BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults.
METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917).
FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred.
INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures.
FUNDING: F Hoffmann-La Roche.
Bibliographical noteFunding Information:
SJ has received grant support from the US National Institutes of Health (NIH) and Roche; and has attended advisory boards for Fraser, Minnesota Independence College & Community, and F Hoffmann-La Roche. JV-V has received research support from NIH, the Simons Foundation, Health Canada, F Hoffmann-La Roche, Janssen, Acadia, and Zynerba; royalties from Springer and Wiley; has attended advisory boards for Roche; serves on the medical or scientific advisory boards for Autism Speaks, the Simons Foundation Autism Research Initiative, and the Brain Behavior Research Foundation; and serves as the co-chair of the Autism and Intellectual Disability Committee for the American Academy of Child and Adolescent Psychiatry. DM receives funding support from the EU/EFPIA/SFARI/Autistica/AUTISM SPEAKS Innovative Medicines Initiative 2 Joint Undertaking (AIMS-2-TRIALS grant number 777394); has received grant support from F Hoffmann-La Roche and Shire; royalties from Springer and Wiley; and has attended advisory boards for F Hoffmann-La Roche and Servier. JM has received research support from F Hoffmann-La Roche; has attended advisory boards for GW Pharmaceuticals and F Hoffmann-La Roche; and was a consultant for Octopharma and TRIS Pharmaceuticals. EAn has received grant support from F Hoffmann-La Roche and SynapDx; royalties from APPI, Springer, and Wiley; has acted as a consultant for Quadrant, F Hoffmann-La Roche, and SynapDx; has received an honorarium for a webinar from AIDE; has a patent on an anxiety meter; has received a study drug from Clinical Research Associates LLC; and has received a study drug and in kind supports from AMO Pharma. CM is an employee of CRO Excelya Germany (formerly KOEHLER eClinical), Freiburg, Germany. EAs is an employee of and has stock options in F Hoffmann-La Roche. JS, KS, and CW are employees of and have stocks and stock options in F Hoffmann-La Roche. TW and GD-B are employees of F Hoffmann-La Roche.
© 2022 Elsevier Ltd
- Antidiuretic Hormone Receptor Antagonists/administration & dosage
- Autism Spectrum Disorder/complications
- Benzodiazepines/administration & dosage
- Communication Disorders/drug therapy
- Double-Blind Method
- Pyridines/administration & dosage
- Treatment Outcome
- Triazoles/administration & dosage
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Randomized Controlled Trial
- Multicenter Study
- Clinical Trial, Phase III
- Journal Article