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Clinical Trial Results:
A Phase III, Multi-Center, Randomized, 24 Week, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate Efficacy and Safety of Bitopertin in Stable Patients With Persistent, Predominant Negative Symptoms of Schizophrenia Treated With Antipsychotics Followed by a 28 Week, Double-Blind Treatment Period

Summary
EudraCT number	2010-020470-42
Trial protocol	CZ IT BG
Global end of trial date	08 Jul 2014

Results information
Results version number	v1(current)
This version publication date	18 Jun 2016
First version publication date	18 Jun 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

WN25308

ISRCTN number

US NCT number

NCT01192880

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

21 Nov 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jul 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

This was a Phase III, multi-center, randomized, 24 week, double-blind, parallel-group, placebo-controlled study to evaluate efficacy and safety of bitopertin (RO4917838) in stable participants with persistent, predominant negative symptoms of schizophrenia treated with anti-psychotics followed by a 28-week, double-blind placebo-controlled treatment period.

Protection of trial subjects

The investigator ensured that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guideline or with local law if it afforded greater protection to the participant. For studies conducted in the European Union/European Economic Area (EU/EEA) countries, the investigator ensured compliance with the EU Clinical Trial Directive [2001/20/EC].For studies conducted in the United States of America (USA) or under US Investigational New Drug (IND), the investigator additionally ensured adherence to the basic principles of “Good Clinical Practice” as outlined in the current version of21 Code of Federal Regulations (CFR), subchapter D, part 312, “Responsibilities of sponsors and Investigators”,part 50, “Protection of Human Patients”, and part 56, “Institutional Review Boards”.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Sep 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 92

Country: Number of subjects enrolled

Czech Republic: 91

Country: Number of subjects enrolled

Italy: 24

Country: Number of subjects enrolled

China: 229

Country: Number of subjects enrolled

Russian Federation: 18

Country: Number of subjects enrolled

United States: 86

Country: Number of subjects enrolled

Japan: 80

Worldwide total number of subjects

620

EEA total number of subjects

207

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)

615

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Screening period was up to 30 days before the first dose of study drug.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Placebo-Treatment Period 1

Arm description

Matching oral placebo doses (10 milligrams [mg] or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 24 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

Oral dose of placebo tablet in the morning with/without food.

Bitopertin 10 mg-Treatment Period 1

Arm description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Bitopertin 20 mg-Treatment Period 1

Arm description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Placebo-Treatment Period 2

Arm description

Matching oral placebo doses (10 mg or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 28 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

Oral dose of placebo tablet in the morning with/without food.

Bitopertin 10 mg-Treatment Period 2

Arm description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 28 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Bitopertin 20 mg-Treatment Period 2

Arm description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 28 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Placebo-Washout Period

Arm description

Matching oral placebo doses (10 mg or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment 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

Oral dose of placebo tablet in the morning with/without food.

Bitopertin 10 mg-Washout Period

Arm description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Bitopertin 10 mg to Placebo-Washout Period

Arm description

Bitopertin 10 mg switched to placebo for duration of washout period; adjunct to stable antipsychotic treatment 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

Oral dose of placebo tablet in the morning with/without food.

Bitopertin 20 mg-Washout Period

Arm description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Bitopertin 20 mg to Placebo-Washout Period

Arm description

Bitopertin 20 mg switched to placebo for duration of washout period; adjunct to stableantipsychotic treatment 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

Oral dose of placebo tablet in the morning with/without food.

Placebo to Bitopertin 10 mg-LTE Period

Arm description

Placebo during previous periods: switched to bitopertin 10 mg adjunct to stableantipsychotic treatment up to 3 years.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Bitopertin 10 mg-LTE Period

Arm description

Bitopertin 10 mg adjunct to stable antipsychotic treatment for up to 3 years.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Bitopertin 20 mg-LTE Period

Arm description

Bitopertin 20 mg adjunct to stable antipsychotic treatment for up to 3 years.

Arm type

Experimental

Investigational medicinal product name

Bitopertin

Investigational medicinal product code

RO4917838

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Oral dose of bitopertin tablet in the morning with/without food.

Placebo – Safety Follow-up Period

Arm description

Participants who were on placebo treatment at the time of discontinuation from study treatment but came for 4-week safety follow-up period were included. No intervention during this period; adjunct to stable antipsychotic treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Bitopertin 10 mg – Safety Follow-up Period

Arm description

Participants who were on bitopertin 10 mg treatment at the time of discontinuation from study treatment but came for 4-week safety follow-up period were included. No intervention during this period; adjunct to stable antipsychotic treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Bitopertin 20 mg – Safety Follow-up Period

Arm description

Participants who were on bitopertin 20 mg treatment at the time of discontinuation from study treatment but came for 4-week safety follow-up period were included. No intervention during this period; adjunct to stable antipsychotic treatment.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Placebo-Treatment Period 1	Bitopertin 10 mg-Treatment Period 1	Bitopertin 20 mg-Treatment Period 1	Placebo-Treatment Period 2	Bitopertin 10 mg-Treatment Period 2	Bitopertin 20 mg-Treatment Period 2	Placebo-Washout Period	Bitopertin 10 mg-Washout Period	Bitopertin 10 mg to Placebo-Washout Period	Bitopertin 20 mg-Washout Period	Bitopertin 20 mg to Placebo-Washout Period	Placebo to Bitopertin 10 mg-LTE Period	Bitopertin 10 mg-LTE Period	Bitopertin 20 mg-LTE Period	Placebo – Safety Follow-up Period	Bitopertin 10 mg – Safety Follow-up Period	Bitopertin 20 mg – Safety Follow-up Period
Started	206	206	208	162	160	157	113	57	58	56	57	94	102	98	113	299	208
Completed	170	166	163	114	117	114	110	54	56	55	57	0	0	0	74	251	158
Not completed	36	40	45	48	43	43	3	3	2	1	0	94	102	98	39	48	50
Adverse event, serious fatal	-	-	1	-	-	1	-	-	-	-	-	-	-	-	-	-	2
Consent withdrawn by subject	7	6	7	3	4	3	-	1	-	-	-	5	7	4	11	18	19
Adverse event, non-fatal	12	9	6	6	1	5	-	-	-	-	-	6	6	4	1	4	2
Protocol violation	-	1	2	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Administrative/other	5	9	13	34	34	31	2	1	2	1	-	76	87	83	11	8	8
Non-compliance	5	9	5	2	4	2	1	1	-	-	-	4	2	4	-	-	-
Unspecified	-	-	-	-	-	-	-	-	-	-	-	1	-	-	-	-	-
Lost to follow-up	3	5	8	3	-	-	-	-	-	-	-	-	-	1	16	18	19
Lack of efficacy	4	1	3	-	-	1	-	-	-	-	-	2	-	2	-	-	-

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	620	620
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	38 ± 12.4	-
Gender categorical
Units: Subjects
Female	230	230
Male	390	390

End points

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Reporting group title

Placebo-Treatment Period 1

Reporting group description

Matching oral placebo doses (10 milligrams [mg] or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 24 weeks.

Reporting group title

Bitopertin 10 mg-Treatment Period 1

Reporting group description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 24 weeks.

Reporting group title

Bitopertin 20 mg-Treatment Period 1

Reporting group description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 24 weeks.

Reporting group title

Placebo-Treatment Period 2

Reporting group description

Matching oral placebo doses (10 mg or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 28 weeks.

Reporting group title

Bitopertin 10 mg-Treatment Period 2

Reporting group description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 28 weeks.

Reporting group title

Bitopertin 20 mg-Treatment Period 2

Reporting group description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 28 weeks.

Reporting group title

Placebo-Washout Period

Reporting group description

Matching oral placebo doses (10 mg or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 4 weeks.

Reporting group title

Bitopertin 10 mg-Washout Period

Reporting group description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 4 weeks.

Reporting group title

Bitopertin 10 mg to Placebo-Washout Period

Reporting group description

Bitopertin 10 mg switched to placebo for duration of washout period; adjunct to stable antipsychotic treatment for 4 weeks.

Reporting group title

Bitopertin 20 mg-Washout Period

Reporting group description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 4 weeks.

Reporting group title

Bitopertin 20 mg to Placebo-Washout Period

Reporting group description

Bitopertin 20 mg switched to placebo for duration of washout period; adjunct to stableantipsychotic treatment for 4 weeks.

Reporting group title

Placebo to Bitopertin 10 mg-LTE Period

Reporting group description

Placebo during previous periods: switched to bitopertin 10 mg adjunct to stableantipsychotic treatment up to 3 years.

Reporting group title

Bitopertin 10 mg-LTE Period

Reporting group description

Bitopertin 10 mg adjunct to stable antipsychotic treatment for up to 3 years.

Reporting group title

Bitopertin 20 mg-LTE Period

Reporting group description

Bitopertin 20 mg adjunct to stable antipsychotic treatment for up to 3 years.

Reporting group title

Placebo – Safety Follow-up Period

Reporting group description

Reporting group title

Bitopertin 10 mg – Safety Follow-up Period

Reporting group description

Reporting group title

Bitopertin 20 mg – Safety Follow-up Period

Reporting group description

Primary: Mean Change From Baseline in Positive and Negative Symptom Scales (PANSS) Negative Symptom Factor Score (NSFS) at Week 24

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End point title

Mean Change From Baseline in Positive and Negative Symptom Scales (PANSS) Negative Symptom Factor Score (NSFS) at Week 24 ^[1]

End point description

The PANSS is a 30-item medical scale used for measuring symptom severity of participants with schizophrenia. The NSFS assesses negative symptoms associated with schizophrenia. The 7 items make up the NSFS are blunted affect, emotional withdrawal, poor rapport,passive/apathetic social withdrawal, lack of spontaneity, flow of conversation, motor retardation and active social avoidance. Each item was rated on a scale from 1 (absent) to 7 (extreme). Total NSFS score ranged from 7 to 49; higher score indicating greater severity of negative symptom psychopathology. Intent to Treat (ITT) Population: Included all randomized participants who received at least 1 dose of double-blind study drug and had at least 1 post-baseline assessment for primary efficacy variable was considered for this analysis. For all analyses of PANSS data the scores were transformed to 0-6 points to express “absent” as 0. Change from baseline in NSFS at Week 24 is reported .

End point type

Primary

End point timeframe

Baseline, Week 24

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arms include treatment period 1 arms (placebo-treatment period 1, bitopertin 10 mg-treatment period 1, and bitopertin 20 mg-treatment period 1) and statistics for these arms is reported.

End point values	Placebo-Treatment Period 1	Bitopertin 10 mg-Treatment Period 1	Bitopertin 20 mg-Treatment Period 1
Number of subjects analysed	201	198	199
Units: units on a scale
least squares mean (standard error)	-5.52 ± 0.341	-5.46 ± 0.344	-5.32 ± 0.346

Statistical analysis I

Statistical analysis description

Primary analysis population was ITT population. For all analyses of PANSS data, scores were transformed into 0-6 points to express “absent” as 0. Mean change from baseline in PANSS NSFS at Week 24 was analyzed using an MMRM incorporating data collected up to 24 weeks of treatment to assess all data collected over time with consideration of the variance−covariance matrix of repeated measures. No imputations for missing data were used in primary analyses.

Comparison groups

Placebo-Treatment Period 1 v Bitopertin 10 mg-Treatment Period 1

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9008

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

1.01

Statistical analysis II

Statistical analysis description

Comparison groups

Placebo-Treatment Period 1 v Bitopertin 20 mg-Treatment Period 1

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6844

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

1.15

Secondary: Mean Change From Baseline in Personal and Social Performance (PSP) Total Score at Week 24

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End point title

Mean Change From Baseline in Personal and Social Performance (PSP) Total Score at Week 24 ^[2]

End point description

The PSP scale was designed to assess the degree of dysfunction a participant exhibits within 4 domains of behavior: a) socially useful activities, b) personal and social relationships, c) self-care, and d) disturbing and aggressive behavior, each rated on 6-point scale (1=absent to 6=very severe). Total transformed score from 1 to 100 is generated from raw score based on clinical interpretation of scores generated in 4 areas of functioning. A score lying between 71 and 100 indicated a good functioning; one between 31 and 70 indicated varying degrees of difficulty, and a score of <=30 indicated functioning so poor that participant required intensive supervision. ITT population was considered for the analysis. Here, number of participants analyzed signifies participants with baseline and at least one post baseline assessment for this endpoint. Change from baseline in NSFS at Week 24 is reported.

End point type

Secondary

End point timeframe

Baseline, Week 24

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arms include treatment period 1 arms (placebo-treatment period 1, bitopertin 10 mg-treatment period 1, and bitopertin 20 mg-treatment period 1) and statistics for these arms is reported.

End point values	Placebo-Treatment Period 1	Bitopertin 10 mg-Treatment Period 1	Bitopertin 20 mg-Treatment Period 1
Number of subjects analysed	201	197	199
Units: units on a scale
least squares mean (standard error)	8.04 ± 0.761	9 ± 0.769	7.83 ± 0.77

Statistical analysis I

Statistical analysis description

Primary analysis population was ITT population. Mean change from baseline in PSP total score at Week 24 was analyzed using an MMRM incorporating data collected up to 24 weeks of treatment to assess all data collected over time with consideration of the variance−covariance matrix of repeated measures. No imputations for missing data were used in primary analyses.

Comparison groups

Placebo-Treatment Period 1 v Bitopertin 10 mg-Treatment Period 1

Number of subjects included in analysis

398

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3763

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

3.08

Statistical analysis II

Statistical analysis description

Comparison groups

Placebo-Treatment Period 1 v Bitopertin 20 mg-Treatment Period 1

Number of subjects included in analysis

400

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8476

Method

Mixed models analysis

Parameter type

Adjusted mean difference

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-2.34

upper limit

1.92

Adverse events

Top of page

Timeframe for reporting adverse events

From screening to 4 weeks after the last dose of the study medication(up to 4 years)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo – Treatment Periods 1 and 2

Reporting group description

Matching oral placebo doses (10 mg or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 52 weeks. Adverse event data reported are for treatment periods 1 and 2.

Reporting group title

Bitopertin 10 mg – Treatment Periods 1 and 2

Reporting group description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 52 weeks. Adverse event data reported are for treatment periods 1 and 2.

Reporting group title

Bitopertin 20 mg – Treatment Periods 1 and 2

Reporting group description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 52 weeks. Adverse event data reported are for treatment periods 1 and 2.

Reporting group title

Placebo – Washout Period

Reporting group description

Matching oral placebo doses (10 mg or 20 mg) in the morning with/without food adjunct to stable antipsychotic treatment for 4 weeks. Adverse event data reported are for washout period.

Reporting group title

Bitopertin 10 mg – Washout Period

Reporting group description

Oral doses of 10 mg bitopertin tablet in the morning with/without food adjunct to stable antipsychotic treatment for 4 weeks. Adverse event data reported are for washout period.

Reporting group title

Bitopertin 10 mg to Placebo – Washout Period

Reporting group description

Bitopertin 10 mg switched to placebo for duration of washout period; adjunct to stable antipsychotic treatment for 4 weeks. Adverse event data reported are for washout period.

Reporting group title

Bitopertin 20 mg – Washout Period

Reporting group description

Oral doses of 20 mg bitopertin tablet in the morning with/without food during adjunct to stable antipsychotic treatment for 4 weeks. Adverse event data reported are for washout period.

Reporting group title

Bitopertin 20 mg to Placebo – Washout Period

Reporting group description

Bitopertin 20 mg switched to placebo for duration of washout period; adjunct to stable antipsychotic treatment for 4 weeks. Adverse event data reported are for washout period.

Reporting group title

Placebo to Bitopertin 10 mg – LTE period

Reporting group description

Placebo during previous periods: switched to bitopertin 10 mg adjunct to stableantipsychotic treatment up to 3 years. Adverse event data reported are for LTE period.

Reporting group title

Bitopertin 10 mg – LTE Period

Reporting group description

Bitopertin 10 mg adjunct to stable antipsychotic treatment for up to 3 years.Adverse event data reported are for LTE period.

Reporting group title

Bitopertin 20 mg – LTE Period

Reporting group description

Bitopertin 20 mg adjunct to stable antipsychotic treatment for up to 3 years. Adverse event data reported are for LTE period.

Reporting group title

Placebo – Safety Follow-up Period

Reporting group description

Participants who were on placebo treatment at the time of discontinuation from study treatment but came for 4-week safety follow-up period were included.No intervention during this period; adjunct to stable antipsychotic treatment. Adverse event data reported are for safety follow-up period.

Reporting group title

Bitopertin 10 mg – Safety Follow-up Period

Reporting group description

Reporting group title

Bitopertin 20 mg – Safety Follow-up Period

Reporting group description

Placebo – Treatment Periods 1 and 2

Bitopertin 10 mg – Treatment Periods 1 and 2

Bitopertin 20 mg – Treatment Periods 1 and 2

Placebo – Washout Period

Bitopertin 10 mg – Washout Period

Bitopertin 10 mg to Placebo – Washout Period

Bitopertin 20 mg – Washout Period

Bitopertin 20 mg to Placebo – Washout Period

Placebo to Bitopertin 10 mg – LTE period

Bitopertin 10 mg – LTE Period

Bitopertin 20 mg – LTE Period

Placebo – Safety Follow-up Period

Bitopertin 10 mg – Safety Follow-up Period

Bitopertin 20 mg – Safety Follow-up Period

Total subjects affected by serious adverse events

subjects affected / exposed

6 / 206 (2.91%)

4 / 206 (1.94%)

6 / 208 (2.88%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

1 / 56 (1.79%)

0 / 57 (0.00%)

3 / 94 (3.19%)

3 / 102 (2.94%)

1 / 98 (1.02%)

2 / 113 (1.77%)

2 / 299 (0.67%)

4 / 208 (1.92%)

number of deaths (all causes)

number of deaths resulting from adverse events

Injury, poisoning and procedural complications

Wrist fracture

subjects affected / exposed

0 / 206 (0.00%)

1 / 206 (0.49%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Chemical poisoning

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Atrioventricular block first degree

subjects affected / exposed

1 / 206 (0.49%)

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Atrioventricular block second degree

subjects affected / exposed

1 / 206 (0.49%)

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myocarditis

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

1 / 299 (0.33%)

0 / 208 (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

Nervous system disorders

Encephalopathy

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Gastritis

subjects affected / exposed

0 / 206 (0.00%)

1 / 206 (0.49%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 206 (0.00%)

1 / 206 (0.49%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Completed suicide

subjects affected / exposed

0 / 206 (0.00%)

2 / 208 (0.96%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 2

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Hepatic function abnormal

subjects affected / exposed

0 / 206 (0.00%)

1 / 208 (0.48%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

1 / 56 (1.79%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

1 / 98 (1.02%)

0 / 113 (0.00%)

0 / 299 (0.00%)

1 / 208 (0.48%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hepatitis

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Psoriasis

subjects affected / exposed

1 / 206 (0.49%)

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Schizophrenia

subjects affected / exposed

2 / 206 (0.97%)

0 / 206 (0.00%)

3 / 208 (1.44%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

1 / 94 (1.06%)

1 / 102 (0.98%)

0 / 98 (0.00%)

2 / 113 (1.77%)

1 / 299 (0.33%)

3 / 208 (1.44%)

occurrences causally related to treatment / all

0 / 2

0 / 0

1 / 3

0 / 0

0 / 1

1 / 1

0 / 0

2 / 2

1 / 1

1 / 3

deaths causally related to treatment / all

0 / 0

Mental disorder

subjects affected / exposed

0 / 206 (0.00%)

1 / 206 (0.49%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (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

1 / 206 (0.49%)

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

1 / 94 (1.06%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Persecutory delusion

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

1 / 94 (1.06%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tension

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Renal failure acute

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

1 / 102 (0.98%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Bronchopneumonia

subjects affected / exposed

1 / 206 (0.49%)

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

0 / 94 (0.00%)

0 / 102 (0.00%)

0 / 98 (0.00%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Placebo – Treatment Periods 1 and 2

Bitopertin 10 mg – Treatment Periods 1 and 2

Bitopertin 20 mg – Treatment Periods 1 and 2

Placebo – Washout Period

Bitopertin 10 mg – Washout Period

Bitopertin 10 mg to Placebo – Washout Period

Bitopertin 20 mg – Washout Period

Bitopertin 20 mg to Placebo – Washout Period

Placebo to Bitopertin 10 mg – LTE period

Bitopertin 10 mg – LTE Period

Bitopertin 20 mg – LTE Period

Placebo – Safety Follow-up Period

Bitopertin 10 mg – Safety Follow-up Period

Bitopertin 20 mg – Safety Follow-up Period

Total subjects affected by non serious adverse events

subjects affected / exposed

30 / 206 (14.56%)

34 / 206 (16.50%)

26 / 208 (12.50%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

14 / 94 (14.89%)

19 / 102 (18.63%)

13 / 98 (13.27%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

Nervous system disorders

Headache

subjects affected / exposed

9 / 206 (4.37%)

16 / 206 (7.77%)

3 / 208 (1.44%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

1 / 94 (1.06%)

7 / 102 (6.86%)

3 / 98 (3.06%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences all number

Infections and infestations

Nasopharyngitis

subjects affected / exposed

23 / 206 (11.17%)

24 / 206 (11.65%)

23 / 208 (11.06%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

11 / 94 (11.70%)

13 / 102 (12.75%)

8 / 98 (8.16%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences all number

Upper respiratory tract infection

subjects affected / exposed

0 / 206 (0.00%)

0 / 208 (0.00%)

0 / 113 (0.00%)

0 / 57 (0.00%)

0 / 58 (0.00%)

0 / 56 (0.00%)

0 / 57 (0.00%)

3 / 94 (3.19%)

3 / 102 (2.94%)

5 / 98 (5.10%)

0 / 113 (0.00%)

0 / 299 (0.00%)

0 / 208 (0.00%)

occurrences all number

More information

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Were there any global substantial amendments to the protocol? Yes

15 Sep 2010

Addition of creatine phosphokinase for laboratory testing; Clarification on procedures for exploratory objective; Rewording and changing the order and number of the items of Work readiness questionnaire (WoRQ); Updates in schedule of assessments and procedures; Clarification on data collection; Spelling/formatting corrections; and Clarification on urinalysis and liver enzymes.

21 Apr 2011

Based on the request of the Health Authorities, the protocol was amended to include additional information related to the Long-term extension period of the study pertaining to withdrawal effects, safety and tolerability of long-term use (beyond 56 weeks) of study drug in combination with anti-psychotics, and long-term effects on the symptoms, functioning and quality of life and caregivers burden. A questionnaire was added to collect data related to past psychiatry history of the participant at the screening visit. The protocol was amended to harmonize with Roche safety reporting requirements with respect to the length of time female participants of reproductive status were being asked to comply with approved contraception methods.

20 Feb 2012

The protocol was amended to include the secondary objective related to evaluation of efficacy for the subgroups of participants defined by complement factor H-related protein 1 (CFHR1) biomarker. Amendment combined the screening and the prospective stabilization periods to shorten the time from the screening to the baseline visit. The study period was defined that it was approximately 4 years in total or until 31st December 2014, whichever came first after a participant completed 56 weeks in the study.

30 Oct 2012

Efficacy and Pharmacoeconomics endpoints section was amended with “SCQ: mean change from baseline at each assessment time” and “Caregiver Global Impression Scales: mean change from baseline at each assessment time”end points. The protocol was amended to include the interim futility analysis based on the primary efficacy endpoint, to be performed by an independent statistician supporting the Independent Data Monitoring Committee (iDMC).

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
08 Jul 2014	Study was prematurely terminated as pre-specified interim futility analysis predicted a low probability of success.	-

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

Study was prematurely terminated as pre-specified interim futility analysis predicted a low probability of success. Consequently the study was terminated with last participant’s last visit on 08 Jul 2014.

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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 Symptom Scales (PANSS) Negative Symptom Factor Score (NSFS) at Week 24

Primary: Mean Change From Baseline in Positive and Negative Symptom Scales (PANSS) Negative Symptom Factor Score (NSFS) at Week 24

Secondary: Mean Change From Baseline in Personal and Social Performance (PSP) Total Score at Week 24

Secondary: Mean Change From Baseline in Personal and Social Performance (PSP) Total Score at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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