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

• ClinicalTrials.gov Identifier: NCT03921528
• Recruitment Status: Completed
• First Posted: April 19, 2019
• Results First Posted: November 17, 2022
• Last Update Posted: April 16, 2024
• Sponsor: Scholar Rock, Inc.
• Information provided by (Responsible Party): Scholar Rock, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Spinal Muscular Atrophy; Spinal Muscular Atrophy Type 3; Spinal Muscular Atrophy Type 2; SMA; Neuromuscular Diseases; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Neuromuscular Manifestations	Biological: SRK-015	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: Active treatment, randomized, double-blind for Cohort 3
• Primary Purpose: Treatment
• Official Title: Phase 2 Active Treatment Study to Evaluate the Efficacy and Safety of SRK-015 in Patients With Later-Onset Spinal Muscular Atrophy (TOPAZ)
• Actual Study Start Date: April 22, 2019
• Actual Primary Completion Date: January 19, 2021
• Actual Study Completion Date: February 28, 2024

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

1. Cohort 1:Change From Baseline in the Revised Hammersmith Scale (RHS) Total Score at Other Prespecified Timepoints [ Time Frame: 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.
2. Cohort 1: Proportion of Patients Achieving Various Magnitudes of Change in RHS Score From Baseline [ Time Frame: 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.
3. Cohort 1: Change From Baseline in 6-Minute Walk Test (6MWT) [ Time Frame: 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.
4. Cohort 1: Change From Baseline in 30-Second Sit-to-Stand [ Time Frame: 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.
5. Cohort 1: Change From Baseline in 10-Meter Walk/Run (From RHS) [ Time Frame: 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.
6. Cohort 1: Change From Baseline in Timed Rise From Floor (From RHS) [ Time Frame: 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.
7. Cohort 2 &3: Change From Baseline in HFMSE Total Score at Other Prespecified Timepoints [ Time Frame: 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.
8. Cohort 2 & 3: Proportion of Patients Achieving Various Magnitudes of Change in HFMSE Score From Baseline [ Time Frame: 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.
9. Cohort 2 & 3: Change in Baseline in Revised Upper Limb Module (RULM) Total Score [ Time Frame: 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.
10. Cohort 2 & 3: Proportion of Patients Achieving a New WHO Motor Development Milestones Relative to Baseline [ Time Frame: 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 will be counted as the final score. The minimum will be 0, which means no motor milestones were achieved; the maximum will be 6, which means all 6 milestones were achieved.
11. Cohort 2 & 3: Proportion of Patients Achieving Various Magnitudes of Change in RULM Score From Baseline [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

Phoenix Children's Hospital

Phoenix, Arizona, United States, 85016

United States, California

Stanford University

Palo Alto, California, United States, 94304

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Maryland

The Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Michigan

Helen DeVos Children's Hospital

Grand Rapids, Michigan, United States, 49503

United States, New York

Columbia University

New York, New York, United States, 10032

United States, North Carolina

Wake Forest School of Medicine

Winston-Salem, North Carolina, United States, 27157

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Texas

Childrens Medical Center Dallas

Dallas, Texas, United States, 75235

United States, Virginia

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States, 23507

Italy

ASST Grande Ospedale Metropolitano Niguarda

Milano, Italy, 20162

Centro Clinico Nemo Pediatrico Policlinico A. Gemelli-Università Cattolica Sacro Cuore

Roma, Italy

Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands, 3584

Spain

Hospital Sant Joan de Déu

Barcelona, Spain

Hospital Universitari i Politecnic La Fe

Valencia, Spain, 46026

Sponsors and Collaborators

Scholar Rock, Inc.

Investigators

• Principal Investigator: Thomas O. Crawford, MD; Johns Hopkins University

  Study Documents (Full-Text)

Documents provided by Scholar Rock, Inc.:

Study Protocol and Statistical Analysis Plan  [PDF] August 3, 2021

More Information

• Responsible Party: Scholar Rock, Inc.
• ClinicalTrials.gov Identifier: NCT03921528
• Other Study ID Numbers: SRK-015-002
• First Posted: April 19, 2019
• Results First Posted: November 17, 2022
• Last Update Posted: April 16, 2024
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Muscular Atrophy; Muscular Atrophy, Spinal; Neuromuscular Diseases; Spinal Muscular Atrophies of Childhood; Neuromuscular Manifestations; Atrophy; Pathological Conditions, Anatomical; Neurologic Manifestations; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Genetic Diseases, Inborn