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

NCT ID: NCT02908685

Last Updated: 2024-04-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 231 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-19
• Study Completion Date: 2023-10-02

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Risdiplam

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Risdiplam

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Risdiplam

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Risdiplam

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Risdiplam

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Risdiplam

Intervention Type: DRUG

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

Interventions

Placebo

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

Intervention Type: DRUG

Risdiplam

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

Intervention Type: DRUG

Other Intervention Names

RO7034067

Eligibility 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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Stanford University Medical Center

Palo Alto, California, United States

Columbia University Medical Center; The Neurological Institute of New York

New York, New York, United States

UZ Gent

Ghent, , Belgium

UZ Leuven Gasthuisberg

Leuven, , Belgium

Chr de La Citadelle

Liège, , Belgium

Instituto de Puericultura E Pediatria Martagão Gesteira

Rio de Janeiro, Rio de Janeiro, Brazil

Alberta Children's Hospital Division of Pediatric Neurology

Calgary, Alberta, Canada

London Health Sciences Centre; Children's Hospital; Pediatrics

London, Ontario, Canada

McGill University Health Centre - Glen Site

Montreal, Quebec, Canada

Peking University First Hospital

Beijing, , China

Children's Hospital of Fudan University

Shanghai, , China

Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics

Zagreb, , Croatia

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

Bron, , France

Hopital Roger Salengro

Lille, , France

CHU de Nantes - Hotel Dieu

Nantes, , France

Hôpital Necker-Enfants Malades; Service de neuropédiatrie

Paris, , France

Hopital Armand Trousseau

Paris, , France

Universitätsklinikum Freiburg; Klinik für Neuropädiatrie und Muskelerkrankungen

Freiburg im Breisgau, , Germany

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

Rome, Lazio, Italy

Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile

Rome, Lazio, Italy

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

Genoa, Liguria, Italy

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

Milan, Lombardy, Italy

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

Milan, Lombardy, Italy

Fukuoka Children's Hospital

Fukuoka, , Japan

Hiroshima University Hospital

Hiroshima, , Japan

Hyogo Medical University Hospital

Hyōgo, , Japan

Minami Kyushu National Hospital

Kagoshima, , Japan

Miyagi Children's Hospital

Miyagi, , Japan

Shiga Medical Center for Children

Shiga, , Japan

Shizuoka Children's Hospital

Shizuoka, , Japan

Jichi Medical University Hospital

Tochigi, , Japan

Center Hospital of the National Center for Global Health and Medicine

Tokyo, , Japan

National Center Of Neurology And Psychiatry Hospital

Tokyo, , Japan

Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology

Gda?sk, , Poland

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

Późna, , Poland

Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie

Warsaw, , Poland

Russian Children Neuromuscular Center of Veltischev

Moscow, Moscow Oblast, Russia

Clinic for Neurology and Psychiatry for Children and Youth

Belgrade, , Serbia

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, Spain

Hospital Universitari Vall d'Hebron; Servicio de Reumatologia

Barcelona, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

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

Ankara, , Turkey (Türkiye)

Hospital Yeditepe University Kozyatagi; Pediatry

Atasehir- Istanbul, , Turkey (Türkiye)

University of Oxford; Department of Paediatrics

Headington, , United Kingdom

Countries

United States; Belgium; Brazil; Canada; China; Croatia; France; Germany; Italy; Japan; Poland; Russia; Serbia; Spain; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 37148485 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34942136 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://roche-sma-clinicaltrials.com

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

Other Identifiers

2016-000750-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BP39055

Identifier Type: -

Identifier Source: org_study_id