WN25309

F. Hoffmann-La Roche AG

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Roche Trial Information Hotline, F. Hoffmann-La Roche AG , 41 61 6878333, global.trial_information@roche.com

Roche Trial Information Hotline, F. Hoffmann-La Roche AG , 41 61 6878333, global.trial_information@roche.com

No

No

No

Final

09 Jun 2014

No

Yes

09 Jun 2014

Yes

The main objectives of this study are : • To evaluate the efficacy of 24 weeks treatment with bitopertin in the Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) in patients with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics • To evaluate the safety and tolerability of 24 weeks of treatment with bitopertin in patients with persistent, predominant negative symptoms of schizophrenia treated with antipsychotics

Signed written informed consent after the scope and nature of the investigation had been explained to them before screening evaluations and willingness to comply with the study restrictions.

27 Oct 2010

No

Yes

Netherlands: 3

Poland: 85

Slovakia: 10

Spain: 38

Germany: 18

Latvia: 12

Lithuania: 40

Turkey: 25

Ukraine: 58

Canada: 51

United States: 73

Brazil: 155

Chile: 26

Taiwan: 27

621

206

0

0

0

0

0

0

609

12

0

Overall period (overall period)

Randomised - controlled

Subjects and investigators remained blinded to the treatment they received throughout the study. In the Follow-up, subjects did not receive drug but they remained blinded to the treatment they had received previously.

No

Placebo

Tablet

Oral use

Matching dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

5 mg taken orally once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

10 mg taken orally once daily in the morning, with or without food

Placebo

Tablet

Oral use

Matching dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

5 mg taken orally once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

10 mg taken orally once daily in the morning, with or without food

Placebo

Tablet

Oral use

Matching dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

5 mg taken orally once daily in the morning, with or without food

Placebo

Tablet

Oral use

Matching dose of 5 or 10 mg tablet taken once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

10 mg taken orally once daily in the morning, with or without food

Placebo

Tablet

Oral use

Matching dose of 10 mg tablet taken once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

10 mg taken orally once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

10 mg taken orally once daily in the morning, with or without food

Bitopertin

RO4917838

Tablet

Oral use

10 mg taken orally once daily in the morning, with or without food

No investigational medicinal product assigned in this arm

No investigational medicinal product assigned in this arm

No investigational medicinal product assigned in this arm

Overall period (overall period)

Placebo - Treatment Period 1

Bitopertin 5 mg - Treatment Period 1

Bitopertin 10 mg - Treatment Period 1

Placebo - Treatment Period 2

Bitopertin 5 mg - Treatment Period 2

Bitopertin 10 mg - Treatment Period 2

Placebo - Washout 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 to Bitopertin 10 mg - Long-Term Extension

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

Bitopertin 10 mg - Long-Term Extension

Placebo - Safety Follow-Up Period

Bitopertin 5 mg - Safety Follow-Up Period

Bitopertin 10 mg - Safety Follow-Up Period

The PANSS is a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. Each of the 30 items is rated on a 7-point scale, from 1 to 7 (absence of to extreme psychopathology). The negative symptom subscale is composed of 7 items: Blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The score on the negative symptom subscale can range from 0 to 49, with a higher score indicating more negative symptom psychopathology. A negative change score indicates improvement. Intent-to-treat population: All randomized participants who received at least 1 dose of double-blind study drug and had at least one post-baseline assessment of the primary efficacy variable. For all analyses of PANSS data, the scores were transformed into 0-6 points to express “absent” as 0.

Primary

Baseline to Week 24

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 and PSP 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 imputation for missing data were used in primary analyses.

Placebo - Treatment Period 1 v Bitopertin 5 mg - Treatment Period 1

408

Pre-specified

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 and PSP 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 imputation for missing data was used in primary analyses.

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

400

Pre-specified

The PSP is a clinician-rated 100-point rating scale subdivided into 10 equal intervals, enabling the determination of small changes in levels of functioning. The ratings are based upon assessment of the patient’s functioning in 4 areas: 1) Socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviors. Each of the 4 areas is rated in 6 degrees of severity (absent, mild, manifest, marked, severe, very severe). Higher scores represent better personal and social functioning, with ratings from 91-100 referring to more than adequate functioning, while scores under 30 refer to poor functioning that intensive supervision is required. A higher score indicates better functioning. A positive change score indicates improvement. Intent-to-treat population: All randomized participants who received at least 1 dose of double-blind study drug and had at least one post-baseline assessment of the primary efficacy variable.

Secondary

Week 24

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 PSP 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 imputation for missing data were used in primary analyses.

Placebo - Treatment Period 1 v Bitopertin 5 mg - Treatment Period 1

408

Pre-specified

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 PSP 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 imputation for missing data were used in primary analyses.

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

400

Pre-specified

From randomization to the end of the study (up to 4 years, 2 months).

17

Placebo through Week 52

Bitopertin 5 mg through Week 52

Bitopertin 10 mg through Week 52

Placebo during washout period

Bitopertin 5 mg during washout period

Bitopertin 5 mg to Placebo during washout period

Bitopertin 10 mg during washout period

Bitopertin 10 mg to placebo during washout period

Placebo to bitopertin 10 mg during long-term extension

Bitopertin 5 mg to bitopertin 10 mg during long-term extension

Bitopertin 10 mg during long-term extension

Placebo during follow-up period

Bitopertin 5 mg during follow-up period

Bitopertin 10 mg during follow-up period