REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome
Purpose
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.
Condition
- Angelman Syndrome
Eligibility
- Eligible Ages
- Between 2 Years and 50 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- 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 clinical diagnosis of Angelman syndrome (AS) with molecular confirmation of 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, X (formerly Twitter), YouTube, TikTok, etc.) from the time of enrollment until they are notified that the study is completed.
Exclusion Criteria
- 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) gene therapy or gene editing. This exclusion criterion does not apply to approved nucleic acid-based vaccines, including mRNA vaccines, which are allowed. 6. Has molecular confirmation of AS due to paternal uniparental disomy, imprinting center defect, or mosaic findings. Other inclusion/exclusion criteria may apply.
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Cohort 1 ION582 80 mg |
Participants (aged 2 to <18 years old) will be administered ION582 80 mg via IT injection Q12W during the double blind and LTE treatment periods. |
|
|
Placebo Comparator Cohort 1 Placebo |
Participants (aged 2 to <18 years old) will be administered ION582 matching placebo via IT injection Q12W during the double-blind treatment period and then administered ION582 40 mg or 80 mg Q12W during the LTE treatment period. |
|
|
Experimental Cohort 2 ION582 80 mg |
Participants (aged 18 to ≤50 years old) will be administered ION582 80 mg via IT injection Q12W during the double blind and LTE treatment periods. |
|
|
Placebo Comparator Cohort 2 Placebo |
Participants (aged 18 to ≤50 years old) will be administered ION582 matching placebo via IT injection Q12W during the double-blind treatment period and then randomized to ION582 40 mg or 80 mg Q12W during the LTE treatment period. |
|
Recruiting Locations
Los Angeles 5368361, California 5332921 90048
San Diego 5391811, California 5332921 92123
Aurora 5412347, Colorado 5417618 80045
Washington D.C. 4140963, District of Columbia 4138106 20011
Miami 4164138, Florida 4155751 33155
Chicago 4887398, Illinois 4896861 60612
Boston 4930956, Massachusetts 6254926 02115
Kansas City 4393217, Missouri 4398678 64108
New York 5128581, New York 5128638 10029
Carrboro 4459343, North Carolina 4482348 27510
Columbus 4509177, Ohio 5165418 43205
Philadelphia 4560349, Pennsylvania 6254927 19104
More Details
- NCT ID
- NCT06914609
- Status
- Recruiting
- Sponsor
- Ionis Pharmaceuticals, Inc.
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 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.