REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome

Официальное название

Phase 3 Study of the Efficacy and Safety of ION582 in Children and Adults With Angelman Syndrome

Обзор

The purpose of this study is to evaluate the efficacy and safety of ION582 in children and adults with Angelman syndrome caused by a deletion or mutation of the UBE3A gene.

Подробное описание

This is a Phase 3, randomized, double-blind, placebo-controlled study in people with Angelman syndrome. The study will consist of 4 periods: a screening period of up to 28 days, an approximate 60-week double blind, placebo-controlled treatment period, followed by an approximate 25-month Long-Term Extension (LTE) treatment period, and an approximate 8-month Post-LTE follow-up period. The study will be comprised of 2 cohorts. Cohort 1 will include pediatric participants, aged 2 to less than (\<)18 years old and serve as the population for evaluation of primary and secondary outcome measures; Cohort 2 will include adult participants, aged 18 to ≤50 years old. Participants will be randomized 1:1 to 80 mg ION582 or placebo during the double-blind placebo-controlled treatment period. Participants from both cohorts completing the placebo-controlled treatment period will be eligible to transition into the LTE Treatment Period wherein all trial participants will receive ION582. Participant, Caregiver, Investigator and Sponsor will remain blinded to the ION582 dose administered to participants during the LTE.

The study initiated in 2024 with three dosing groups (40 mg ION582, 80 mg ION582, and placebo). Following additional review of data from the ongoing Phase 1/2 trial of ION582 (HALOS), REVEAL was amended in December 2025 to its current form as a two-arm study: 80 mg ION582 and placebo. Following the amendment, participants who were randomized to receive 40 mg ION582 will be transitioned to receive 80 mg ION582.

Вмешательства

• Препарат ION582
  ION582 will be administered by IT injection.
• Препарат Placebo
  ION582 matching placebo will be administered by IT injection.

Первичные конечные точки

• Change in Performance on the Expressive Communication Subdomain Raw Score of the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) Without Caregiver Input in Cohort 1 [Срок оценки: Baseline and Week 52]

Вторичные конечные точки (9)

• Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Cognition Subdomain Raw Score Without Caregiver Input [Срок оценки: Baseline and Week 52]
• Change in Symptoms of Angelman Syndrome -Clinician Global Impression of Change (SAS-CGI-C): Overall AS [Срок оценки: Baseline and Week 52]
• Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Receptive Communication Subdomain Raw Score [Срок оценки: Baseline and Week 52]
• Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Daily Living Skills, Personal Subdomain Raw Score [Срок оценки: Baseline and Week 52]
• Change in Symptoms of Angelman Syndrome - Clinician Global Impression of Change (SAS-CGI-C): Sleep Problems [Срок оценки: Baseline and Week 52]
• Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Fine Motor Subdomain Raw Score Without Caregiver Input [Срок оценки: Baseline to Week 52]
• Change in Observer-Reported Communication Ability (ORCA): Overall Emerging T Score [Срок оценки: Baseline and Week 52]
• Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Срок оценки: Up to Week 52]
• Change in Vital Signs and Clinical Laboratory Results [Срок оценки: Baseline and Week 52]

Критерии участия

Критерии включения

• The participants caregiver(s)/ legally authorized representative must have given written informed consent and any authorizations required by local law and be able to comply with all study requirements.
• Medically stable and can undergo sedation and/or general anesthesia without intubation.
• Male or female between 2 and lesser than or equal to (≤)50 years of age, depending on specific cohort, at the time of the in-clinic Screening visit.
• Participant has a clinical diagnosis of Angelman syndrome (AS) with molecular confirmation of either Ubiquitin-protein ligase E3A (UBE3A) deletion or UBE3A mutation.
• Currently receiving stable doses of concomitant medications typically prescribed for AS, such as anti-epileptic medication, behavioral management medications, sleep medications, gabapentin, cannabidiol, and special diets, supplements, or nutritional support for at least 8 weeks prior to the Baseline visit.
• Legally authorized representative/caregiver(s) agree(s) not to post any of the participant's personal medical data or information related to the study on any website or social media site (e.g., Facebook, Instagram, X (formerly Twitter), YouTube, TikTok, etc.) from the time of enrollment until they are notified that the study is completed.

Критерии исключения

• Must not have any clinically significant abnormalities in medical history (e.g., major surgery within 3 months of screening), or on physical examination for which treatment with an antisense oligonucleotide (ASO) would be contraindicated or which, in the opinion of the Principal Investigator (PI), could confound the results of this study.
• Known brain or spinal disease that would interfere with the lumbar puncture (LP) procedure, cerebrospinal fluid (CSF) circulation, or presence of other factors would affect the safety of the LP procedure.
• Must not have any other conditions, which, in the opinion of the Investigator, would make the participant unsuitable for inclusion or could interfere with the participant participating in or completing the study.
• Must not have any laboratory abnormalities or any other clinically significant abnormalities that would, as assessed by the Investigator, at screening or Baseline, render a participant unsuitable for inclusion.
• Previous treatment with an oligonucleotide (including small interfering ribonucleic acid (RNA) \[siRNA\], ASOs) gene therapy or gene editing. This exclusion criterion does not apply to approved nucleic acid-based vaccines, including mRNA vaccines, which are allowed.
• Has molecular confirmation of AS due to paternal uniparental disomy, imprinting center defect, or mosaic findings.

Other inclusion/exclusion criteria may apply.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

США · 18 центров

• Cedars-Sinai Medical Center — Los Angeles
• UCLA Clinical & Translational Research Center (CTRC) — Los Angeles
• Rady Children's Hospital — San Diego
• Colorado Children's Hospital Research Institute — Aurora
• Children's National Hospital — Washington D.C.
• Nicklaus Children's Hospital — Miami
• Children's Healthcare of Atlanta — Atlanta
• Rush University Medical Center — Chicago
• … и ещё 10 центров

Австралия · 4 центра

• Queensland Children's Hospital — South Brisbane
• Austin Hospital — Heidelberg
• Perth Children's Hospital — Nedlands
• Sydney Children's Hospital — Randwick

Канада · 4 центра

• London Health Science Centre - Children's Hospital — London
• McGill University Health Centre — Montreal
• University of Alberta Hospital — Edmonton
• British Columbia Children's Hospital — Vancouver

Италия · 4 центра

• Associazione La Nostra Famiglia - IRCCS Eugenio Medea — Conegliano
• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan
• Azienda Ospedaliero Universitaria Pisana — Pisa
• Ospedale Pediatrico Bambino Gesù — Roma

Япония · 2 центра

• Osaka Women's and Children's Hospital — Izumi
• National Center of Neurology and Psychiatry — Kodaira

South Korea · 2 центра

• Seoul National University Hospital — Seoul
• Samsung Medical Center — Seoul

Испания · 2 центра

• Hospital Sant Joan de Deu — Barcelona
• Corporacio Sanitaria Parc Tauli - Hospital de Sabadell — Sabadell

Великобритания · 2 центра

• Great Ormond Street Hospital for Children - NHS Foundation Trust — London
• John Radcliffe Hospital — Oxford

Германия · 1 центр

• Klinikum der Ludwig-Maximilians-Universitaet Muenchen — München

Израиль · 1 центр

• Sheba Medical Center — Ramat Gan

Польша · 1 центр

• Uniwersyteckie Centrum Kliniczne — Gdansk

Сингапур · 1 центр

• KK Women's and Children's Hospital — Singapore

Идентификаторы

NCT: NCT06914609 · ION582-CS2 · 2024-519711-33-00 · U1111-1319-2765

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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