A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy (Jewelfish)

• ClinicalTrials.gov Identifier: NCT03032172
• Recruitment Status: Active, not recruiting
• First Posted: January 26, 2017
• Last Update Posted: April 24, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 24, 2017
• First Posted Date: January 26, 2017
• Last Update Posted Date: April 24, 2023
• Actual Study Start Date: March 3, 2017
• Estimated Primary Completion Date: December 27, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 19, 2020)

• Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Scale, V 4.0 [ Time Frame: Baseline up to 5 years ]
• Percentage of Participants With Emergence or Worsening of Symptoms As Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) (Adult Version for Adults and Adolescents, Pediatric Version for Patients Aged 6-11 Years) [ Time Frame: Baseline up to 5 years ]
• Percentage of Participants With Protocol Defined Clinically Significant Changes in Ophthalmological Assessments [ Time Frame: Baseline up to 5 years ]
• Percentage of Participants With Protocol Defined Clinically Significant Changes in Neurological Assessments [ Time Frame: Baseline up to 5 years ]
• Tanner Staging Among all Participants Aged From 9 to 17 Years [ Time Frame: Baseline up to 5 years ]
• Mean Plasma Concentration of Risdiplam [ Time Frame: Up to 2 years ]
• Maximum Plasma Concentration (Cmax) of Risdiplam [ Time Frame: Up to 2 years ]
• Area Under the Plasma Concentration Versus Curve (AUC) of Risdiplam [ Time Frame: Up to 2 years ]
• Concentration of Risdiplam at the End of Dosing Interval (Ctrough) [ Time Frame: Up to 2 years ]
• Mean Plasma Concentration of Risdiplam Metabolite [ Time Frame: Up to 2 years ]
• Cmax of Risdiplam Metabolite [ Time Frame: Up to 2 years ]
• AUC of Risdiplam Metabolite [ Time Frame: Up to 2 years ]
• Ctrough of Risdiplam Metabolite [ Time Frame: Up to 2 years ]

Original Primary Outcome Measures (submitted: January 24, 2017)

• Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: From screening up to 160 weeks ]
• Percentage of Participants With Suicidal Ideation or Behavior, As Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to 104 weeks (assessed at baseline [Day1]; Days 119, 182, 364, 546, 728; early withdrawal visit [up to Week 104]) ]
• Percentage of Participants With Protocol Defined Clinically Significant Changes in Ophthalmological Assessments [ Time Frame: Baseline up to 104 weeks (assessed at Weeks 8, 17, 26, 35, 43, 52, 61, 70, 78, 87, 96, 104; early withdrawal visit [up to Week 104]) ]
• Tanner Staging Among all Participants Aged From 12 to 17 Years [ Time Frame: Month 24 ]
• Mean Plasma Concentration of RO7034067 [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• Maximum Plasma Concentration (Cmax) of RO7034067 [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• Area Under the Plasma Concentration Versus Curve (AUC) of RO7034067 [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• Concentration of RO7034067 at the End of Dosing Interval (Ctrough) [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• Mean Plasma Concentration of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• Cmax of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• AUC of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
• Ctrough of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]

Current Secondary Outcome Measures (submitted: July 19, 2020)

• SMN messenger Ribonucleic Acid (mRNA) Level in Blood [ Time Frame: Up to 2 years ]
• SMN Protein Levels in Blood [ Time Frame: Up to 2 years ]

Original Secondary Outcome Measures (submitted: January 24, 2017)

• SMN messenger Ribonucleic Acid (mRNA) Level in Blood [ Time Frame: Day -1; predose (0 hr) on Days 7, 14, 183; 4 hr postdose on Days 1, 28, 365; Day 729; early withdrawal visit (up to Week 104); follow-up visit 1 (Week 112) ]
• SMN Protein Levels in Blood [ Time Frame: Day -1; predose (0 hr) on Days 7, 14, 183; 4 hr postdose on Days 28, 365; Day 729; early withdrawal visit (up to Week 104); follow-up visit 1 (Week 112) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy
• Official Title: An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in Adult and Pediatric Patients With Spinal Muscular Atrophy
• Brief Summary: This is a multi-center, exploratory, non-comparative, and open-label study to investigate the safety, tolerability, PK, and PK/PD relationship of risdiplam in adults, children and infants with Spinal Muscular Atrophy (SMA) previously enrolled in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previously treated with nusinersen, olesoxime or AVXS-101.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Spinal Muscular Atrophy

Intervention

Drug: Risdiplam

Risdiplam will be administered orally once daily.

Other Name: RO7034067

Study Arms

Experimental: Risdiplam

Participants will receive multiple doses of risdiplam orally once daily for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label extension (OLE) phase.

Intervention: Drug: Risdiplam

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 30, 2020): 174
• Original Estimated Enrollment (submitted: January 24, 2017): 24
• Estimated Study Completion Date: December 27, 2024
• Estimated Primary Completion Date: December 27, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Confirmed diagnosis of 5q-autosomal recessive SMA
• Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previous treatment with any of the following: 1.) Nusinersen (defined as having received >= 4 doses of nusinersen, provided that the last dose was received >= 90 days prior to screening) or 2.) Olesoxime (provided that the last dose was received <= 12 months and >= 90 days prior to screening) or 3.) AVXS-101 (provided that the time of treatment was >= 12 months prior to screening)
• Adequately recovered from any acute illness at the time of screening and considered well enough to participate in the opinion of the Investigator
• For women of childbearing potential: negative blood pregnancy test at screening, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs for at least 28 days after the final dose of study drug
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
• For participants aged 2 years or younger at screening: 1.) Parent or caregiver of participant is willing to consider nasogastric, naso-jejunal or gastrostomy tube placement, as recommended by the Investigator, during the study to maintain safe hydration, nutrition and treatment delivery; 2.) Parent or caregiver of participant is willing to consider the use of non-invasive ventilation, as recommended by the Investigator during the study

Exclusion Criteria:

• Inability to meet study requirements
• Concomitant participation in any investigational drug or device study
• With the exception of studies of olesoxime, AVXS-101, or nusinersen: 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
• Any history of gene or cell therapy, with the exception of AVXS-101
• Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
• Inadequate venous or capillary blood access for the study procedures, in the opinion of the Investigator
• For patients aged < 2 years, hospitalization for a pulmonary event within 2 months prior to screening and pulmonary function not fully recovered at the time of screening
• Lactating women
• Suspicion of regular consumption of drugs of abuse
• For adults and adolescents only, positive urine test for drugs of abuse or alcohol at screening or Day -1 visit
• Presence of clinically significant electrocardiogram (ECG) abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease
• History of malignancy if not considered cured
• For participants aged > 6 years, significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
• 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 for spinal muscular atrophy (within <6 weeks prior to enrollment) 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
• Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study
• Recent history (less than one year) of ophthalmological diseases
• Any prior use of an inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 elimination half-lives, whichever is longer) prior to dosing

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 60 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Germany, Italy, Netherlands, Poland, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03032172
• Other Study ID Numbers: BP39054; 2016-004184-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: April 2023