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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)

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ClinicalTrials.gov Identifier: NCT02908685
Recruitment Status : Active, not recruiting
First Posted : September 21, 2016
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 19, 2016
First Posted Date  ICMJE September 21, 2016
Last Update Posted Date June 5, 2019
Actual Study Start Date  ICMJE October 20, 2016
Estimated Primary Completion Date September 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2018)
  • Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Score at Month 12 [ Time Frame: Baseline (Day -1) and Month 12 ]
  • Part 1: Recommended Part 2 Dose of Risdiplam [ Time Frame: 120 days ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 19, 2016)
  • Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Score at Month 12 [ Time Frame: Baseline (Day -1) and Month 12 ]
  • Part 1: Recommended Part 2 Dose of RO7034067 [ Time Frame: 120 days ]
Change History Complete list of historical versions of study NCT02908685 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2018)
  • 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 ]
  • Survival of Motor Neuron (SMN) Protein Levels in Blood [ Time Frame: Part 2: Days -1, 7, 28, 120, 246, 365, 729 ]
  • Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • 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 ]
  • Percentage of Participants who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in Forced Vital Capacity (FVC) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the Peak Cough Flow (PCF) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Percentage of Participants who Experience at Least One Disease-Related Adverse Event [ Time Frame: Baseline up to Month 12 ]
  • 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 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 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 ]
  • Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 24 months ]
  • Change from Baseline in the MFM Domain 1 (D1) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the MFM Domain 2 (D2) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the MFM Domain 3 (D3) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Percentage of Participants with Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Baseline (Day-1), Day 120, Day 248, Day 386, Day 647, Day 729 ]
  • Percentage of Participants by Clinical Global Impression of Change (CGI-C) Scale Ratings [ Time Frame: Month 12 ]
  • Change from Baseline in SMA Independence Scale (SMAIS) Total Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Percentage of Participants who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2016)
  • 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 ]
  • Survival of Motor Neuron (SMN) Protein Levels in Blood [ Time Frame: Part 2: Days -1, 7, 28, 120, 246, 365, 729 ]
  • Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • 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 ]
  • Percentage of Participants who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in Forced Vital Capacity (FVC) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the Peak Cough Flow (PCF) at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change From Baseline in Neuromuscular Disease Domain Score as Assessed by Pediatric Quality of Life Inventory (PedsQL) 3.0 Neuromuscular Module at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change From Baseline in Total Score of the PedsQL 4.0 Generic Core Scale at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Percentage of Participants who Experience at Least One Disease-Related Adverse Event [ Time Frame: Baseline up to Month 12 ]
  • Part 1 and 2: Maximum Plasma Concentration (Cmax) of RO7034067 [ 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 1 and 2: Area Under the Curve (AUC) of RO7034067 [ 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 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of RO7034067 [ Time Frame: Part 1 and 2: Pre-dose (Hour 0) on Days 7, 14, 28, 56, 120, 246, 365, 490, 609, 729 ]
  • Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 24 months ]
  • Change from Baseline in the MFM Domain 1 (D1) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the MFM Domain 2 (D2) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the MFM Domain 3 (D3) Score at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12 [ Time Frame: Baseline (Day-1) and Month 12 ]
  • Percentage of Participants with Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Baseline (Day-1), Day 120, Day 248, Day 386, Day 647, Day 729 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants
Official Title  ICMJE A Two Part Seamless, Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7034067 in Type 2 and 3 Spinal Muscular Atrophy Patients
Brief Summary Multi-center, randomized, double-blind, placebo-controlled, Phase II 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Muscular Atrophy, Spinal
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Part 1 Group A: Adolescents and Adults (Risdiplam)
    Adolescent and adult participants aged 12-25 years will receive Risdiplam for 12 weeks. Once 12-week treatment is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be followed up in open-label extension (OLE) phase.
    Intervention: Drug: Risdiplam
  • Placebo Comparator: Part 1 Group A: Adults and Adolescents (Placebo)
    Adolescent and adult participants aged 12-25 years will receive placebo matching to Risdiplam for 12 weeks. Once 12-week treatment is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be followed up in OLE phase.
    Interventions:
    • Drug: Placebo
    • Drug: Risdiplam
  • Placebo Comparator: Part 1 Group B: Children (Placebo)
    Children aged 2-11 years will receive placebo matching to Risdiplam for 12 weeks. Once 12-week treatment is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be followed up in OLE phase.
    Interventions:
    • Drug: Placebo
    • Drug: Risdiplam
  • Experimental: Part 1 Group B: Children (Risdiplam)
    Children aged 2-11 years will receive Risdiplam for 12 weeks. Once 12-week treatment is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be followed up in OLE phase.
    Intervention: Drug: Risdiplam
  • Placebo Comparator: Part 2: Placebo
    Participants aged 2-25 years will receive placebo matching to Risdiplam. After 12 months of treatment with placebo, participants will be switched to Risdiplam and treatment will then continue until Month 24. After 24-month treatment, participants will be offered the opportunity to enter the OLE phase.
    Interventions:
    • Drug: Placebo
    • Drug: Risdiplam
  • 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, for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the OLE phase.
    Intervention: Drug: Risdiplam
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 2, 2019)
231
Original Estimated Enrollment  ICMJE
 (submitted: September 19, 2016)
186
Estimated Study Completion Date  ICMJE September 2, 2023
Estimated Primary Completion Date September 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 25 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Brazil,   Canada,   China,   Croatia,   France,   Germany,   Italy,   Japan,   Poland,   Russian Federation,   Serbia,   Spain,   Turkey,   United States
Removed Location Countries Argentina,   Australia,   Sweden,   Switzerland,   Taiwan,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02908685
Other Study ID Numbers  ICMJE BP39055
2016-000750-35 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP