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A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA). (EMBRACE)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02462759
First Posted: June 4, 2015
Last Update Posted: September 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Biogen
  Purpose
The primary objective of Part 1 of this study is to assess the safety and tolerability of Nusinersen in participants with SMA who are not eligible to participate in the clinical studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537). The secondary objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in participants with SMA. The primary objective of Part 2 of this study is to assess the long-term safety and tolerability of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments. The secondary objective of Part 2 of this study is to examine the PK of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments.

Condition Intervention Phase
Spinal Muscular Atrophy Drug: Nusinersen Procedure: Sham Procedure Phase 2

Access to an investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-blind, Sham-procedure Controlled Study to Assess the Safety and Tolerability and Explore the Efficacy of ISIS 396443 (BIIB058) Administered Intrathecally in Subjects With Spinal Muscular Atrophy Who Are Not Eligible to Participate in the Clinical Studies ISIS 396443-CS3B or ISIS 396443-CS4

Resource links provided by NLM:


Further study details as provided by Biogen:

Primary Outcome Measures:
  • Number of participants with adverse events and serious adverse events [ Time Frame: Up to 44 months ]
    Part 1: 14 months Part 2: 30 months

  • Change from Baseline in clinical laboratory parameters [ Time Frame: Baseline and 14 months (Part 1) and 30 months (Part 2) ]
    Assessed by the following laboratory tests: Blood chemistry: total protein, albumin, creatinine, cystatin C, creatine phosphokinase, blood urea nitrogen, total bilirubin (direct and indirect), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, calcium, phosphorus, chloride, sodium, potassium. Hematology: red blood cells, hemoglobin, hematocrit, platelets, white blood cells, white blood cell differential. Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, red blood cells, white blood cells, epithelial cells, bacteria, casts, crystals

  • Change from Baseline in electrocardiograms (ECGs) [ Time Frame: Baseline and 14 months (Part 1) and 30 months (Part 2) ]
  • Change from Baseline in vital signs [ Time Frame: Baseline and 14 months (Part 1) and 30 months (Part 2) ]
    Vital signs will be assessed by: Resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide

  • Change from Baseline in neurological examination outcomes [ Time Frame: Baseline and 14 months (Part 1) and 30 months (Part 2) ]
    Assessed by the following neurological examination: mental status, level of consciousness, sensory motor function, cranial nerve function, and reflexes

  • Activated partial thromboplastin time (aPTT) [ Time Frame: Baseline ]
  • Partial thromboplastin time (PTT) [ Time Frame: Baseline ]
  • International normalized ratio (INR) [ Time Frame: Baseline ]
  • Urine total protein [ Time Frame: Baseline ]
  • Change from Baseline in Head Circumference [ Time Frame: Part 2: Baseline and 30 Months ]
  • Change from Baseline in Chest Circumference [ Time Frame: Part 2: Baseline and 30 Months ]
  • Change from Baseline in Arm Circumference [ Time Frame: Part 2: Baseline and 30 Months ]
  • Change from Baseline in Weight for Age [ Time Frame: Part 2: Baseline and 30 Months ]
  • Change from Baseline in Weight for Length [ Time Frame: Part 2: Baseline and 30 Months ]
  • Change from Baseline in Head to Chest Circumference Ratio [ Time Frame: Part 2: Baseline and 30 Months ]
  • Change from Baseline in Body Length [ Time Frame: Part 2: Baseline and 30 Months ]

Secondary Outcome Measures:
  • Nusinersen plasma concentration [ Time Frame: Up to Day 897 ]

    Part 1:

    Day 1 post dose, Days 64, 183, and end of Part 1

    Part 2 (participants randomized to drug):

    Day 1 post dose, Days 239, 477, 715, and Part 2 final follow-up

    Part 2 (participants randomized to sham):

    Day 1 post dose, Days 64, 183, 540, 778, and Part 2 Final follow-up


  • Nusinersen cerebrospinal fluid (CSF) concentration [ Time Frame: Up to Day 897 ]

    Part 1:

    Predose Days 1, 15, 29, 64, 183, 302

    Part 2 (participants randomized to drug):

    Predose Days 1, 120, 239, 358, 477, 596, 715

    Part 2 (participants randomized to sham):

    Predose Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778


  • Nusinersen plasma antibodies [ Time Frame: Up to Day 897 ]
    Anti-Nusinersen plasma antibody concentrations will be assessed in Part 2.


Enrollment: 21
Actual Study Start Date: August 19, 2015
Estimated Study Completion Date: April 9, 2019
Estimated Primary Completion Date: April 9, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nusinersen
Administered by intrathecal injection.
Drug: Nusinersen
Administered by intrathecal injection.
Other Names:
  • BIIB058
  • ISIS SMNRx
  • ISIS 396443
  • Spinraza
Sham Comparator: Sham Procedure
Small needle prick on the lower back at the location where the IT injection is normally made.
Procedure: Sham Procedure
Small needle prick on the lower back at the location where the IT injection is normally made.

Detailed Description:
Part 2 is an Open Label extension phase.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound heterozygote.
  • Onset of clinical signs and symptoms consistent with SMA at ≤6 months of age and have documentation of 3 SMN2 copies OR onset of clinical signs and symptoms consistent with SMA at ≤6 months of age, >7 months of age (211 days) at screening, and have documentation of 2 SMN2 copies OR onset of clinical signs and symptoms consistent with SMA at >6 months of age, are ≤18 months of age at screening, and have documentation of 2 or 3 SMN2 copies.
  • Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedures.
  • Medical care, such as routine immunizations meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA, in the opinion of the Investigator.
  • Participants with 2 SMN2 copies must reside within approximately 9 hours' ground-travel distance from a participating study site for the duration of the study.

Key Exclusion Criteria:

  • Meets additional study related criteria.
  • Any previous exposure to ISIS 396443; previous dosing in this study or previous studies with ISIS 396443.
  • Signs or symptoms of SMA present at birth or within the first week after birth.
  • Ventilation for ≥16 hours per day continuously for >21 days at screening.
  • Permanent tracheostomy, implanted shunt for CSF drainage, or implanted central nervous system (CNS) catheter at screening.
  • History of brain or spinal cord disease that would interfere with the LP procedure, CSF circulation, or safety assessments.
  • Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional support within 2 months prior to screening, or hospitalization for surgery planned during the study.
  • Clinically significant abnormalities in hematology or clinical chemistry parameters or Electrocardiogram (ECG), as assessed by the Investigator.
  • Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device within 30 days prior to screening. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation.

For Part 2 only:

To be eligible to participate in Part 2 of this study, participants must meet the following eligibility criteria at the time of consent to participate in Part 2:

Participation in Part 1 and completion of the End of Part 1 Evaluation assessments.

Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study and to provide signed and dated informed consent on the Part 2 informed consent form (ICF) and authorization to use confidential health information in accordance with national and local participant privacy regulations.

Able to complete all study procedures, measurements, and visits, and parent or legal guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.

Participants will be excluded from the Part 2 if they meet the following exclusion criterion at the time of consent into Part 2 of the study:

Any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in Part 2. The Investigator must reassess the subject's medical fitness for participation and consider any diseases that would preclude treatment.

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

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02462759


Locations
United States, California
David Geffen School of Medicine at UCLA
Los Angeles, California, United States, 90095-8344
United States, Connecticut
Connecticut Childrens Medical
Hartford, Connecticut, United States, 06106
United States, Maryland
The Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Minnesota
Gillette Children's Specialty Healthcare
Saint Paul, Minnesota, United States, 55101
United States, Texas
The University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75235
United States, Washington
Seattle Children's Research Institute
Seattle, Washington, United States, 98105
Germany
LMU-Campus Innenstadt
Muenchen, Germany, 80337
Sponsors and Collaborators
Biogen
Investigators
Study Director: Medical Director Biogen
  More Information

Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02462759     History of Changes
Other Study ID Numbers: 232SM202
2014-003657-33 ( EudraCT Number )
First Submitted: May 14, 2015
First Posted: June 4, 2015
Last Update Posted: September 21, 2017
Last Verified: September 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Biogen:
EMBRACE
Spinal Muscular Atrophy
SMA

Additional relevant MeSH terms:
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases