Clinical trial NCT02462759: A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: EMBRACE
SMA
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2015-06-04
Enrollment: 21
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: Part 2 is an Open Label extension phase.

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
measure: Number of Participants With Change From Baseline in Clinical Laboratory Parameters
timeFrame: Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
measure: Number of Participants With Change From Baseline in Electrocardiograms (ECGs)
timeFrame: Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
measure: Number of Participants With Change From Baseline in Vital Signs
timeFrame: Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
measure: Change From Baseline in Head Circumference
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Change From Baseline in Chest Circumference
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Change From Baseline in Arm Circumference
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Change From Baseline in Weight for Age
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Change From Baseline in Weight
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Change From Baseline in Head to Chest Circumference (HCC) Ratio
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Change From Baseline in Body Length
timeFrame: Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Number of Participants With Change From Baseline in Neurological Examination Outcomes
timeFrame: Part 1: Baseline to Day 422; Part 2: Baseline to Day 596
measure: Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT]
timeFrame: Part 2: Up to 1080 days
measure: Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT]
timeFrame: Part 2: Up to 1080 days
measure: Number of Participants With Change From Baseline in International Normalized Ratio [INR])
timeFrame: Part 2: Up to 1080 days
measure: Number of Participants With Presence of Urine Total Protein Post-baseline
timeFrame: Part 2: Up to 1080 days
Secondary outcomes:
measure: Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study
timeFrame: Pre-dose on Days 64, 183, 540 and 659
measure: Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study
timeFrame: Pre-dose on Days 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
measure: Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study
timeFrame: Pre-dose on Days 15, 29, 64, 183, 302, 422 and 540
measure: CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study
timeFrame: Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018
measure: Number of Participants With Plasma Antibodies to ISIS 396443
timeFrame: Part 2: Baseline to Day 596
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: Hartford
country: United States
facility: Connecticut Childrens Medical
state: Connecticut
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Saint Paul
country: United States
facility: Gillette Children's Specialty Healthcare
state: Minnesota
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Research Institute
state: Washington
city: Muenchen
country: Germany
facility: LMU-Campus Innenstadt
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Acsadi G, Crawford TO, Muller-Felber W, Shieh PB, Richardson R, Natarajan N, Castro D, Ramirez-Schrempp D, Gambino G, Sun P, Farwell W. Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study. Muscle Nerve. 2021 May;63(5):668-677. doi: 10.1002/mus.27187. Epub 2021 Feb 16.