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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
74
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.
UCLA Neuropsychiatric Institute
Los Angeles, California, United States
Rady Children's Hospital - San Diego
San Diego, California, United States
Rush Medical Center
Chicago, Illinois, United States
Mayo Clinic - Rochester
Rochester, Minnesota, United States
Columbia University Medical Center
New York, New York, United States
Carolina Institute for Development DisabilitiesUniversity of North Carolina/School of Medicine
Carrboro, North Carolina, United States
Baylor College of Med
Houston, Texas, United States
Ospedale Pediatrico Bambino Gesù
Rome, Lazio, Italy
Erasmus MC / location Sophia Kinderziekenhuis
Rotterdam, Netherlands
Hospital Sant Joan De Deu
Esplugues de Llobregas, Barcelona, Spain
...and 2 more locations
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline to last visit or early withdrawal
Time to Maximum Concentration (Tmax) for RO7248824
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.
Time frame: Baseline to last visit or early withdrawal
Maximum Plasma Concentration Observed (Cmax) for RO7248824
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.
Time frame: 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
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.
Time frame: Baseline to last visit or early withdrawal
AUC From Time 0 to Infinity (AUCinf) for RO7248824
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.
Time frame: Baseline to last visit or early withdrawal
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