Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Susan Perlman, Howard Lederman, Guenter Janhofer, Dirk Thye, Steve Wu, Samuel I Pascual, Andreea Nissenkorn, Kollencheri P Vinayan, Anand Venkateswar, Pramod Pal, Luca Benatti, Thomas Crawford, Mauro Magnani, Vincenzo Leuzzi, Monique Ryan, Suresh Kumar, Rupam Borgohain, Sheffali Gulati, Riadh Gouider, Isabelle Meyts, William Whitehouse, Ravi Yadav, Elisa Fazzi, Asbjørg Stray-Pedersen, Mary Kay Koenig, Vrajesh Udani, Stefan Zielen, Biljana Horn, Matthias Kieslich, Anaita Hegde, Barbara Pietrucha

Journal: The Lancet. Neurology 2024;23(9):871-882

PMID: 39152028

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia.

METHODS

This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 22 centres in 12 countries (Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the UK, and the USA). Eligible participants were children aged 6 years or older weighing more than 15 kg who met clinical criteria for ataxia telangiectasia but who had preserved autonomous gait. Participants were randomly assigned (1:1:1) to low-dose (approximately 5-10 mg), or high-dose (approximately 14-22 mg) intra-erythrocyte dexamethasone sodium phosphate, or placebo, using an independent interactive web response system, with minimisation for sex and age (6-9 years vs ≥10 years). Intravenous intra-erythrocyte dexamethasone sodium phosphate was administered once a month for 6 months. Participants, employees of the sponsor, investigators, all raters of efficacy endpoints, and central reviewers were masked to treatment assignment and dose allocations. The primary efficacy endpoint was change in the modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to month 6, assessed in the modified intention-to-treat (mITT) population, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline efficacy assessment. This trial is registered with Clinicaltrials.gov (NCT02770807) and is complete.

FINDINGS

Between March 2, 2017, and May 13, 2021, 239 children were assessed for eligibility, of whom 176 were randomly assigned. One patient assigned to high-dose intra-erythrocyte dexamethasone sodium phosphate did not initiate treatment. 175 patients received at least one dose of treatment (59 patients received the low dose and 57 received the high dose of intra-erythrocyte dexamethasone sodium phosphate, and 59 received placebo). The mITT population comprised 164 participants (56 children in the low-dose group, 54 children in the high-dose group, and 54 in the placebo group). Compared with the placebo group, no differences were identified with regard to change in mICARS score from baseline to 6 months in the low-dose group (least squares mean difference -1·37 [95% CI -2·932 to 0·190]) or the high-dose group (-1·40 [-2·957 to 0·152]; p=0·0765). Adverse events were reported in 43 (73%) of 59 participants in the low-dose group, 47 (82%) of 57 participants in the high-dose group, and 43 (73%) of 59 participants in the placebo group. Serious adverse events were observed in six (10%) of 59 participants in the low-dose group, seven (12%) of 57 participants in the high-dose group, and seven (12%) of 59 participants in the placebo group. There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths.

INTERPRETATION

Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. Studies of intra-erythrocyte delivery of dexamethasone sodium phosphate will continue in participants aged 6-9 years, on the basis of findings from subgroup analyses from this trial.

FUNDING

EryDel and Quince Therapeutics.

Address: Department of Pediatrics, Goethe University, Frankfurt, Germany.; Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.; EryDel, Bresso, Italy.; Department of Biomolecular Sciences, University of Urbino, Urbino, Italy.; Department of Neurology, Royal Children's Hospital, Parkville, VIC, Australia.; Department of Pediatrics, University Hospital Leuven, Leuven, Belgium.; Department of Pediatrics, Centre of Excellence and Advanced Research for Childhood Neuro-developmental Disorders and Child Neurology Division, All India Institute of Medical Sciences, New Delhi, India.; Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.; Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.; Department of Neurology, Jaslok Hospital and Medical Research Center, Mumbai, India.; Department of Neurology, Vijaya Hospital, Chennai, India.; Pediatric Neurology, Hinduja National Hospital and Research Center, Mumbai, India.; Pediatric Neurology, Amrita Institute of Medical Sciences, Kochi, India.; Children's Neurology Clinic, Sheba Medical Centre, Tel-Hashomer, School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Child Neurology and Psychiatry Unit, Civil Hospital, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.; Department of Neurosciences and Mental Health, La Sapienza University, Rome, Italy.; Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.; Department of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.; Department of Pediatric Neurology, Hospital Universitario La Paz Madrid, Madrid, Spain.; Neurology Department, Clinical Investigation Center "Neurosciences and Mental Health", Razi Hospital, Tunis, Tunisia.; Department of Pediatrics, Division of Child and Adolescent Neurology, UT Health, McGovern Medical School, Houston, TX, USA.; Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Department of Neurology, Ataxia Center, and Huntington's Disease Center of Excellence, University of California, Los Angeles, CA, USA.; Quince Therapeutics, South San Francisco, CA, USA.; Quince Therapeutics, South San Francisco, CA, USA. Electronic address: [email protected].; Paediatric Neurology, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust and School of Medicine University of Nottingham, Nottingham, UK.; Division of Pediatric Allergy and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

DOI: 10.1016/S1474-4422(24)00220-5

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MeSH Terms: Humans, Dexamethasone, Double-Blind Method, Child, Female, Male, Adolescent, Ataxia Telangiectasia, Treatment Outcome, Erythrocytes