This was a Phase III multi-center, single dose (1.2 x 10\^14 vector genomes), randomized, sham controlled, double-blind study that investigates the efficacy, safety and tolerability of OAV101B in treatment naive, sitting and never ambulatory SMA patients 2 to \<18 years of age.
Eligible participants received a single administration of OAV101B at the dose of 1.2 x 10\^14 vector genomes intrathecally or the sham procedure on Day 1 (Treatment Period 1), and were followed for a period of 52 weeks for Period 1. In Period 2, participants who received the sham treatment in Period 1 were administered OAV101B, and participants who received OAV101B in Period 1 underwent the sham procedure. Participants were followed up for 12 weeks in Period 2. The study consisted of a Screening and Baseline Period followed by two Treatment and Follow-up Periods. Participants were admitted to the hospital on Day 1 (or Day -1 as per local standards of care). After receiving OAV101B or the sham procedure on Day 1, participants underwent in-patient safety monitoring through Day 2 and optionally for Day 3. After Period 1, eligible participants could continue to Period 2 subsequently entering Period 2 in a rolling seamless fashion as participants completed Follow-up Period 1. In Treatment Period 2, eligible participants who received a sham procedure on Study Day 1 of Treatment Period 1 were hospitalized to receive OAV101B on Week 52 + 1 day and participants who received OAV101B on Study Day 1 of Treatment Period 1 were hospitalized to receive a sham procedure on the Week 52 + 1 Day. The total duration of the study including both Period 1 and Period 2 was 64 weeks. At the end of the study, all participants who received OAV101B were eligible to enroll in a long-term follow-up study to monitor long-term safety and efficacy. Approximately 125 participants were planned to be randomized in a 3:2 ratio to receive OAV101B (N= \~75) or a sham procedure (N= \~50). The unequal randomization ratio allowed more participants to receive active treatment in Period 1. It was anticipated that approximately 65 randomized participants would be aged 2 to \<5 years and approximately 60 randomized participants would be aged 5 to \<18 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
126
Gene therapy
The sham procedure will consist of a small needle prick on the lower back at the location where the LP injection is normally made. The needle will break the skin, but no needle insertion for lumbar puncture will occur.
Change From Baseline at the End of Period 1 in the Hammersmith Functional Motor Scale Expanded - Total Score - 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.
Time frame: Baseline, Week 52 (or Week 48)
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
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.
Time frame: Baseline, Week 52 (or Week 48)
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
The RULM is a validated SMA specific assessment of motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. The scale consists of 19 scorable items: 18 items scored on 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). Total scores range from 0-37 points. Higher scores reflect higher level of motor ability.
Time frame: Baseline, Week 52 (or Week 48)
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
The RULM is a validated SMA specific assessment of motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. The scale consists of 19 scorable items: 18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). Total scores range from 0-37 points. Higher scores reflect higher level of motor ability.
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Connecticut Children's Medical Center
Farmington, Connecticut, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Clinic for Special Children
Strasburg, Pennsylvania, United States
St Jude Children's Research Hospital
Memphis, Tennessee, United States
Child Hosp Of The Kings Daughters
Norfolk, Virginia, United States
Children's Specialty Group/CHKD
Norfolk, Virginia, United States
Novartis Investigative Site
Curitiba, Paraná, Brazil
Novartis Investigative Site
São Paulo, São Paulo, Brazil
Novartis Investigative Site
Beijing, Beijing Municipality, China
Novartis Investigative Site
Chongqing, Chongqing Municipality, China
...and 32 more locations
Time frame: Baseline, Week 52 (or Week 48)
% of Participants Who Achieved at Least a 3-point Improvement From Baseline in HFMSE Total Score at the End of Follow-up Period 1 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.
Time frame: Baseline, Week 52 (or Week 48) (end of Period 1)
% of Participants Who Achieved at Least a 3-point Improvement From Baseline in HFMSE Total Score at the End of Follow-up Period 1 for Participants Aged ≥ 2 to < 5 Years
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.
Time frame: Baseline, Week 52 (or Week 48)(end of Period 1)
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. A Treatment Emergent Adverse Event (TEAE) is defined as an event that emerges during treatment, having been absent pretreatment, or worsens relative to the pretreatment state. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments. pt = participant pts = participants
Time frame: Adverse events are reported from the start of treatment period 1 plus 64 weeks, up to a maximum time period of 64 weeks.
Number of Participants With Adverse Events of Special Interest (AESI)
An AESI is primarily defined by using standard Medical Dictionary for Regulatory Activities (MedDRA) queries, and identified as follows: * Hepatotoxicity * Thrombocytopenia * Cardiac adverse events * Signs and symptoms that may be suggestive of dorsal root ganglia toxicity * Thrombotic microangiopathy * New malignancies Adverse events for Periods 1 and 2 are combined in the overall OAV101 arm because the same active treatment (and same single dose) was administered in either Period1 or Period 2. Because this is a gene therapy, which permanently impacts the genetics of the study participant, participants randomized to OAV101 in Period 1 are still considered on treatment with OAV101 in Period 2 (after receiving sham control in Period 2). Therefore, adverse events for the Sham arm can only be considered from Period 1.
Time frame: Adverse events are reported from the start of treatment period 1 plus 64 weeks, up to a maximum time period of 64 weeks.
Number (and Percentage) of Patients With Intracardiac Thrombi
Intracardiac thrombi is defined as the presence of thrombus on post-baseline echocardiograms. Events for Periods 1 and 2 are combined in the overall OAV101 arm because the same active treatment (and same single dose) was administered in either Period1 or Period 2. Because this is a gene therapy, which permanently impacts the genetics of the study participant, participants randomized to OAV101 in Period 1 are still considered on treatment with OAV101 in Period 2 (after receiving sham control in Period 2). Therefore, events for the Sham arm can only be considered from Period 1.
Time frame: Baseline up to 64 weeks
Number(and Percentage) of Patients With Low Cardiac Function
Low cardiac function is defined as left ventricular ejection fraction \<56% or left ventricular fractional shortening \<28% on post-baseline echocardigrams. Events for Periods 1 and 2 are combined in the overall OAV101 arm because the same active treatment (and same single dose) was administered in either Period1 or Period 2. Because this is a gene therapy, which permanently impacts the genetics of the study participant, participants randomized to OAV101 in Period 1 are still considered on treatment with OAV101 in Period 2 (after receiving sham control in Period 2). Therefore, events for the Sham arm can only be considered from Period 1.
Time frame: Baseline up to 64 weeks