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

Phase 2TerminatedNCT02462759

Biogen21 enrolled

Overview

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.

Part 2 is an Open Label extension phase.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Spinal Muscular Atrophy

Interventions

Eligibility

Sex: ALL

Medical Language ↔ Plain English

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.

Locations (7)

David Geffen School of Medicine at UCLA

Los Angeles, California, United States

Connecticut Childrens Medical

Hartford, Connecticut, United States

The Johns Hopkins Hospital

Baltimore, Maryland, United States

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, United States

The University of Texas Southwestern Medical Center

Dallas, Texas, United States

Seattle Children's Research Institute

Seattle, Washington, United States

LMU-Campus Innenstadt

München, Germany

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

Time frame: Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)

Number of Participants With Change From Baseline in Clinical Laboratory Parameters

Clinically significant changes in laboratory parameters were evaluated for assessing the safety of ISIS 396443.

Time frame: Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)

Number of Participants With Change From Baseline in Electrocardiograms (ECGs)

Clinically significant changes in ECG measurements were evaluated for assessing the safety of ISIS 396443.

Time frame: Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596

Number of Participants With Change From Baseline in Vital Signs

Clinically significant changes in vital signs were evaluated for assessing the safety of ISIS 396443. Vital signs that were assessed included resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.

Time frame: Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596

Change From Baseline in Head Circumference

Participants were analyzed for change in growth parameter of head circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the head circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days \<=1 as Baseline; Days \>1 to \<= 22 as Day 15;Days \>22 to \<=47 as Day 29;Days \>47 to \<= 123 as Day 64;Days \>123 to \<=242 as Day 183;Days \>242 to \<=362 as Day 302;Days \>362 to \<=482 as Day 422;Days \>482 to \<= 600 as Day 540;Days \>600 to \<= 719 as Day 659;Days \>719 to \<= 838 as Day 778;Days \>838 to \<= 958 as Day 898;Days \>958 to \<= 1078 as Day 1018;Days \>1078 to \<= 1198 as Day 1138.