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

Phase 2 Active Treatment Study to Evaluate the Efficacy and Safety of SRK-015 in Patients With Later-Onset Spinal Muscular Atrophy (TOPAZ)

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.

Study Overview

• Status: Completed
• Conditions: Neuromuscular Diseases; Neuromuscular Manifestations; Atrophy; Muscular Atrophy; Spinal Muscular Atrophy; Muscular Atrophy, Spinal; Spinal Muscular Atrophy Type 3; SMA; Spinal Muscular Atrophy Type 2
• Intervention / Treatment: Biological: SRK-015

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20162
    • ASST Grande Ospedale Metropolitano Niguarda
  • Roma, Italy
    • Centro Clinico Nemo Pediatrico Policlinico A. Gemelli-Università Cattolica Sacro Cuore
• Netherlands
  • Utrecht, Netherlands, 3584
    • Universitair Medisch Centrum Utrecht
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan De Deu
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest School of Medicine
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Texas
    • Dallas, Texas, United States, 75235
      • Childrens Medical Center Dallas
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Ambulatory Type 3 SMA	Biological: SRK-015; SRK-015 is a fully human anti-proMyostatin monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/lambda isotype that binds to human pro/latent myostatin with high affinity. SRK-015 will be administered every 4 weeks by intravenous infusion.
Experimental: Cohort 2; Type 2 SMA / Non-Ambulatory Type 3 SMA	Biological: SRK-015; SRK-015 is a fully human anti-proMyostatin monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/lambda isotype that binds to human pro/latent myostatin with high affinity. SRK-015 will be administered every 4 weeks by intravenous infusion.
Experimental: Cohort 3; Type 2 SMA	Biological: SRK-015; SRK-015 is a fully human anti-proMyostatin monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/lambda isotype that binds to human pro/latent myostatin with high affinity. SRK-015 will be administered every 4 weeks by intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 2 and Cohort 3: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Total Score at Day 364 (Visit 15) [Month 12]	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.	Baseline up to 12 months
Cohort 1: Change From Baseline in the Revised Hammersmith Scale (RHS) Total Score at Day 364 (Visit 15) [Month 12]	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.	Baseline up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1:Change From Baseline in the Revised Hammersmith Scale (RHS) Total Score at Other Prespecified Timepoints	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.	Baseline to 12 months
Cohort 1: Proportion of Patients Achieving Various Magnitudes of Change in RHS Score From Baseline	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.	Baseline to 12 months
Cohort 1: Change From Baseline in 6-Minute Walk Test (6MWT)	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.	Baseline to 12 months
Cohort 1: Change From Baseline in 30-Second Sit-to-Stand	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.	Baseline to 12 months
Cohort 2 &3: Change From Baseline in HFMSE Total Score at Other Prespecified Timepoints	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.	Baseline to 12 months
Cohort 2 & 3: Proportion of Patients Achieving Various Magnitudes of Change in HFMSE Score From Baseline	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.	Baseline to 12 months
Cohort 2 & 3: Change in Baseline in Revised Upper Limb Module (RULM) Total Score	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.	Baseline to 12 months
Cohort 2 & 3: Proportion of Patients Achieving Various Magnitudes of Change in RULM Score From Baseline	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.	Baseline to 12 months
Cohort 1: Change From Baseline in 10-Meter Walk/Run (From RHS)	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.	Baseline to 12 months
Cohort 1: Change From Baseline in Timed Rise From Floor (From RHS)	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.	Baseline to 12 months
Cohort 2 & 3: Proportion of Patients Achieving a New WHO Motor Development Milestones Relative to Baseline	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.	Baseline to 12 months

Collaborators and Investigators

• Sponsor: Scholar Rock, Inc.
• Investigators: Principal Investigator: Thomas O. Crawford, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2019
• Primary Completion (Actual): January 19, 2021
• Study Completion (Actual): February 28, 2024

Study Registration Dates

• First Submitted: April 16, 2019
• First Submitted That Met QC Criteria: April 16, 2019
• First Posted (Actual): April 19, 2019

Study Record Updates

• Last Update Posted (Estimated): December 2, 2024
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Central Nervous System Diseases; Nervous System Diseases; Pathological Conditions, Anatomical; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Spinal Cord Diseases; Motor Neuron Disease; Atrophy; Muscular Atrophy; Muscular Atrophy, Spinal; Neuromuscular Diseases; Spinal Muscular Atrophies of Childhood; Neuromuscular Manifestations
• Other Study ID Numbers: SRK-015-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No