Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy

NCT02913482 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: BP390562016-000778-40
• Study Type: interventional
• Target: 62
• Locations: 16 countries
• Sites: 32

Brief Summary

Open-label, multi-center clinical study is to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and efficacy of Risdiplam (RO7034067) in infants with Type 1 spinal muscular atrophy (SMA). The study consists of two parts, an exploratory dose finding part (Part 1) and a confirmatory part (Part 2) which will investigate Risdiplam (RO7034067) for 24-months at the dose selected in Part 1.

Conditions

Muscular Atrophy, Spinal

Outcome Measures

Primary Outcomes (2)

• Part 1: Selected Part 2 Dose of Risdiplam

  All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The 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.

  Minimum of 2 weeks at steady state exposure

• Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at Month 12

  The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

  Month 12

Secondary Outcomes (31)

• Part 2: Percentage of Infants Who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12

  Month 12

• Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12

  Month 8, Month 12

• Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24

  Month 8, Month 12, Month 24

• Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24

  Baseline, Month 12, Month 24

• Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8

  Month 8

Study Arms (2)

Part 1 (Dose Finding): Risdiplam (RO7034067)

EXPERIMENTAL

Participants will receive multiple ascending doses of risdiplam (RO7034067), administered orally once daily for a minimum of 4 weeks to select the dose for Part 2. During the first year of treatment, most participants will switch to the Part 2 dose. During the second year of treatment, all Part 1 participants will be receiving the Part 2 dose. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.

Drug: Risdiplam

Part 2 (Confirmatory): Risdiplam (RO7034067)

EXPERIMENTAL

Participants will receive risdiplam (RO7034067), administered orally once daily at the dose defined in Part 1 of the study, for a duration of 24 months. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose.

Drug: Risdiplam

Interventions

Risdiplam DRUG

Risdiplam will be administered orally.

Also known as: RO7034067, Evrysdi

Part 1 (Dose Finding): Risdiplam (RO7034067); Part 2 (Confirmatory): Risdiplam (RO7034067)

Eligibility Criteria

• Age: 1 Month - 7 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Clinical history, signs or symptoms attributable to Type 1 SMA with onset after 28 days but prior to the age of 3 months
• Gestational age of 37 to 42 weeks
• Confirmed diagnosis of 5q-autosomal recessive SMA
• Participants has two survival motor neuron 2 (SMN2) gene copies, as confirmed by central testing
• Body weight greater than or equal to (\>=) third percentile for age, using appropriate country-specific guidelines
• Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
• Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator

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, whichever is longer
• Concomitant or previous administration of SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy study
• Any history of cell therapy
• Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
• Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
• Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
• Participants requiring invasive ventilation or tracheostomy
• Participants requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation less than \[\<\] 95 percent \[%\]) with or without ventilator support
• Participants with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening
• Multiple or fixed contractures and/or hip subluxation or dislocation at birth
• Presence of non-SMA related concurrent syndromes or diseases
• 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
• Any inhibitor of cytochrome P450 (CYP) 3A4 and/or any Organic Cation Transporter 2 (OCT-2) and multidrug and toxin extrusion (MATE) substrates taken within 2 weeks and/or any inducer of CYP3A4 taken within 4 weeks (or within 5-times the elimination half-life, whichever is longer) prior to dosing or participants (and the mother, if breastfeeding the infant) taking any nutrients known to modulate CYP3A activity and any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
• Prior use (at any time in the participants lives) and/or anticipated need for quinolones (chloroquine and hydroxychloroquine), thioridazine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxycholoroquine, thioridazine, vigabatrin, retigabine or drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled.
• Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (32)

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Ann and Robert H. Lurie Children Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Boston Childrens Hospital

Boston, Massachusetts, 02115, 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

Hospital das Clinicas - FMUSP_X; Neurologia

São Paulo, São Paulo, 05403-000, Brazil

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 Armand Trousseau

Paris, 75571, France

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

Hyogo Medical University Hospital

Hyōgo, 663-8501, Japan

Location

Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology

Gda?sk, 80-952, Poland

Location

The Children?s Memorial Health Institute Department of Neurology and Epileptology

Warsaw, 04-730, Poland

Location

Russian Children Neuromuscular Center of Veltischev

Moscow, Moscow Oblast, 125412, Russia

Location

King Faisal Specialist Hospital and Research Centre Building

Riyadh, 11211, Saudi Arabia

Location

Institute for Mother and Child Dr. Vukan Cupic

Belgrade, 11000, Serbia

Location

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, 08950, Spain

Location

Hospital Universitari Vall d'Hebron; Area Genética Clínica y Molecular

Barcelona, 08035, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

Universitäts-Kinderspital (UKBB) Neuropädiatrie

Basel, 4005, Switzerland

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

Ams of Ukraine; Inst. of Neurology, Psychiatry & Narcology

Kharkiv, 61068, Ukraine

Location

Related Publications (5)

• 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

• Masson R, Mazurkiewicz-Beldzinska M, Rose K, Servais L, Xiong H, Zanoteli E, Baranello G, Bruno C, Day JW, Deconinck N, Klein A, Mercuri E, Vlodavets D, Wang Y, Dodman A, El-Khairi M, Gorni K, Jaber B, Kletzl H, Gaki E, Fontoura P, Darras BT; FIREFISH Study Group. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022 Dec;21(12):1110-1119. doi: 10.1016/S1474-4422(22)00339-8. Epub 2022 Oct 14.

  PMID: 36244364 DERIVED

• Cances C, Vlodavets D, Comi GP, Masson R, Mazurkiewicz-Beldzinska M, Saito K, Zanoteli E, Dodman A, El-Khairi M, Gorni K, Gravestock I, Hoffart J, Scalco RS, Darras BT; ANCHOVY Working Group. Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study. Orphanet J Rare Dis. 2022 Jul 29;17(1):300. doi: 10.1186/s13023-022-02455-x.

  PMID: 35906608 DERIVED

• Darras BT, Masson R, Mazurkiewicz-Beldzinska M, Rose K, Xiong H, Zanoteli E, Baranello G, Bruno C, Vlodavets D, Wang Y, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

  PMID: 34320287 DERIVED

• Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, Mercuri E, Rose K, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Seabrook T, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021 Mar 11;384(10):915-923. doi: 10.1056/NEJMoa2009965. Epub 2021 Feb 24.

  PMID: 33626251 DERIVED

Related Links

• roche-sma-clinicaltrials.com provides information about the Roche Firefish clinical trial NCT02913482 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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2016
• First Posted: September 23, 2016
• Study Start: December 23, 2016
• Primary Completion: November 14, 2019
• Study Completion: December 22, 2023
• Last Updated: August 7, 2024
• Results First Posted: January 8, 2021

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share

Locations

BR (2); IT (5); FR (2); CH (1); RU (1); SE (1); CR (1); US (4); SA (1); ES (3); TU (2); BE (3); UA (1); CN (2); JP (1); PL (2)