1. Incidence of total adverse events and specific adverse events were similar between the emraclidine groups and placebo.
2. There was an initial, modest increase in heart rate and blood pressure with emraclidine that was deemed not clinically significant by week 6.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Antipsychotics typically work by reducing dopaminergic neurotransmission in the brain, as dopamine hyperactivity has been thought to play a role in the positive symptoms of schizophrenia. An unfortunate result of dopaminergic blockade are extrapyramidal symptoms. Emraclidine is a novel M4 receptor positive allosteric modulator which has shown benefit for symptoms of schizophrenia while potentially reducing side effects. This study aimed to assess the safety and tolerability of emraclidine in a two-part randomized controlled phase one trial. Participants with schizophrenia were enrolled and randomized to either placebo or two doses of emraclidine. In result, the incidence of adverse events was similar between the emraclidine groups and the placebo group. The most common adverse event was headache, which did not differ between placebo and treatment groups. Additionally, there was an increase in blood pressure seen with emraclidine which had decreased over time and was deemed not clinically significant by week 6. Limitations of this study include a small sample size with a mostly Black and male participants. Future large-scale randomized controlled trials will be needed to assess the efficacy of emraclidine as a treatment for schizophrenia. Nevertheless, this study provides evidence that emraclidine is a safe and well-tolerated potential treatment for schizophrenia.
In-Depth [randomized controlled trial]: This study was a two-part phase 1b randomized controlled trail conducted in the USA. Eligible participants met the DSM-5 diagnostic criteria of schizophrenia as confirmed by the Mini International Neuropsychiatric Interview and demonstrated mild extrapyramidal symptoms at screening. Exclusion criteria include having another DSM-5 diagnosis other than schizophrenia. Part A was a multiple ascending-dose study of participants with stable schizophrenia to determine the safety and tolerability of emraclidine. A total of 44 participants completed Part A. From Part A, there were no serious adverse events or deaths. The most frequently reported adverse events were headache (10%), dizziness (5%), insomnia (5%), and weight gain (5%).
Part B was a randomized control trial in participants with active schizophrenia using the two highest doses from Part A. In Part B, a total of 81 participants were randomized 1:1:1 to placebo, emraclidine 30 mg daily, and emraclidine 20 mg twice daily for 6 weeks. There were 6 discontinuations in each group for a final total of 21 participants in each that completed the study. The mean age of participants in Part B was 40 years and the majority were male. There were adverse events reported in 14 of 27 (52%) of the placebo group, 15 of 27 (56%) of the emraclidine 20 mg twice daily group and 14 of 27 (52%) of the emraclidine 30 mg once daily group. There were three serious adverse events, but these were not felt to be related to treatment allocation. The most common adverse events were similar to those in Part A; however, these were similar in the emraclidine groups and placebo. There was a modest increase in blood pressure seen at various time points in both emraclidine groups, but this trended down until week 6 and was not considered clinically meaningful compared to placebo.
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