Article Summary
Clinical Summary: A Phase 2b Multicenter Study to Evaluate Basmisanil as an Adjunctive Treatment in Patients With Cognitive Impairment Associated With Schizophrenia
Cognitive impairment associated with schizophrenia is a major driver of poor long-term functional outcomes, yet no approved treatment is available. This trial tested whether adjunctive basmisanil could improve cognition in clinically stable patients and whether age or cognitive subtype could help identify a responder group.
Design
This multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 2b study investigated the efficacy of 24 weeks of basmisanil treatment on cognitive deficits in stable CIAS patients treated with antipsychotics.
N
The study enrolled 214 patients across 37 sites in the US, 213 of whom received treatment.
Population
The study included male and female subjects aged between 18 and 50 years with a diagnosis of schizophrenia according to DSM-5.
Duration
The study consisted of a screening phase of 5 weeks (including baseline 1 and baseline 2 visits), a 24-week double-blinded treatment phase including a 1-week inpatient study for the first 40 subjects to allow close observation of symptoms and rule out any exacerbation of their psychosis, and a 4-week follow-up phase.
Key Findings
- On the primary outcome, 24 weeks of treatment with 240 mg basmisanil twice a day did not improve cognition versus placebo on the MCCB neurocognitive composite T-score: mean changes from baseline were 1.08± 5.78 [SD] for placebo and 1.36±4.80 [SD] for 240 mg basmisanil (ES=0.05, P =.793).
- The preplanned interim analysis showed the 80 mg group had a less than 20% probability of reaching an ES of at least 0.35, so recruitment into this group was stopped after approximately 30 patients per arm had completed 12 weeks of treatment.
- A single secondary memory measure showed a signal at week 24, with the delayed recall condition VPA total raw score II reaching an ES of 0.45 (P<.1), but there were no significant treatment effects on verbal learning, working memory, or any other individual MCCB cognitive domains.
- Prespecified subgroup analyses did not identify a clinically useful responder group: older patients showed a numerical treatment effect of ES =0.39, younger patients showed ES=−0.32, and cognitive subtype effects were ES=0.27 for preserved, ES =0 for deteriorated, and ES=−0.04 for compromised.
- Attrition was substantial, with 81 (37.9%) patients withdrawing prematurely, but safety-related withdrawals ranged from 3.7% to 5.6%; serious AEs occurred at the same frequency in the 240 mg treatment (4 events) and placebo (5 events) groups, and worsening of psychosis was reported in 3.8% with 240 mg basmisanil versus 6.2% with placebo.
Clinical Bottom Line
Adjunctive basmisanil did not improve global cognition in schizophrenia over 24 weeks and did not show a convincing benefit in prespecified age or cognitive subtype groups. Its acceptable tolerability does not offset the lack of efficacy for CIAS.
Practice Implications
- Do not use basmisanil as a procognitive adjunct for CIAS based on these data, because the primary endpoint showed essentially no advantage over placebo (ES=0.05, P =.793).
- Interpret isolated positive signals cautiously when they are limited to a single secondary measure such as VPA delayed recall condition II (ES of 0.45 [P<.1]) without corroboration across global cognition, other cognitive domains, functional measures, or symptom scales.
- Do not expect younger patients or those with deteriorated cognition to derive greater benefit from basmisanil, since the prespecified subgroup analyses failed to confirm those hypotheses and numerical effects favored older patients and the preserved subtype.
- In future CIAS trials, consider repeated pre-baseline cognitive testing, as the study reported no improvement in the placebo group at week 12 and a placebo-group change of 1.08 at the second assessment, below the 1.9 points cited from prior controlled trials.
