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Spinal Muscular AtrophyPhase 3CHERISHNCT02292537

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

A Phase 3 study testing Nusinersen in people with Spinal Muscular Atrophy, run by Biogen at 24 sites in 10 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 2 to 12 years
Conditions the study is for
Spinal Muscular Atrophy
What is being tested?
Nusinersen
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
126 participants
Where
24 sitesin 10 countries
Study dates
24 Nov 2014to 20 Feb 2017
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

24 sites in 10 countries.

24 sites in 10 countries

United States11 sites
  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Boston Children's Hospital

    Boston, Massachusetts, 02115

  • Ann and Robert H. Lurie Children's Hospital of Chicago

    Chicago, Illinois, 60611

  • Children's Medical Center

    Dallas, Texas, 75235

  • UCLA Clinical and Translational Research Center

    Los Angeles, California, 90095

  • Columbia University Medical Center

    New York, New York, 10032

  • Nemours Children's Hospital

    Orlando, Florida, 32827

  • Lucile Packard Children's Hospital at Stanford

    Palo Alto, California, 94304

  • Children's Hospital of Philadelphia - Neurology

    Philadelphia, Pennsylvania, 19104

  • Oregon Health & Science University

    Portland, Oregon, 97239

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

Canada2 sites
  • Children's Hospital - London Health Sciences Centre

    London, Ontario, N6A 5W9

  • McGill University Health Centre-Glen Site-CIM

    Montreal, Quebec, H4A 3JI

Other trials in Canada

Germany2 sites
  • Universitatsklinikum Essen

    Essen

  • University Hospital Freiberg, Center for Paediatrics and Adolescent Medicine, Department of Neuropaediatrics and Muscular Disease

    Freiburg im Breisgau

Other trials in Germany

Italy2 sites
  • AOU Policlinico G. Martino Dipartimento di Neuroscienze e Centro Clinico Nemo Sud

    Messina

  • Fondazione Policlinico Universitario Agostino Gemelli-Universita Cattolica de Sacro Cuore-UOC Neuropsichiatre Infantile

    Rome

Other trials in Italy

Japan2 sites
  • Hyogo College of Medicine

    Nishinomya-shi, Hyōgo

  • Tokyo Women's Medical University

    Shinjuku-ku, Tokyo

Other trials in Japan

France1 site
  • Armand Trousseau Hospital, I-Motion, Clinical Trials Platform

    Paris

Other trials in France

Hong Kong1 site
  • The University of Hong Kong, Queen Mary Hospital, Department of Paediatrics and Adolescent Medicine

    Hong Kong, Hong Kong SAR

Other trials in Hong Kong

South Korea1 site
  • Seoul National University Children's Hospital

    Seoul, Korea

Other trials in South Korea

Spain1 site
  • Hospital Sant Joan de Deu

    Barcelona

Other trials in Spain

Sweden1 site
  • University of Gothenburg, The Queen Silvia Children's Hospital

    Gothenburg

Other trials in Sweden

About this study

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

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.

Read the 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.

Being tested
Nusinersen, Sham procedure
Keywords
Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, CHERISH, IONIS-SMNRx, IONIS-SMN Rx
Medical subject headings
Muscular Atrophy, Spinal

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NusinersenDrug

    Also called Sprinraza, ISIS 396443, IONIS-SMN Rx, BIIB058

    Administered by intrathecal (IT) lumbar puncture (LP) injection

  • Sham procedureProcedure or surgery

    Small needle prick on the lower back at the location where the IT injection is normally made

Study groups in NCT02292537
Study groupRoleWhat they receive
NusinersenExperimentalNusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.
Receives: Drug: Nusinersen
Sham procedureSham comparatorSham comparator on Days 1, 29, 85 and 274.
Receives: Procedure: Sham procedure

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline and Month 15

Secondary outcomes (14)
  1. 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.

    Measured: Baseline and Month 15

  2. 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.

    Measured: Month 15

  3. 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.

    Measured: Month 15

  4. 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.

    Measured: Baseline and Month 15

  5. 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.

    Measured: Month 15

  6. 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.

    Measured: Month 15

  7. 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.

    Measured: Baseline through Month 15

  8. Number of Participants With Clinically Significant Vital Sign Abnormalities

    Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.

    Measured: Baseline through Month 15

  9. Number of Participants With Clinically Significant Weight Abnormalities

    Weight changes assessed from Baseline to Month 15.

    Measured: Baseline through Month 15

  10. 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.

    Measured: Baseline through Month 15

  11. Number of Participants With Clinically Significant Physical Examination Abnormalities

    Physical examination changes were assessed for clinical significance.

    Measured: Baseline through Month 15

  12. Number of Participants With Clinically Significant Laboratory Parameter Abnormalities

    Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.

    Measured: Baseline through Month 15

  13. 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.

    Measured: Baseline through Month 15

  14. 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.

    Measured: Baseline through Month 15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Nov 2014 (estimated)
  2. Study start24 Nov 2014
  3. Primary completion20 Feb 2017
  4. Study completion20 Feb 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
126 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02292537
Sponsor's protocol ID
ISIS 396443-CS4
Other IDs
2014-001947-18, 2014
Acronym
CHERISH
Status last verified
Feb 2021
First submitted
12 Nov 2014
Last updated
17 Feb 2021
Data monitoring committee
Yes
Expanded access
Available

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.

    PubMed 31420846
  • 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.

    PubMed 29443664

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nusinersen in people with Spinal Muscular Atrophy, run by Biogen at 24 sites in 10 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, Canada, Germany, Italy, Japan and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Feb 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15 (time frame: Baseline and Month 15). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02292537, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2021.

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