Efficacy and safety of adjunctive bitopertin versus placebo in patients with suboptimally controlled symptoms of schizophrenia treated with antipsychotics: results from three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies in the SearchLyte clinical trial programme.

BACKGROUND: Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, offer an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment. METHODS: SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1:1:1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks' treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]). FINDINGS: Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean difference in score -1·37, 95% CI -2·27 to -0·47; p=0·0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: -3·77, 95% CI -4·40 to -3·14; p=0·3142. Results from the other two studies also did not differ from placebo (TwiLyte 0·58, 95% CI -0·34 to 1·50, p=0·22 for 10 mg and 0·43, -0·49 to 1·36, p=0·36 for 20 mg; MoonLyte 0·06, 95% CI -0·79 to 0·92, p=0·88 for 5 mg and 0·44, -0·41 to 1·28, p=0·31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation. INTERPRETATION: Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might offer only modest benefit to suboptimal responders to antipsychotics, if any. FUNDING: F Hoffmann-La Roche.

Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program.

OBJECTIVE: The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA). METHODS: This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented. RESULTS: Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, -1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups. CONCLUSIONS: In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX. TRIAL REGISTRATION: STAGE ClinicalTrials.gov NCT00406419 SCRIPT ClinicalTrials.gov NCT00476996 FILM ClinicalTrials.gov NCT00485589 FEATURE ClinicalTrials.gov NCT00673920.

Cerebellar mechanisms in eyeblink conditioning.

A recent model of cerebellar learning in eyeblink conditioning predicts two sites of plasticity, the cerebellar cortex and cerebellar nuclei, which store information relating to timing and driving the movement, respectively. Consistent with this idea, lesions of the cortex or reversible "disconnections" of Purkinje cell output to the nuclei have been shown to disrupt response timing to produce short-latency conditioned eyeblinks. To better characterize potential cortical and nuclear plasticities, we analyzed the effects upon nictitating membrane (NM) and eyeblink conditioned responses (CRs) of different drugs administered to the cortex and to the nuclei. When either excitatory or inhibitory inputs to the cerebellar cortical lobule HVI were blocked by infusions of the AMPA receptor antagonist CNQX or the GABA-A receptor antagonists picrotoxin or SR95531, CRs were abolished. Similarly GABA-A receptor antagonists in the cerebellar nuclei abolished CRs. CR latencies were never shortened. However, blockade of AMPA/kainate receptor-mediated excitatory transmission to the nuclei had no effect upon CR frequencies or latencies. These results suggest that normal cortical and nuclear function is required for performance of NM and eyeblink CRs. We saw no evidence that CRs can be driven by AMPA/kainate receptor-mediated transmission from mossy fiber afferents to the cerebellar nuclei. So, although plasticity in the cerebellar nuclei is not ruled out, it is unlikely that a long-term change in AMPA receptor-mediated transmission from mossy fiber inputs to the nuclei is an essential mechanism in eyeblink conditioning. Our findings indicate that a fully functional olivo-cortico-nuclear loop is required to express all characteristics of associatively conditioned responses.