2 weeks, after which the score steadily increased (Figure 1; panel 34). In the LOCF analysis of each PANSS positive subscale score (FAS, ANCOVA), treatment with BX20 or BX30 was statistically significantly better than that with PBO after 6 weeks.

PANSS negative
Clinical Study 1 : The following table presents the mean PANSS negative subscale score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The bifeprunox 5 mg, 20 mg and risperidone 6 mg groups showed the greatest improvement over time. Estimates of treatment effect (Bifeprunox-Placebo) at endpoint LOCF were -1.0, -0.3, -1.4 for the bifeprunox 5 mg, 10 mg, and 20 mg groups, respectively. A statistically significantly greater decrease in the PANSS negative subscale score was 3 weeks (uncorrected p = 0.013) for the bifeprunox 20 mg group versus placebo and end point (LOCF) (uncorrected p = 0.0). 026).

  For observational analysis of changes from baseline in the PANSS negative subscale score, the decrease in score over time showed an improvement in each of the bifeprunox treatment groups. A statistically significant treatment effect of bifeprunox was observed at 2 weeks for the bifeprunox 5 mg group compared to placebo (p = 0.032). There were no other significant differences.

Clinical Study 2 : The following table presents the PANSS negative symptom subscale score at baseline for the ITT population and changes from baseline by visit using LOCF. The mean change (SD) from baseline to endpoint in the PANSS negative symptom subscale score was −3.1 (5.6) for the 30 mg bifeprunox group and −2.2 (5. 4) -1.8 (5.6) for the placebo group and -3.8 (5.5) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -1.4 for the 30 mg bifeprunox group and -0.9 for the 40 mg bifeprunox group. SEP1 did not yield significant results and therefore SEP2 and SEP3 were not evaluated.

The 30 mg bifeprunox treatment group showed a significant difference from the placebo at the endpoint (nominal p = 0.027). A significant difference between the 30 mg bifeprunox and placebo treatment groups was also observed from 2 to 4 weeks (p < 0.021). There were no differences between the placebo and 40 mg bifeprunox dose groups at any time point (1-6 weeks) during the study.

Clinical Study 3 : The following table presents the PANSS negative symptom subscale score at baseline for the ITT population and changes from baseline by visit using LOCF. The mean change from baseline to endpoint (SD) in the PANSS negative symptom subscale score was −3.3 (5.0) for the 20 mg bifeprunox group and −3.1 (5. 5 for the 30 mg bifeprunox group). 2) -2.4 (5.1) for the placebo group and -4.6 (5.2) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -0.9 for the 20 mg bifeprunox group and -0.6 for the 30 mg bifeprunox group. The difference in nominal p-value ( < 0.05) is the difference between the placebo group and the bifeprunox dose group at 6 weeks / endpoint or at any other time point under study (1-4 weeks). It was not recognized between.

Clinical study 4 : Mean PANSS negative subscale score (FAS, LOCF) decreased in both BX groups up to 6 weeks, after which the score was stable (Figure 2; panel 35). In the PBO group, the score decreased to 4 weeks, after which the score tended to increase (panel 35).

  In the LOCF analysis by visit of mean PANSS negative subscale scores (FAS, ANCOVA), treatment with BX20 or with BX30 was more statistical than that with PBO at all time points except for weeks 2 and 4 for BX30 Was significantly better.

PANSS data for clinical study 4 The average PANSS total score (FAS, LOCF) decreased over time in both BX groups up to 9 weeks, after which the score was stable (panel 28). In the PBO group, the average PANSS total score decreased to 2 weeks, after which the score steadily increased (panel 28).

  LOCF analysis of the PANSS total score (panel 28) shows that the PANSS total score in the BX group remained stable when supplemented with the final observations. The changes in both BX groups were statistically significantly better than those in the PBO group after 6 weeks. Furthermore, BX20 was statistically significantly better than PBO after 4 weeks. OC analysis of the PANSS total score shows that patients who continued the study improved over time (panel 29). The changes in both BX groups were statistically significantly better than those in the PBO group at multiple time points, including 6 weeks but excluding 6 months.

  The difference between LOCF and POCF analysis indicates that many patients who withdrew had an exacerbation in their PANSS total score and withdrew at the first visit where exacerbations were seen. This is consistent with the study design that requires the patient to withdraw from the study, at least if it gets a little worse.

  For other efficacy variables, the trend in efficacy scores over time was similar, except for the CDSS, where the baseline level indicates that the patients included in the study were not depressed.

Overall psychopathology score
Clinical study 1 : The overall psychopathological score decreased from baseline to 6 weeks for each of the bifeprunox treatment groups as shown in the table below. The estimated treatment effect of bifeprunox using LOCF was -2.2, 0.4 and -2.8 for the bifeprunox 5 mg, 10 mg and 20 mg groups, respectively. The bifeprunox 20 mg group is more statistical than placebo at 2 weeks (uncorrected p = 0.029), 3 weeks (uncorrected p = 0.032), and endpoint (LOCF) (uncorrected p = 0.016). Had a significantly greater decrease.

  For observational analysis of changes from baseline in the PANSS General Psychopathology Subscale Score, the decrease in score over time showed improvement in each of the bifeprunox treatment groups. The statistically significant treatment effect of bifeprunox on placebo was 2 weeks (p = 0.038) for the bifeprunox 20 mg group versus placebo at 6 weeks for the bifeprunox 5 mg group (p = 0.0). 017). There were no other significant differences.

Clinical Study 2 : The mean PANSS total psychopathology subscale score at baseline for the ITT population (LOCF) and changes from baseline in the PANSS total psychopathology subscale at each baseline visit are presented in the table below . The mean change from baseline to endpoint (SD) in the PANSS General Psychopathology Subscale Score was −6.0 (10.2) for the 30 mg bifeprunox group and −3.8 (10 for the 40 mg bifeprunox group). .1), -3.5 (9.7) for the placebo group, and -8.6 (9.8) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -2.5 for the 30 mg bifeprunox group and -0.7 for the 40 mg bifeprunox group. A significant difference was observed between the 30 mg bifeprunox group and placebo from 2 weeks to the end point (p < 0.025). There was no significant difference between the 40 mg bifeprunox group and placebo at any time point during the study (1 week to endpoint).

Clinical study 3 : Baseline mean PANSS total psychopathology subscale score at ITT population (LOCF) and changes from baseline in PANSS total psychopathology subscale scores at each baseline visit are presented in the table below To do. The mean change from baseline to endpoint (SD) in the PANSS General Psychopathology Subscale Score was −6.1 (10.7) for the 20 mg bifeprunox group and −5.8 (10 for the 30 mg bifeprunox group). .3), -4.8 (10.0) for the placebo group, and -10.5 (9.4) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -1.5 for the 20 mg bifeprunox group and -0.9 for the 30 mg bifeprunox group. There was no significant difference between the placebo group and either of the two bifeprunox dose groups at the endpoint or at any other time point (1-4 weeks) under study.

Clinical Study 4 : The average PANSS total psychopathology subscale score generally followed the same pattern as the PANSS total score. Mean PANSS general psychopathology subscale score (FAS, LOCF) decreased in both BX groups up to 6 weeks, after which the score was stable (Figure 3; panel 36). In the PBO group, the average PANSS general psychopathology subscale score decreased to 2 weeks, after which the score steadily increased (panel 36).

  Both BX20 and BX30 were statistically significantly better than PBO after 9 weeks in the LOCF analysis by visit of the PANSS General Psychopathology Subscale Score (FAS, ANCOVA). Furthermore, BX20 was statistically significantly better than PBO at 6 weeks.

BPRS total score
Clinical Study 1 : As shown in the table below, the bifeprunox 20 mg group showed a greater change in BPRS total score than the placebo group. Any time point starting from 2 weeks (uncorrected p = 0.042); 3 weeks (uncorrected p = 0.020); 4 weeks (uncorrected p = 0.024); endpoint (LOCF) (uncorrected p = 0.012), there was a statistically significant treatment group difference for bifeprunox 20 mg versus placebo.

  A similar trend observed in the LOCF analysis was observed in the change from baseline in the BPRS total score analysis using the observed values. Comparison of bifeprunox treatment effects on placebo was statistically significant at 6 weeks for the 5 mg group only (p = 0.024). There were no other significant comparisons.

Clinical Study 2 : The following table presents the change from baseline in the mean BPRS total score at baseline (from PANSS) and the BPRS total score at each baseline visit for the ITT population (LOCF). The mean change from baseline to endpoint (SD) in the BPRS total score was −8.1 (12.3) for the 30 mg bifeprunox group, −6.5 (11.7) for the 40 mg bifeprunox group, It was -4.9 (11.5) for the placebo group and -12. 2 (11.7) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -3.2 for the 30 mg bifeprunox group and -1.9 for the 40 mg bifeprunox group. Significant differences were observed between the 30 mg bifeprunox group and placebo from 2 weeks to the end point (p < 0.019). There was no significant difference between the 40 mg bifeprunox group and placebo at any time point during the study (1 week to endpoint).

Clinical Study 3 : The following table presents the change from baseline in the mean BPRS total score at baseline (from PANSS) and the BPRS total score at each baseline visit for the ITT population (LOCF). The mean change from baseline to endpoint (SD) in the BPRS total score was −8.5 (11.9) for the 20 mg bifeprunox group, −7.9 (12.0) for the 30 mg bifeprunox group, It was -6.7 (11.7) for the placebo group and -13.2 (10.7) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -2.1 for the 20 mg bifeprunox group and -1.1 for the 30 mg bifeprunox group. There was no significant difference between the placebo group and either of the two bifeprunox dose groups at the endpoint or at any other time point (1-4 weeks) under study.

BPRS psychosis cluster score
Clinical Study 1 : The following table presents the mean BPRS psychosis cluster score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The treatment effect values (bifeprunox-placebo) at the endpoint LOCF were -0.9, 0.4, and -1.1 for the bifeprunox 5 mg, 10 mg, and 20 mg groups, respectively. A statistically significantly greater decrease (uncorrected p = 0.044) in the difference between the mean change from baseline at the bifeprunox and placebo endpoints (LOCF) is the BPRS of the bifeprunox 20 mg group versus placebo. It was found in the psychosis cluster score.

  For observational analysis of changes from baseline in the BPRS psychosis cluster score, a greater decrease in score was seen for each of the three bifeprunox treatment groups starting at 4 weeks compared to placebo. There was no statistically significant difference.

Clinical Study 2 : The following table presents the mean BPRS psychosis cluster score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The mean change (SD) from baseline to endpoint in the BPRS psychosis cluster score was -3.2 (4.2) for the 30 mg bifeprunox group and -2.6 (4.4) for the 40 mg bifeprunox group. -1.8 (3.5) for the placebo group and -4.9 (4.0) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -1.4 for the 30 mg bifeprunox group and -1.0 for the 40 mg bifeprunox group. A significant difference was observed between the 30 mg bifeprunox group and placebo from 2 weeks to the end point (p < 0.002). There was a significant difference between the 40 mg bifeprunox group and placebo at the end point (p = 0.031) and at 2 and 3 weeks (p < 0.036).

Clinical Study 3 : The following table presents the mean BPRS psychosis cluster score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The mean change (SD) from baseline to endpoint in the BPRS psychosis cluster score was −3.1 (3.9) for the 20 mg bifeprunox group and −3.2 (4.4) for the 30 mg bifeprunox group. , -2.6 (4.0) for the placebo group and -4.9 (4.0) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -0.6 for the 20 mg bifeprunox group and -0.5 for the 30 mg bifeprunox group. There was no significant difference between the placebo group and either of the two bifeprunox dose groups at the endpoint or at any other time point (1-4 weeks) under study.

CGI-S
Clinical Study 1 : The following table presents the mean CGI disease severity score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The treatment effect values (bifeprunox-placebo) at the endpoint LOCF were -0.31, 0.12, and -0.19 for the bifeprunox 5 mg, 10 mg, and 20 mg groups, respectively. Compared to treatment group, statistically significant in bifeprunox 20 mg versus placebo at 2 weeks (p = 0.008), 3 weeks (p = 0.020) and 4 weeks (p = 0.032) A large decrease was shown, but not at the endpoint (LOCF). The treatment group comparison of bifeprunox 5 mg vs placebo was significant at 3 weeks (p = 0.049), 4 weeks (p = 0.033) and endpoint (LOCF) (p = 0.013).

Clinical Study 2 : The table below presents the mean CGI-S score at baseline for the ITT population (LOCF) and the mean change from baseline by visit using LOCF. The mean change (SD) from baseline to endpoint in the CGI disease severity score was −0.69 (1.19) for the 30 mg bifeprunox group and −0.54 (1.12) for the 40 mg bifeprunox group. ), -0.37 (1.07) for the placebo group, and -1.06 (1.20) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -0.28 for the 30 mg bifeprunox group and -0.18 for the 40 mg bifeprunox group. No statistically significant difference in change from baseline to endpoint in CGI-S was seen for the 30 mg bifeprunox treatment group compared to placebo on a step-down basis (corrected p = 0.0). 056). The 30 mg bifeprunox group showed a significant difference from the placebo at the endpoint (nominal p = 0.028). A significant difference between the 30 mg bifeprunox and placebo treatment groups was also observed between 2 and 4 weeks (p < 0.015). There were no differences between the placebo and 40 mg bifeprunox dose groups at any time point (1-4 weeks) during the study.

Clinical Study 3 : The following table presents the mean CGI disease severity score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The mean change from baseline to endpoint (SD) in the CGI disease severity score was −0.63 (0.98) for the 20 mg bifeprunox group and −0.62 (1.03) for the 30 mg bifeprunox group. ), -0.49 (1.06) for the placebo group, and -1.03 (1.00) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox-placebo) were: -0.13 for the 20 mg bifeprunox group and -0.09 for the 30 mg bifeprunox group. Difference in nominal p-value (p < 0.05) between placebo and bifeprunox dose groups at 6 weeks / endpoint or at any other time point under study (1-4 weeks) Was not noticeable.

CGI-I
Clinical study 1 : As shown in Table 24, improvement was observed in the CGI improvement score of the 20 mg bifeprunox treatment group. Treatment group differences were statistically significant at 1 week (p = 0.040) and 2 weeks (p = 0.016) for the bifeprunox 20 mg group versus placebo in the LOCF analysis, but at the endpoint It wasn't. There were no other significant differences.

Clinical study 2 : Proportion of patients reporting moderate or marked improvement from baseline to endpoint (LOCF): 36% in the 30 mg bifeprunox group, 28% in the 40 mg bifeprunox group, 25% in the placebo group And 52% in the risperidone group (table below). There was no significant difference between the placebo and either of the two bifeprunox dose groups at the endpoint; however, the significant difference between the 30 mg bifeprunox group and the placebo was between 2 and 4 weeks. Was seen (p < 0.024). There was no significant difference between the 40 mg bifeprunox group and placebo at any time point during the study (1 week to endpoint). Data from 2 weeks to endpoint are summarized in the table below.

Clinical Study 3 : The following table presents the frequency of the seven categories of CGI improvement assessment per visit using LOCF for the ITT population. Statistical differences between treatment groups with respect to mean CGI improvement score were assessed using a CMH test stratified by pooled facilities applied to the frequency of 7 CGI improvement categories using a modified rigid score. From baseline to endpoint (obtained by summing up the corresponding individual proportions in Table 23), the proportion of patients reporting combined moderate or prominent improvement was: 38% in the 20 mg bifeprunox group, 30 mg bifé The prunox group was 34%, the placebo group was 32%, and the olanzapine group was 46%. A comparison of the 20 mg bifeprunox group to the placebo group at the endpoint was found to be significant (p = 0.027). The treatment comparison of the 30 mg bifeprunox group versus the placebo group was not significant (p = 0.162). There were no significant differences between the placebo group and either of the two bifeprunox dose groups at any other time point (1-4 weeks) during the study.

PANSS responder rate
Clinical Study 1 : The PANSS responder rate was higher for each of the bifeprunox treatment groups compared to the placebo group. The PANSS responder rates were 28%, 24% and 34% for the three dose groups, respectively, using the 20% definition from the study protocol. PANSS responder rates using all four definitions are presented in the table below.

  Significant differences in PANSS responder rates using LOCF were found using the 25% definition of bifeprunox 5 mg versus placebo and for the 25%, 30% and 35% definitions of the bifeprunox 20 mg group versus placebo.

Clinical Study 2 : A PANSS responder was defined as a patient whose PANSS total score was reduced by more than 20% from baseline to endpoint based on LOCF data. As an exploratory analysis, responder rates were also analyzed using the 30%, 35%, 40% and 50% definitions of responders. A summary of the PANSS responder rate at the endpoint (LOCF) is presented in Table 25 below.

  The PANSS responder rate was slightly higher for the two bifeprunox treatment groups compared to the placebo group. The PANSS 20% responder rate was: 36% in the 30 mg bifeprunox group, 30% in the 40 mg bifeprunox group, 26% in the placebo group, and 54% in the risperidone group. However, the difference between the 30 mg bifeprunox group and placebo was not significant (p = 0.052). The PANSS 30% responder rate was: 24% in the 30 mg bifeprunox group, 22% in the 40 mg bifeprunox group, 14% in the placebo group, and 31% in the risperidone group. The difference between the 30 mg bifeprunox group and placebo was significant (p = 0.019). A significant difference between the 30 mg bifeprunox group and placebo was also seen for the 35% and 50% responder rates.

Clinical Study 3 : A PANSS responder was defined as a patient whose PANSS total score decreased by more than 20% from baseline to endpoint. As an exploratory analysis, responder rates were also analyzed using the 30%, 35%, 40% and 50% definitions of responders. A summary of the PANSS responder rate at the endpoint (LOCF) is presented in the table below. The 20% PANSS responder rate was slightly higher for the two bifeprunox treatment groups compared to the placebo group: 42% of patients in the 20 mg bifeprunox group, 39% of patients in the 30 mg bifeprunox group, and in the placebo group 32% of patients and 54% of patients in the olanzapine group improved by more than 20% from baseline to endpoint in the PANSS total score. The difference between the 20 mg bifeprunox group and the approached placebo group is significant (p = 0.061). However, the difference between 20 mg or 30 mg bifeprunox group and placebo group was not significant (all p> 0.118) when using more stringent criteria for responder definition (30% -50%) .

Clinical Study 4 : Percentage of patients (PANSS responders) with > 25%, > 35%, > 45% or > 55% reduction in PANSS total score relative to baseline at each visit is indicated by LOCF (Figure 4; Panel 42).

CGI responder rate
Clinical Study 1 : A CGI responder is defined as a patient classified as “significantly improved” or “moderately improved” on the CGI Improvement Rating Scale. The CGI responder rate in the bifeprunox 5 mg and 20 mg groups was higher than the responder rate in the placebo group. There were no statistically significant differences for any of the three bifeprunox dose groups when compared to placebo.

Clinical Study 2 : A CGI responder is defined as a patient classified as “significantly improved” or “moderately improved” on the CGI Improvement Rating Scale. A summary of CGI-I responder rates at the endpoint (LOCF) is presented in the table below. The CGI-I responder rate was: 36% in the 30 mg bifeprunox group, 28% in the 40 mg bifeprunox group, 25% in the placebo group, and 52% in the risperidone group. There was a significant difference between the 30 mg bifeprunox group and the placebo (p = 0.039).

Clinical Study 3 : A CGI responder is defined as a patient classified as “significantly improved” or “moderately improved” on the CGI Improvement Rating Scale. A summary of CGI-I responder rates at the endpoint (LOCF) is presented in Table 3.10.0 (LOCF) and Table 26. The CGI-I responder rate was: 38% in the 20 mg bifeprunox group, 34% in the 30 mg bifeprunox group, 32% in the placebo group, and 46% in the olanzapine group. There was no significant difference between the placebo group and either of the two bifeprunox dose groups.

CDSS
Clinical Study 2 : The Calgary Depression Rating Scale score for schizophrenia is presented in the table below. This table presents the mean CDSS score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The mean change from baseline to endpoint (SD) in the CDSS score (LOCF) was -0.66 (3.64) for the 30 mg bifeprunox group and 0.01 (3.66) for the 40 mg bifeprunox group , -0.39 (3.45) for the placebo group and -0.89 (3.42) for the risperidone group. Treatment effect values at endpoint LOCF (bifeprunox, placebo) were: -0.38 for the 30 mg bifeprunox group and 0.29 for the 40 mg bifeprunox group. There was no significant difference between placebo and either of the two bifeprunox dose groups at the end point or at any other time point under study (1-4 weeks).

Clinical Study 3 : The following table presents the mean CDSS score at baseline for the ITT population and the mean change from baseline by visit using LOCF. The mean change (SD) from baseline to endpoint in the CDSS score (LOCF) was −1.30 (3.85) for the 20 mg bifeprunox group and −0.79 (3.02) for the 30 mg bifeprunox group. ), -0.59 (4.20) for the placebo group and -1.47 (3.95) for the olanzapine group. Treatment effect values at endpoint LOCF (bifeprunox, placebo) were: -0.54 for the 20 mg bifeprunox group and -0.34 for the 20 mg bifeprunox group. There was no significant difference between the placebo group and either of the two bifeprunox dose groups at the endpoint or at any other time point (1-4 weeks) under study.

Clinical study 4 : The percentage of patients with a CGI-I score < 2 at each visit (CGI-I responder; FAS, LOCF) is shown below in the table (FIG. 5; panel 43).

EPS
EPS was assessed using adverse events expressed under treatment such as inability to sit, dyskinesia, Parkinsonism, etc. and / or official rating scales such as SAS, BAS and / or AIMS.

Simpson Angus Assessment Scale 16 (SAS)
SAS is used to measure Parkinsonism type symptoms in patients who have been administered antipsychotic drugs. The rating scale consists of 10 items, each rated on a 5-point rating scale between 0 (no symptoms at all) and 4 (existence of extreme forms of symptoms). The SAS total score is defined as the sum of all item scores and ranges from 0-40. A SAS total score of up to 3 is considered normal.

Barnes Acathisia Rating Scale 17 (BAS)
BAS is used to assess the observable restless movement of drug-induced restlessness and any distress associated with perceived restlessness and restlessness. The rating scale consists of 3 items, rated from 0 (no symptom of inability to sit still) to 3 (serious inability to sit still).
The BAS total score is defined as the sum of these three BAS item scores and ranges from 0-9. In addition, a global clinical assessment of inability to sit is rated from 0 (no symptoms of inability to sit) to 5 (serious inability to sit).

Abnormal involuntary movement rating scale 18 (AIMS)
The AIMS devised to record the occurrence of dyskinesia movement consists of 12 items. Items 1-7 measure specific involuntary movements on a rating scale from 0 (none) to 4 (severe). Items 8-10 measure a comprehensive assessment of abnormal movements on a rating scale from 0 (no awareness) to 4 (awareness, severe pain). Items 11 and 12 are questions about the patient's dental symptoms answered yes / no. The total score is calculated by summing AIMS items 1-10 and is between 0 and 40; the non-inclusive total score is calculated by summing items 1-7.

Clinical study 1 :

Clinical study 2 :

Clinical study 3 :

Clinical study 4 :
The proportion of patients with TEAE associated with EPS was lower in the PBO group (4%) than in any of the BX groups (BX20: 10%; BX30: 15%). The EPS-related TEAEs in which there were > 3 patients in any BX group versus the PBO group included: BX20-non-sitting; BX30-dyskinesia, non-sitting, extrapyramidal disorders. Overall, 15 patients had EPS-related TEAEs leading to withdrawal (2 in the PBO group; 4 in the BX20 group; 9 in the BX30 group).

SAS, BAS and AIMS
Clinical Study 1 : The Simpson-Angus Rating Scale overall score was assessed as normal or abnormal at baseline and endpoint. Percentage of patients with normal and abnormal scores at each time point. At baseline, the percentage of patients with abnormal SAS scores was between 8% and 12%. At endpoint, the percentage of patients with abnormal SAS scores was between 3% and 10%. The proportion of patients with abnormal SAS scores decreased between baseline and endpoint in all treatment groups. There was no statistically significant difference between treatment groups in the proportion of patients that shifted between categories from baseline to endpoint (p = 0.800).

  The BAS score consists of an objective score, an awareness score for restlessness, a score for pain associated with restlessness, a 3-item total score, and a comprehensive clinical assessment score. There were no statistically significant differences between treatment groups at baseline or endpoint in terms of objective score, restlessness awareness score, restlessness-related distress score, 3-item total score or comprehensive clinical assessment score .

  There were no statistically significant differences between treatment groups in the proportion of patients that shifted between categories from baseline to endpoint in the BAS total score or BAS global clinical assessment score. There were no statistically significant differences between treatment groups at baseline or endpoint. There was no statistically significant difference between treatment groups in the value of change from baseline to endpoint.

Clinical Study 2 : The Simpson-Angus Rating Scale overall score was assessed as normal or abnormal at baseline and endpoint. At baseline, the percentage of patients with abnormal SAS scores was: 14% in the 30 mg bifeprunox group, 11% in the 40 mg bifeprunox group, 7% in the placebo group, and 6% in the risperidone group. The proportion of patients with abnormal SAS scores between baseline and endpoint decreased in the bifeprunox group, remained unchanged in the placebo group, and increased in the risperidone group. At endpoint, the proportion of patients with abnormal SAS scores ranged from 7% in the 40 mg bifeprunox and placebo group to 14% in the risperidone group.

  The shift from normal at baseline to abnormal at endpoint was observed in the other three treatment groups (30 mg bifeprunox: 1 patient, <1%; 40 mg bifeprunox: 5 patients, 4%; placebo: It was highest in the risperidone group (19 patients, 12%) compared to 6 patients, 4%). A statistically significant difference (p <0.001) was observed between treatment groups.

The BAS score consists of an objective score, an awareness score for restlessness, a score for pain associated with restlessness, a 3-item total score, and a comprehensive clinical assessment score. Objective score (p = 0.093), Awareness score of restlessness (p = 0.368), Distress score related to restlessness (p = 0.777), 3 item total score (p = 0.0). 433) or the overall clinical evaluation score of non-sitting (p = 0.541), there was no statistically significant difference across treatment groups at endpoint. There was also no statistically significant difference across the treatment groups at baseline for the above rating scale (p > 0.168).

  The statistically significant difference across treatment groups in the proportion of patients shifting between categories from baseline to endpoint in the BAS total score (p = 0.482) or BAS global clinical assessment score (p = 0.911) is There wasn't.

  Statistically significant across treatment groups at baseline (mean range = 1.0-1.2; p = 0.923) or endpoint (mean range = 0.9-1.6; p = 0.138) There was no difference. There was no statistically significant difference across treatment groups in the value of change from baseline to endpoint (mean range = −0.3 to 0.4; p = 0.138).

Clinical Study 3 : The Simpson-Angus Rating Scale overall score was assessed as normal or abnormal at baseline and endpoint. At baseline, the proportion of patients with abnormal SAS scores was between 6% and 10%. At endpoint, the percentage of patients with abnormal SAS scores was between 3% and 8%. The proportion of patients with abnormal SAS scores decreased between baseline and endpoint in all treatment groups. There was no statistically significant difference between treatment groups in the proportion of patients that shifted between categories from baseline to endpoint (p = 0.463). The BAS score consists of an objective score, an awareness score for restlessness, a score for pain associated with restlessness, a 3-item total score, and a comprehensive clinical assessment score. Objective score (p = 0.421), Awareness score of restlessness (p = 0.484), Distress score related to restlessness (p = 0.254), 3 item total score (p = 0. 865) or the overall clinical evaluation score (p = 0.518), there was no statistically significant difference between treatment groups at endpoint. There was a statistically significant difference between treatment groups at baseline for subjective distress scores associated with restlessness (p = 0.029), but not for any other scores.

  Statistically significant differences between treatment groups in the proportion of patients shifting between categories from baseline to endpoint in BAS total score (p = 0.008) or BAS global clinical assessment score (p = 0.525) There was no.

  There were no statistically significant differences between treatment groups at baseline (p = 0.362) or endpoint (p = 0.187). There was no statistically significant difference between treatment groups in the value of change from baseline to endpoint (p = 0.187).

Clinical study 4 :
SAS
At baseline, the average SAS total score in all three treatment groups was between 2.17 and 2.33.

  There is a slight variation in the average SAS total score in all three treatment groups during the study, and at 6 months, the average SAS total score is between 0.57 and 1.16 (APTS, OC); At baseline and at 6 months, the average total score was within the normal range. The corrected mean maximum change from baseline to 6 months in the SAS total score was <1 in each treatment group (APTS, OC, ANCOVA). There were no clinically relevant differences between any of the treatment groups in the SAS total score.

  At baseline, the majority of patients (PBO: 74%; BX20: 71%; BX30: 72%) were normal with respect to SAS status, and the percentage of normal patients increased at 6 months (PBO: 85%) BX20: 89%; BX30: 78%). There was no statistically significant difference between any of the treatment groups in the shift in SAS status (category: unchanged; abnormal → normal; normal → abnormal).

BAS
At baseline, the average BAS total score in all three treatment groups was between 0.44 and 0.46. There was a slight variation in the average BAS total score in all three treatment groups during the study, and at 6 months the average BAS total score was between 0.05 and 0.17 (APTS, OC). The corrected mean maximum change in baseline BAS from baseline to 6 months was <0.6 in each treatment group (APTS, OC, ANCOVA). There was no clinically relevant difference in BAS total score between any of the treatment groups.

For the BAS global assessment score, the trend is similar: there is a slight variation in the average BAS global assessment score in all three treatment groups during the study; the average score is 0.22-0.26 at baseline, And it was between 0.07 and 0.14 in 6 months (APTS, OC
). There were no clinically relevant differences between any of the treatment groups in the BAS global assessment score at 6 months (APTS, OC). There was no statistically significant difference between any of the treatment groups in the distribution of BAS items 1, 2 or 3.

AIMS
The average AIMS total score in all three treatment groups was low and between 1.04 and 1.35 at baseline. There is an initial increase in mean score corrected for all treatment groups (maximum in BX30 group), after which the mean score decreases over time; at 6 months, the score returns to baseline levels in all three treatment groups (PBO: 0.11; BX20: 1.08; BX30: 0.86 (APTS, OC)). The corrected mean change in the AIMS total score in the BX20 (all time points) and BX30 (5 and 6 months) groups was not statistically significantly different from that in the PBO group, while the BX30 (1 week to 4 months) group The corrected mean change in was not. The corrected mean maximum change from baseline to 6 months in the AIMS total score was small (PBO: 0.39; BX20: 1.21; BX30: 2.45, APTS, OC, ANCOVA). None of the differences were considered clinically significant.

body weight
Clinical study 1 :
A slight decrease in body weight was observed in the bifeprunox treatment group, but not in the placebo treatment group. At endpoint, the mean weight loss of patients in the bifeprunox treatment group was approximately 1 lb (5 mg bifeprunox, −1.0 lb; 10 mg bifeprunox, −1.3 lb; 20 mg bifeprunox, −0. 6 lb). The placebo-treated group had an average weight gain of 1.9 lb.

Statistical tests for changes from baseline in body weight were performed using a methodology similar to that used for the secondary efficacy parameters (ANCOVA model with treatment and baseline weight factors). Paired comparisons of the bifeprunox treatment group versus placebo were all statistically significant for the difference between the mean changes from baseline in the bifeprunox and placebo endpoints (bifeprunox 5 mg [p = 0.025], bifeprunox 10 mg [p = 0.000] and bifeprunox 20 mg [p = 0.031]).

  The average body weight change of patients in the risperidone treatment group was an increase of 4.8 lb.

Weight gain: The proportion of patients whose weight gained more than 7% in the bifeprunox treatment group (2-4%) was less than or similar to the rate seen in the placebo treatment group (5%). In the risperidone treatment group, 13% of patients increased their body weight by > 7%.

Weight loss: The percentage of patients whose weight decreased more than 7% was in the bifeprunox treatment group (5 mg, 6%; 10 mg, 7%; 20 mg, 8%) than in the placebo treatment group (3%) it was high. No patients in the risperidone treatment group lost their weight > 7%.

Clinical study 2 :
A slight decrease in mean body weight was observed at the endpoint in the bifeprunox-treated and placebo groups, while an increase was seen for the risperidone-treated group (Table below). At endpoint, mean body weight change was: -2.2 lb in the 30 mg bifeprunox group; -1.9 lb in the 40 mg bifeprunox group; 0.5 lb in the placebo group; and 3.2 lb in the risperidone group there were. In the bifeprunox treatment group, the mean change at 6 weeks was higher than that at the endpoint.

Clinical study 3 : A slight decrease in mean body weight was observed in the bifeprunox-treated and placebo groups, while an increase was observed for the olanzapine-treated group. At endpoint, mean body weight changes were: -2.3 lb in the 20 mg bifeprunox group; -1.1 lb in the 30 mg bifeprunox group; -1.3 lb in the placebo group; and 5.2 lb in the olanzapine group Met. The average change at 6 weeks was similar to that at the endpoint (table below).

The incidence of significantly abnormal ( > 7%) weight loss was similar between bifeprunox-treated and placebo groups (20 mg bifeprunox: 6%; 30 mg bifeprunox: 5%; placebo: 5% ), And low in the olanzapine treatment group (<1%). In the incidence of significantly abnormal ( > 7%) increase in body weight, the olanzapine treatment group compared to 5% in the 30 mg bifeprunox experienced, 1% in the 20 mg bifeprunox, and 5% in the placebo group In 19%, the opposite was seen.

Clinical study 4 :
Body weight and BMI and their changes relative to baseline are summarized in the table below. In all groups, corrected mean body weight and BMI decreased from baseline to 6 months. The corrected mean body weight change (APTS, OC, ANCOVA) from baseline to 6 months was -0.8 kg in the PBO group, -0.3 kg in the BX20 group, and -0.5 kg in the BX30 group. The corrected mean weight loss in the BX20 and BX30 groups was not statistically significantly different from that in the PBO group.

  Weight loss was reported as TEAE for patients in all treatment groups (PBO: 5%; BX20: 8%; BX30: 8%) (panel 45). Increased body weight was reported as TEAE for patients in the PBO group (1.8%) and in the BX30 group (1.2%).

  Adjusted mean weight change from baseline to 6 months in patients with / without nausea and / or vomiting (APTS, LOCF, ANCOVA), patients with nausea and / or vomiting have greater weight loss However, patients in all groups were shown to lose weight regardless of having nausea and / or vomiting (PBO: -0.6 vs. -1.9 kg; BX20: -1.0 vs. -1.9 kg; BX30: -1.1 vs. -2.3 kg).

Time to exacerbation
Clinical study 4 :
The primary efficacy variable was time to exacerbation and analysis was based on FAS. The primary efficacy analysis dismissed the hypothesis of equal time to exacerbation of schizophrenia in the three treatment groups (p = 0.008). The proportion of patients exacerbated was 59% in the PBO group, 41% in the BX20 group, and 38% in the BX30 group. The Cox proportional hazard model gives an approximate hazard ratio of 0.66 (BX20) and 0.65 (BX30) for PBO; that is, the risk of exacerbation is in patients in the PBO group than in patients in the BX20 or BX30 group About 1.5 times higher.

A pairwise comparison of each of the BX groups with the PBO group then showed that patients in the BX group had a statistically significantly longer time to exacerbation of schizophrenia than patients in the PBO group (BX20: p = 0.008 and BX30: p = 0.006). The primary efficacy analysis was repeated for PPS. Since the majority of patients in PPS participated in the majority of the study, the results were very close to the results of the main analysis for both the estimated hazard ratio and the p-value obtained. This explains the robustness of the main efficacy analysis conclusions.

Lipid profile
Clinical study 4 : Corrected mean HDL cholesterol levels increased from baseline to 6 months in all three treatment groups regardless of fasting / non-fasting conditions (PBO: 0.04 / 0.06 (fasting) / Non-fasting); BX20: 0.07 / 0.08; BX30: 0.07 / 0.08 mmol / L). There was no statistically significant difference between any of the BX groups and the PBO group. Corrected mean triglyceride values decreased from baseline to 6 months in all three treatment groups regardless of fasting / non-fasting conditions (PBO: -0.06 / -0.22 (fasting / non-fasting) BX20: -0.16 / -0.21; BX30: -0.37 / -0.03 mmol / L). There was no statistically significant difference between any of the BX groups (except BX30 (fasting)) and the PBO group.

  Corrected mean fasting glucose values increased from baseline to 6 months in all three treatment groups (PBO: 0.10; BX20: 0.13; BX30: 0.09 mmol / L), and any of the BX groups There was no statistically significant difference between the heel and the PBO group.

  Panel 50 below summarizes lipid profiles at baseline (mean values) and at 6 months (mean change from baseline) in fasting and non-fasting patients. Calculated mean total cholesterol and mean LDL decreased from baseline to 6 months in all groups (except non-fasting PBO patients) regardless of treatment and fasting / non-fasting conditions. Calculated average VLDL and average triglycerides decreased from baseline to 6 months in all groups (except non-fasting BX30 patients) regardless of treatment and fasting / non-fasting conditions. Mean HDL increased from baseline to 6 months in all groups regardless of treatment and fasting / non-fasting conditions.

Hyperglycemia and diabetes Hyperglycemia, which is prominent in some cases and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. The incidence of hyperglycemia and diabetes-related adverse events (such as hyperglycemia, elevated blood sugar, impaired glucose tolerance, diabetes, poorly controlled diabetes) in patients treated with bifeprunox is a 6 week placebo control 0.5% (5/1050) in the trial and 0.6% (3/469) in placebo-treated patients. None of the patients reported hyperglycemia or diabetes-related adverse events in the 26-week placebo-controlled trial. Evaluation of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the potential for increased background risk of diabetes in patients with schizophrenia and the increasing incidence of diabetes in the general population. Given these confounding factors, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies that did not include bifeprunox suggest an increased risk of hyperglycemia-related adverse events that occurred under treatment in patients treated with atypical antipsychotics included in these studies. Since bifeprunox was not commercially available at the time these studies were conducted, it is not known whether bifeprunox is associated with this increased risk. An accurate risk estimate for hyperglycemia-related adverse events in patients treated with atypical antipsychotics is not available.

PR, QT, QTc, QRS
Clinical study 1 : Changes in PR, QT, QTc, QRS interval and heart rate over time were assessed by assessing the mean change between baseline and endpoint. There was little change in mean values of PR, QTc or QRS interval between baseline and endpoint in any treatment group. The average change in these intervals was between about -2 msec to 4 msec. There was no trend of mean change by treatment group. The change in mean heart rate between baseline and endpoint was between -1.5 bpm and 0.9 bpm. There was no trend of mean change by treatment group.

Clinical study 2 : The change in PR, QT, QTc, QRS interval and heart rate over time was assessed by assessing the mean change between baseline and endpoint. There was little change in mean values of PR, QTc or QRS interval between baseline and endpoint in any treatment group. The range of average change across treatment groups is: PR = −2.5 msec to 0.2 msec; QT = −2.8 msec to 7 msec; QTc = 0.4 msec to 3.9 msec; QRS = −0.4 msec to 1.4 msec there were. There was no trend of mean change by treatment group. The change in mean heart rate between baseline and endpoint across the treatment group was approximately between -1.3 bpm and 1.7 bpm. There was no trend of mean change by treatment group.

Clinical study 3 : Changes in PR, QT, QTc, QRS interval and heart rate over time were assessed by assessing the change in mean between baseline and endpoint. For these summaries, the Bazett corrected QT interval was presented as QTc. There was little change in mean values of PR, QTc or QRS interval between baseline and endpoint in any treatment group. The average change in these intervals was between about 3 msec and 4 msec. There was no trend of mean change by treatment group. The change in average heart rate between baseline and endpoint was between -1 bpm and 1 bpm. There was no trend of mean change by treatment group.

Example 3a: Pharmacokinetics of bifeprunox The purpose of this study is to evaluate the pharmacokinetics (PK) of bifeprunox. The bifeprunox PK in healthy subjects was examined based on a pooled analysis of PK parameters from 21 clinical pharmacology studies. The pooled analysis included PK profiles after single and multiple doses to 132 and 399 subjects, respectively, and examined the potential effects of age, sex, weight and race. In addition, PK in patients with schizophrenia was examined using a sample-based population PK method from 376 patients in the Phase II study and 434 patients in the Phase III study. Bifeprunox was rapidly absorbed after oral administration (t _max of 1.5-2 hours at all dose levels). Bifeprunox multiple dose PK was proportional to dose in the range of 20-40 mg / day. The steady state average apparent clearance and apparent distribution volume were 62.2 L / h and 1300 L, respectively. Bifeprunox was excreted with an average plasma steady state half-life of 14.4 hours. Administration of a 40 mg dose on a standard high fat diet was associated with a slight delay in t _max (1.5 hours) and a slight increase in C _max (10%) and AUC (29%). Bifeprunox is approximately 99% bound to serum proteins. Bifeprunox is metabolized by CYP2C9, CYP3A4 and to a lesser extent CYP2D6. Bifeprunox exposure was increased by co-administration with fluconazole (CYP2C9 inhibitor) and, to a small extent, ketoconazole (CYP3A4 inhibitor), but with co-administration with paroxetine (CYP2D6 inhibitor) and famotidine (H2 antagonist). It was not increased. Bifeprunox exposure was reduced by co-administration of carbamazepine (CYP3A4 inducer). Co-administration of bifeprunox with narrow therapeutic index compounds warfarin and lithium (see Example 3b) did not affect the PK of these compounds to any relevant degree. Higher plasma levels of bifeprunox were observed in CYP2C9 slow / intermediate metabolizers than in subjects with normal enzyme activity. After a single oral administration of bifeprunox labeled with [14C], 13% and 74% of the radioactivity was excreted in urine and feces, respectively. There were no clinically significant effects related to age, sex, weight or race on bifeprunox PK. PK in patients with schizophrenia was similar to that seen in healthy subjects.

  One conclusion of this study is that bifeprunox is rapidly absorbed after oral administration; the mean elimination half-life is about 14 hours. Multiple dose PK was proportional to dose in the range of 20-40 mg. Bifeprunox has a low interaction potential.

Example 3b: Pharmacokinetic interaction of lithium and bifeprunox in healthy male subjects Objective: The partial agonist of dopamine D2 and 5-HT1A receptor, bifeprunox, has been developed for the treatment of schizophrenia . Because bifeprunox can be used in combination with the mood stabilizer lithium for the treatment of patients with psychosis and mood disorders, the effects of multiple doses of bifeprunox on the pharmacokinetic (PK) profile of lithium evaluated. Lithium has a narrow therapeutic index that can complicate treatment, and serum levels greater than 1.5 mmol / L have a greater risk of lithium toxicity than lower levels. Method: This was a single center, double-blind, randomized, placebo-controlled, parallel design study in 48 healthy male subjects. All subjects will take lithium (450 mg) twice a day, open-label, again on days 1-8 and again on days 9-20 if serum levels were stable on days 5-7. It was scheduled. Subjects whose serum levels were stable on days 5-7 received 450 mg of lithium twice daily, plus placebo or ascending dose of bifeprunox (0.025-40 mg) once daily on days 9-17. And it was included in what was randomized to take placebo or bifeprunox 40 mg on days 18-21. Only a single morning dose of 450 mg lithium was administered on day 21. Bifeprunox and placebo groups using ANCOVA with the baseline values of lithium measured on day 8 for lithium, steady state Cmax, AUC and renal clearance (CL-R) values over the dosing interval (0-t) Compared between. Results: There was a slight increase in the mean Cmax and AUC (0-t) of lithium in the bifeprunox group, but the ratio of the geometric least squares means and 90% confidence interval of the two treatments AUC, Cmax and CL-R (CI) was within a predetermined range of 0.80 to 1.25. The treatment ratio and 90% CI for Cmax, AUC (0-t) and CL-R were 1.11 (90% CI: 1.01-1.20), 1.13 (90% CI: 1.06), respectively. To 1.21) and 0.94 (90% CI: 0.87 to 1.02). Administration of up to 40 mg bifeprunox per day and 450 mg lithium twice daily was well tolerated. Conclusion: There were no clinically relevant effects of co-administration of multiple doses of bifeprunox on lithium steady state pharmacokinetics. The results suggest that lithium dosage adjustment is not required during co-administration with bifeprunox.

Example 4: Efficacy and safety of bifeprunox in the treatment of patients with acute exacerbation schizophrenia Objective: To evaluate the efficacy and safety of bifeprunox in the treatment of acute disease patients with schizophrenia.

Evaluation: The 6-week randomized placebo-controlled risperidone reference dose-study study included 589 randomly sampled patients with an acute exacerbation of schizophrenia (DSM-IV-TR). Patients randomized to bifeprunox 5 mg (n = 115), bifeprunox 10 mg (n = 120), bifeprunox 20 mg (n = 115), placebo (n = 119) or risperidone 6 mg (n = 120) Assigned to. Treatment with all bifeprunox doses starts with a target dose of 0.125 mg daily, 0.25 mg for 2 days, 0.5 mg for 3 days, 1 mg for 4 days, 2 mg for 5 days and Titration to 5 mg on day 6, 10 mg on day 7 or 20 mg on day 8 while treatment with risperidone was titrated over 3 days. Positive and negative symptom rating scale from baseline to endpoint (PAN
The change in SS) total score was the primary outcome measure. Secondary efficacy rating scales include: PANSS positive, PANSS negative, PANSS general psychopathology (GPP) score, PANSS-derived simplified psychiatric symptom rating scale (BPRS) score, clinical general impression disease severity (CGI-S), CGI -I improvement (CGI-I) score as well as responder rate were included. Safety and tolerability assessments included extrapyramidal symptoms (EPS), weight gain, lipid profile and serum prolactin. Risperidone was included for assay sensitivity.

  Results: The reduction in the total PANSS score for bifeprunox was statistically significant (P <0.05) compared to placebo at 3 and 6 weeks / endpoint for the 20 mg dose. A positive effect of bifeprunox 20 mg was also observed on the secondary efficacy rating scale PANSS positive, negative, GPP subscale, BPRS and responder rate. Risperidone 6 mg was statistically significant at the endpoint compared to placebo for all efficacy measures. The most common adverse events (incidence> 5% and twice the placebo) included: dyspepsia, nausea, vomiting and constipation. The dose relationship was not clear for any of the most frequent adverse events. Bifeprunox was associated with decreased prolactin levels and a proportion of EPS that was comparable to placebo. In addition, patients taking bifeprunox experience a statistically significant (P <0.05) weight loss and non-fasting triglycerides (P <0.005) and total cholesterol (P <0.05) compared to placebo. P <0.005) showed a statistically significant improvement.

  Conclusion: In this study, bifeprunox 20 mg was shown to be effective in the treatment of acute schizophrenia. Bifeprunox may have safety benefits due to weight loss and improved lipid profile.

Claims (45)

  A daily dose of bifeprunox for the treatment of patients with CNS disorders, wherein the dose is 20-30 mg of at least one bifeprunox compound.   The dose of claim 1 for the treatment of a patient having schizophrenia.   The dose according to claim 1 or 2, wherein the dose is a dose once a day.   4. A dose according to any one of claims 1 to 3 for long-term treatment of a patient with schizophrenia.   5. A dose according to any one of claims 1 to 4 for maintaining clinical stability in patients with schizophrenia.   6. The dose of claim 5, wherein the dose is 20 mg of at least one bifeprunox compound.   6. The dose of claim 5, wherein the dose is 30 mg of at least one bifeprunox compound.   4. A dose according to any one of claims 1 to 3 for the treatment of a patient having acute exacerbation schizophrenia.   9. The dose of claim 8, wherein the dose is 20 mg of at least one bifeprunox compound.   The dose according to any one of claims 1 to 9, wherein the bifeprunox compound is bifeprunox mesylate.   11. The dose of claim 10, wherein the bifeprunox compound is the alpha polymorph of bifepsnox mesylate.   A pharmaceutical composition comprising 30 mg of at least one bifeprunox compound and at least one pharmaceutically acceptable carrier for use in the treatment of a patient with schizophrenia.   A pharmaceutical composition comprising 20 mg of at least one bifeprunox compound and at least one pharmaceutically acceptable carrier for use in the treatment of a patient with schizophrenia.   14. A pharmaceutical composition according to claim 12 or 13 for use in the long term treatment of patients with schizophrenia.   15. A pharmaceutical composition according to any one of claims 12 to 14 for use in maintaining clinical stability in patients with schizophrenia.   14. A pharmaceutical composition according to claim 12 or 13 for use in the treatment of a patient having acute exacerbation schizophrenia.   The pharmaceutical composition according to any one of claims 12 to 16, wherein the bifeprunox compound is bifeprunox mesylate.   18. The pharmaceutical composition of claim 17, wherein the bifeprunox compound is the alpha polymorph of bifeprunox mesylate.   Bifeprunox for use in long-term treatment of patients with schizophrenia.   20. Bifeprunox for use according to claim 19 in the treatment of patients with stable schizophrenia.   Bifeprunox for use in the treatment of patients with stable schizophrenia.   The bifeprunox for use according to any one of claims 19 to 21, wherein a daily dose of 20-30 mg of at least one bifeprunox compound is administered to the patient.   23. The bifeprunox for use according to claim 22, wherein a daily dose of 20 mg of at least one bifeprunox compound is administered to the patient.   23. The bifeprunox for use according to claim 22, wherein a daily dose of 30 mg of at least one bifeprunox compound is administered to the patient.   Bifeprunox for use in the treatment of patients with acute exacerbation schizophrenia.   26. The bifeprunox for use according to claim 25, wherein a daily dose of 20 mg of at least one bifeprunox compound is administered to the patient.   26. The bifeprunox for use according to claim 25, wherein a daily dose of 30 mg of at least one bifeprunox compound is administered to the patient.   28. Bifeprunox for use according to any one of claims 19 to 27, wherein at least one bifeprunox compound is administered in combination with a mood stabilizer lithium.   Bifeprunox for use in the treatment of patients with psychosis and mood disorders wherein at least one bifeprunox compound is administered in combination with the mood stabilizer lithium.   28. Bifeprunox for use according to any one of claims 19 to 27, wherein at least one bifeprunox compound is administered in combination with an antidepressant.   32. The bifeprunox for use according to claim 30, wherein the antidepressant is paroxetine.   32. The bifeprunox according to any one of claims 19 to 31, wherein the bifeprunox compound is bifeprunox mesylate.   33. The bifeprunox of claim 32, wherein the bifeprunox compound is an alpha polymorph of bifeprunox mesylate.   A kit for the treatment of patients with psychosis and mood disorders comprising a composition comprising at least one bifeprunox compound and a composition comprising a mood stabilizer lithium.   A kit for the treatment of a patient with a CNS disorder comprising a composition comprising at least one bifeprunox compound and a composition comprising an antidepressant.   36. The kit of claim 35, wherein the antiepileptic agent is paroxetine.   37. The kit according to any one of claims 34 to 36, wherein the bifeprunox compound is bifeprunox mesylate.   38. The kit of claim 37, wherein the bifeprunox compound is an alpha polymorph of bifeprunox mesylate.   Bifeprunox for the manufacture of a medicament for the treatment of patients with schizophrenia, wherein a daily dose of 20-30 mg of at least one bifeprunox compound is administered to the patient and the treatment results in a favorable metabolic profile Use of.   Treatment with bifeprunox in patients with schizophrenia is selected from weight gain, impaired triglyceride and / or total cholesterol levels, hyperglycemia and / or the occurrence of one or more diabetes-related adverse events 41. Use of claim 40 to prevent and / or reduce side effects.   Use of bifeprunox for the manufacture of a medicament for the treatment of patients with stable schizophrenia, wherein a daily dose of 20-30 mg of at least one bifeprunox compound is administered to the patient.   Use of bifeprunox for the manufacture of a medicament for the treatment of a patient with acute exacerbation schizophrenia, wherein a daily dose of 20-30 mg of at least one bifeprunox compound is administered to the patient.   43. Use according to any one of claims 39 to 42, wherein the bifeprunox compound is bifeprunox mesylate.   44. The use of claim 43, wherein the bifeprunox compound is the alpha polymorph of bifeprunox mesylate.   Bifeprunox for use in the treatment of patients with schizophrenia who have weight problems or are prone to weight problems.

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