A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA) (CHERISH)

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

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.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Nusinersen; Procedure: Sham procedure

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.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital - London Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H4A 3JI
      • McGill University Health Centre-Glen Site-CIM
• France
  • Paris, France
    • Armand Trousseau Hospital, I-Motion, Clinical Trials Platform
• Germany
  • Essen, Germany
    • Universitätsklinikum Essen
  • Freiburg, Germany
    • University Hospital Freiberg, Center for Paediatrics and Adolescent Medicine, Department of Neuropaediatrics and Muscular Disease
• Hong Kong
  • Hong Kong SAR
    • Hong Kong, Hong Kong SAR, Hong Kong
      • The University of Hong Kong, Queen Mary Hospital, Department of Paediatrics and Adolescent Medicine
• Italy
  • Messina, Italy
    • AOU Policlinico G. Martino Dipartimento di Neuroscienze e Centro Clinico Nemo Sud
  • Rome, Italy
    • Fondazione Policlinico Universitario Agostino Gemelli-Universita Cattolica de Sacro Cuore-UOC Neuropsichiatre Infantile
• Japan
  • Hyogo
    • Nishinomya-shi, Hyogo, Japan
      • Hyogo College of Medicine
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan
      • Tokyo Women's Medical University
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of
      • Seoul National University Children's Hospital
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Deu
• Sweden
  • Gothenburg, Sweden
    • University of Gothenburg, The Queen Silvia Children's Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Clinical and Translational Research Center
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital at Stanford
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia - Neurology
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 12 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nusinersen; Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.	Drug: Nusinersen; Administered by intrathecal (IT) lumbar puncture (LP) injection; Other Names: ISIS 396443; BIIB058; IONIS-SMN Rx; Sprinraza
SHAM_COMPARATOR: Sham procedure; Sham comparator on Days 1, 29, 85 and 274.	Procedure: Sham procedure; Small needle prick on the lower back at the location where the IT injection is normally made

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15	The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.	Baseline and Month 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15	The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.	Baseline and Month 15
Proportion of Participants That Achieved Any New Motor Milestone at Month 15	New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.	Month 15
Number of New Motor Milestones Achieved Per Participant	New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.	Month 15
Change From Baseline in Revised Upper Limb Module (RULM) Test	The RULM Test is used in patients with SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test has a total of 20 items with an entry item that serves as functional class identification and does not contribute to the total score. The remaining 19 scorable items reflect different functional domains and are graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). There is only 1 item (item I) that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for a total score range of 0-37, with higher scores increased great upper limb function. A positive change from Baseline indicates improvement.	Baseline and Month 15
Proportion of Participants That Achieved Standing Alone	If the participant was unable to achieve standing alone at Baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.	Month 15
Proportion of Participants That Achieved Walking With Assistance	If the participant was unable to achieve walking with assistance at baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.	Month 15
Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)	AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death; an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.	Baseline through Month 15
Number of Participants With Clinically Significant Vital Sign Abnormalities	Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.	Baseline through Month 15
Number of Participants With Clinically Significant Weight Abnormalities	Weight changes assessed from Baseline to Month 15.	Baseline through Month 15
Number of Participants With Clinically Significant Neurological Examination Abnormalities	Neurological changes assessed for clinical significance include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.	Baseline through Month 15
Number of Participants With Clinically Significant Physical Examination Abnormalities	Physical examination changes were assessed for clinical significance.	Baseline through Month 15
Number of Participants With Clinically Significant Laboratory Parameter Abnormalities	Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.	Baseline through Month 15
Number of Participants With Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results	The number of participants with abnormal, clinically relevant worsening, defined as participants with an ECG interpreted as abnormal and clinically relevant, with a comparison with Baseline value is reported.	Baseline through Month 15
Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure	Concomitant medications include prescription and over-the-counter medications administered to participants on or after the first day of study treatment.	Baseline through Month 15

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Cure SMA
• Muscular Dystrophy Association
• National Organization for Rare Diseases

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 24, 2014
• Primary Completion (ACTUAL): February 20, 2017
• Study Completion (ACTUAL): February 20, 2017

Study Registration Dates

• First Submitted: November 12, 2014
• First Submitted That Met QC Criteria: November 12, 2014
• First Posted (ESTIMATE): November 17, 2014

Study Record Updates

• Last Update Posted (ACTUAL): February 17, 2021
• Last Update Submitted That Met QC Criteria: February 12, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx; ISIS 396443; IONIS-SMNRx; IONIS-SMN Rx; ISIS-SMN Rx; CHERISH
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: ISIS 396443-CS4; 2014-001947-18 (EUDRACT_NUMBER)