Clinical trial NCT02193074: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
Official title: A Phase 3, Randomized, Double-Blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Infantile-onset Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS-SMN Rx
ISIS 396443
IONIS-SMNRx
IONIS-SMN Rx
Spinraza
ENDEAR
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2014-07-17
Enrollment: 122
Sex: ALL
Maximum age (years): 210
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally (IT) to participants with infantile-onset with infantile-onset spinal muscular atrophy (SMA). The secondary objective of the study is to examine the safety and tolerability of nusinersen administered intrathecally to participants with infantile-onset SMA.

Detailed description: This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc..

In August 2016, sponsorship of the trial was transferred to Biogen.

Eligibility criteria: Key Inclusion Criteria:

* Be born (gestational age) between 37 and 42 weeks
* Be medically diagnosed with spinal muscular atrophy (SMA)
* Have Survival Motor Neuron2 (SMN2) Copy number = 2
* Body weight equal to or greater than 3rd percentile for age using appropriate country-specific guidelines
* Be able to follow all study procedures
* Reside within approximately 9 hours ground-travel distance from a participating study center, for the duration of the study

Key Exclusion Criteria:

* Hypoxemia (oxygen \[O2\] saturation awake less than 96% or O2 saturation asleep less than 96%, without ventilation support) during screening evaluation
* Clinically significant abnormalities in hematology or clinical chemistry parameters or Electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit that would render the participant unsuitable for participation in the study
* Participant's parent or legal guardian is not willing to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Percentage of Motor Milestones Responders
timeFrame: assessed at the later of the Day 183, Day 302, or Day 394 study visits
measure: Time to Death or Permanent Ventilation
timeFrame: Day 91, Day 182, Day 273, Day 364, Day 394
Secondary outcomes:
measure: Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders
timeFrame: assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
measure: Summary of Time to Death
timeFrame: Day 91, Day 182, Day 273, Day 364, Day 394
measure: Percentage of Participants Not Requiring Permanent Ventilation
timeFrame: Up to Day 394
measure: Percentage of Compound Muscular Action Potential (CMAP) Responders
timeFrame: assessed at the later of the Day 183, Day 302, or Day 394 study visits
measure: Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration
timeFrame: Day 91, Day 182, Day 273, Day 364, Day 394
measure: Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration
timeFrame: Day 91, Day 182, Day 273, Day 364, Day 394
measure: Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs
timeFrame: Screening through Day 394 (± 7 days) or early termination
measure: Number of Participants With AEs Corresponding to Changes in Hematology Values
timeFrame: up to Day 394 (± 7 days) or early termination
measure: Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
timeFrame: up to Day 394 (± 7 days) or early termination
measure: Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
timeFrame: up to Day 394 (± 7 days) or early termination
measure: Summary of Shifts in 12-lead Electrocardiogram (ECG) Results
timeFrame: up to Day 394 (± 7 days) or early termination
measure: Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
timeFrame: up to Day 394 (± 7 days) or early termination
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke Children's Hospital
state: North Carolina
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia - Neurology
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center/Children's Medical Center Dallas
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center (University of Utah)
state: Utah
city: Sydney
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children's Hospital, Children's Neuroscience Centre
state: Victoria
city: Brussels
country: Belgium
facility: Hôpital Universitaire des Enfants Reine FABIOLA (HUDERF)
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital/UBC
state: British Columbia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Paris
country: France
facility: Institut de Myologie
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Freiburg
country: Germany
facility: Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen
city: Genova
country: Italy
facility: Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative
city: Rome
country: Italy
facility: Pediatric Neurology Unit, Catholic University
city: Nishinomiya
country: Japan
facility: Hyogo College of Medicine
state: Hyogo
city: Tokyo
country: Japan
facility: Tokyo Women's Medical University
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz, Pediatric Neurology Department
city: Gothenburg
country: Sweden
facility: University of Gothenburg, The Queen Silvia Children's Hospital
city: Ankara
country: Turkey
facility: Hacettepe Children's Hospital
city: London
country: United Kingdom
facility: UCL Institute of Child Health/Great Ormond Street
city: Newcastle
country: United Kingdom
facility: MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.
citation: Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, Pivneva I, Wu EQ, Arjunji R, Feltner D, Sproule DM. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1. Adv Ther. 2019 May;36(5):1164-1176. doi: 10.1007/s12325-019-00923-8. Epub 2019 Mar 16.
citation: Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.
citation: Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. doi: 10.1016/S0140-6736(16)31408-8. Epub 2016 Dec 7.