Clinical trial NCT02386553: A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Official title: An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: NURTURE
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2015-03-12
Enrollment: 25
Sex: ALL
Minimum age (years): 6
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: The primary objective of the study is to examine the efficacy of multiple doses of Nusinersen administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA). Secondary objectives of this study are to examine the effects of Nusinersen in infants with genetically diagnosed and presymptomatic SMA.


Eligibility criteria: Key Inclusion Criteria:

* Age ≤ 6 weeks at first dose.
* Genetic documentation of 5q SMA homozygous gene deletion or mutation or compound heterozygous mutation.
* Genetic documentation of 2 or 3 copies of survival motor neuron 2 (SMN2).
* Ulnar compound muscle action potential (CMAP) ≥ 1 mV at Baseline.
* Gestational age of 37 to 42 weeks for singleton births; gestational age of 34 to 42 weeks for twins.
* Meet additional study related criteria.

Key Exclusion Criteria:

* Hypoxemia (oxygen saturation \<96% awake or asleep without any supplemental oxygen or respiratory support).
* Any clinical signs or symptoms at Screening or immediately prior to the first dosing (Day 1) that are, in the opinion of the Investigator, strongly suggestive of SMA.
* Clinically significant abnormalities in hematology or clinical chemistry parameters.
* Treatment with an investigational drug given for the treatment of SMA biological agent, or device. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation.
* Meet additional study related criteria.

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

Primary outcomes:
measure: Time to death or respiratory intervention
timeFrame: Up to Day 2891
Secondary outcomes:
measure: Percentage of participants developing clinically manifested spinal muscular atrophy (SMA)
timeFrame: At 13 and 24 months of age
measure: Percentage of participants alive
timeFrame: At 13 months, and 2, 3, 4, 5, 6, 7 and 8 years of age
measure: Percentage of participants who attained motor milestones assessed as part of the Hammersmith Infant Neurological Examination (HINE)
timeFrame: At 13 and 24 months of age
measure: Percentage of participants who attained motor milestones as assessed by World Health Organization (WHO) criteria
timeFrame: Up to Day 2891
measure: Change from Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale
timeFrame: Up to Day 2891
measure: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE)
timeFrame: Up to Day 2891
measure: Change from Baseline in weight for age/length
timeFrame: Up to Day 2891
measure: Change from Baseline in head circumference
timeFrame: Up to Day 2891
measure: Change from Baseline in chest circumference ratio
timeFrame: Up to Day 2891
measure: Change from Baseline in head to chest circumference ratio
timeFrame: Up to Day 2891
measure: Change from Baseline in arm circumference ratio
timeFrame: Up to Day 2891
measure: Incidence of adverse events (AEs) and/or serious adverse events (SAEs)
timeFrame: Up to Day 2891
measure: Change from Baseline in clinical laboratory parameters
timeFrame: Up to Day 2891
measure: Change from Baseline in electrocardiograms (ECGs)
timeFrame: Up to Day 2891
measure: Change from Baseline in vital signs
timeFrame: Up to Day 2891
measure: Change from Baseline in neurological examinations
timeFrame: Up to Day 2891
measure: Cerebrospinal fluid (CSF) and plasma Nusinersen concentrations
timeFrame: Up to Day 2801
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: David Geffen School of Medicine
state: California
city: Sacramento
country: United States
facility: University of California Davis Health System
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Orlando
country: United States
facility: Nemours Children's Hospital, Orlando
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Research Institute
state: Washington
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital de Pediatria Dr. J. P. Garrahan
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Calgary
country: Canada
facility: University of Calgary - Alberta Children's Hospital
state: Alberta
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
state: Baden-Württemberg
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
state: Lazio
city: Milano
country: Italy
facility: Fondazione Serena Onlus - Centro Clinico Nemo
city: Doha
country: Qatar
facility: Hamad General Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Istanbul
country: Turkey
facility: Yeditepe University Medical School Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: Greater London
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
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.