Clinical trial NCT06914609: REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome
Official title: Phase 3 Study of the Efficacy and Safety of ION582 in Children and Adults With Angelman Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Angelman Syndrome
Keywords: ION582
Angelman Syndrome
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2025-04-06
Enrollment: 210
Sex: ALL
Minimum age (years): 2
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 1:1:1 to 40 mg ION582, 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.

Eligibility criteria: Key Inclusion Criteria:

1. 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.
2. Medically stable and can undergo sedation and/or general anesthesia without intubation.
3. 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.
4. Participant has a documented diagnosis of Angelman syndrome (AS) due to either Ubiquitin-protein ligase E3A (UBE3A) deletion or UBE3A mutation.
5. 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.
6. 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, Twitter, YouTube, TikTok, etc.) from the time of enrollment until they are notified that the study is completed.

Key Exclusion Criteria:

1. 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.
2. 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.
3. 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.
4. 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.
5. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid (RNA) \[siRNA\], ASOs) or gene therapy. This exclusion criterion does not apply to coronavirus disease 2019 (COVID-19) vaccinations, which are allowed.
6. Has documented molecular AS confirmation of paternal uniparental disomy or imprinting center defect.

Other inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Change in Performance on the Expressive Communication Subdomain Raw Score of the Bayley Scales for Infant and Toddler Development-4 (Bayley-4) in Cohort 1
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Cognition Subdomain Raw Score
timeFrame: Baseline and Week 52
measure: Change in Symptoms of Angelman Syndrome -Clinician Global Impression of Change (SAS-CGI-C): Overall AS
timeFrame: Baseline and Week 52
measure: Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Receptive Communication Subdomain Raw Score
timeFrame: Baseline and Week 52
measure: Change in Vineland Adaptive Behavior Scale-3 (Vineland-3): Daily Living Skills, Personal Subdomain Raw Score
timeFrame: Baseline and Week 52
measure: Change in Symptoms of Angelman Syndrome - Clinician Global Impression of Change (SAS-CGI-C): Sleep Problems
timeFrame: Baseline and Week 52
measure: Change in Bayley Scales for Infant and Toddler Development-4 (Bayley-4): Fine Motor Subdomain Raw Score
timeFrame: Baseline to Week 52
measure: Change in Observer-Reported Communication Ability (ORCA): Overall T score
timeFrame: Baseline and Week 52
measure: Percentage of Participants with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 52
measure: Change in Vital Signs and Clinical Laboratory Results
timeFrame: Baseline and Week 52
Other outcomes:
Locations:
city: Carrboro
country: United States
facility: University of North Carolina at Chapel Hill School of Medicine
state: North Carolina
Study officials:
References: