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

Molecular Autism - 2022
Suma Jacob1, Evdokia Anagnostou2, Eric Hollander3, Roger J. Jou4, Nora McNamara5, Linmarie Sikich6, Russell H. Tobe7, Declan Murphy8, James T. McCracken9, Elizabeth Ashford10, Chris Chatham11, Susanne Clinch10, Janice Smith10, Kevin Sanders12, Lorraine Murtagh11, Jana Noeldeke11, Jeremy Veenstra‐VanderWeele13
1Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA
2Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, ON, Canada
3Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, New York, NY, USA
4Child Study Center, Yale School of Medicine, New Haven, CT, USA
5Department of Psychiatry, University Hospitals, Cleveland, OH, USA
6Department of Psychiatry and Behavioral Sciences, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
7Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
8Kings College London, London, UK
9David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
10F. Hoffmann-La Roche Ltd, Welwyn Garden City, UK
11F. Hoffmann-La Roche Ltd, Basel, Switzerland
12F. Hoffmann-La Roche Ltd, Genentech, South San Francisco, CA, USA
13Columbia University and New York State Psychiatric Institute, New York, NY, USA

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

Dietz PM, Rose CE, McArthur D, Maenner M. National and state estimates of adults with autism spectrum disorder. J Autism Dev Disord. 2020;50:4258–66.

Masi A, DeMayo MM, Glozier N, Guastella AJ. An overview of autism spectrum disorder, heterogeneity and treatment options. Neurosci Bull. 2017;33:183–93.

Mason D, McConachie H, Garland D, Petrou A, Rodgers J, Parr JR. Predictors of quality of life for autistic adults. Autism Res. 2018;11:1138–47.

Centers for Disease Control and Prevention. Treatment and Intervention Services for Autism Spectrum Disorder. https://www.cdc.gov/ncbddd/autism/treatment.html. Accessed 9 Dec 2021.

DeFilippis M, Wagner KD. Treatment of autism spectrum disorder in children and adolescents. Psychopharmacol Bull. 2016;46:18–41.

Dawson G, Burner K. Behavioral interventions in children and adolescents with autism spectrum disorder: a review of recent findings. Curr Opin Pediatr. 2011;23:616–20.

Vismara LA, Colombi C, Rogers SJ. Can one hour per week of therapy lead to lasting changes in young children with autism? Autism. 2009;13:93–115.

Bolognani F, Del Valle Rubido, Squassante L, Wandel C, Derks M, Murtagh L, et al. A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder. Sci Transl Med. 2019;11:eaat7838.

Parker KJ, Oztan O, Libove RA, Mohsin N, Karhson DS, Sumiyoshi RD, et al. A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Sci Transl Med. 2019;11:eaau7356.

Kompier NF, Keysers C, Gazzola V, Lucassen PJ, Krugers HJ. Early life adversity and adult social behavior: focus on arginine vasopressin and oxytocin as potential mediators. Front Behav Neurosci. 2019;13:143.

Umbricht D, Del Valle RM, Hollander E, McCracken JT, Shic F, Scahill L, et al. A single dose, randomized, controlled proof-of-mechanism study of a novel vasopressin 1a receptor antagonist (RG7713) in high-functioning adults with autism spectrum disorder. Neuropsychopharmacol. 2017;42:1914–23.

Ratni H, Rogers-Evans M, Bissantz C, Grundschober C, Moreau J-L, Schuler F, et al. Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenic and scaffold hopping approach. J Med Chem. 2015;58:2275–89.

Jacob S, Veenstra-Vanderweele J, Murphy D, McCracken J, Smith J, Sanders K, et al. Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial. Lancet Psychiatry. 2022;9:199–210.

Hollander E, Jacob S, Jou RJ, McNamara N, Sikich L, Tobe R, et al. A phase 2 randomized controlled trial of balovaptan in pediatric participants with autism spectrum disorder. JAACAP. 2020;59:S262–3.

Haflioadottir SH, Juhl CB, Nielsen SM, Henriksen M, Harries IA, Bliddal H, et al. Placebo response and effect in randomized clinical trials: meta-research with focus on contextual effects. Trials. 2021;22:493.

Evers AWM, Colloca L, Blease C, Annoni M, Atlas LY, Bendetti F, et al. Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosom. 2018;87:204–10.

Kobak KA, Leuchter A, DeBrota D, Engelhardt N, Williams JBW, Cook IA, et al. Site versus centralized raters in a clinical depression trial—impact on patient selection and placebo response. J Clin Psychopharmacol. 2010;30:193–7.

Williams JB, Popp D, Kobak KA, Detke MJ. The power of expectation bias. Eur Psychiatry. 2012;27:1.

Siafis S, Ciray O, Schneider-Thoma J, Bighelli I, Krause M, Rodolico A, et al. Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis. Mol Autism. 2020;11:66.

Jones BDM, Razza LB, Weissman CR, Karbi J, Vine J. Magnitude of the placebo response across treatment modalities used for treatment-resistent depression in adults—a systematic review and meta-analysis. JAMA Psychiat. 2021;4:e2125531.

Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170:723–33.

Dobson ET, Strawn JR. Placebo response in pediatric anxiety disorders: implications for clinical trial design and interpretation. J Child Adolesc Psychopharmacol. 2016;26:686–93.

Rutherford BR, Pott E, Tandler JM, Wall MM, Roose SP, Lieberman JA. Placebo response in antipsychotic clinical trials—a meta-analysis. JAMA Psychiat. 2014;71:1409–21.

Kubo K, Fleichhacker WW, Suzuki T, Yasui-Furukori N, Mimura M, Uchida H. Placebo effects in adult and adolescent patients with schizophrenia: combined analysis of nine RCTs. Acta Psychiatr Scand. 2019;139:108–16.

Luu S, Province H, Berry-Kravis E, Hagerman R, Hessl D, Vaidya D, et al. Response to placebo in Fragile X syndrome clinical trials: an initial analysis. Brain Sci. 2020;10:629.

Dunlop BW, Thase ME, Wun CC, Fayyad R, Guico-Pabia CJ, Musgnung J, et al. A meta-analysis of factors impacting detection of antidepressant efficacy in clinical trials: the importance of academic sites. Neuropsychopharmacology. 2012;37:2830–6.

Fraugas D, Diaz-Caneja CM, Pina-Camacho L, Umbricht D, Arango C. Predictors of placebo response in pharmacological clinical trials of negative symptoms in schizophrenia: a meta-regression analysis. Schizophr Bull. 2018;45:57–68.

Meister R, Abbas M, Antel J, Peters T, Pan Y, Bingel U, et al. Placebo response rates and potential modifiers in double-blind randomized controlled trials of second and newer generation antidepressants for major depressive disorder in children and adolescents: a systematic review and meta-regression analysis. Eur Child Adolesc Psychiatry. 2020;29:253–73.

Brogger-Mikkelsen M, Ali Z, Zibert JR, Andersen AD, Thomsen SF. Online patient recruitment in clinical trials: systematic review and meta-analysis. J Med Internet Res. 2020;22:e22179.

King BH, Dukes K, Donnelly CL, Sikich L, McCracken JT, Scahill L, et al. Baseline factors predicting placebo response to treatment in children and adolescents with autism spectrum disorders: a multisite randomized clinical trial. JAMA Pediatr. 2013;167:1045–52.

Yoo H. Genetics of autism spectrum disorder: current status and possible clinical applications. Exp Neurobiol. 2015;24:257–72.

Cataldo I, Azhari A, Esposito G. A review of oxytocin and arginine-vasopressin receptors and their modulation of autism spectrum disorder. Front Mol Neurosci. 2018;11:27.

Charman T, Loth E, Tillmann J, Crawley D, Wooldridge C, Goyard D, et al. The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation. Mol Autism. 2017;8:27.

Stavropoulos KKM, Baker E. Priming the pathway: combining oxytocin and behavioral intervention to improve outcomes in autism spectrum disorder: In: Wu W, Kostoglou-Athanassiou I, editors. Oxytocin and health [internet]. London: IntechOpen; 2021. https://www.intechopen.com/chapters/76208. https://doi.org/10.5772/intechopen.96859

Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015;5:e640.

Anagnostou EJ, Jones N, Huerta M, Halladay AK, Wang P, Scahill L, et al. Measuring social communication behaviors as a treatment endpoint in individuals with autism spectrum disorder. Autism. 2015;19:622–36.

Brugha TS, Doos L, Tempier A, Einfeld S, Howlin P. Outcome measures in intervention trials for adults with autism spectrum disorders; a systematic review of assessments of core autism features and associated emotional and behavioural problems. Int J Methods Psychiatr Res. 2015;24:99–115.

Bolte EE, Diehl JJ. Measurement tools and target symptoms/skills used to assess treatment response for individuals with autism spectrum disorder. J Autism Dev Disord. 2013;43:2491–501.

Akhondzadeh S, Fallah J, Mohammadi MR, Imani R, Mohammadi M, Salehi B, et al. Double-blind placebo-controlled trial of pentoxifylline added to risperidone: effects on aberrant behavior in children with autism. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:32–6.

Scahill L, Aman MG, Lecavalier L, Halladay AK, Bishop SL, Bodfish JW, et al. Measuring repetitive behaviors as a treatment endpoint in youth with autism spectrum disorder. Autism. 2015;19:38–52.

Moricke E, Buitelaar JK, Rommelse NNJ. Do we need multiple informants when assessing autistic traits? The degree of report bias on offspring, self, and spouse ratings. J Autism Dev Disord. 2016;46:164–75.

Del Valle RM, McCracken JT, Hollander E, Shic F, Noeldeke J, Boak L, et al. In search of biomarkers for autism spectrum disorder. Autism Res. 2018;11:1567–79.

Klin A. Biomarkers in autism spectrum disorder: challenges, advances, and the need for biomarkers of relevance to public health. Focus (Am Psychiatr Publ). 2018;16:135–42.

Georgescu AL, Koehler JC, Weiske J, Vogeley K, Koutsouleris N, Falter-Wagner C. Machine learning to study social interaction difficulties in ASD. Front Robot AI. 2019;6:132.

Baksh RA, Abrahams S, Bertlich M, Cameron R, Jany S, Dorrian T, et al. Social cognition in adults with autism spectrum disorders: validation of the Edinburgh Social Cognition Test (ESCoT). Clin Neuropsychol. 2021;35:1275–93.

McPartland JC, Bernier RA, Jeste SS, Dawson G, Nelson CA, Chawarska K, et al. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): scientific context, study design, and progress toward biomarker qualification. Front Integr Neurosci. 2020;14:16.

Holiga Š, Hipp JF, Chatham CH, Garces P, Spooren W, D’Ardhuy XL, et al. Patients with autism spectrum disorders display reproducible functional connectivity alterations. Sci Transl Med. 2019;11:eaat9223.

Eichler HG, Koenig F, Arlett P, Enzmann H, Humphreys A, Petavy F, et al. Are novel, nonrandomized analytic methods fit for decision making? The need for prospective, controlled, and transparent validation. Clin Pharmacol Ther. 2020;107:773–9.

ClinicalTrials.gov. NCT03611075 (2018). A Study to Evaluate Scales for Repetitive and Restricted Behaviors in Children, Adolescents, and Adults With Autism Spectrum Disorder (ASD). https://clinicaltrials.gov/ct2/show/NCT03611075. Accessed 9 Dec 2021.

Coravos A, Khozin S, Mandl KD. Developing and adopting safe and effective digital biomarkers to improve patient outcomes. NPJ Digit Med. 2019;2:14.

Egger HL, Dawson G, Hashemi J, Carpenter KLH, Espinosa S, Campbell K, et al. Automatic emotion and attention analysis of young children at home: a ResearchKit autism feasibility study. NPJ Digit Med. 2018;1:20.

Ness SL, Bangerter A, Manyakov NV, Lewin D, Boice M, Skalkin A, et al. An observational study with the Janssen Autism Knowledge Engine (JAKE®) in individuals with autism spectrum disorder. Front Neurosci. 2019;13:111.

O'Sullivan J, Nobbs D, Slater D, Kilchenmann T, Cheng WY, Murtagh L, et al. Remote assessment of ASD in clinical trials: automated analysis of natural conversation. Presented at the International Society for Autism Research (INSAR) Virtual Annual Meeting 2021. Abstract 446.017.

Voss C, Schwartz J, Daniels J, Kline A, Haber N, Washington P, et al. Effect of wearable digital intervention for improving socialization in children with autism spectrum disorder: a randomized clinical trial. JAMA Pediatr. 2019;173:446–54.

Grzadzinski R, Lord C. Commentary: insights into the development of the Brief Observation of Social Communication Change (BOSCC). J Ment Health Clin Psychol. 2018;2:15–8.

Rutherford BR, Wall MM, Brown PJ, Choo T-H, Wager TD, Peterson BS, et al. Patient expectancy as a mediator of placebo effects in antidepressant clinical trials. Am J Psychiatry. 2017;174:135–42.

Curcovic M, Kosec A. Significance of participants’ expectations in managing the placebo effect in antidepressant research. Front Psychiatry. 2019;10:713.

Lord C, Charman T, Havdahl A, Carbone P, Anagnostou E, Boyd B, et al. The Lancet Commission on the future of care and clinical research in autism. Lancet. 2022;399:271–334.

Bigirumurame T, Uwimpuhwe G, Wason J. Sequential multiple assignment randomized trial studies should report all key components: a systematic review. J Clin Epidemiol. 2022;142:152–60.

Liu Y, Wang Y, Zeng D. Sequential multiple assignment randomization trials with enrichment design. Biometrics. 2017;73:378–90.

Thông tin
Thông tin xuất bản

Molecular Autism

Thông tin tác giả