A Study to assess the safety and tolerability of ISIS 396443 in participants with spinal muscular atrophy (SMA).

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2014-003657-33-DE
• Date of registration: 05/05/2015
• Prospective Registration: Yes
• Primary sponsor: Biogen Idec Research Limited
• Public title: A Study to assess the safety and tolerability of ISIS 396443 in participants with spinal muscular atrophy (SMA).
• Scientific 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 - EMBRACE
• Date of first enrolment: 21/09/2015
• Target sample size: 16
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003657-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: sham-procedure controlled; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, United Kingdom, United States

Contacts

• Name: Medical Director
• Affiliation: Biogen

• Name: Medical Director
• Affiliation: Biogen

Key inclusion & exclusion criteria

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.
- Subjects with 2 SMN2 copies must reside within approximately 9 hours’ ground-travel distance from a participating study site for the duration of the study.

For Part 2 only:
- 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.

NOTE: Other protocol defined Inclusion criteria may apply.
Are the trial subjects under 18? yes
Number of subjects for this age range: 21
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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
- 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 Exclusion criteria may
apply.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Spinal Muscular Atrophy
MedDRA version: 20.1 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Trade Name: Spinraza
Product Name: Survival of Motor Neuron 2 (SMN2) Splicing Modulator Antisense Oligonucleotide
Product Code: ISIS 396443 (BIIB058)
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Nusinersen
CAS Number: 1258984-36-9
Current Sponsor code: ISIS 396443 (BIIB058)
Other descriptive name: ISIS 396443 (BIIB058)
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.4-

Primary Outcome(s)

Main Objective: 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 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.

Secondary Objective: The secondary objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in participants with SMA.
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.

Primary end point(s): - Number of participants with adverse events and serious adverse events up to 44 months
- Change from Baseline in clinical laboratory parameters at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in electrocardiograms (ECGs) at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in vital signs at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in neurological examination outcomes at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in growth parameters at Baseline (Part 1) and 30 months (Part 2)
- Activated partial thromboplastin time (aPTT) at Baseline
- Partial thromboplastin time (PTT) at Baseline
- International normalized ratio (INR) at Baseline
- Urine total protein at Baseline

Timepoint(s) of evaluation of this end point: up to 44 months

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 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

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

Secondary end point(s): - Nusinersen plasma concentration up to Day 897
- Nusinersen cerebrospinal fluid (CSF) concentration up to Day 897
- Nusinersen plasma antibodies up to Day 897

Secondary ID(s)

232SM202

NCT02462759

Source(s) of Monetary Support

Biogen Idec Research Limited

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 12/04/2019
• Date Completed: 24/09/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-003657-33/results