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Clinical Trial Results:
Phase III, Multi-Center, Randomized, 12-Week, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate Efficacy and Safety of RO4917838 in Patients With Sub-Optimally Controlled Symptoms of Schizophrenia Treated With Antipsychotics Followed by a 40-Week Double-Blind, Parallel-Group, Placebo-Controlled Treatment Period

Summary
EudraCT number	2010-020616-11
Trial protocol	DE ES LT LV SK NL
Global end of trial date	04 Jul 2014

Results information
Results version number	v1(current)
This version publication date	19 Nov 2016
First version publication date	19 Nov 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

WN25306

ISRCTN number

US NCT number

NCT01235585

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Jul 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Jul 2014

Global end of trial reached?

Yes

Global end of trial date

04 Jul 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

This was a phase III, multi-center, randomized, 12-week, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of bitopertin (RO4917838) in participants with sub-optimally controlled symptoms of schizophrenia treated with anti-psychotics, followed by a 44-week double- blind, parallel-group, placebo-controlled treatment period (40-week treatment period followed by a 4-week washout period). The primary objectives of the study were as follows: 1. To evaluate the efficacy after 12 weeks of treatment with bitopertin versus placebo as adjunct to antipsychotics, in the Positive and Negative Syndrome Scale (PANSS) positive symptom factor score in participants with sub-optimally controlled symptoms of schizophrenia; 2. To evaluate the safety and tolerability after 12 weeks of treatment with bitopertin versus placebo as adjunct to antipsychotics, in participants with sub-optimally controlled symptoms of schizophrenia.

Protection of trial subjects

The study was conducted in accordance with the principles of “Declaration of Helsinki” and Good Clinical Practice according to the regulations and procedures consistent with the protocol. Approval from Institutional Review Board (IRB) / Ethics Committee (EC) was obtained before study start and was documented in a letter to the investigator specifying the date on which the committee met and granted the approval. An approval from the relevant regulatory authority was also obtained prior to the start of study. All the protocol amendments were submitted to IRB/EC and to the regulatory authorities in accordance with the local regulatory requirements. A written informed consent was obtained from the participants and care givers prior to the participation in the study. All new safety information that resulted in significant changes in the risk/benefit assessment were reviewed and updated in the informed consent form, as necessary. Consent to the expanded pharmacokinetics (PK) assessments and long-term extension period was also obtained from the participants and caregivers, as necessary.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Nov 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 42

Country: Number of subjects enrolled

Slovakia: 14

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Latvia: 4

Country: Number of subjects enrolled

Lithuania: 36

Country: Number of subjects enrolled

Turkey: 22

Country: Number of subjects enrolled

Ukraine: 45

Country: Number of subjects enrolled

Canada: 42

Country: Number of subjects enrolled

United States: 177

Country: Number of subjects enrolled

Brazil: 122

Country: Number of subjects enrolled

Chile: 22

Country: Number of subjects enrolled

Taiwan: 17

Worldwide total number of subjects

588

EEA total number of subjects

141

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

569

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study included 2 treatment periods, Treatment Period 1 (12-Week double blind treatment) and Treatment Period 2 (44-week double blind treatment), and Long Term Extension Period (for 3 years).

Screening details

A total of 597 participants were randomized to receive treatment, 5 participants were randomized to another bitopertin study first and not included in safety population. A further 4 participants were not treated, and therefore, 588 participants were available in safety population. All participants received antipsychotic treatment at baseline.

Period 1 title

Treatment Period 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Bitopertin 5 mg

Arm description

Participants received bitopertin 5 milligrams (mg) oral tablet once a day (QD) for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 5 mg oral tablet QD in the morning, with or without food.

Bitopertin 10 mg

Arm description

Participants received bitopertin 10 mg oral tablet QD for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD in the morning, with or without food.

Placebo

Arm description

Participants received placebo-matched to bitopertin QD for 12 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo-matched to bitopertin 5 or 10 mg oral tablet QD in the morning, with or without food.

Number of subjects in period 1	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Started	195	200	193
Completed	170	175	159
Not completed	25	25	34
Consent withdrawn by subject	3	8	8
Protocol violation	4	1	3
Death	-	-	1
Adverse event	9	9	11
Non-compliance	3	5	2
Administrative/Other	3	-	1
Lost to follow-up	3	2	8

Period 2 title

Treatment Period 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Bitoperin 5 mg

Arm description

Participants received bitopertin 5 mg oral tablet QD from Week 13 to Week 52.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 5 mg oral tablet QD in the morning, with or without food.

Bitopertin 10 mg

Arm description

Participants received bitopertin 10 mg oral tablet QD from Week 13 to Week 52.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD in the morning, with or without food.

Placebo

Arm description

Participants received placebo-matched to bitopertin from Week 13 to Week 52.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo-matched to bitopertin 5 or 10 mg oral tablet QD in the morning, with or without food.

Number of subjects in period 2	Bitoperin 5 mg	Bitopertin 10 mg	Placebo
Started	167	173	159
Completed	79	89	84
Not completed	88	84	75
Consent withdrawn by subject	7	10	9
Protocol violation	-	3	3
Adverse event	8	10	9
Non-compliance	3	2	2
Administrative/Other	64	55	51
Lost to follow-up	4	2	1
Lack of efficacy	2	2	-

Period 3 title

Washout Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Bitopertin 5 mg

Arm description

Participants received bitopertin 5 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 5 mg oral tablet QD in the morning, with or without food.

Bitopertin 5 mg to Placebo

Arm description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo-matched to bitopertin oral tablet QD in the morning, with or without food.

Bitopertin 10 mg

Arm description

Participants received bitopertin 10 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD in the morning, with or without food.

Bitopertin 10 mg to Placebo

Arm description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo-matched to bitopertin oral tablet QD in the morning, with or without food.

Placebo

Arm description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matched to bitopertin 5 or 10 mg oral tablet QD in the morning, with or without food.

Number of subjects in period 3	Bitopertin 5 mg	Bitopertin 5 mg to Placebo	Bitopertin 10 mg	Bitopertin 10 mg to Placebo	Placebo
Started	39	40	44	43	81
Completed	39	34	43	43	77
Not completed	0	6	1	0	4
Consent withdrawn by subject	-	1	-	-	-
Death	-	-	-	-	1
Non-compliance	-	2	-	-	1
Administrative/Other	-	3	1	-	2

Period 4 title

Long-Term Extension

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Placebo to Bitopertin 10 mg

Arm description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD up to 3 years, with or without food.

Bitopertin 5 mg to Bitopertin 10 mg

Arm description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD up to 3 years, with or without food.

Bitopertin 10 mg

Arm description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD up to 3 years, with or without food.

Number of subjects in period 4	Placebo to Bitopertin 10 mg	Bitopertin 5 mg to Bitopertin 10 mg	Bitopertin 10 mg
Started	70	62	74
Completed	0	0	0
Not completed	70	62	74
Consent withdrawn by subject	3	1	5
Protocol violation	1	-	1
Adverse event	1	3	5
Administrative/Other	64	57	62
Lost to follow-up	-	-	1
Lack of efficacy	1	1	-

Period 5 title

Safety Follow-up Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Bitopertin 5 mg

Arm description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 5 mg QD, for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 5 mg oral tablet QD in the morning, with or without food.

Bitopertin 10 mg

Arm description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 10 mg QD, for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Bitopertin 10 mg oral tablet QD in the morning, with or without food.

Placebo

Arm description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received placebo-matched to bitopertin, for 4 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo-matched to bitopertin 5 or 10 mg oral tablet QD in the morning, with or without food.

Number of subjects in period 5	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Started	133	332	123
Completed	88	281	85
Not completed	45	51	38
Consent withdrawn by subject	16	15	15
Death	-	-	1
Adverse event	1	3	5
Administrative/Other	9	10	2
Lost to follow-up	19	23	15

Baseline characteristics

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Reporting group title

Bitopertin 5 mg

Reporting group description

Participants received bitopertin 5 milligrams (mg) oral tablet once a day (QD) for 12 weeks.

Reporting group title

Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD for 12 weeks.

Reporting group title

Placebo

Reporting group description

Participants received placebo-matched to bitopertin QD for 12 weeks.

Reporting group values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo	Total
Number of subjects	195	200	193
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	43.4 ± 12.2	40.7 ± 12.6	41.9 ± 12.3	-
Gender categorical
Units: Subjects
Female	71	55	60	186
Male	124	145	133	402

End points

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Reporting group title

Bitopertin 5 mg

Reporting group description

Participants received bitopertin 5 milligrams (mg) oral tablet once a day (QD) for 12 weeks.

Reporting group title

Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD for 12 weeks.

Reporting group title

Placebo

Reporting group description

Participants received placebo-matched to bitopertin QD for 12 weeks.

Reporting group title

Bitoperin 5 mg

Reporting group description

Participants received bitopertin 5 mg oral tablet QD from Week 13 to Week 52.

Reporting group title

Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD from Week 13 to Week 52.

Reporting group title

Placebo

Reporting group description

Participants received placebo-matched to bitopertin from Week 13 to Week 52.

Reporting group title

Bitopertin 5 mg

Reporting group description

Participants received bitopertin 5 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Bitopertin 5 mg to Placebo

Reporting group description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Bitopertin 10 mg to Placebo

Reporting group description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Placebo

Reporting group description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Placebo to Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Reporting group title

Bitopertin 5 mg to Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Reporting group title

Bitopertin 10 mg

Reporting group description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Reporting group title

Bitopertin 5 mg

Reporting group description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 5 mg QD, for 4 weeks.

Reporting group title

Bitopertin 10 mg

Reporting group description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 10 mg QD, for 4 weeks.

Reporting group title

Placebo

Reporting group description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received placebo-matched to bitopertin, for 4 weeks.

Subject analysis set title

Bitopertin 5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received bitopertin 5 mg oral tablet QD in the morning with/without food for 12 weeks (Week 0 to Week 12) in Treatment Period 1 and for 40 weeks (Week 13 to Week 52) in Treatment Period 2.

Subject analysis set title

Bitopertin 10 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received bitopertin 10 mg oral tablet QD in the morning with/without food for 12 weeks (Week 0 to Week 12) in Treatment Period 1 and for 40 weeks (Week 13 to Week 52) in Treatment Period 2.

Subject analysis set title

Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received placebo-matched to bitopertin taken QD in the morning with/without food for 12 weeks (Week 0 to Week 12) in Treatment Period 1 and for 40 weeks (Week 13 to Week 52) in Treatment Period 2.

Subject analysis set title

ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized participants who received at least 1 dose of double-blind study medication and had at least 1 post-baseline assessment of the primary efficacy variable.

Primary: Mean Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Symptoms Factor Score (PSFS) at Week 12

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End point title

Mean Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Symptoms Factor Score (PSFS) at Week 12

End point description

The PANSS is a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. The symptoms are rated on a 7-point scale capturing 1= Absent to 7=Extreme psychopathology. Each item of the PANSS is rated on a 7-point scale, on the basis of the following anchors: 1= Absent; 2= Minimal; 3= Mild; 4= Moderate; 5= Moderately severe; 6= Severe; 7= Extreme. Further assessment of symptoms using a factor analysis of the PANSS was calculated for PSFS which consists of the following items (Delusions [P1], Hallucinatory behavior [P3], Grandiosity [P5], Suspiciousness [P6], Stereotyped thinking [N7], Somatic concern [G1], Unusual thought content [G9] and Lack of judgment and insight [G12]). Scores were transformed to 0 to 6 points with higher scores indicating greater severity of symptoms. If any item score contributing to the factor score is missing, then the factor will be set to missing. ITT population.

End point type

Primary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)	-4.53 (-5.13 to -3.93)	-4.16 (-4.75 to -3.57)	-4.59 (-5.2 to -3.98)

PANSS PSFS : Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on Mixed-Effect Model Repeated Measure (MMRM) using unstructured covariance matrix. Change = Baseline + Week + Treatment +Treatment * Week

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8823

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.79

upper limit

0.92

Variability estimate

Standard error of the mean

Dispersion value

0.434

PANSS PSFS : Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3117

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

1.28

Variability estimate

Standard error of the mean

Dispersion value

0.431

Secondary: Mean Change from Baseline in PANSS Total Score at Week 12

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End point title

Mean Change from Baseline in PANSS Total Score at Week 12

End point description

The PANSS is a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. The symptoms are rated on a 7-point scale capturing 1= Absent to 7= Extreme psychopathology. Each item of the PANSS is rated on a 7-point scale, on the basis of the following anchors: 1= Absent; 2= Minimal; 3= Mild; 4= Moderate; 5= Moderately severe; 6= Severe; 7= Extreme. The total PANSS sum score of all the items ranges from 30 to 210. Higher score indicates greater severity of symptoms. The assessment for each of the 30 items were provided in the electronic case report form to allow calculation of a total score describing overall symptomatology as well as scores for positive, negative, and general psychopathology. If any item score contributing to the factor score is missing, then the factor will be set to missing. ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)	-11.41 (-12.99 to -9.83)	-10.5 (-12.06 to -8.95)	-12.1 (-13.7 to -10.49)

PANSS Total Score: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5499

Method

Mixed-Effect Model Repeated Measures

Parameter type

Adjusted Mean Difference

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

-1.57

upper limit

2.94

Variability estimate

Standard error of the mean

Dispersion value

1.147

PANSS Total Score: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment +Treatment * Week

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1625

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

-0.64

upper limit

3.83

Variability estimate

Standard error of the mean

Dispersion value

1.139

Secondary: Mean Change from Baseline in PANSS Subscale Score at Week 12

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End point title

Mean Change from Baseline in PANSS Subscale Score at Week 12

End point description

The PANSS is a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. PANSS subscales include positive subscale (PSS), negative subscale (NSS) and general psychopathology subscale (GPSS). Negative and positive subscales includes 7-items each and general psychopathology subscale includes 16 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total negative and positive scores= 7 to 49 each, with higher score indicating greater severity and total general psychopathology score= 16 to 112, with higher score indicating greater severity. If any item score contributing to the factor score is missing, then the factor will be set to missing. ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)
PANSS Positive Subscale Score	-4.43 (-5.01 to -3.84)	-4.13 (-4.7 to -3.55)	-4.42 (-5.02 to -3.83)
PANSS Negative Subscale Score	-1.97 (-2.45 to -1.48)	-1.72 (-2.19 to -1.24)	-2.07 (-2.56 to -1.57)
PANSS General Psychopathology Subscale Score	-5 (-5.84 to -4.16)	-4.71 (-5.53 to -3.88)	-5.65 (-6.51 to -4.79)

PSS: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9927 ^[1]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.84

upper limit

0.83

Variability estimate

Standard error of the mean

Dispersion value

0.425

Notes
[1] - Unadjusted p-value for pairwise comparisons with placebo was presented.

PSS: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4831 ^[2]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

1.12

Variability estimate

Standard error of the mean

Dispersion value

0.422

Notes
[2] - Unadjusted p-value for pairwise comparisons with placebo was presented.

NSS: Placebo versus Biopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7797 ^[3]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

0.79

Variability estimate

Standard error of the mean

Dispersion value

0.352

Notes
[3] - Unadjusted p-value for pairwise comparisons with placebo was presented.

NSS: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3141 ^[4]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-0.33

upper limit

1.04

Variability estimate

Standard error of the mean

Dispersion value

0.349

Notes
[4] - Unadjusted p-value for pairwise comparisons with placebo was presented.

GPSS: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2883 ^[5]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-0.55

upper limit

1.85

Variability estimate

Standard error of the mean

Dispersion value

0.61

Notes
[5] - Unadjusted p-value for pairwise comparisons with placebo was presented.

GPSS: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1197 ^[6]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

2.13

Variability estimate

Standard error of the mean

Dispersion value

0.606

Notes
[6] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Secondary: Mean Change from Baseline in PANSS Symptom Factor Score at Week 12

Top of page

End point title

Mean Change from Baseline in PANSS Symptom Factor Score at Week 12

End point description

The PANSS is a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. PANSS factor score included negative symptoms factor (NSF) score (7-items), disorganized thought/cognition factor (DT/CF) score (7-items), anxiety/depression factor (A/DF) score (4-items), and uncontrolled hostility/excitement factor (UH/EF) score (4-items). Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total negative symptoms and disorganized thought/cognition factor scores = 1 to 7 each, with higher score indicating greater severity and total anxiety/depression factor score and uncontrolled hostility/excitement scores = 1 to 4 each, with higher score indicating greater severity. If any item score contributing to the factor score is missing, then the factor will be set to missing. ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)
PANSS Negative Symptom Factor Score	-2.04 (-2.55 to -1.53)	-1.91 (-2.41 to -1.41)	-2.11 (-2.63 to -1.59)
PANSS Disorganized Thoughts/Cognition Factor Score	-2.01 (-2.43 to -1.59)	-1.95 (-2.37 to -1.53)	-2.38 (-2.81 to -1.95)
PANSS Anxiety/Depression Factor Score	-1.46 (-1.81 to -1.11)	-1.63 (-1.97 to -1.28)	-1.77 (-2.13 to -1.41)
PANSS Hostility/Excitement Factor Score	-1.38 (-1.71 to -1.05)	-0.97 (-1.29 to -0.65)	-1.34 (-1.67 to -1)

NSF: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8568 ^[7]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

0.79

Variability estimate

Standard error of the mean

Dispersion value

0.37

Notes
[7] - Unadjusted p-value for pairwise comparisons with placebo was presented.

NSF: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5899 ^[8]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

0.92

Variability estimate

Standard error of the mean

Dispersion value

0.367

Notes
[8] - Unadjusted p-value for pairwise comparisons with placebo was presented.

DT/CF: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week

Comparison groups

Placebo v Bitopertin 5 mg

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2311 ^[9]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.97

Variability estimate

Standard error of the mean

Dispersion value

0.307

Notes
[9] - Unadjusted p-value for pairwise comparisons with placebo was presented.

DT/CF: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.1616

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

1.03

Variability estimate

Standard error of the mean

Dispersion value

0.305

Notes
[10] - Unadjusted p-value for pairwise comparisons with placebo was presented.

A/DF: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2215 ^[11]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

0.81

Variability estimate

Standard error of the mean

Dispersion value

0.255

Notes
[11] - Unadjusted p-value for pairwise comparisons with placebo was presented.

A/DF: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5816 ^[12]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

0.64

Variability estimate

Standard error of the mean

Dispersion value

0.253

Notes
[12] - Unadjusted p-value for pairwise comparisons with placebo was presented.

UH/EF: Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8515 ^[13]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.42

Variability estimate

Standard error of the mean

Dispersion value

0.238

Notes
[13] - Unadjusted p-value for pairwise comparisons with placebo was presented.

UH/EF: Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1192 ^[14]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.83

Variability estimate

Standard error of the mean

Dispersion value

0.237

Notes
[14] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Secondary: Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS at Week 12

Top of page

End point title

Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS at Week 12

End point description

PANSS: 30-item scale designed to capture degree of severity for many symptoms in schizophrenia. Symptoms are rated on 7-point scale capturing 1= Absent to 7= Extreme psychopathology. Each item rated on 7-point scale on basis of following anchors: 1= Absent; 2= Minimal; 3= Mild; 4= Moderate; 5= Moderately severe; 6= Severe; 7= Extreme. Further assessment of symptoms using factor analysis of PANSS was calculated for PSFS which consists of following items (Delusions [P1], Hallucinatory behavior [P3], Grandiosity [P5], Suspiciousness [P6], Stereotyped thinking [N7], Somatic concern [G1], Unusual thought content [G9] and Lack of judgment and insight [G12]). Scores were transformed to 0 to 6 points with higher scores indicating greater severity of symptoms. If any item score contributing to factor score is missing, then factor will be set to missing. A PANSS 20% responder was defined as participant who had reduction from baseline of at least 20% in PANSS PSFS at Week 12. ITT population.

End point type

Secondary

End point timeframe

Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: percentage of participants
number (not applicable)	55.6	51.3	53.8

Placebo versus Bitopertin 5 mg

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7571 ^[15]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[15] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Placebo versus Bitopertin 10 mg

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.623 ^[16]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[16] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Secondary: Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS At Least at Two Out of the Three Last Post-Baseline Assessments

Top of page

End point title

Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS At Least at Two Out of the Three Last Post-Baseline Assessments

End point description

PANSS: 30-item scale designed to capture degree of severity for many symptoms in schizophrenia. The symptoms are rated on 7-point scale capturing 1= absent to 7=extreme psychopathology. Each item of PANSS rated on 7-point scale on basis of following anchors: 1= Absent; 2= Minimal; 3= Mild; 4= Moderate; 5= Moderately severe; 6= Severe; 7= Extreme. Further assessment of symptoms using factor analysis of PANSS was calculated for PSFS which consists of following items (Delusions [P1], Hallucinatory behavior [P3], Grandiosity [P5], Suspiciousness [P6], Stereotyped thinking [N7], Somatic concern [G1], Unusual thought content [G9] and Lack of judgment and insight [G12]). Scores were transformed to 0 to 6 points with higher scores indicating greater severity of symptoms. A PANSS 20% responder was defined as a participant who had a reduction from baseline of at least 20% in the PANSS PSFS at least at two of three last post-baseline assessments during the initial 12 weeks. ITT population.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: percentage of participants
number (not applicable)	39	37.7	39.2

Placebo versus Bitopertin 5 mg

Comparison groups

Placebo v Bitopertin 5 mg

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9606 ^[17]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[17] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Placebo versus Bitopertin 10 mg

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8088 ^[18]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[18] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in Clinical Global Impression-Improvement (CGI-I) Overall Rating Score at Week 12

Top of page

End point title

Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in Clinical Global Impression-Improvement (CGI-I) Overall Rating Score at Week 12

End point description

The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention. The CGI-I score ranges from 1-7, where 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Percentage of participants with a rating of either 'Much' or 'Very Much' improvement in CGI-I overall rating score at Week 12 is reported. ITT population. Here, Number of subjects analyzed = number of participants analyzed for this endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	185
Units: percentage of participants
number (not applicable)	15.5	15.7	16.8

Placebo versus Bitopertin 5 mg

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7275 ^[19]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[19] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Placebo versus Bitopertin 10 mg

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7534 ^[20]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[20] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Overall Rating Score At Least at Two of the Three Last Post-Baseline Assessments

Top of page

End point title

Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Overall Rating Score At Least at Two of the Three Last Post-Baseline Assessments

End point description

The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention. The CGI-I score ranges from 1-7, where 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Percentage of participants with a rating of either 'Much' or 'Very Much' improvement in CGI-I overall rating score at least at two out of the three last post-baseline assessments during the initial 12 weeks is reported. ITT population. Here, Number of subjects analyzed = number of participants analyzed for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	185
Units: percentage of participants
number (not applicable)	10.7	10.5	10.8

Placebo versus Bitopertin 5 mg

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9503 ^[21]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[21] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Placebo versus Bitopertin 10 mg

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8778 ^[22]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[22] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score at Week 12

Top of page

End point title

Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score at Week 12

End point description

The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention. The CGI-I score ranges from 1-7, where 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Percentage of participants with a rating of either 'Much' or 'Very Much' improvement in CGI-I positive symptom rating score at Week 12 is reported. ITT population. Here, Number of subjects analyzed = number of participants analyzed for this endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	185
Units: percentage of participants
number (not applicable)	18.7	19.4	18.9

Placebo versus Bitopertin 5 mg

Comparison groups

Placebo v Bitopertin 5 mg

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9331 ^[23]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[23] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Placebo versus Bitopertin 10 mg

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9727 ^[24]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[24] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score At Least at Two of the Three Last Post-Baseline Assessments

Top of page

End point title

Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score At Least at Two of the Three Last Post-Baseline Assessments

End point description

The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention. The CGI-I score ranges from 1-7, where 1= very much improved; 2= much improved; 3= minimally improved; 4= no change; 5= minimally worse; 6= much worse; or 7= very much worse. Percentage of participants with a rating of either 'Much' or 'Very Much' improvement in CGI-I positive symptom rating score at least at two out of the three last post-baseline assessments during the initial 12 weeks is reported. ITT population. Here, Number (No.) of subjects analyzed = number of participants (pts) analyzed for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	185
Units: percentage of participants
number (not applicable)	12.8	14.7	13

Placebo versus Bitopertin 5 mg

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9501 ^[25]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[25] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Placebo versus Bitopertin 10 mg

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6807 ^[26]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[26] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline as stratification variables.

Secondary: Percentage of Participants With at Least 20% Improvement From Baseline in the PANSS PSFS and With a CGI-I Positive Symptoms Rating of Either 'Much' or 'Very Much' Improved at Week 12

Top of page

End point title

Percentage of Participants With at Least 20% Improvement From Baseline in the PANSS PSFS and With a CGI-I Positive Symptoms Rating of Either 'Much' or 'Very Much' Improved at Week 12

End point description

PANSS: 30-item scale designed to capture degree of severity for many symptoms in schizophrenia. Symptoms are rated on 7-point scale capturing 1= Absent to 7= Extreme psychopathology. Each item rated on 7-point scale on basis of following anchors: 1= Absent; 2= Minimal; 3= Mild; 4= Moderate; 5= Moderately severe; 6= Severe; 7= Extreme. Assessment of symptoms using factor analysis of PANSS was calculated for PSFS which consists of items (Delusions [P1], Hallucinatory behavior [P3], Grandiosity [P5], Suspiciousness [P6], Stereotyped thinking [N7], Somatic concern [G1], Unusual thought content [G9] and Lack of judgment and insight [G12]). Scores were transformed to 0 to 6 points with higher scores indicating greater severity of symptoms. CGI-I is used to assess the clinical change as compared to symptoms at baseline using 7-point scale, score ranges from 1-7, where 1= very much improved to 7= very much worse. ITT population. No. of subjects analyzed= no. of pts analyzed for the endpoint.

End point type

Secondary

End point timeframe

Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	185
Units: percentage of participants
number (not applicable)	18.2	17.8	17.3

Placebo versus Bitopertin 5 mg

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8342 ^[27]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[27] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline was used as stratification variable.

Placebo versus Bitopertin 10 mg

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

376

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9463 ^[28]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[28] - Unadjusted p-value with region and type of primary antipsychotic background medication at baseline was used as stratification variable.

Secondary: Mean Change from Baseline in Clinical Global Impression – Severity (CGI-S) Overall Symptoms Rating Score at Week 12

Top of page

End point title

Mean Change from Baseline in Clinical Global Impression – Severity (CGI-S) Overall Symptoms Rating Score at Week 12

End point description

The CGI-S reflects the severity of illness on a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. Participant was assessed on severity of mental illness at the time of rating 1= normal, not at all ill; 2= borderline mentally ill; 3= mildly ill; 4= moderately ill; 5= markedly ill; 6= severely ill; or 7= extremely ill. The improvement in symptoms is represented by negative values. ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)	-0.51 (-0.62 to -0.41)	-0.46 (-0.56 to -0.36)	-0.57 (-0.68 to -0.46)

Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4353 ^[29]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.21

Variability estimate

Standard error of the mean

Dispersion value

0.076

Notes
[29] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Placebo v Bitopertin 10 mg

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1404 ^[30]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.26

Variability estimate

Standard error of the mean

Dispersion value

0.075

Notes
[30] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Secondary: Mean Change from Baseline in CGI-S Positive Symptoms Rating Score at Week 12

Top of page

End point title

Mean Change from Baseline in CGI-S Positive Symptoms Rating Score at Week 12

End point description

The CGI-S reflects the severity of illness on a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. Participant was assessed on severity of mental illness at the time of rating 1= normal, not at all ill; 2= borderline mentally ill; 3= mildly ill; 4= moderately ill; 5= markedly ill; 6= severely ill; 7= extremely ill. The improvement in symptoms is represented by negative values. ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)	-0.61 (-0.72 to -0.5)	-0.56 (-0.66 to -0.45)	-0.6 (-0.71 to -0.49)

Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Placebo v Bitopertin 5 mg

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8853 ^[31]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.078

Notes
[31] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Placebo versus Bitopertin 10 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5668 ^[32]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.078

Notes
[32] - Unadjusted p-values for pairwise comparisons with placebo were presented.

Secondary: Mean Change from Baseline in Personal and Social Performance (PSP) Total Score at Week 12

Top of page

End point title

Mean Change from Baseline in Personal and Social Performance (PSP) Total Score at Week 12

End point description

The PSP scale assesses degree of a participant's dysfunction within 4 domains of behavior: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior. Score ranges from 1 to 100, divided into 10 equal intervals to rate degree of difficulty ('1= absent' to '6= very severe') in each of the 4 domains. Based on 4 domains there will be one total score. Participants with score of 71 to 100 have mild degree of difficulty; from 31 to 70 have varying degrees of disability; less than or equal to 30 have functioning so poorly as to require intensive supervision. ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Bitopertin 5 mg	Bitopertin 10 mg	Placebo
Number of subjects analysed	187	191	186
Units: units on a scale
least squares mean (confidence interval 95%)	6.04 (4.86 to 7.22)	5.42 (4.26 to 6.59)	5.53 (4.33 to 6.74)

Placebo versus Bitopertin 5 mg

Statistical analysis description

Estimates were from analysis based on MMRM using unstructured covariance matrix. Change = Baseline + Week + Treatment + Treatment * Week.

Comparison groups

Bitopertin 5 mg v Placebo

Number of subjects included in analysis

373

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5583 ^[33]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.18

upper limit

2.19

Variability estimate

Standard error of the mean

Dispersion value

0.858

Notes
[33] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Placebo versus Bitopertin 10 mg

Comparison groups

Bitopertin 10 mg v Placebo

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8955 ^[34]

Method

Mixed-Effect Model Repeated Measure

Parameter type

Adjusted Mean Difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-1.78

upper limit

1.56

Variability estimate

Standard error of the mean

Dispersion value

0.851

Notes
[34] - Unadjusted p-value for pairwise comparisons with placebo was presented.

Adverse events

Top of page

Timeframe for reporting adverse events

Up to Safety follow-up period (approximately 4 years)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Bitopertin 5 mg – Treatment Period

Reporting group description

Reporting group title

Bitopertin 10 mg – Treatment Period

Reporting group description

Reporting group title

Placebo – Treatment Period

Reporting group description

Reporting group title

Bitopertin 5 mg – Washout Period

Reporting group description

Participants received bitopertin 5 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Bitopertin 5 mg to Placebo - Washout Period

Reporting group description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Bitopertin 10 mg - Washout Period

Reporting group description

Participants received bitopertin 10 mg oral tablet QD during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Bitopertin 10 mg to Placebo – Washout Period

Reporting group description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Placebo – Washout Period

Reporting group description

Participants received matching placebo to bitopertin during the 4-week washout period (Week 52 to Week 56).

Reporting group title

Placebo to Bitopertin 10 mg – Long-Term Extension

Reporting group description

Participants received bitopertin 10 mg oral tablet QD, up to 3 years.

Reporting group title

Bitopertin 5 mg to Bitopertin 10 mg - Long-Term Extension

Reporting group description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Reporting group title

Bitopertin 10 mg - Long-Term Extension

Reporting group description

Participants received bitopertin 10 mg oral tablet QD up to 3 years.

Reporting group title

Bitopertin 5 mg - Safety Follow-up Period

Reporting group description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 5 mg QD, for 4 weeks.

Reporting group title

Bitopertin 10 mg – Safety Follow-up Period

Reporting group description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received bitopertin 10 mg QD, for 4 weeks.

Reporting group title

Placebo – Safety Follow-up Period

Reporting group description

All participants who withdrew early from the study or whose treatment was discontinued during the Long-Term Extension received placebo-matched to bitopertin, for 4 weeks.

Bitopertin 5 mg – Treatment Period

Bitopertin 10 mg – Treatment Period

Placebo – Treatment Period

Bitopertin 5 mg – Washout Period

Bitopertin 5 mg to Placebo - Washout Period

Bitopertin 10 mg - Washout Period

Bitopertin 10 mg to Placebo – Washout Period

Placebo – Washout Period

Placebo to Bitopertin 10 mg – Long-Term Extension

Bitopertin 5 mg to Bitopertin 10 mg - Long-Term Extension

Bitopertin 10 mg - Long-Term Extension

Bitopertin 5 mg - Safety Follow-up Period

Bitopertin 10 mg – Safety Follow-up Period

Placebo – Safety Follow-up Period

Total subjects affected by serious adverse events

subjects affected / exposed

7 / 195 (3.59%)

7 / 200 (3.50%)

15 / 193 (7.77%)

0 / 39 (0.00%)

0 / 40 (0.00%)

1 / 44 (2.27%)

0 / 43 (0.00%)

1 / 81 (1.23%)

4 / 70 (5.71%)

3 / 62 (4.84%)

6 / 74 (8.11%)

1 / 133 (0.75%)

4 / 332 (1.20%)

5 / 123 (4.07%)

number of deaths (all causes)

number of deaths resulting from adverse events

Vascular disorders

Bleeding varicose vein

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Surgical and medical procedures

Abortion induced

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

1 / 133 (0.75%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Pyrexia

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

1 / 193 (0.52%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

1 / 62 (1.61%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 195 (0.00%)

1 / 200 (0.50%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chronic obstructive pulmonary disease

subjects affected / exposed

1 / 195 (0.51%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Mood altered

subjects affected / exposed

0 / 195 (0.00%)

1 / 200 (0.50%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychotic disorder

subjects affected / exposed

0 / 195 (0.00%)

1 / 200 (0.50%)

5 / 193 (2.59%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

1 / 62 (1.61%)

2 / 74 (2.70%)

0 / 133 (0.00%)

1 / 332 (0.30%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

1 / 1

2 / 5

0 / 0

0 / 1

0 / 2

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Schizophrenia

subjects affected / exposed

2 / 195 (1.03%)

1 / 200 (0.50%)

3 / 193 (1.55%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

2 / 70 (2.86%)

1 / 62 (1.61%)

2 / 74 (2.70%)

0 / 133 (0.00%)

3 / 332 (0.90%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

1 / 2

0 / 1

1 / 3

0 / 0

0 / 3

0 / 1

0 / 2

0 / 0

1 / 4

0 / 1

deaths causally related to treatment / all

0 / 0

Anxiety

subjects affected / exposed

1 / 195 (0.51%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Suicidal ideation

subjects affected / exposed

1 / 195 (0.51%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

2 / 74 (2.70%)

0 / 133 (0.00%)

1 / 332 (0.30%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abnormal behaviour

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

1 / 62 (1.61%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Agitation

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Femur fracture

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

1 / 193 (0.52%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Road traffic accident

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

1 / 193 (0.52%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Myocardial infarction

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

2 / 193 (1.04%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cardio-respiratory arrest

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

1 / 81 (1.23%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Parkinsonism

subjects affected / exposed

1 / 195 (0.51%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ischaemic Stroke

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

1 / 70 (1.43%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Spinal cord compression

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Upper gastrointestinal haemorrhage

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

1 / 193 (0.52%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholelithiasis

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

1 / 70 (1.43%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Renal failure acute

subjects affected / exposed

1 / 195 (0.51%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Cervical spinal stenosis

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Intervertebral disc protrusion

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

1 / 123 (0.81%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abscess limb

subjects affected / exposed

0 / 195 (0.00%)

1 / 200 (0.50%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 195 (0.00%)

1 / 200 (0.50%)

2 / 193 (1.04%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

1 / 74 (1.35%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Scrotal abscess

subjects affected / exposed

0 / 195 (0.00%)

1 / 200 (0.50%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mastitis

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

1 / 193 (0.52%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abscess sweat gland

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

1 / 44 (2.27%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Bitopertin 5 mg – Treatment Period

Bitopertin 10 mg – Treatment Period

Placebo – Treatment Period

Bitopertin 5 mg – Washout Period

Bitopertin 5 mg to Placebo - Washout Period

Bitopertin 10 mg - Washout Period

Bitopertin 10 mg to Placebo – Washout Period

Placebo – Washout Period

Placebo to Bitopertin 10 mg – Long-Term Extension

Bitopertin 5 mg to Bitopertin 10 mg - Long-Term Extension

Bitopertin 10 mg - Long-Term Extension

Bitopertin 5 mg - Safety Follow-up Period

Bitopertin 10 mg – Safety Follow-up Period

Placebo – Safety Follow-up Period

Total subjects affected by non serious adverse events

subjects affected / exposed

53 / 195 (27.18%)

50 / 200 (25.00%)

45 / 193 (23.32%)

0 / 39 (0.00%)

2 / 40 (5.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

1 / 81 (1.23%)

7 / 70 (10.00%)

6 / 62 (9.68%)

10 / 74 (13.51%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

Investigations

Weight increased

subjects affected / exposed

5 / 195 (2.56%)

7 / 200 (3.50%)

11 / 193 (5.70%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Nervous system disorders

Headache

subjects affected / exposed

19 / 195 (9.74%)

11 / 200 (5.50%)

6 / 193 (3.11%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Somnolence

subjects affected / exposed

9 / 195 (4.62%)

10 / 200 (5.00%)

7 / 193 (3.63%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Gastrointestinal disorders

Diarrhoea

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

1 / 70 (1.43%)

0 / 62 (0.00%)

4 / 74 (5.41%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Psychiatric disorders

Anxiety

subjects affected / exposed

9 / 195 (4.62%)

13 / 200 (6.50%)

10 / 193 (5.18%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Insomnia

subjects affected / exposed

11 / 195 (5.64%)

11 / 200 (5.50%)

10 / 193 (5.18%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

0 / 70 (0.00%)

0 / 62 (0.00%)

0 / 74 (0.00%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Schizophrenia

subjects affected / exposed

0 / 195 (0.00%)

0 / 200 (0.00%)

0 / 193 (0.00%)

0 / 39 (0.00%)

0 / 40 (0.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

0 / 81 (0.00%)

2 / 70 (2.86%)

2 / 62 (3.23%)

5 / 74 (6.76%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

Infections and infestations

Nasopharyngitis

subjects affected / exposed

13 / 195 (6.67%)

11 / 200 (5.50%)

11 / 193 (5.70%)

0 / 39 (0.00%)

2 / 40 (5.00%)

0 / 44 (0.00%)

0 / 43 (0.00%)

1 / 81 (1.23%)

4 / 70 (5.71%)

5 / 62 (8.06%)

2 / 74 (2.70%)

0 / 133 (0.00%)

0 / 332 (0.00%)

0 / 123 (0.00%)

occurrences all number

More information

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Were there any global substantial amendments to the protocol? Yes

22 Sep 2010

Version B: - Addition of Liver enzymes (aspartate aminotransferase or alanine aminotransferase at or above 3x upper limit of normal (ULN), or bilirubin at above 2x ULN to the exclusion criteria. - Editorial clarification for secondary objective time point for safety and tolerability. - Addition of text to clarify processes around participant randomization. - Minor changes to schedule of assessments for physical examination, Clinical Global Impression - Improvement, and electrocardiogram. - A new table was created to clarify visits in long-term extension.

21 Apr 2011

Version C: - More details on the long-term extension were provided following the request from Health Authorities. - Exploratory objectives, safety, efficacy and pharmacoeconomic endpoints were updated for the long-term extension period. - Inclusion of Food and Drug Administration requirements for analysis of iron inclusion bodies. - Entry criteria for treatment period 2 and long-term extension were updated. - Local urine pregnancy testing was amended to be performed at randomization. - For participants requiring pyscho-social and/or rehabilitative therapies during treatment period, the protocol was amended to include this after treatment period 1 was complete. -Video Enhancement of Rater Interviewing for Independent Evaluation of Data was included in the description of system for PANSS. - Inclusion and exclusion criteria were updated. Reporting of Adverse Events were amended. Overall risk and benefit assessment added. - Clarified on restricted and prohibited concomitant medication. Administrative changes were updated.

20 Feb 2012

Version D: - Addition of biomarker defined subpopulations as a secondary objective. - Clarification of timing of screening and prospective stabilization period. - Clarification of exclusionary hemoglobin criterion in males from 13 to 12 grams per deciliter, body mass index of less than 18.5 or greater than 40 kilograms per square meter, wash out times for depot and long acting antipyschotics, and updated the requirements for past use of clozapine. - Updated dosing of concomitant antipsychotics for inclusion criteria. - The definition of caregiver in the inclusion criteria was revised. - Added eszopiclone (Lunesta) to the list of restricted medications. - Additional follow-up for treatment withdrawal and at Week-52 initiation of washout, and clarification of withdrawal process. - Included description of an exploratory electrophysiological biomarker substudy to evaluate the effects of adjunctive RO4917838 treatment on neurocognitive deficits and assess candidate electrophysiological biomarkers in participants with schizophrenia. - New guidance was added regarding withdrawal for hepatic abnormalities. - Administrative changes were reported.

30 May 2012

Version D-1 (Country Specific): - Modification of the Caregiver Burden Assessment/Questionnaire. - The Schizophrenia Caregiver Questionnaire added the caregiver global impression scale to evaluate participant’s severity of illness and change in severity of illness over time from a caregiver’s perspective.

01 Nov 2012

Version E: - This version E combined the approach for Modification of the Caregiver Burden Assessment/Questionnaire in Version D and D-1. - Inclusion of futility analysis. - Addition of biomarker defined subpopulation: complement factor H-related protein 1 high subgroup to the objectives. - Change in data safety monitoring board to independent data monitoring committee. - Modification to exclusion criteria relevant to body mass index. - Addition of 12-lead electrocardiogram assessment in long-term extension. - Changes in serious adverse event reporting, definition of safety population, and length of study. - Removal of per protocol population. - Administrative changes were reported.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Results of many secondary endpoints were not reported as the study was terminated early due to failure in demonstration of adjunctive therapy with bitopertin in primary endpoint.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Symptoms Factor Score (PSFS) at Week 12

Primary: Mean Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Symptoms Factor Score (PSFS) at Week 12

Secondary: Mean Change from Baseline in PANSS Total Score at Week 12

Secondary: Mean Change from Baseline in PANSS Total Score at Week 12

Secondary: Mean Change from Baseline in PANSS Subscale Score at Week 12

Secondary: Mean Change from Baseline in PANSS Subscale Score at Week 12

Secondary: Mean Change from Baseline in PANSS Symptom Factor Score at Week 12

Secondary: Mean Change from Baseline in PANSS Symptom Factor Score at Week 12

Secondary: Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS at Week 12

Secondary: Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS at Week 12

Secondary: Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS At Least at Two Out of the Three Last Post-Baseline Assessments

Secondary: Percentage of Participants with a 20% or Greater Improvement in PANSS PSFS At Least at Two Out of the Three Last Post-Baseline Assessments

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in Clinical Global Impression-Improvement (CGI-I) Overall Rating Score at Week 12

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in Clinical Global Impression-Improvement (CGI-I) Overall Rating Score at Week 12

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Overall Rating Score At Least at Two of the Three Last Post-Baseline Assessments

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Overall Rating Score At Least at Two of the Three Last Post-Baseline Assessments

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score at Week 12

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score at Week 12

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score At Least at Two of the Three Last Post-Baseline Assessments

Secondary: Percentage of Participants with a Rating of Either 'Much' or 'Very Much' Improvement in CGI-I Positive Symptom Rating Score At Least at Two of the Three Last Post-Baseline Assessments

Secondary: Percentage of Participants With at Least 20% Improvement From Baseline in the PANSS PSFS and With a CGI-I Positive Symptoms Rating of Either 'Much' or 'Very Much' Improved at Week 12

Secondary: Percentage of Participants With at Least 20% Improvement From Baseline in the PANSS PSFS and With a CGI-I Positive Symptoms Rating of Either 'Much' or 'Very Much' Improved at Week 12

Secondary: Mean Change from Baseline in Clinical Global Impression – Severity (CGI-S) Overall Symptoms Rating Score at Week 12

Secondary: Mean Change from Baseline in Clinical Global Impression – Severity (CGI-S) Overall Symptoms Rating Score at Week 12

Secondary: Mean Change from Baseline in CGI-S Positive Symptoms Rating Score at Week 12

Secondary: Mean Change from Baseline in CGI-S Positive Symptoms Rating Score at Week 12

Secondary: Mean Change from Baseline in Personal and Social Performance (PSP) Total Score at Week 12

Secondary: Mean Change from Baseline in Personal and Social Performance (PSP) Total Score at Week 12

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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