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

• Register: ClinicalTrials.gov
• Last refreshed on: 6 November 2023
• Main ID: NCT02908685
• Date of registration: 19/09/2016
• Prospective Registration: Yes
• Primary sponsor: Hoffmann-La Roche
• Public title: 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
• Scientific 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
• Date of first enrolment: October 20, 2016
• Target sample size: 231
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/ct2/show/NCT02908685
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Canada, China, Croatia, France, Germany, Italy, Japan, Poland, Russian Federation, Serbia, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Clinical Trials
• Affiliation: Hoffmann-La Roche

Key inclusion & exclusion 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



Age minimum: 2 Years
Age maximum: 25 Years
Gender: All

Health Condition(s) or Problem(s) studied

Muscular Atrophy, Spinal

Intervention(s)

Drug: Placebo

Drug: Risdiplam

Primary Outcome(s)

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]

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)]

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)]

Secondary Outcome(s)

Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam [Time Frame: Part 1 and 2: 1, 2, 4, 6 hours post dose on Day 1; Pre-dose (Hour 0) on Days 7, 14, 56 (Part 2), 120, 246, 490, 729; pre-dose (Hour 0) and 1, 2, 4, 6 hours post dose on Days 28, 56 (Part 1), 365, 609]

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]

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]

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]

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]

Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time Frame: Day 1 on risdiplam up to end of study (up to approximately 7 years)]

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]

Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 [Time Frame: Baseline (Day-1) and Month 12]

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]

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]

Survival of Motor Neuron 2 (SMN2) Messenger Ribonucleic Acid (mRNA) Levels in Blood [Time Frame: Part 2: Days -1, 1, 7, 28, 120, 246, 365, 729]

Part 1 and 2: Area Under the Curve (AUC) of Risdiplam [Time Frame: Part 1 and 2: 1, 2, 4, 6 hours post dose on Day 1; Pre-dose (Hour 0) on Days 7, 14, 56 (Part 2), 120, 246, 490, 729; pre-dose (Hour 0) and 1, 2, 4, 6 hours post dose on Days 28, 56 (Part 1), 365, 609]

Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 [Time Frame: Baseline (Day-1) and Month 12]

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]

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]

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]

Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 [Time Frame: Baseline (Day-1) and Month 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]

Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam [Time Frame: Part 1 and 2: Pre-dose (Hour 0) on Days 7, 14, 28, 56, 120, 246, 365, 490, 609, 729]

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]

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]

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]

Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 [Time Frame: Baseline (Day-1) and Month 12]

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)]

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]

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]

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]

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]

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]

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]

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)]

Survival of Motor Neuron (SMN) Protein Levels in Blood [Time Frame: Part 2: Days -1, 7, 28, 120, 246, 365, 729]

Secondary ID(s)

BP39055

2016-000750-35

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 15/06/2021
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02908685