Risdiplam in Patients With Spinal Muscular Atrophy Previously Treated With Nusinersen (RISE)

Risdiplam Exchange in Patients With Spinal Muscular Atrophy (SMA) Previously and Exclusively Treated With Nusinersen

Risdiplam Exchange (RISE) is a study of spinal muscular atrophy (SMA) patients who crossover to 36 months of open-label risdiplam monotherapy following a comparable period of nusinersen treatment. The schedule of assessments (SOAs) carry over seamlessly for the cohort from studies done while treated with nusinersen and continue to track the most informative outcomes from that trial (e.g. nine hole peg test and grip strength), while adding the Box and Block Test (BBT) as an additional measure of upper limb endurance and function.

Study Overview

• Status: Active, not recruiting
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Risdiplam

Detailed Description

Risdiplam is an orally bioavailable small molecule that distributes into the central nervous system (CNS) and peripheral tissues where it modifies SMN2 pre-mRNA splicing and increases tissue SMN protein levels. It was approved by the U.S. Food and Drug Administration for all SMA patients older than 2 months of age in August 2020.

Clinical trial data prompted us to consider risdiplam a reasonable alternative to nusinersen administered intrathecally or by subcutaneous intrathecal catheter (SIC) for patients with more advanced SMA. Considered within this clinical context, risdiplam presents a significant advantage by eliminating the risks of mechanical failure, intrathecal bleeding, and CNS infection associated with the SIC device. The schedule of assessments (SOAs) used in this cohort during the previous three-year period as part of a nusinersen study provide us with an established framework for data collection. Thus, the overall clinical experience with risdiplam as compared to nusinersen can be assessed using a prospective, crossover design in a real-world setting.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Strasburg, Pennsylvania, United States, 17579
      • Clinic for Special Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Biallelic SMN1 deletions
• 3 or 4 copies of SMN2
• Prior treatment with nusinersen for a minimum of 22 months

Exclusion Criteria:

• Prior treatment with SMN gene replacement therapy
• Prior exposure to another investigational agent.
• Confounding neuromuscular disorder other than SMA

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-label crossover; Participants crossover to 36 months of open-label risdiplam mono therapy following a comparable period of nusinersen treatment.	Drug: Risdiplam; administered to participants per product label insert

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparative intrasubject performance on nine hole peg test (NHPT)	Time in seconds to place and subsequently remove nine one inch pegs in holes assessed in dominant and non dominant hands	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intrasubject changes in lower limb and overall motor function	Revised Hammersmith Scale (RHS) of 33 items with grades of 0 (unable),1 (attempted, not completed) and 2 (achieves task); the greater the sum total, the higher overall motor function.	36 months
Intrasubject changes in upper limb motor function	box and block test (BBT): number of 1 inch wood blocks moved from one compartment to an adjacent one over a wall within 5 minutes, with more blocks moved corresponding to higher upper limb motor function	36 months
Intrasubject change in pulmonary function	maximal inspiratory pressure (MIP) and mean expiratory pressure (MEP), measured in centimeters of water displaced	36 months
Frequency and type of adverse events	laboratory testing, self-reported, and observed during the study	36 months
Comparative intrasubject change in grip strength	hand-held dynamometry (MyoGrip and MyoPinch) measures force in Newtons	36 months

Collaborators and Investigators

• Sponsor: Clinic for Special Children
• Collaborators: Genentech, Inc.

Publications and helpful links

General Publications

• Strauss KA, Carson VJ, Brigatti KW, Young M, Robinson DL, Hendrickson C, Fox MD, Reed RM, Puffenberger EG, Mackenzie W, Miller F. Preliminary Safety and Tolerability of a Novel Subcutaneous Intrathecal Catheter System for Repeated Outpatient Dosing of Nusinersen to Children and Adults With Spinal Muscular Atrophy. J Pediatr Orthop. 2018 Nov/Dec;38(10):e610-e617. doi: 10.1097/BPO.0000000000001247.
• Carson VJ, Young M, Brigatti KW, Robinson DL, Reed RM, Sohn J, Petrillo M, Farwell W, Miller F, Strauss KA. Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy. Muscle Nerve. 2022 Jan;65(1):51-59. doi: 10.1002/mus.27425. Epub 2021 Oct 19.
• Ribero VA, Daigl M, Marti Y, Gorni K, Evans R, Scott DA, Mahajan A, Abrams KR, Hawkins N. How does risdiplam compare with other treatments for Types 1-3 spinal muscular atrophy: a systematic literature review and indirect treatment comparison. J Comp Eff Res. 2022 Apr;11(5):347-370. doi: 10.2217/cer-2021-0216. Epub 2022 Jan 18.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): June 15, 2026

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: August 29, 2022
• First Posted (Actual): August 31, 2022

Study Record Updates

• Last Update Posted (Actual): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: prospective; risdiplam; nusinersen
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Physiological Effects of Drugs; Peripheral Nervous System Agents; Neuromuscular Agents; Risdiplam
• Other Study ID Numbers: RISE

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
• product manufactured in and exported from the U.S.: No