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

NCT02908685 | Completed Phase 2 Results

• 2 other identifiers: BP390552016-000750-35
• Study Type: interventional
• Target: 231
• Locations: 16 countries
• Sites: 45

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.

Conditions

Muscular Atrophy, Spinal

Outcome Measures

Primary Outcomes (3)

• Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg

  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.

  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 BW of <20kg

  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.

  Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)

• Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at 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.

  Baseline (Day-1) and Month 12

Secondary Outcomes (30)

• Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12

  At Month 12

• Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12

  Baseline (Day-1) and Month 12

• Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12

  Baseline (Day-1) and Month 12

• Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years

  Baseline (Day-1) and Month 12

• Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

  Baseline (Day-1) and Month 12

Study Arms (6)

Part 1 Group A: Adolescents and Adults (Risdiplam)

EXPERIMENTAL

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

Part 1 Group A: Adolescents and Adults (Placebo)

PLACEBO COMPARATOR

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; Drug: Risdiplam

Part 1 Group B: Children (Placebo)

PLACEBO COMPARATOR

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; Drug: Risdiplam

Part 1 Group B: Children (Risdiplam)

EXPERIMENTAL

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

Part 2: Placebo

PLACEBO COMPARATOR

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; Drug: Risdiplam

Part 2: Risdiplam

EXPERIMENTAL

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

Interventions

Placebo DRUG

Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).

Part 1 Group A: Adolescents and Adults (Placebo); Part 1 Group B: Children (Placebo); Part 2: Placebo

Risdiplam DRUG

Risdiplam will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube).

Also known as: RO7034067

Part 1 Group A: Adolescents and Adults (Placebo); Part 1 Group A: Adolescents and Adults (Risdiplam); Part 1 Group B: Children (Placebo); Part 1 Group B: Children (Risdiplam); Part 2: Placebo; Part 2: Risdiplam

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (45)

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Columbia University Medical Center; The Neurological Institute of New York

New York, New York, 10032, United States

Location

UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven Gasthuisberg

Leuven, 3000, Belgium

Location

Chr de La Citadelle

Liège, 4000, Belgium

Location

Instituto de Puericultura E Pediatria Martagão Gesteira

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

Location

Alberta Children's Hospital Division of Pediatric Neurology

Calgary, Alberta, T3B 6A8, Canada

Location

London Health Sciences Centre; Children's Hospital; Pediatrics

London, Ontario, N6A 5W9, Canada

Location

McGill University Health Centre - Glen Site

Montreal, Quebec, H4A 3J1, Canada

Location

Peking University First Hospital

Beijing, 100034, China

Location

Children's Hospital of Fudan University

Shanghai, 201102, China

Location

Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics

Zagreb, 10000, Croatia

Location

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

Bron, 69677, France

Location

Hopital Roger Salengro

Lille, 59037, France

Location

CHU de Nantes - Hotel Dieu

Nantes, 44093, France

Location

Hôpital Necker-Enfants Malades; Service de neuropédiatrie

Paris, 75015, France

Location

Hopital Armand Trousseau

Paris, 75571, France

Location

Universitätsklinikum Freiburg; Klinik für Neuropädiatrie und Muskelerkrankungen

Freiburg im Breisgau, 79106, Germany

Location

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

Rome, Lazio, 00165, Italy

Location

Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile

Rome, Lazio, 00168, Italy

Location

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

Genoa, Liguria, 16147, Italy

Location

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

Milan, Lombardy, 20122, Italy

Location

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

Milan, Lombardy, 20133, Italy

Location

Fukuoka Children's Hospital

Fukuoka, 813-0017, Japan

Location

Hiroshima University Hospital

Hiroshima, 734-8551, Japan

Location

Hyogo Medical University Hospital

Hyōgo, 663-8501, Japan

Location

Minami Kyushu National Hospital

Kagoshima, 899-5293, Japan

Location

Miyagi Children's Hospital

Miyagi, 989-3126, Japan

Location

Shiga Medical Center for Children

Shiga, 524-0022, Japan

Location

Shizuoka Children's Hospital

Shizuoka, 420-8660, Japan

Location

Jichi Medical University Hospital

Tochigi, 329-0498, Japan

Location

Center Hospital of the National Center for Global Health and Medicine

Tokyo, 162-0052, Japan

Location

National Center Of Neurology And Psychiatry Hospital

Tokyo, 187-8551, Japan

Location

Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology

Gda?sk, 80-952, Poland

Location

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

Późna, 60-355, Poland

Location

Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie

Warsaw, 02-097, Poland

Location

Russian Children Neuromuscular Center of Veltischev

Moscow, Moscow Oblast, 125412, Russia

Location

Clinic for Neurology and Psychiatry for Children and Youth

Belgrade, 11000, Serbia

Location

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, 08950, Spain

Location

Hospital Universitari Vall d'Hebron; Servicio de Reumatologia

Barcelona, 08035, Spain

Location

Hospital Universitario La Paz

Madrid, 280146, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

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

Ankara, 06100, Turkey (Türkiye)

Location

Hospital Yeditepe University Kozyatagi; Pediatry

Atasehir- Istanbul, 34752, Turkey (Türkiye)

Location

University of Oxford; Department of Paediatrics

Headington, OX3 9DU, United Kingdom

Location

Related Publications (2)

• Cleary Y, Kletzl H, Grimsey P, Heinig K, Ogungbenro K, Silber Baumann HE, Frey N, Aarons L, Galetin A, Gertz M. Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children. Clin Pharmacokinet. 2023 Jun;62(6):891-904. doi: 10.1007/s40262-023-01241-7. Epub 2023 May 6.

  PMID: 37148485 DERIVED

• 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.

  PMID: 34942136 DERIVED

Related Links

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

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Risdiplam

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: September 19, 2016
• First Posted: September 21, 2016
• Study Start: October 19, 2016
• Primary Completion: September 6, 2019
• Study Completion: October 2, 2023
• Last Updated: April 24, 2024
• Results First Posted: June 15, 2021

Record last verified: 2024-03

Locations

GB (1); DE (1); CN (2); JP (10); ES (4); CA (3); PL (3); RU (1); BR (1); IT (5); TU (2); CR (1); FR (5); US (2); BE (3); SE (1)