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Efficacy and Safety of Bitopertin in Patients with Schizophrenia And

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Efficacy and Safety of Bitopertin in Patients with Schizophrenia And ORIGINAL ARTICLE Print ISSN 1738-3684 / On-line ISSN 1976-3026 https://doi.org/10.4306/pi.2017.14.1.63 OPEN ACCESS Efficacy and Safety of Bitopertin in Patients with Schizophrenia and Predominant Negative Symptoms: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 2 Trial Yoshio Hirayasu1 , Shin-Ichi Sato2, Norifumi Shuto2, Miwa Nakano2, and Teruhiko Higuchi3 1Department of Psychiatry, Yokohama City University Graduate School of Medicine, Yokohama, Japan 2Chugai Pharmaceutical Co., Ltd., Tokyo, Japan 3National Center of Neurology and Psychiatry, Tokyo, Japan ObjectiveaaThe aim of the present study was to perform a subgroup analysis of data from a phase II global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bitopertin, a glycine reuptake inhibitor that activates N-methyl- D-aspartate receptors by increasing the concentration of glycine in the synaptic cleft, in Japanese and non-Japanese patients with schizo- phrenia and predominant negative symptoms. MethodsaaPatients with schizophrenia and predominant negative symptoms on one or two antipsychotic drugs, including atypical anti- psychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, and paliperidone) as the primary treatment, received bitopertin (10, 30, or 60 mg/day) or placebo once daily for 8 weeks as an add-on treatment. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score (NSFS). ResultsaaThe efficacy of bitopertin (10 mg and 30 mg) was similar between Japanese and non-Japanese patients. In the bitopertin 60-mg group, no difference from the placebo group was observed in Japanese or non-Japanese patients. The response to placebo was lower in Japanese patients, and there was a trend towards a greater difference in the change in PANSS NSFS between the placebo group and the 10- mg and 30-mg groups among Japanese patients. The safety profile of bitopertin was favorable in Japanese and non-Japanese patients. ConclusionaaAccording to this subgroup analysis from a global phase II study of bitopertin, there was no difference in terms of efficacy and safety between Japanese and non-Japanese patients. Psychiatry Investig 2017;14(1):63-73 Key Wordsaa Bitopertin, Japan, Negative symptoms, Schizophrenia, Placebo response. INTRODUCTION symptoms seem to have a greater impact on social function- ing than do positive symptoms.3 Patients with schizophrenia experience positive symptoms Conventional antipsychotic drugs do not provide sufficient (e.g., hallucinations, delusions, catatonic symptoms, and in- improvement in negative symptoms; thus, effective treatments coherence of thought), negative symptoms (e.g., social with- to satisfy this unmet need are anticipated.4,5 Because N-meth- drawal and blunted affect), and cognitive deficits. Reportedly, yl-D-aspartate receptor (NMDAR) inhibitors, such as phency- negative symptoms are closely related to functional impair- clidine and ketamine, induce not only positive but also nega- ments regarding the maintenance of personal care, perfor- tive symptoms and cognitive deficits in healthy adults,6-9 mance of household chores, learning, ability to work or attend NMDAR dysfunction has been proposed as a factor contribut- school, and interacting with others.1,2 Additionally, these ing to the negative symptoms of schizophrenia.10 Therefore, Received: November 26, 2015 Revised: May 5, 2016 NMDA enhancers, such as glycine reuptake inhibitors (GRIs), Accepted: May 5, 2016 Available online: September 9, 2016 may improve negative symptoms. Correspondence: Yoshio Hirayasu, MD, PhD Bitopertin, a GRI that selectively inhibits a glycine trans- Department of Psychiatry, Yokohama City University Graduate School of Medi- cine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan porter, GlyT1, activates NMDAR by increasing the concen- Tel: +81-45-787-2667, Fax: +81-45-783-2540 tration of glycine in the synaptic cleft.11 A proof-of-concept, E-mail: [email protected] cc This is an Open Access article distributed under the terms of the Creative Commons global phase II study was conducted to investigate the clini- Attribution Non-Commercial License (http://creativecommons.org/licenses/by- cal effect of bitopertin on negative symptoms in patients with ) nc/3.0 which permits unrestricted non-commercial use, distribution, and reproduc- 12 tion in any medium, provided the original work is properly cited. schizophrenia. A significant improvement was observed in Copyright © 2017 Korean Neuropsychiatric Association 63 Bitopertin for Schizophrenia Symptoms 477 assessed for eligibility 343 recruited 20 failed to complete prospective run-in period 323 randomized 82 given bitopertin, 81 given bitopertin, 79 given bitopertin, 81 given placebo 10 mg/day 30 mg/day 60 mg/day J N-J J N-J J N-J J N-J 10 71 10 72 9 72 9 70 Withdrawals, No. (%) - 11 (15) 2 (20) 9 (13) 1 (11) 15 (21) 1 (11) 11 (16) Reason for withdrawal, No. (%) Safety reasons - 1 (1) - 1 (1) - 7 (10) 1 (11) 7 (10) Adverse event/intercurrent illness - - - 1 (1) - 7 (10) 1 (11) 6 (9) Low hemoglobin - 1 (1) - - - - - 1 (1) Nonsafety reasons - 10 (14) 2 (20) 8 (11) 1 (11) 8 (11) - 4 (6) Failure to return - 2 (3) - 5 (7) - 3 (4) - - Withdrew consent - 2 (3) 2 (20) 1 (1) 1 (11) - - 2 (3) Refused treatment - 4 (6) - - - 3 (4) - - Other violation - 2 (3) - 2 (3) - 1 (1) - 1 (1) Administrative/other - - - - - 1 (1) - 1 (1) Safety patients, No. 10 70 10 72 9 72 9 69 Total excluded from safety - 1 - - - - - 1 Did not receive study medication - 1 - - - - - 1 Intent-to-treat patients, No. 10 67 10 71 9 68 9 68 Total excluded from intent to treat* - 4 - 1 - 4 - 2 Missed postbaseline efficacy - 4 - 1 - 4 - 2 Did not receive study medication - 1 - - - - - 1 Modified intent-to-treat patients, No. 10 64 9 67 8 65 8 65 Total excluded from modified intent to treat* - 7 1 5 1 7 1 5 Patient rated by a decertified rater - 2 1 3 1 2 1 3 Patient not in ITT population - 4 - 1 - 4 - 2 In center that failed audit - 1 - 1 - 1 - - Per-protocol patients, No. 10 51 7 53 7 50 7 46 Total excluded from per protocol* - 20 3 19 2 22 2 24 Missing primary efficacy score at baseline or during treatment - 8 2 10 1 10 1 10 Did not complete 8-wk treatment - 7 2 7 1 11 1 9 Positive drug screen during treatment - 5 1 6 - 4 - 9 Patient rated by a decertified rater - 2 1 3 1 2 1 3 Patient not in ITT population - 4 - 1 - 4 - 2 Compliance <80% or >120% - - - 3 - 1 - - In center that failed audit - 1 - 1 - 1 - - Did not receive study medication as randomized - 1 - - - 1 - - Figure 1. CONSORT diagram. *some patients were excluded for more than one reason. J: Japanese, N-J: non-Japanese. 64 Psychiatry Investig 2017;14(1):63-73 Y Hirayasu et al. the 10-mg and 30-mg groups compared with the placebo population. group in the per-protocol population, and also a trend to- To the best of our knowledge, this was the first global study ward improvement was observed in the intent-to-treat (ITT) in the field of psychiatry, led by Europe and the US and in- Table 1. Analysis populations and baseline characteristics of the ITT population Bitopertin Placebo 10 mg/day 30 mg/day 60 mg/day Characteristic J N-J J N-J J N-J J N-J N=10 N=67 N=10 N=71 N=9 N=68 N=9 N=68 Analysis population, N All randomized 10 71 10 72 9 72 9 70 Safety (≥1 dose) 10 70 10 72 9 72 9 69 Intent to treat 10 67 10 71 9 68 9 68 Modified intent to treat 10 64 9 67 8 65 8 65 Per protocol 10 51 7 53 7 50 7 46 Demographic Male, N (%) 7 (70) 40 (60) 6 (60) 51 (72) 1 (11) 43 (63) 6 (67) 46 (68) Age, mean (SD), years 38 (11) 39 (10) 43 (10) 40 (10) 37 (10) 41 (10) 40 (8) 39 (10) BMI, mean (SD), kg/m2 25 (3) 29 (6) 24 (4) 29 (5) 27 (6) 29 (6) 24 (4) 28 (6) Primary antipsychotic treatment, N (%) Aripiprazole 2 (20) 6 (9) 2 (20) 7 (10) 3 (33) 7 (10) 2 (22) 6 (9) Olanzapine 2 (20) 19 (28) 2 (20) 21 (30) 1 (11) 20 (29) 2 (22) 20 (29) Quetiapine 1 (10) 9 (13) 2 (20) 10 (14) - 10 (15) 1 (11) 10 (15) Risperidone related 5 (50) 32 (48) 4 (40) 31 (44) 5 (56) 28 (41) 4 (44) 31 (46) Paliperidone* - 10 (15) - 9 (13) - 4 (6) - 4 (6) Risperidone (incl. risperidone 5 (50) 22 (33) 4 (40) 22 (31) 5 (56) 24 (35) 4 (44) 27 (40) long-acting injection*) Benzodiazepine treatment, N (%) Total at least one treatment 1 (10) 19 (28) 8 (80) 17 (24) 5 (56) 17 (25) 8 (89) 18 (26) Clonazepam 1 (10) 5 (7) 2 (20) 5 (7) 3 (33) 4 (6) - 8 (12) Lorazepam 1 (10) 6 (9) - 4 (6) 2 (22) 3 (4) 3 (33) 6 (9) Alprazolam - 4 (6) 1 (10) 6 (8) 1 (11) 5 (7) - 3 (4) Diazepam 1 (10) 2 (3) - 2 (3) - 2 (3) - - Flunitrazepam - - 5 (50) - - - 4 (44) - Nitrazepam - - 2 (20) - 1 (11) - - - Quazepam - - 2 (20) - - - - - Triazolam - - 2 (20) - - - - - Brotizolam 1 (10) - - - - - 2 (22) - Bromazepam - - - - 1 (11) 1 (1) 1 (11) 1 (1) Etizolam - - 1 (10) - - - 1 (11) - Lormetazepam 1 (10) - - - - - 1 (11) - Ethyl loflazepate - - - - - - 1 (11) - Flurazepam - - - - - - 1 (11) - Prazepam - - - - - 1 (1) - - Cinolazepam - 1 (1) - - - - - - Estazolam - - - - - 1 (1) - - Temazepam - 1 (1) - - - - - - www.psychiatryinvestigation.org 65 Bitopertin for Schizophrenia Symptoms Table 1. Analysis populations and baseline characteristics of the ITT population (continued) Bitopertin Placebo 10 mg/day 30 mg/day 60 mg/day Characteristic J N-J J N-J J N-J J N-J N=10 N=67 N=10 N=71 N=9 N=68 N=9 N=68 Baseline psychopathology and functioning, mean (SE) PANSS Total score 83.4 (2.7) 78.2 (1.0) 79.4 (3.7) 79.4 (1.1) 83.4 (3.3) 79.5 (1.3) 83.4 (2.6) 77.9 (1.0) Negative symptom factor score 26.6 (1.4) 25.9 (0.4) 26.1 (1.6) 25.8 (0.4) 28.0 (1.7) 26.3
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