A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of RO7248824 in Participants With Angelman Syndrome (AS)
An Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of RO7248824 in Participants With Angelman Syndrome
3 other identifiers
interventional
74
4 countries
12
Brief Summary
This is a phase I, multicenter, non-randomized, adaptive, open-label, multiple ascending, intra-participant, dose-escalation study with a long-term extension (LTE) part and an optional open-label extension (OOE) part. The objective of the study is to investigate the safety, tolerability, PK and PD of RO7248824 administered intrathecally (IT) in participants with AS. Two linked sets of dose escalation cohorts are planned based on two different age groups, namely participants with AS aged ≥ 5 to ≤ 12 years in cohorts A1 to A5 (with at least 2 participants ≤ 8 years old in each cohort) and AS participants aged ≥ 1 to ≤ 4 years in cohorts B1 to B5. The two sets of cohorts will be run in parallel, with each cohort A1 to A5 preceding and gating the linked cohort B1 to B5 (e.g., A1 precedes B1).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Aug 2020
Longer than P75 for phase_1
12 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 9, 2020
CompletedFirst Posted
Study publicly available on registry
June 11, 2020
CompletedStudy Start
First participant enrolled
August 19, 2020
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 31, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
July 31, 2025
CompletedAugust 24, 2025
August 1, 2025
5 years
June 9, 2020
August 22, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (11)
Frequency and Severity of Adverse Events (AEs)
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal. OOE part: From baseline OOE visit to final OOE visit (Day 420) or early termination.
Baseline to last visit or early withdrawal
Frequency and Severity of Serious Adverse Events (SAEs)
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal. OOE part: From baseline OOE visit to final OOE visit (Day 420) or early termination.
Baseline to last visit or early withdrawal
Number of Participants Discontinued Treatment due to AEs
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal. OOE part: From baseline OOE visit to final OOE visit (Day 420) or early termination.
Baseline to last visit or early withdrawal
Frequency of Abnormal Laboratory Findings (Blood, Cerebrospinal Fluid [CSF] and Urinalysis)
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal. OOE part: From baseline OOE visit to final OOE visit (Day 420) or early termination.
Baseline to last visit or early withdrawal
Frequency of Abnormal Vital Signs
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal.
Baseline to last visit or early withdrawal
Frequency of Abnormal Electrocardiography (ECG) Values
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal.
Baseline to last visit or early withdrawal
Mean Changes From Baseline in Temperature Over Time
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal.
Baseline to last visit or early withdrawal
Mean Changes From Baseline in Systolic Blood Pressure Over Time
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal.
Baseline to last visit or early withdrawal
Mean Changes From Baseline in Diastolic Blood Pressure Over Time
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal.
Baseline to last visit or early withdrawal
Mean Changes From Baseline in Heartrate Over Time
MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal.
Baseline to last visit or early withdrawal
Mean Changes From Baseline in Respiratory Rate Over Time
MAD part: From the baseline MAD visit to the final MAD visit (Day 365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (Day 1092) or early withdrawal.
Baseline to last visit or early withdrawal
Secondary Outcomes (4)
Time to Maximum Concentration (Tmax) for RO7248824
Baseline to last visit or early withdrawal
Maximum Plasma Concentration Observed (Cmax) for RO7248824
Baseline to last visit or early withdrawal
Area Under Curve (AUC) From Time 0 to Time of Last Sampling Point or Last Quantifiable Sample, Whichever Comes First (AUC last) for RO7248824
Baseline to last visit or early withdrawal
AUC From Time 0 to Infinity (AUCinf) for RO7248824
Baseline to last visit or early withdrawal
Study Arms (19)
Cohort A1 RO7248824
EXPERIMENTALParticipants 5-12 years
Cohort A2 RO7248824
EXPERIMENTALParticipants 5-12 years
Cohort A3 RO7248824
EXPERIMENTALParticipants 5-12 years
Cohort A4 RO7248824
EXPERIMENTALParticipants 5-12 years
Cohort A5 RO7248824
EXPERIMENTALParticipants 5-12 years
Cohort B1 RO7248824
EXPERIMENTALParticipants 1-4 years
Cohort B2 RO7248824
EXPERIMENTALParticipants 1-4 years
Cohort B3 RO7248824
EXPERIMENTALParticipants 1-4 years
Cohort B4 RO7248824
EXPERIMENTALParticipants 1-4 years
Cohort B5 RO7248824
EXPERIMENTALParticipants 1-4 years
LTE: Cohort EA1 RO7248824
EXPERIMENTALNew participants (age 5-12) enrolling directly in the LTE part
LTE: Cohort EA2 RO7248824
EXPERIMENTALParticipants continuing from multiple ascending dose (MAD) cohorts A1 and A2
LTE: Cohort EA3 RO7248824
EXPERIMENTALParticipants continuing from MAD cohorts A3 and A4
LTE: Cohort EA4 RO7248824
EXPERIMENTALParticipants continuing from MAD Cohort A5
LTE: Cohort EB1 RO7248824
EXPERIMENTALNew participants (age 1-4) enrolling directly into the LTE
LTE: Cohort EB2 RO7248824
EXPERIMENTALParticipants continuing from MAD cohorts B1 and B2
LTE: Cohort EB3 RO7248824
EXPERIMENTALParticipants continuing from MAD cohorts B3 and B4
LTE: Cohort EB4 RO7248824
EXPERIMENTALParticipants continuing from MAD Cohort B5
OOE: RO7248824
EXPERIMENTALParticipants in the LTE part of the study will be given the opportunity to participate in the OOE part.
Interventions
In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.
Eligibility Criteria
You may qualify if:
- The participant has a parent, caregiver or legal representative (hereinafter "caregiver") who is reliable, competent and at least 18 years of age. The caregiver is willing and able to accompany the participant to clinic visits and to be available to the Investigational Site by phone or email if needed and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of participant's ongoing condition to respond to any inquiries about the participant from personnel from the Study Site.
- A caregiver must be able to consent for the participant according to International Council on Harmonisation (ICH) and local regulations.
- Ability to comply with all study requirements.
- Have adequate supportive psychosocial circumstances.
- Able to tolerate blood draws.
- Able to undergo lumbar puncture (LP) and IT injection, under sedation or anesthesia if needed and as determined appropriate by the Investigator.
- Stable medical status for at least 4 weeks prior to Screening and at the time of enrollment.
- Body weight of ≥ 7 kg
- Participant must be ≥ 1 to ≤ 12 years of age at the time of signing of the informed consent by the caregiver.
- Clinical diagnosis of AS confirmed by a molecular diagnosis with genotypic classification of either Ubiquitin-protein ligase E3A (UBE3A) mutation of the maternal allele or deletion on the maternally inherited chromosome 15q11q13 that includes the UBE3A gene and is less than 7 megabyte (Mb) in size.
- Reproductive Status:
- Some of the provisions that follow may have limited applicability based on the age range of study participants (i.e., up to the age of 12) and the nature of the disease understudy. These provisions are nonetheless included for purposes of completeness in order:
- A) Female Participants
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- Women of non-childbearing potential.
- +6 more criteria
You may not qualify if:
- Diagnostic Assessments
- Clinically-significant laboratory, vital sign or electrocardiography (ECG) abnormalities at Screening
- Type of Participants and Disease Characteristics
- Molecular diagnosis of AS with genotypic classification: Paternal Uniparental Disomy (UPD) of 15q11-13; UBE3A Imprinting center defect (ID); A partial molecular diagnosis of AS, that cannot exclude (UPD)or ID despite appropriate genetic testing.
- Clinically relevant hematological, hepatic, cardiac or renal disease or event, in the judgement of the Investigator.
- Any concomitant condition that might interfere with the clinical evaluation of AS and that is not related to AS.
- Known history of human immunodeficiency virus (HIV) or hepatitis B virus (HBV) or hepatitis C virus (HCV).
- Any condition that increases risk of meningitis.
- History of bleeding diathesis or coagulopathy.
- A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment
- History of clinically significant post-lumbar-puncture headache of moderate or severe intensity and/or blood patch
- Malignancy within 5 years of Screening
- Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
- Premature birth with gestational age at birth below 34 weeks.
- History of hypersensitivity to the investigational medicinal product (IMP), antisense oligonucleotides, or any excipients.
- +9 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (12)
UCLA Neuropsychiatric Institute
Los Angeles, California, 90024, United States
Rady Children's Hospital - San Diego
San Diego, California, 92123, United States
Rush Medical Center
Chicago, Illinois, 60612, United States
Mayo Clinic - Rochester
Rochester, Minnesota, 55905, United States
Columbia University Medical Center
New York, New York, 10032, United States
Carolina Institute for Development DisabilitiesUniversity of North Carolina/School of Medicine
Carrboro, North Carolina, 27510, United States
Baylor College of Med
Houston, Texas, 77030, United States
Ospedale Pediatrico Bambino Gesù
Rome, Lazio, 00165, Italy
Erasmus MC / location Sophia Kinderziekenhuis
Rotterdam, 3015 GJ, Netherlands
Hospital Sant Joan De Deu
Esplugues de Llobregas, Barcelona, 08950, Spain
Corporacio Sanitaria Parc Tauli
Sabadell, Barcelona, 08208, Spain
Hospital Universitario Virgen del Rocío
Seville, 41013, Spain
Related Publications (1)
Hipp JF, Bacino CA, Bird LM, Bruenig-Traebert I, Chan D, de Wit MC, Fontoura P, Hooper G, Jagasia R, Krishnan ML, Murtagh L, Noci A, Martinez AR, Schwab D, Serrano M, Shen MD, Tillmann J, Tjeertes J, Vincenzi B, Berry-Kravis E, Bonni A; Rugonersen Study Group; all TANGELO investigators. The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial. Nat Med. 2025 Sep;31(9):2936-2945. doi: 10.1038/s41591-025-03784-7. Epub 2025 Jul 11.
PMID: 40646322DERIVED
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Study Officials
- STUDY DIRECTOR
Clinical Trials
Hoffmann-La Roche
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 9, 2020
First Posted
June 11, 2020
Study Start
August 19, 2020
Primary Completion
July 31, 2025
Study Completion
July 31, 2025
Last Updated
August 24, 2025
Record last verified: 2025-08
Data Sharing
- IPD Sharing
- Will share
Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm).