Type 2 Spinal Muscular Atrophy
Conditions
Keywords
Zolgensma, OAV101, AVXS 101, gene therapy, Muscle atrophy, SMA, spinal muscular atrophy, muscle function, myopathy, muscle wasting, atrophied muscle, loss of muscle strength, pediatric
Brief summary
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.
Detailed description
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.
Interventions
GENETICOAV101
Gene therapy
PROCEDURESham control
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
A participant will receive a single, one-time dose of OAV101.
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: * Diagnostic confirmation during screening period of 5q SMA * The patient must be treatment naive (historical or current use) for all SMN-targeting therapies (e.g., risdiplam (Evrysdi) and nusinersen (Spinraza)). * 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. Key
Exclusion criteria
* Anti-adeno-associated virus serotype 9 (AAV9) antibody titer reported as elevated (reference to \> 1:50 or validated result consistent with being elevated) at screening as determined by sponsor designated lab. * Infectious process (e.g., viral, bacterial) or febrile illness within 30 days prior to OAV101 treatment or sham procedure * Hepatic dysfunction (i.e. alanine aminotransferase (ALT), total bilirubin, gamma-glutamyl transferase (GGT) or glutamate dehydrogenase (GLDH), \> upper limit of normal (ULN). * Requiring invasive ventilation, awake noninvasive ventilation for \> 6 hours during a 24-hour period, noninvasive ventilation for \> 12 hours during a 24-hour period or requiring tracheostomy * Complications at screening that would interfere with motor efficacy assessments including but not limited to, severe contractures or Cobb angle \> 40 in a sitting position * Surgery for scoliosis or hip fixation in the 12 months prior to Screening or planned within the next 64 weeks * Clinically significant sensory abnormalities in the neurological examination at Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, Week 52 (or Week 48) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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, Week 52 (or Week 48) | 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. |
| 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, Week 52 (or Week 48) | 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. |
| % 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 | Baseline, Week 52 (or Week 48) (end of Period 1) | 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. |
| % 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 | Baseline, Week 52 (or Week 48)(end of Period 1) | 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. |
| 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, Week 52 (or Week 48) | 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. |
| Number of Participants With Adverse Events of Special Interest (AESI) | Adverse events are reported from the start of treatment period 1 plus 64 weeks, up to a maximum time period of 64 weeks. | 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. |
| Number (and Percentage) of Patients With Intracardiac Thrombi | Baseline up to 64 weeks | 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. |
| Number(and Percentage) of Patients With Low Cardiac Function | Baseline up to 64 weeks | 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. |
| Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Adverse events are reported from the start of treatment period 1 plus 64 weeks, up to a maximum time period of 64 weeks. | 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 |
Countries
Brazil, China, Denmark, India, Malaysia, Mexico, Saudi Arabia, Singapore, South Africa, Taiwan, Thailand, United States, Vietnam
Participant flow
Pre-assignment details
121 total participants were treated with a single dose of OAV101B (either in Period 1 (even if they did not complete Period 1) or Period 2).
Participants by arm
| Arm | Count |
|---|---|
| OAV101 First, Then Sham Control OAV101 administered as a single, one-time intrathecal dose of 1.2 x 10\^14 vector genomes (vg) in Period 1, then a skin prick in the lumbar region without any medication in Period 2 | 75 |
| Sham Control First, Then OAV101 A skin prick in the lumbar region without any medication in Period 1, then OAV101 administered as a single, one-time intrathecal dose of 1.2 x 10\^14 vector genomes (vg) in Period 2 | 51 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 - First Intervention (52 weeks) | Adverse Event | 0 | 1 |
| Period 1 - First Intervention (52 weeks) | Guardian decision | 1 | 0 |
| Period 1 - First Intervention (52 weeks) | Physician Decision | 1 | 0 |
| Period 1 - First Intervention (52 weeks) | Protocol-specified withdrawal criterion met | 6 | 4 |
Baseline characteristics
| Characteristic | Sham Control First, Then OAV101 | OAV101 First, Then Sham Control | Total |
|---|---|---|---|
| Age, Continuous | 5.68 years STANDARD_DEVIATION 3.045 | 5.71 years STANDARD_DEVIATION 3.575 | 5.70 years STANDARD_DEVIATION 3.358 |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 49 Participants | 74 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 23 Participants | 41 Participants | 64 Participants |
| Sex: Female, Male Male | 28 Participants | 34 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 51 | 0 / 121 |
| other Total, other adverse events | 63 / 75 | 43 / 51 | 85 / 121 |
| serious Total, serious adverse events | 21 / 75 | 17 / 51 | 34 / 121 |
Outcome results
Primary
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)
Population: Full Analysis Set - all participants who were treated in treatment period 1 with a valid measurement (including 1 pt who dropped out between Week 48 and week 52; The data collected at Week 48 are included in this table.) (Participants who early terminated before Week 48 are not included).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OAV101 First, Then Sham Control | 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 | 2.39 Scores on a scale | Standard Error 0.439 |
| Sham Control First, Then OAV101 | 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 | 0.51 Scores on a scale | Standard Error 0.532 |
Comparison: Change from baseline at End of Follow-up Period 1p-value: 0.007495% CI: [0.51, 3.25]Mixed Models Analysis
Secondary
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)
Population: Full Analysis Set - all participants who were treated in treatment period 1 with a valid measurement in the 2 to \<5 years age group. (Participants who early terminated before Week 48 are not included.)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OAV101 First, Then Sham Control | 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 | 3.00 Scores on a scale | Standard Error 0.569 |
| Sham Control First, Then OAV101 | 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 | 1.56 Scores on a scale | Standard Error 0.683 |
Comparison: Change from baseline at End of Follow-up Period 1p-value: 0.109795% CI: [-0.33, 3.22]Mixed Models Analysis
Secondary
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)
Population: Full Analysis Set - all participants who were treated in treatment period 1 with a valid measurement (including 1 pt who dropped out between Week 48 and week 52; The data collected at Week 48 are included in this table.) (Participants who early terminated before Week 48 are not included).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OAV101 First, Then Sham Control | 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 | 2.44 Scores on a scale | Standard Error 0.381 |
| Sham Control First, Then OAV101 | 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 | 0.92 Scores on a scale | Standard Error 0.462 |
Comparison: Change from baseline at End of Follow-up Period 1p-value: 0.012295% CI: [0.34, 2.71]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 52 (or Week 48)
Population: Full Analysis Set - all participants who were treated in treatment period 1 with a valid measurement in the 2 to \<5 years age group. (Participants who early terminated before Week 48 are not included.)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OAV101 First, Then Sham Control | 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 | 3.27 Scores on a scale | Standard Error 0.535 |
| Sham Control First, Then OAV101 | 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 | 1.82 Scores on a scale | Standard Error 0.642 |
Comparison: Change from baseline at End of Follow-up Period 1p-value: 0.087395% CI: [-0.22, 3.12]Mixed Models Analysis
Secondary
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
Population: Safety analysis set - all treated participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OAV101 First, Then Sham Control | Number (and Percentage) of Patients With Intracardiac Thrombi | 0 Participants |
| Sham Control First, Then OAV101 | Number (and Percentage) of Patients With Intracardiac Thrombi | 1 Participants |
| Overall OAV101 in Periods 1 and 2 | Number (and Percentage) of Patients With Intracardiac Thrombi | 1 Participants |
Secondary
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
Population: Safety analysis set - all treated participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OAV101 First, Then Sham Control | Number(and Percentage) of Patients With Low Cardiac Function | 8 Participants |
| Sham Control First, Then OAV101 | Number(and Percentage) of Patients With Low Cardiac Function | 9 Participants |
| Overall OAV101 in Periods 1 and 2 | Number(and Percentage) of Patients With Low Cardiac Function | 17 Participants |
Secondary
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.
Population: Safety analysis set - all treated participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OAV101 First, Then Sham Control | Number of Participants With Adverse Events of Special Interest (AESI) | Hepatotoxicity | 7 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Adverse Events of Special Interest (AESI) | Transient thrombocytopenia | 4 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Adverse Events of Special Interest (AESI) | Cardiac adverse events | 0 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Adverse Events of Special Interest (AESI) | Signs and symptoms that may be suggestive of dorsal root ganglia toxicity | 2 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Adverse Events of Special Interest (AESI) | Thrombotic microangiopathy | 0 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Adverse Events of Special Interest (AESI) | New malignancies | 0 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Adverse Events of Special Interest (AESI) | New malignancies | 0 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Adverse Events of Special Interest (AESI) | Hepatotoxicity | 5 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Adverse Events of Special Interest (AESI) | Signs and symptoms that may be suggestive of dorsal root ganglia toxicity | 1 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Adverse Events of Special Interest (AESI) | Thrombotic microangiopathy | 0 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Adverse Events of Special Interest (AESI) | Transient thrombocytopenia | 2 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Adverse Events of Special Interest (AESI) | Cardiac adverse events | 0 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Adverse Events of Special Interest (AESI) | Transient thrombocytopenia | 9 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Adverse Events of Special Interest (AESI) | Cardiac adverse events | 0 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Adverse Events of Special Interest (AESI) | New malignancies | 0 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Adverse Events of Special Interest (AESI) | Signs and symptoms that may be suggestive of dorsal root ganglia toxicity | 3 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Adverse Events of Special Interest (AESI) | Hepatotoxicity | 10 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Adverse Events of Special Interest (AESI) | Thrombotic microangiopathy | 0 Participants |
Secondary
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.
Population: Safety analysis set - all treated pts.~AEs 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 2. Because this is a gene therapy, which permanently impacts the genetics of the study pt, pts randomized to OAV101 in Period 1 are still considered on treatment with OAV101 in Period 2 (after receiving sham control in Period 2). Therefore, AEs for the Sham arm can only be considered from Period 1.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event | 74 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event related to study treatment | 27 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any serious treatment-emergent adverse event | 21 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any serious treatment-emergent adverse event related to study treatment | 8 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any severe treatment-emergent adverse event | 8 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event leading to study discontinuation | 0 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event leading to death | 0 Participants |
| OAV101 First, Then Sham Control | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event of special interest | 12 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any serious treatment-emergent adverse event | 17 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event leading to death | 0 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any serious treatment-emergent adverse event related to study treatment | 1 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any severe treatment-emergent adverse event | 9 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event leading to study discontinuation | 1 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event | 46 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event related to study treatment | 5 Participants |
| Sham Control First, Then OAV101 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event of special interest | 7 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any serious treatment-emergent adverse event | 34 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event related to study treatment | 36 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event | 104 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any serious treatment-emergent adverse event related to study treatment | 12 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event leading to death | 0 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event leading to study discontinuation | 0 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any severe treatment-emergent adverse event | 12 Participants |
| Overall OAV101 in Periods 1 and 2 | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | Any treatment-emergent adverse event of special interest | 21 Participants |
Secondary
% 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)
Population: Full Analysis Set - all participants who were treated in treatment period 1 with a valid measurement in the 2 to \<5 years age group. (Participants who early terminated before Week 48 are not included.)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OAV101 First, Then Sham Control | % 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 | 48.8 % of participants |
| Sham Control First, Then OAV101 | % 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 | 37.9 % of participants |
Comparison: End of Followup Period 1 (Week 52)p-value: 0.644895% CI: [0.46, 3.56]Regression, Logistic
Secondary
% 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)
Population: Full Analysis Set - all participants who were treated in treatment period 1 with a valid measurement (including 1 pt who dropped out between Week 48 and week 52; The data collected at Week 48 are included in this table.) (Participants who early terminated before Week 48 are not included).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OAV101 First, Then Sham Control | % 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 | 39.2 % of participants |
| Sham Control First, Then OAV101 | % 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 | 26.0 % of participants |
Comparison: End of Followup Period 1 (Week 52)p-value: 0.087995% CI: [0.9, 4.57]Regression, Logistic