start date: December 21, 2021
estimated completion: October 4, 2024
last updated: October 25, 2021
phase of development:
Phase 3
size / enrollment: 125
study description: This is a multi-center, randomized, sham-controlled, double-blind study to investigate the safety, tolerability, and efficacy of IT OAV101 in SMA participants, sitting and never ambulatory. The study will enroll treatment naive Type 2 SMA participants who are ≥ 2 years to < 18 years who harbor biallelic SMN1 pathogenic variants in SMN1 and 2-4 copies of SMN2. The study consists of a Screening and a Baseline Period followed by a Treatment Period 1 and Follow-up Period 1 (total of 52 weeks) and a Treatment and Follow-up Period 2 (total of 12 weeks). The total trial duration period is 64 weeks.
The study will include a standard screening period that will last 45 to 60 days, during which eligibility will be assessed and baseline assessments will be performed prior to treatment. Participants who meet eligibility criteria at screening and baseline visits will be randomized in a 3:2 ratio to receive OAV101 by lumbar intrathecal injection or to receive a sham procedure.
Treatment Period 1 consists of OAV101/sham administration with in-patient hospitalization on Study Day 1, Day 2 and Day 3 (optional). Treatment Period 1 is followed by a 52-week out-patient Follow-Up Period 1 for safety and efficacy assessments .
At the time point each participant completes Follow-up Period 1, those who are eligible will subsequently enter into Treatment Period 2. Entry into Treatment Period 2 will occur immediately after each participant completes their participation in Follow-up Period 1. In Treatment Period 2, eligible participants who received a sham procedure on Study Day 1 of Treatment Period 1 will be hospitalized to receive OAV101 and participants who received OAV101 on Study Day 1 of Treatment Period 1 will be hospitalized to receive a sham procedure on Week 52 +1 Day. A sham procedure is a skin prick in the lumbar region without any medication. In-patient observation will continue on Week 52 +2 Days and Week 52 +3 Days (optional). Treatment Period 2 is followed by a 12-week follow-up period for safety and efficacy assessments. Blinding is maintained for all patients during both Treatment Period 1 and 2. At the end of the study all participants will be eligible to enroll in a long-term follow-up study (15 years) to monitor long-term safety and efficacy.
During the study, participants will complete visits as defined in the Schedule of Assessments. Prednisolone treatment will be given per study protocol.
Safety monitoring will be performed as per study schedule and protocol requirements. Safety for the participants enrolled in the study will be evaluated by a designated group of unblinded study team members together with the Data Monitoring (DMC) as described in the charter.
The primary analysis will be performed after all participants have completed Week 52 or discontinued prior to Week 52. A final analysis will be performed after all participants have completed Week 52 (or discontinued prior to Week 64).
primary outcomes:
- Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 18 years age group
The HFMSE is a validated SMA specific assessment devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE contains 33 items rated from 0 (unable to perform) to 2 (performs without modification/adaptation/compensation). Total scores range from 0-66. Higher scores indicate higher levels of motor ability.
- Baseline up to 52 weeks
secondary outcomes:
- Change from baseline in HFMSE total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 5 years age group
Baseline up to 52 weeks
- Change from baseline in Revised Upper Limb Module (RULM) total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 18 years age group
Baseline up to 52 weeks
- Change from baseline in the RULM total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 5 years age group
Baseline up to 52 weeks
- Number of participants with treatment emergent Adverse Events and Serious Adverse Events
Baseline up to 52 weeks
inclusion criteria:
• Eligible Ages: 2 - 17
• Eligible Sexes: all
Inclusion criteria:
Diagnostic confirmation during screening period of spinal muscular atrophy (SMA) caused by biallelic pathogenic variants affecting survival motor neuron 1 (SMN1) and 2-4 copies of survival motor neuron 2 (SMN2)
Naive to survival motor neuron (SMN) dependent treatments (e.g., risdiplam and nusinersen).
Onset of clinical signs and symptoms at ≥ 6 months of age
A complete Hammersmith Functional Motor Scale - Expanded (HFMSE) assessment during the screening period for trial eligibility
Able to sit independently at screening, but has never had the ability to walk independently.
exclusion criteria: criteria:
Anti-adeno-associated virus serotype 9 (AAV9) antibody titers > 1:50 at screening as determined by sponsor designated central lab. NOTE: A negative anti-AAV9 antibody titer is defined as ≤ 1:50.
Infectious process (e.g. viral, bacterial) or febrile illness within two weeks prior to start of screening, and up to OAV101 treatment or sham procedure
Hepatic dysfunction (i.e., aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, gamma-glutamyl transferase (GGT) or glutamate dehydrogenase (GLDH), > upper limit of normal (ULN).
Requiring invasive ventilatory support, or awake noninvasive ventilatory support for > 6 hours during a 24-hour period, or noninvasive ventilatory support for > 12 hours during a 24-hour period.
Complications at screening, as determined by the Investigator, that would impact the participant's ability to perform the motor efficacy assessments.
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