A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia.

ABSTRACT

INTRODUCTION: TAK-063 is a potent, selective inhibitor of phosphodiesterase 10A, an enzyme selectively expressed in medium spiny neurons of the striatum. This randomized, parallel-group study evaluated the efficacy and safety of 20-mg daily TAK-063 versus placebo in subjects with acutely exacerbated symptoms of schizophrenia (NCT02477020). METHODS: Adults aged 18 to 65 with diagnosed schizophrenia and psychotic symptoms that exacerbated within 60 days before screening were included. Subjects who discontinued psychotropic medications before screening were randomized 11 to 6 weeks of placebo (n = 81) or 20-mg TAK-063 (n = 83). Weekly efficacy visits were conducted during the treatment period, and dose de-escalation was allowed (blinded) to 10-mg TAK-063 for intolerability. RESULTS: The primary endpoint, change from baseline in the Positive and Negative Syndrome Scale total score at week 6, was not achieved (least-squares mean difference vs placebo [standard error] = -5.46 [3.44]; p = 0.115). Secondary endpoints were generally supportive of antipsychotic efficacy. Consistent with previous phase 1 studies, TAK-063 was safe and well tolerated, and most adverse events were mild or moderate in severity and did not result in discontinuation. No deaths occurred, and the incidence of akathisia and dystonia, categories of extrapyramidal syndromes, was more frequent in the TAK-063 group than placebo. CONCLUSIONS: Although the study did not meet the primary endpoint (effect size = 0.308), the effects of TAK-063 on the primary and secondary endpoints may be suggestive of antipsychotic activity. Interpretation of these results is confounded by a relatively high placebo effect and a lack of dose-ranging or active reference.