Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program

Abstract

Background Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials. Discussion points The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results. Conclusion Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

Efficacy and safety of V1a receptor antagonists in autism spectrum disorder: A meta‐analysis

“…In the final stage of screening, four studies that met the selection criteria were included in the meta‐analysis (Table S1). The included studies (Bolognani et al, 2019; Hollander et al, 2022; Jacob et al, 2022; Umbricht et al, 2017) used different duration of treatment and doses of V 1a receptor antagonists, which were considered separate units of analysis; hence, a total of eight units of analysis were dealt with in this meta‐analysis. Assessment of the risk of bias has been presented in Table S2, summarizing the judgement of the reviewers about each risk of bias domain across all included studies.…”

“…All four included studies (Bolognani et al, 2019; Hollander et al, 2022; Jacob et al, 2022; Umbricht et al, 2017) used the Vineland II Total Adaptive Behavior Composite (ABC) score for change in the assessment of ASD symptom scores. The test for heterogeneity among the included studies was significant (Chi 2 = 18.41; p = 0.01; I 2 = 62%).…”

“…Three (Bolognani et al, 2019; Hollander et al, 2022; Jacob et al, 2022) out of four included studies reported Vineland II daily living skills domain scores. The test for heterogeneity among the included studies was non‐significant (Chi 2 = 7.89; p = 0.25; I 2 = 24%).…”

“…There is evidence from previous studies that showed the role of V 1a antagonists in social communication in autism. In autistic individuals, balovaptan and RG7713 have been tested in a few randomized clinical trials showing contradictory results (Jacob et al, 2022). Hollander et al (2022) and Bolognani et al (2019) showed significant improvement in core symptoms; however, studies by Umbricht et al (2017) and Jacob et al (2022) showed no significant improvement in core symptoms of ASD.…”

“…In autistic individuals, balovaptan and RG7713 have been tested in a few randomized clinical trials showing contradictory results (Jacob et al, 2022). Hollander et al (2022) and Bolognani et al (2019) showed significant improvement in core symptoms; however, studies by Umbricht et al (2017) and Jacob et al (2022) showed no significant improvement in core symptoms of ASD. As the results from these clinical trials are conflicting and non‐conclusive, the present meta‐analysis was conducted to evaluate the safety and efficacy of V 1a antagonists in ASD compared to a placebo.…”