Clinical trial NCT02908685: 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: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Muscular Atrophy, Spinal
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-09-21
Enrollment: 231
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg
timeFrame: Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
measure: Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg
timeFrame: Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
measure: Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12
timeFrame: Baseline (Day-1) and Month 12
Secondary outcomes:
measure: Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12
timeFrame: At Month 12
measure: Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12
timeFrame: At Month 12
measure: 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
timeFrame: At Month 12
measure: 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
timeFrame: At Month 12
measure: Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years
timeFrame: Baseline (Day-1) and Month 12
measure: Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12
timeFrame: Baseline (Day-1) and Month 12
measure: 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
timeFrame: At Month 12
measure: Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12
timeFrame: Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
measure: Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12
timeFrame: Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
measure: Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period
timeFrame: Day 1 up to 12 months of the placebo-controlled period
measure: Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period
timeFrame: Day 1 up to 12 months of the placebo-controlled period
measure: 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
timeFrame: Day 1 up to 12 months of the placebo-controlled period
measure: 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
timeFrame: Day 1 up to 12 months of the placebo-controlled period
measure: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood
timeFrame: Part 1: Day -1, pre-dose of Weeks 1, 2 (>/= 12 years only), 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52. Part 2: Day -1, pre-dose of Weeks 1, 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52.
measure: Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5
timeFrame: Day 1: 1, 2, 4, 6 h postdose, Weeks 4, 8 (Part 1 only), 52, 87: pre-dose, 1, 2, 4, 6 h post-dose and Weeks 1 (Day 7), 2, 8 (Part 2 only) 17, 35, 70, 104: predose
measure: Part 1 and 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit
timeFrame: Year 5 visit pre-dose, 1, 2, 4, 6, 24 hours post-dose
measure: Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5
timeFrame: The last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration.
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: New York
country: United States
facility: Columbia University Medical Center; The Neurological Institute of New York
state: New York
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Liège
country: Belgium
facility: Chr de La Citadelle
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura E Pediatria Martagão Gesteira
state: RJ
city: Calgary
country: Canada
facility: Alberta Children's Hospital Division of Pediatric Neurology
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre; Children's Hospital; Pediatrics
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre - Glen Site
state: Quebec
city: Beijing City
country: China
facility: Peking University First Hospital
city: Shanghai
country: China
facility: Children's Hospital of Fudan University
city: Zagreb
country: Croatia
facility: Clinical Medical Center Zagreb; University Hospital Rebro Department of Paediatrics
city: Bron
country: France
facility: Hopital Femme Mere Enfant; Medecine Physique et Readaptation Pediatrique ? L?ESCALE
city: Lille
country: France
facility: Hopital Roger Salengro
city: Nantes
country: France
facility: CHU de Nantes - Hotel Dieu
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades; Service de neuropédiatrie
city: Paris
country: France
facility: Hopital Armand Trousseau
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg; Klinik für Neuropädiatrie und Muskelerkrankungen
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù; U.O. Malattie Neuromuscolari e Neurodegenerative
state: Lazio
city: Roma
country: Italy
facility: Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile
state: Lazio
city: Genova
country: Italy
facility: IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative
state: Liguria
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa di Neurologia
state: Lombardia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico ?Carlo Besta?; UO di Neurologia dello Sviluppo
state: Lombardia
city: Fukuoka
country: Japan
facility: Fukuoka Children's Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hyogo
country: Japan
facility: Hyogo Medical University Hospital
city: Kagoshima
country: Japan
facility: Minami Kyushu National Hospital
city: Miyagi
country: Japan
facility: Miyagi Children's Hospital
city: Shiga
country: Japan
facility: Shiga Medical Center for Children
city: Shizuoka
country: Japan
facility: Shizuoka Children's Hospital
city: Tochigi
country: Japan
facility: Jichi Medical University Hospital
city: Tokyo
country: Japan
facility: Center Hospital of the National Center for Global Health and Medicine
city: Tokyo
country: Japan
facility: National Center Of Neurology And Psychiatry Hospital
city: Gda?sk
country: Poland
facility: Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology
city: Pozna?
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu; Od. Kliniczny Neurologii Dzieci i M?odziezy
city: Warszawa
country: Poland
facility: Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie
city: Moscow
country: Russian Federation
facility: Russian Children Neuromuscular Center of Veltischev
state: Moskovskaja Oblast
city: Belgrade
country: Serbia
facility: Clinic for Neurology and Psychiatry for Children and Youth
city: Esplugues De Llobregas
country: Spain
facility: Hospital Sant Joan De Deu
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Servicio de Reumatologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Ankara
country: Turkey
facility: Hacettepe University, School of Medicine; Pediatrics Department; Pediatrics Child Neurology Unit
city: Atasehir- Istanbul
country: Turkey
facility: Hospital Yeditepe University Kozyatagi; Pediatry
city: Headington
country: United Kingdom
facility: University of Oxford; Department of Paediatrics
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.