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.

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.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests AN reports participation in a consortium that obtained the Horizon 2020 grant for this project. AS-P received study materials and the study drug from EryDel for this trial; reports grants for research in ataxia telangiectasia (AT children's project, AEFAT, Action for AT, Klinbeforsk, and Dam Foundation); and is the president of the Norwegian Society for Medical Genetics. EF received funding to her institution from EryDel for this project. GJ is employed as a chief medical officer by EryDel and Quince Therapeutics; was medical monitor for this trial; and received stock options from the sponsors. IM reports consulting fees, honoraria, or travel expenses from Boehringer-Ingelheim, Takeda, and CSL-Behring, for work unrelated to this project; and has held unpaid leadership positions in the past (president of the European Society for Immunodeficiencies Society, Monoclonal Antibodies for Children with Primary Immunodeficiencies, and International Patient Organisation for Primary Immunodeficiencies). KV reports honoraria from MedLink Neurology and holds leadership positions (secretary general of the Indian Epilepsy Society and Asian Epilepsy Academy). LB has a leadership role in Newron Pharmaceuticals; has received stock options from Quince Therapeutics; was the chief executive officer of EryDel; and holds a board position with Quince Therapeutics. MKK reports funding to her institution from EryDel for this trial; funding from Quince Therapeutics for the expanded access programme; and travel expenses from EryDel for attendance at the investigator meeting. MM received a grant and travel support from EryDel; holds a leadership position with Diatheva; and has stock options in EryDel and Quince Therapeutics. PP received grants from EryDel for this trial, paid to his institution; reports research grants from the Indian Council of Medical Research, Department of Science and Technology Science and Engineering Research Board, the Science and Engineering Research Board, Department of Biotechnology, Welcome-Department of Biotechnology, Promoting Academic research Conversion to Enterprise, Scientific Knowledge for Ageing and Neurological Ailments, and the Michael J Fox Foundation all paid to his institution; honoraria as a speaker from the International Parkinson and Movement Disorder Society, Movement Disorders Societies of Korea, Taiwan, and Bangladesh, and the National Institute of Mental Health and Neurosciences; holds leadership positions including chair of the education committee of the International Parkison's and Movement Disorders Society; and is the unpaid editor-in-chief of Annals of Movement Disorders. RY reports research grants from the Indian Council of Medical Research, Parkinson's and Movement Disorders Research Fund of the National Institute of Mental Health and Neurosciences, and the SKAN foundation; book royalties from Jaypee; speaker honoraria from International Parkison's and Movement Disorders Society; and holds a leadership role in the Parkinson's Society of Karnataka. RG reports participation on data safety monitoring or advisory boards for Biogen, Hikma, Merck, Roche, and Sanofi. TC received consulting fees from Syneos Health Communications and Scholar Rock; honoraria for CME educational programme development from Med Force and the Muscular Dystrophy Association; and participation on safety monitoring or advisory boards for Taysha Giant Axonal Neuropathy. WW reports grants from EryDel to their institution for this trial; is a member of a data safety monitoring board for a clinical trial of A-TC7 in ataxia telangiectasia; and is a trustee of the charity Syncope Trust & Reflex Anoxic Seizures. HL declares reports grants and equipment from EryDel to their institution for this trial; consulting fees from EryDel for analysis of adverse events and presentation to the US Food and Drug Administration; and travel expenses from EryDel for attending investigator meetings for this trial. VU received grants from EryDel to his institution for this trial. SZ declares that Frankfurt University was funded by the Horizon grant from the EU and by EryDel for conducting this trial; research grants outside submitted work (Palas GmbH Company Karlsruhe Germany and Ministry of Health of the German Republic); consulting fees or honoraria from Engelhard GmbH, Boehringer Ingelheim, Allergy Therapeutics, AstraZeneca, Sanofi Aventis, EryDel SpA, and Lofarma; and is a member of the European Academy of Allergy and Clinical Immunology guidelines group on allergic asthma. MK received grants from EryDel for this trial and funding from Quince Therapeutics for the expanded access programme; consulting fees from Desitin Pharma, Eisai Pharma, STADA pharm, and Life Science Consulting; travel expenses from Desitin Pharma; reports participation on a data safety monitoring board for Eisai Pharma; and is a board member and the vice president of the Neuropaediatric Society (Germany, Austria, and Switzerland). BH reports personal fees from Quince Therapeutics for her work in Clinical Development; received travel expenses from Quince Therapeutics for the investigator's meeting; is a consultant for Foundation for the Accreditation of Cellular Therapy; holds an unpaid position as the founder and chair of Florida Pediatric BMT and Cell Therapy Consortium (FPBCC) for 2018–23; and has received multiple grants for the work of the FPBCC. DT is the chief medical officer and chief executive officer of Quince Therapeutics. AV, BP, MR, RB, SIP, SG, SW, SP, VL, and AH declare no competing interests.