A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants (SUNFISH)

• ClinicalTrials.gov Identifier: NCT02908685
• Recruitment Status: Completed
• First Posted: September 21, 2016
• Results First Posted: June 15, 2021
• Last Update Posted: April 24, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

Multi-center, randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of Risdiplam in adult and pediatric participants with Type 2 and Type 3 SMA. The study consists of two parts, an exploratory dose finding part (Part 1) of Risdiplam for 12 weeks and a confirmatory part (Part 2) of Risdiplam for 24 months.

Condition or disease	Intervention/treatment	Phase
Muscular Atrophy, Spinal	Drug: Placebo; Drug: Risdiplam	Phase 2

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 231 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Two Part Seamless, Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy Patients
• Actual Study Start Date: October 19, 2016
• Actual Primary Completion Date: September 6, 2019
• Actual Study Completion Date: October 2, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 Group A: Adolescents and Adults (Risdiplam); Adolescent and adult participants aged 12-25 years will receive risdiplam for at least 12 weeks. Once the placebo-controlled period is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.	Drug: Risdiplam; Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Other Name: RO7034067
Placebo Comparator: Part 1 Group A: Adolescents and Adults (Placebo); Adolescent and adult participants aged 12-25 years will receive placebo matching to risdiplam for at least 12 weeks. Once placebo-controlled period is completed, participants will be first switched to their cohort risdiplam dose. After the Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.	Drug: Placebo; Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Drug: Risdiplam; Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Other Name: RO7034067
Placebo Comparator: Part 1 Group B: Children (Placebo); Children aged 2-11 years will receive placebo matching to risdiplam for at least 12 weeks. Once placebo-controlled period is completed, participants will be first switched to their cohort risdiplam dose. After the Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.	Drug: Placebo; Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Drug: Risdiplam; Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Other Name: RO7034067
Experimental: Part 1 Group B: Children (Risdiplam); Children aged 2-11 years will receive risdiplam for at least 12 weeks. Once the placebo-controlled period is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase.	Drug: Risdiplam; Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Other Name: RO7034067
Placebo Comparator: Part 2: Placebo; Participants aged 2-25 years will receive placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants will be switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment until Month 24. After Month 24, participants will be offered the opportunity to enter the open-label phase.	Drug: Placebo; Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Drug: Risdiplam; Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Other Name: RO7034067
Experimental: Part 2: Risdiplam; Participants aged 2-25 years will receive risdiplam at the dose selected based on the results from Part 1 of the study (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20 kg), for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label phase.	Drug: Risdiplam; Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).; Other Name: RO7034067

Outcome Measures

Primary Outcome Measures :

1. Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg [ Time Frame: Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017) ]
   The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
2. Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg [ Time Frame: Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017) ]
   The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
3. Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
   The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.

Secondary Outcome Measures :

1. Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 [ Time Frame: At Month 12 ]
   The MFM32 comprises 32 items that evaluate physical function. The scoring of each task uses a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. A change in MFM32 total score of threshold >/=3 represents marked improvement in this measure. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
2. Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
   The RULM is a 20 items scale that assesses the proximal and distal motor functions of the arm. There is an entry item and the remaining 18 items are scored on the 3 point scale of: 0: cannot complete task independently; 1: modified method but can complete task independently; 2: completes task without any assistance, and with 1 item scored on a 2 point scale of as a can/cannot score with 1 as the highest score. The RULM total score is the sum of 19 items scores with range of 0-37, and the entry item does not contribute to the total score. Higher scores indicate greater upper limb function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
3. Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
   The HFMSE scale contains 33 items, which are scored on a 3-point Likert-type scale (0-2) and summed to derive the total score, with lower scores indicating greater impairment. The HFMSE contains a series of assessments designed to assess important functional abilities, including standing, transfers, ambulation, and proximal and axial function. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate greater motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
4. Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years [ Time Frame: Baseline (Day-1) and Month 12 ]
   Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced vital capacity (FVC) is the total volume that can be exhaled after inhaling maximally. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on the efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
5. Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
   The SMA Independence Scale (SMAIS) was developed specifically for SMA participants in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
6. Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 [ Time Frame: At Month 12 ]
   The Clinical Global Impression of Change (CGI-C) is used to score a clinician's impression of a participant's change in global health. The CGI-C is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "improved" included responses of "very much improved, "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
7. Part 2: Percentage of Participants Who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12 [ Time Frame: At Month 12 ]
   The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
8. Part 2: Percentage of Participants Who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12 [ Time Frame: At Month 12 ]
   The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0-cannot initiate the task or maintain the starting position; 1-performs the task partially; 2-performs the task incompletely or imperfectly; 3-performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the total score. Higher scores indicate increased motor function. Standard error of measurement (SEM) is derived using 32 items scores and total scores at baseline. Change from baseline > = one SEM is equivalent to a change >= 4. Logistic regression analysis was performed based on efficacy hypothetical estimand included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
9. Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
   The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1 items score are summed and expressed on 0-100 scale for the MFM D1 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
10. Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D2 items score are summed and expressed on 0-100 scale for the MFM D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
11. Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D3 items score are summed and expressed on 0-100 scale for the MFM D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
12. Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D1+D2 items score are summed and expressed on 0-100 scale for the MFM D1+D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
13. Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The D2+D3 items score are summed and expressed on 0-100 scale for the MFM D2+D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
14. Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years [ Time Frame: Baseline (Day-1) and Month 12 ]
    Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Forced expiratory volume (FEV1) is the volume forcefully exhaled in the first second of the forced vital capacity test. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
15. Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years [ Time Frame: Baseline (Day-1) and Month 12 ]
    Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all participants aged 6 or older. Peak cough flow (PCF) is an assessment of cough strength. The best % predicted value out of all attempts were used for the analysis MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
16. Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
    The Sniff Nasal Inspiratory Pressure (SNIP) is a volitional, non-invasive test of inspiratory muscle strength that has been successfully applied to children > 2 years of age. Advantages include the simplicity of the maneuver and the absence of a mouthpiece, which is particularly helpful for participants with SMA, who may have bulbar weakness. SNIP also has the advantage of measuring inspiratory pressure during a natural maneuver that is easily performed even by young children with neuromuscular disorders. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
17. Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years [ Time Frame: Baseline (Day-1) and Month 12 ]
    The maximal inspiratory pressure (MIP) is a non-invasive test of muscle strength, which measures the maximum strength of the diaphragm and other inspiratory muscles. MIP was measured in participants aged 6 or older. Participants were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
18. Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years [ Time Frame: Baseline (Day-1) and Month 12 ]
    The maximal expiratory pressure (MEP) is a non-invasive test of muscle strength, which measures the maximum strength of the abdominal muscles and other expiratory muscles. MEP was measured in participants aged 6 or older. Participants were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
19. Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
    The SMAIS was developed specifically for SMA participants in order to assess function-related independence. It contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
20. Part 2: Percentage of Participants Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 [ Time Frame: At Month 12 ]
    The CGI-C is used to score a clinician's impression of a participant's change in global health. It is a single item measure of change in global health, using seven response options: "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", and "very much worse". Participants considered as "no change or improved" included responses of "no change", "very much improved", "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
21. Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12 [ Time Frame: Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019) ]
    Disease-related adverse events (AEs) were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms. This basket was defined based on a group of CDC terms selected from an age and gender matched case control study comparing CDC code rates observed in participants with and without SMA using commercially available insurance claim data (CLAIMS and Market scan data). The lowest level terms included in each basket, coded using the latest version of MedDRA; Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
22. Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12 [ Time Frame: Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019) ]
    Disease-related AEs were collected through the AE reporting of the study, and the disease-related AE rate was adjusted for patient years (AE rate per 100 patient-years). They were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms and Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
23. Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period [ Time Frame: Day 1 up to 12 months of the placebo-controlled period ]
    An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
24. Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period [ Time Frame: Day 1 up to 12 months of the placebo-controlled period ]
    An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
25. Part 2: Number of Participants Aged 6-25 Years With Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period [ Time Frame: Day 1 up to 12 months of the placebo-controlled period ]
    The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for participants aged 6 years and older.
26. Part 2: Number of Participants Aged 6-25 Years With Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period [ Time Frame: Day 1 up to 12 months of the placebo-controlled period ]
    The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for participants aged 6 years and older.
27. Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood [ Time Frame: Part 1: Day -1, pre-dose of Weeks 1, 2 (>/= 12 years only), 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52. Part 2: Day -1, pre-dose of Weeks 1, 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52. ]
28. Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5 [ Time Frame: Day 1: 1, 2, 4, 6 h postdose, Weeks 4, 8 (Part 1 only), 52, 87: pre-dose, 1, 2, 4, 6 h post-dose and Weeks 1 (Day 7), 2, 8 (Part 2 only) 17, 35, 70, 104: predose ]
    Reported here is the maximum observed concentration throughout the observation period.
29. Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit [ Time Frame: Year 5 visit pre-dose, 1, 2, 4, 6, 24 hours post-dose ]
30. Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 [ Time Frame: The last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration. ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 25 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Confirmed diagnosis of 5q-autosomal recessive SMA
• Negative blood pregnancy test at screening and agreement to comply with measures to prevent pregnancy and restrictions on sperm donation
• For Part 1: Type 2 or 3 SMA ambulant or non-ambulant
• For Part 2: 1) Type 2 or 3 SMA non-ambulant; 2) RULM entry item A greater than or equal to 2; 3) ability to sit independently as assessed by item 9 of the MFM

Exclusion Criteria:

• Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening, or 5 half-lives of the drug, whichever is longer
• Concomitant or previous administration of a SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care
• Any history of cell therapy
• Hospitalization for a pulmonary event within the last 2 months or planned at time of screening
• Surgery for scoliosis or hip fixation in the one year preceding screening or planned within the next 18 months
• Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
• Presence of clinically significant electrocardiogram abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease indicating a safety risk for participants as determined by the Investigator
• Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
• Recently initiated treatment (within less than [<] 6 months prior to randomization) with oral salbutamol or another beta 2-adrenergic agonist taken orally
• Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed
• Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to Risdiplam or to the constituents of its formulation
• Recent history (less than one year) of ophthalmological diseases
• Participants requiring invasive ventilation or tracheostomy

Contacts and Locations

Locations

United States, California

Stanford University Medical Center

Palo Alto, California, United States, 94304

United States, New York

Columbia University Medical Center; The Neurological Institute of New York

New York, New York, United States, 10032

Belgium

UZ Gent

Gent, Belgium, 9000

UZ Leuven Gasthuisberg

Leuven, Belgium, 3000

Chr de La Citadelle

Liège, Belgium, 4000

Brazil

Instituto de Puericultura E Pediatria Martagão Gesteira

Rio de Janeiro, RJ, Brazil, CEP 21941-912

Canada, Alberta

Alberta Children's Hospital Division of Pediatric Neurology

Calgary, Alberta, Canada, T3B 6A8

Canada, Ontario

London Health Sciences Centre; Children's Hospital; Pediatrics

London, Ontario, Canada, N6A 5W9

Canada, Quebec

McGill University Health Centre - Glen Site

Montreal, Quebec, Canada, H4A 3J1

China

Peking University First Hospital

Beijing City, China, 100034

Children's Hospital of Fudan University

Shanghai, China, 201102

Croatia

Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics

Zagreb, Croatia, 10000

France

Hopital Femme Mere Enfant; Medecine Physique et Readaptation Pediatrique ? L?ESCALE

Bron, France, 69677

Hopital Roger Salengro

Lille, France, 59037

CHU de Nantes - Hotel Dieu

Nantes, France, 44093

Hôpital Necker-Enfants Malades; Service de neuropédiatrie

Paris, France, 75015

Hopital Armand Trousseau

Paris, France, 75571

Germany

Universitätsklinikum Freiburg; Klinik für Neuropädiatrie und Muskelerkrankungen

Freiburg, Germany, 79106

Italy

IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative

Roma, Lazio, Italy, 00165

Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile

Roma, Lazio, Italy, 00168

IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative

Genova, Liguria, Italy, 16147

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa di Neurologia

Milano, Lombardia, Italy, 20122

Fondazione IRCCS Istituto Neurologico ?Carlo Besta?; UO di Neurologia dello Sviluppo

Milano, Lombardia, Italy, 20133

Japan

Fukuoka Children's Hospital

Fukuoka, Japan, 813-0017

Hiroshima University Hospital

Hiroshima, Japan, 734-8551

Hyogo Medical University Hospital

Hyogo, Japan, 663-8501

Minami Kyushu National Hospital

Kagoshima, Japan, 899-5293

Miyagi Children's Hospital

Miyagi, Japan, 989-3126

Shiga Medical Center for Children

Shiga, Japan, 524-0022

Shizuoka Children's Hospital

Shizuoka, Japan, 420-8660

Jichi Medical University Hospital

Tochigi, Japan, 329-0498

Center Hospital of the National Center for Global Health and Medicine

Tokyo, Japan, 162-0052

National Center Of Neurology And Psychiatry Hospital

Tokyo, Japan, 187-8551

Poland

Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology

Gda?sk, Poland, 80-952

Uniwersytecki Szpital Kliniczny w Poznaniu; Od. Kliniczny Neurologii Dzieci i M?odziezy

Pozna?, Poland, 60-355

Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie

Warszawa, Poland, 02-097

Russian Federation

Russian Children Neuromuscular Center of Veltischev

Moscow, Moskovskaja Oblast, Russian Federation, 125412

Serbia

Clinic for Neurology and Psychiatry for Children and Youth

Belgrade, Serbia, 11000

Spain

Hospital Sant Joan De Deu

Esplugues De Llobregas, Barcelona, Spain, 08950

Hospital Universitari Vall d'Hebron; Servicio de Reumatologia

Barcelona, Spain, 08035

Hospital Universitario La Paz

Madrid, Spain, 280146

Hospital Universitario Virgen del Rocío

Sevilla, Spain, 41013

Turkey

Hacettepe University, School of Medicine; Pediatrics Department; Pediatrics Child Neurology Unit

Ankara, Turkey, 06100

Hospital Yeditepe University Kozyatagi; Pediatry

Atasehir- Istanbul, Turkey, 34752

United Kingdom

University of Oxford; Department of Paediatrics

Headington, United Kingdom, OX3 9DU

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:

Study Protocol  [PDF] June 22, 2020

Statistical Analysis Plan  [PDF] March 12, 2021

More Information

Additional Information:

roche-sma-clinicaltrials.com provides information about the Roche Sunfish clinical trial NCT02908685 and molecule being investigated in SMA. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mercuri E, Deconinck N, Mazzone ES, Nascimento A, Oskoui M, Saito K, Vuillerot C, Baranello G, Boespflug-Tanguy O, Goemans N, Kirschner J, Kostera-Pruszczyk A, Servais L, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Staunton H, Yeung WY, Martin C, Fontoura P, Day JW; SUNFISH Study Group. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum In: Lancet Neurol. 2022 Feb;21(2):e2. Lancet Neurol. 2022 Mar;21(3):e3. Lancet Neurol. 2022 May;21(5):e5.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02908685
• Other Study ID Numbers: BP39055; 2016-000750-35 ( EudraCT Number )
• First Posted: September 21, 2016
• Results First Posted: June 15, 2021
• Last Update Posted: April 24, 2024
• Last Verified: March 2024

Additional relevant MeSH terms:

Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Spinal Cord Diseases; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases; Risdiplam; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs