An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy

Phase 2

Completed

• Conditions: Spinal Muscular Atrophy; Spinal Muscular Atrophy Type 2; Neuromuscular Diseases; Muscular Atrophy; SMA; Spinal Muscular Atrophy Type 3; Atrophy; Muscular Atrophy, Spinal; Neuromuscular Manifestations
• Interventions: Biological: SRK-015

• Registration Number: NCT03921528
• Lead Sponsor: Scholar Rock, Inc.

Brief Summary

The TOPAZ study will assess the safety and efficacy of SRK-015 in later-onset Spinal Muscular Atrophy (SMA Type 2 and Type 3) in pediatric and adult patients.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-04-16
• Study First Submitted QC: 2019-04-16
• Study First Posted: 2019-04-19
• Study Start: 2019-04-22
• Primary Completion: 2021-01-19
• Results First Submitted: 2022-01-19
• Results First Submitted QC: 2022-10-24
• Results First Posted: 2022-11-17
• Study Completion: 2024-02-28
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-25
• Last Update Posted: 2024-12-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

• Age 5 through 21 years old at the time of screening for Cohorts 1 and 2; Age ≥2 years old at the time of screening for Cohort 3.

• Documented diagnosis of 5q SMA.

• Diagnosed as later-onset (e.g., Type 2 or Type 3) SMA prior to receiving any treatment with therapy approved for SMA.

• Non-ambulatory patients must be able to sit independently (sits up straight with head erect for at least 10 seconds; does not use arms or hands to balance body or support position) per World Health Organization (WHO) motor milestones definition at screening.

• Ambulatory patients must have the ability to independently ambulate without aids or orthotics over 10 meters in 30 seconds or less at screening.

• Receiving the same background SMA therapy (e.g., on an approved survival motor neuron (SMN) upregulator therapy such as nusinersen, or not on any SMA therapy) for at least 6 months prior to screening and anticipated to remain on that therapy throughout the duration of the study.

  • If receiving the SMN upregulator therapy nusinersen, must have completed the loading regimen and initiated maintenance dosing (i.e., completed at least one maintenance dose) with at least 4 weeks after the first maintenance dose having elapsed prior to screening.

• Nutritional status stable over the past 6 months and anticipated to be stable throughout the duration of the study.

• Have no physical limitations that would prevent the patient from undergoing motor function outcome measures throughout the duration of the study.

• Able to receive study drug infusions and provide blood samples through the use of a peripheral intravenous (IV) or a long-term IV access device that the patient has placed for reasons independent from the study throughout the duration of the study.

• Able to adhere to the requirements of the protocol, including travel to the study center and completing all study procedures and study visits.

• For patients who are expected to have reached reproductive maturity by the end of the study, adhere to study specific contraception requirements.

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Exclusion Criteria

• Use of tracheostomy with positive pressure.
• Use of chronic daytime non-invasive ventilatory support for >16 hours daily in the 2 weeks prior to dosing, or anticipated to regularly receive such daytime ventilator support chronically over the duration of the study.
• Any acute or co-morbid condition interfering with the well-being of the patient within 14 days of screening, including active systemic infection, the need for acute treatment or inpatient observation due to any reason.
• Severe scoliosis and/or contractures at screening. Based on clinical judgement, any scoliosis or contractures present must be stable over the past 6 months, anticipated to be stable for the duration of the study and not prevent the patient from being evaluated on any functional outcome measures throughout the duration of the study.
• Pregnant or breastfeeding.
• Major orthopedic or other interventional procedure, including spine or hip surgery, considered to have the potential to substantially limit the ability of the patient to be evaluated on any functional outcome measures, within 6 months prior to screening, or anticipated for the duration of the study.
• Prior history of a hypersensitivity reaction to a monoclonal antibody (mAb) or recombinant protein bearing an Fc domain (such as a soluble receptor- Fc fusion protein).
• Use of systemic corticosteroids within 60 days prior to screening. Inhaled or topical steroids are allowed.
• Treatment with investigational drugs within 3 months prior to screening.
• Use of therapies with potentially significant muscle effects (such as androgens, insulin-like growth factor, growth hormone, systemic betaagonist, botulinum toxin, or muscle relaxants) or muscle-enhancing supplements within 60 days prior to screening.
• Patient has any other condition, which in the opinion of the Investigator may compromise safety or compliance, would preclude the patient from successful completion of the study, or interfere with the interpretation of the results.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	SRK-015	Ambulatory Type 3 SMA
Cohort 2	SRK-015	Type 2 SMA / Non-Ambulatory Type 3 SMA
Cohort 3	SRK-015	Type 2 SMA

Primary Outcome Measures

Name	Time	Method
Cohort 1: Change From Baseline in the Revised Hammersmith Scale (RHS) Total Score at Day 364 (Visit 15) [Month 12]	Baseline up to 12 months	The Revised Hammersmith Scale (RHS) is a 36 item clinical assessment of physical abilities in patients with Type 2 SMA and ambulatory or nonambulatory patients with Type 3 SMA. For the ambulatory Type 3 patients 5-21 years of age in Cohort 1 (N=23), the primary endpoint was the change from baseline in RHS total score at month 12. The RHS has a minimum achievable score of 0 and a maximum achievable score of 69. The RHS includes 33 items that are graded on a scale of 0, 1, 2, where 0 denotes the lowest level and 2 denotes the highest level of ability/function. The remaining 3 items are scored 0 or 1, where 0 denotes an inability and 1 denotes an ability to achieve. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
Cohort 2 and Cohort 3: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Total Score at Day 364 (Visit 15) [Month 12]	Baseline up to 12 months	Cohort 2: For the nonambulatory Type 2 and Type 3 patients 5-21 years of age in Cohort 2 (N=15), the primary efficacy endpoint was the change from baseline in HFMSE total score at month 12.; Cohort 3: For the nonambulatory Type 2 patients ≥2 years of age in Cohort 3 (N=20), the primary efficacy endpoint was the change from baseline in HFMSE total score at month 12.; The Hammersmith Functional Motor Scale Expanded (HFMSE) assesses the physical abilities of patients with Type 2 and Type 3 SMA comprises 33 items graded on a scale of 0, 1, or 2, where 0 denotes unable, 1 denotes performed with modification or adaptation, and 2 denotes performed without modification or adaptation.

Secondary Outcome Measures

Name	Time	Method
Cohort 1:Change From Baseline in the Revised Hammersmith Scale (RHS) Total Score at Other Prespecified Timepoints	Baseline to 12 months	The Revised Hammersmith Scale (RHS) is a 36 item clinical assessment of physical abilities in patients with Type 2 SMA and ambulatory or nonambulatory patients with Type 3 SMA; it has a maximum achievable score of 69. The RHS includes 33 items that are graded on a scale of 0, 1, 2, where 0 denotes the lowest level and 2 denotes the highest level of ability/function. The remaining 3 items are scored 0 or 1, where 0 denotes an inability and 1 denotes an ability to achieve.
Cohort 1: Proportion of Patients Achieving Various Magnitudes of Change in RHS Score From Baseline	Baseline to 12 months	The Revised Hammersmith Scale (RHS) is a 36 item clinical assessment of physical abilities in patients with Type 2 SMA and ambulatory or nonambulatory patients with Type 3 SMA; it has a maximum achievable score of 69. The RHS includes 33 items that are graded on a scale of 0, 1, 2, where 0 denotes the lowest level and 2 denotes the highest level of ability/function. The remaining 3 items are scored 0 or 1, where 0 denotes an inability and 1 denotes an ability to achieve.
Cohort 1: Change From Baseline in 6-Minute Walk Test (6MWT)	Baseline to 12 months	6-Minute Walk Test The 6-Minute Walk Test (6MWT) is an assessment of exercise capacity and fatigue used for ambulatory patients with later-onset SMA who are directed to walk along a 25 meter course as fast as possible over 6 minutes.
Cohort 1: Change From Baseline in 30-Second Sit-to-Stand	Baseline to 12 months	The 30-Second Sit-to-Stand Test is an assessment of functional lower-limb strength that measures the maximal number of times a patient can transition from sitting to standing in 30 seconds.
Cohort 1: Change From Baseline in 10-Meter Walk/Run (From RHS)	Baseline to 12 months	The 10 Meter Walk/Run test is an enhanced function of the RHS used for ambulatory patients with Type 3 SMA. It is a measure of the time taken to walk/run 10 meters. The time to perform is summarized only for patients able to complete the RHS 10-meter walk/run item.
Cohort 1: Change From Baseline in Timed Rise From Floor (From RHS)	Baseline to 12 months	The timed rise from floor test is an enhanced function of the RHS used for ambulatory patients with Type 3 SMA. It is a measure of the time taken to rise to standing from the floor. The time to rise from floor is summarized only for patients able to complete the RHS rise from floor item.
Cohort 2 &3: Change From Baseline in HFMSE Total Score at Other Prespecified Timepoints	Baseline to 12 months	The Hammersmith Functional Motor Scale Expanded (HFMSE) assesses the physical abilities of patients with Type 2 and Type 3 SMA comprises 33 items graded on a scale of 0, 1, or 2, where 0 denotes unable, 1 denotes performed with modification or adaptation, and 2 denotes performed without modification or adaptation.
Cohort 2 & 3: Proportion of Patients Achieving Various Magnitudes of Change in HFMSE Score From Baseline	Baseline to 12 months	The Hammersmith Functional Motor Scale Expanded (HFMSE) assesses the physical abilities of patients with Type 2 and Type 3 SMA comprises 33 items graded on a scale of 0, 1, or 2, where 0 denotes unable, 1 denotes performed with modification or adaptation, and 2 denotes performed without modification or adaptation.
Cohort 2 & 3: Change in Baseline in Revised Upper Limb Module (RULM) Total Score	Baseline to 12 months	The RULM is a 20 item assessment of upper limb function in nonambulatory patients with SMA that was performed for patients who were 30 months of age or older at baseline. The 19 scored items assess functions that relate to everyday life, such as pressing a button and picking up a token; these items are scored 0, 1, or 2, where 0 denotes unable, 1 denotes able with modification, and 2 denotes able with no modification. The maximum score achievable is 37.
Cohort 2 & 3: Proportion of Patients Achieving a New WHO Motor Development Milestones Relative to Baseline	Baseline to 12 months	The WHO Multicenter Growth Reference Study performance criteria is being utilized to assess the World Health Organization (WHO) motor development milestones of patients with Type 2 and nonambulatory Type 3 SMA enrolled in Cohort 2 and Cohort 3 relative to baseline. The WHO milestone assessment consists of six items which were selected because they have been considered to be universal, fundamental, and simple to test and evaluate, they include 1) sitting without support, 2) hands and knees crawling, 3) standing with assistance, 4) walking with assistance, 5) standing alone, and 6) walking without assistance. Each item is recorded as 1 (unable), 2 (refusal), 3 (Yes) or 9 (did not test). The number of 3s was counted as the final score. The minimum was 0, which means no motor milestones were achieved; the maximum was 6, which means all 6 milestones were achieved.
Cohort 2 & 3: Proportion of Patients Achieving Various Magnitudes of Change in RULM Score From Baseline	Baseline to 12 months	The RULM is a 20 item assessment of upper limb function in nonambulatory patients with SMA that was performed for patients who were 30 months of age or older at baseline. The 19 scored items assess functions that relate to everyday life, such as pressing a button and picking up a token; these items are scored 0, 1, or 2, where 0 denotes unable, 1 denotes able with modification, and 2 denotes able with no modification. The maximum score achievable is 37.

Trial Locations

Locations (16)

Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Universitair Medisch Centrum Utrecht; 🇳🇱 Utrecht, Netherlands

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Childrens Medical Center Dallas; 🇺🇸 Dallas, Texas, United States

Centro Clinico Nemo Pediatrico Policlinico A. Gemelli-Università Cattolica Sacro Cuore; 🇮🇹 Roma, Italy

Hospital Universitari i Politecnic La Fe; 🇪🇸 Valencia, Spain

ASST Grande Ospedale Metropolitano Niguarda; 🇮🇹 Milano, Italy

Children's Hospital of The King's Daughters; 🇺🇸 Norfolk, Virginia, United States

Columbia University; 🇺🇸 New York, New York, United States

The Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Stanford University; 🇺🇸 Palo Alto, California, United States

Hospital Sant Joan de Déu; 🇪🇸 Barcelona, Spain

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Phoenix Children's Hospital; 🇺🇸 Phoenix, Arizona, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Wake Forest School of Medicine; 🇺🇸 Winston-Salem, North Carolina, United States