Clinical trial NCT02292537: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)
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 Later-onset Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS-SMN Rx
ISIS 396443
CHERISH
IONIS-SMNRx
IONIS-SMN Rx
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2014-11-17
Enrollment: 126
Sex: ALL
Minimum age (years): 2
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy (SMA). The secondary objective is to examine the safety and tolerability of nusinersen administered intrathecally to participants with later-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:

* Parent or guardian has signed informed consent and, if indicated per participant's age and institutional guidelines, participant has signed informed assent
* Be medically diagnosed with Spinal Muscular Atrophy (SMA)
* Have onset of clinical signs and symptoms consistent with SMA at greater than 6 months of age
* Be able to sit independently, but has never had the ability to walk independently
* Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater than or equal to 10 and less than or equal to 54 at Screening
* Be able to complete all study procedures, measurements and visits and parent or guardian and subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
* Have an estimated life expectancy of greater than 2 years from Screening, in the opinion of the Investigator
* Meet age-appropriate institutional criteria for use of anesthesia and sedation, if use is planned for study procedures
* For subjects who have reached reproductive maturity, satisfy study contraceptive requirements

Key Exclusion Criteria:

* Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for greater than 6 hours during a 24 hour period, at Screening
* Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
* Severe contractures or severe scoliosis evident on X-ray examination at Screening
* Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support within 2 months of Screening or planned during the duration of the study
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
* History of brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT) that would interfere with the LP procedures or cerebrospinal fluid (CSF) circulation
* Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter
* History of bacterial meningitis
* Dosing with IONIS-SMN Rx in any previous clinical study
* Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject's ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline
* 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 subject unsuitable for inclusion
* Treatment with another investigational drug (e.g., oral albuterol or salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of Screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation.
* Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures.

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

Primary outcomes:
measure: Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15
timeFrame: Baseline and Month 15
Secondary outcomes:
measure: Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15
timeFrame: Baseline and Month 15
measure: Proportion of Participants That Achieved Any New Motor Milestone at Month 15
timeFrame: Month 15
measure: Number of New Motor Milestones Achieved Per Participant
timeFrame: Month 15
measure: Change From Baseline in Revised Upper Limb Module (RULM) Test
timeFrame: Baseline and Month 15
measure: Proportion of Participants That Achieved Standing Alone
timeFrame: Month 15
measure: Proportion of Participants That Achieved Walking With Assistance
timeFrame: Month 15
measure: Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline through Month 15
measure: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: Baseline through Month 15
measure: Number of Participants With Clinically Significant Weight Abnormalities
timeFrame: Baseline through Month 15
measure: Number of Participants With Clinically Significant Neurological Examination Abnormalities
timeFrame: Baseline through Month 15
measure: Number of Participants With Clinically Significant Physical Examination Abnormalities
timeFrame: Baseline through Month 15
measure: Number of Participants With Clinically Significant Laboratory Parameter Abnormalities
timeFrame: Baseline through Month 15
measure: Number of Participants With Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results
timeFrame: Baseline through Month 15
measure: Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure
timeFrame: Baseline through Month 15
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Clinical and Translational Research Center
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford
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: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia - Neurology
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Medical Center
state: Texas
city: London
country: Canada
facility: Children's Hospital - London Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre-Glen Site-CIM
state: Quebec
city: Paris
country: France
facility: Armand Trousseau Hospital, I-Motion, Clinical Trials Platform
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Freiburg
country: Germany
facility: University Hospital Freiberg, Center for Paediatrics and Adolescent Medicine, Department of Neuropaediatrics and Muscular Disease
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong, Queen Mary Hospital, Department of Paediatrics and Adolescent Medicine
state: Hong Kong SAR
city: Messina
country: Italy
facility: AOU Policlinico G. Martino Dipartimento di Neuroscienze e Centro Clinico Nemo Sud
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli-Universita Cattolica de Sacro Cuore-UOC Neuropsichiatre Infantile
city: Nishinomya-shi
country: Japan
facility: Hyogo College of Medicine
state: Hyogo
city: Shinjuku-ku
country: Japan
facility: Tokyo Women's Medical University
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Seoul National University Children's Hospital
state: Korea
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Gothenburg
country: Sweden
facility: University of Gothenburg, The Queen Silvia Children's Hospital
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: Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, Iannaccone ST, Kirschner J, Kuntz NL, Saito K, Shieh PB, Tulinius M, Mazzone ES, Montes J, Bishop KM, Yang Q, Foster R, Gheuens S, Bennett CF, Farwell W, Schneider E, De Vivo DC, Finkel RS; CHERISH Study Group. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018 Feb 15;378(7):625-635. doi: 10.1056/NEJMoa1710504.