Clinical trial NCT02913482: Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy
Official title: A Two Part Seamless, Open-label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Infants With Type 1 Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Muscular Atrophy, Spinal
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-09-23
Enrollment: 62
Sex: ALL
Minimum age (years): 1
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* Therapeutic use, defined as use for 8 weeks or longer, of the following medications within 90 days prior to enrollment: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, medications known to or suspected of causing retinal toxicity (deferoxamine, topiramate, latanoprost, niacin, rosiglitazone, tamoxifen, canthaxanthine, sildenafil, and interferon) and medications with known phototoxicity liabilities (e.g., oral retinoids including over-the-counter \[OTC\] formulations, amiodarone, phenothiazines and use of minocycline)

Primary outcomes:
measure: Part 1: Selected Part 2 Dose of Risdiplam
timeFrame: Minimum of 2 weeks at steady state exposure
measure: 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
timeFrame: Month 12
Secondary outcomes:
measure: 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
timeFrame: Month 12
measure: Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12
timeFrame: Month 8, Month 12
measure: 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
timeFrame: Month 8, Month 12, Month 24
measure: Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24
timeFrame: Baseline, Month 12, Month 24
measure: 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
timeFrame: Month 8
measure: Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12
timeFrame: Month 12
measure: Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24
timeFrame: Month 24
measure: Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24
timeFrame: Month 24
measure: Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24
timeFrame: Month 24
measure: Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24
timeFrame: Month 24
measure: Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24
timeFrame: Month 24
measure: Part 2: Time to Death
timeFrame: Up to 24 months
measure: Part 2: Time to Death or Permanent Ventilation
timeFrame: Up to 24 months
measure: Part 2: Time to Permanent Ventilation
timeFrame: Up to 24 months
measure: Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 2: Percentage of Infants Who Are Alive at Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12
timeFrame: Month 12
measure: Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24
timeFrame: Month 12, Month 24
measure: Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose up to 30 days after last dose of risdiplam (up to 60 months)
measure: Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation
timeFrame: From first dose up to 30 days after last dose of risdiplam (up to 60 months)
measure: Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption
timeFrame: From first dose up to 30 days after last dose of risdiplam (up to 60 months)
measure: Part 2: Anthropometric Examination of Weight Measured in Kilograms
timeFrame: Month 12, Month 24
measure: Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters
timeFrame: Month 12, Month 24
measure: Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam
timeFrame: Day 1: 2, 4, 6, 24 hours post dose; Days 14, 119, 245, 364, 427, 490, 609, 728: predose ; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours post dose
measure: Part 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit
timeFrame: Year 5 visit: pre-dose
measure: Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5
timeFrame: Predose at Year 5
measure: Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood
timeFrame: Days 1, 28, 119, 245, 364, 609, 728, 819 and 1820
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Childrens Hospital
state: Massachusetts
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: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP_X; Neurologia
state: SP
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: Paris
country: France
facility: Hopital Armand Trousseau
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: Hyogo
country: Japan
facility: Hyogo Medical University Hospital
city: Gda?sk
country: Poland
facility: Szpital Gdanskiego Uniwersytetu Medycznego; Clinic of developmental neurology
city: Warszawa
country: Poland
facility: The Children?s Memorial Health Institute Department of Neurology and Epileptology
city: Moscow
country: Russian Federation
facility: Russian Children Neuromuscular Center of Veltischev
state: Moskovskaja Oblast
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital and Research Centre Building
city: Belgrade
country: Serbia
facility: Institute for Mother and Child Dr. Vukan Cupic
city: Esplugues De Llobregas
country: Spain
facility: Hospital Sant Joan De Deu
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Area Genética Clínica y Molecular
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Basel
country: Switzerland
facility: Universitäts-Kinderspital (UKBB) Neuropädiatrie
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: Kharkov
country: Ukraine
facility: Ams of Ukraine; Inst. of Neurology, Psychiatry & Narcology
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.