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

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ClinicalTrials.gov Identifier: NCT02292537
Recruitment Status : Completed
First Posted : November 17, 2014
Results First Posted : February 21, 2018
Last Update Posted : February 21, 2018
Sponsor:
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE November 12, 2014
First Posted Date  ICMJE November 17, 2014
Results First Submitted Date October 17, 2017
Results First Posted Date February 21, 2018
Last Update Posted Date February 21, 2018
Actual Study Start Date  ICMJE November 24, 2014
Actual Primary Completion Date February 20, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2018)
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15 [ Time Frame: Baseline and 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 12, 2014)
Change from baseline in Hammersmith Functional Motor Scale - Expanded score [ Time Frame: At 15 Months ]
Change History Complete list of historical versions of study NCT02292537 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2018)
  • Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15 [ Time Frame: Baseline and 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.
  • Proportion of Participants That Achieved Any New Motor Milestone at Month 15 [ Time Frame: 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.
  • Number of New Motor Milestones Achieved Per Participant [ Time Frame: 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.
  • Change From Baseline in Revised Upper Limb Module (RULM) Test [ Time Frame: Baseline and Month 15 ]
    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.
  • Proportion of Participants That Achieved Standing Alone [ Time Frame: Month 15 ]
    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.
  • Proportion of Participants That Achieved Walking With Assistance [ Time Frame: Month 15 ]
    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.
  • Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline through Month 15 ]
    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.
  • Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Baseline through Month 15 ]
    Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.
  • Number of Participants With Clinically Significant Weight Abnormalities [ Time Frame: Baseline through Month 15 ]
    Weight changes assessed from Baseline to Month 15.
  • Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: Baseline through Month 15 ]
    Neurological changes assessed for clinical significance include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.
  • Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: Baseline through Month 15 ]
    Physical examination changes were assessed for clinical significance.
  • Number of Participants With Clinically Significant Laboratory Parameter Abnormalities [ Time Frame: Baseline through Month 15 ]
    Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.
  • Number of Participants With Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results [ Time Frame: Baseline through Month 15 ]
    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.
  • Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure [ Time Frame: Baseline through Month 15 ]
    Concomitant medications include prescription and over-the-counter medications administered to participants on or after the first day of study treatment.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2014)
  • Proportion of subjects who achieve a 3-point increase from baseline in Hammersmith Functional Motor Scale - Expanded score [ Time Frame: At 15 Months ]
  • Proportion of subject that achieve any new motor milestone [ Time Frame: At 15 Months ]
  • Number of motor milestones achieved per subject [ Time Frame: At 15 Months ]
  • Change from baseline in Upper Limb Module Test [ Time Frame: At 15 Months ]
  • Proportion of subjects that achieve standing alone [ Time Frame: At 15 months ]
  • Proportion of subject that achieve walking with assistance [ Time Frame: At 15 Months ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Spinal Muscular Atrophy
Intervention  ICMJE
  • Drug: Nusinersen
    Administered by intrathecal (IT) lumbar puncture (LP) injection
    Other Names:
    • Sprinraza
    • ISIS 396443
    • IONIS-SMN Rx
    • BIIB058
  • Procedure: Sham procedure
    Small needle prick on the lower back at the location where the IT injection is normally made
Study Arms
  • Experimental: Nusinersen
    Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.
    Intervention: Drug: Nusinersen
  • Sham Comparator: Sham procedure
    Sham comparator on Days 1, 29, 85 and 274.
    Intervention: Procedure: Sham procedure
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 22, 2017)
126
Original Estimated Enrollment  ICMJE
 (submitted: November 12, 2014)
117
Actual Study Completion Date February 20, 2017
Actual Primary Completion Date February 20, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender
Sexes Eligible for Study: All
Ages 2 Years to 12 Years   (Child)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Germany,   Hong Kong,   Italy,   Japan,   Korea, Republic of,   Spain,   Sweden,   United States
Removed Location Countries United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02292537
Other Study ID Numbers  ICMJE ISIS 396443-CS4
2014-001947-18 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP