An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy

NCT01703988 | Completed Phase 1 Results DMC

• 2 other identifiers: ISIS 396443 - CS22017-000327-27
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 4

Brief Summary

This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA). Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.

Conditions

Spinal Muscular Atrophy

Keywords

Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx; ISIS 396443

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs

  An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.

  Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days

Secondary Outcomes (5)

• Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)

  Day 1 and Day 85

• Plasma Pharmacokinetics: Time to Reach Cmax in Plasma

  Day 1 and Day 85

• Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)

  Day 1 and Day 85

• Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations

  Day 1, Day 29, and Day 85

• Urine Pharmacokinetics: Renal Clearance, Cohort 4

  Day 1 and Day 85

Study Arms (4)

Nusinersen 3 mg

EXPERIMENTAL

3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection

Drug: Nusinersen

Nusinersen 6 mg

EXPERIMENTAL

6 mg nusinersen on Days 1, 29, 85, IT injection

Drug: Nusinersen

Nusinersen 9 mg

EXPERIMENTAL

9 mg nusinersen on Days 1 and 85, IT injection

Drug: Nusinersen

Nusinersen 12 mg

EXPERIMENTAL

12 mg nusinersen on Days 1, 29, 85, IT injection

Drug: Nusinersen

Interventions

Nusinersen DRUG

Single IT injection for each dose

Also known as: ISIS-SMNRx, ISIS 396443, BIIB058, Spinraza

Nusinersen 12 mg; Nusinersen 3 mg; Nusinersen 6 mg; Nusinersen 9 mg

Eligibility Criteria

• Age: 2 Years - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
• Clinical signs attributable to SMA
• Able to complete all study procedures, measurements, and visits and parent/patient has adequately supportive psychosocial circumstances, in the opinion of the Investigator
• Estimated life expectancy \> 2 years from Screening
• Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

You may not qualify if:

• Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
• Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
• Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
• Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event 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 that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation
• Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter
• History of bacterial meningitis
• Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
• Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
• Treatment with investigational drug, 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 or cell transplantation
• Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures.

Sponsors & Collaborators

• Biogen: lead

Study Sites (4)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

UT Southwestern Medical Center - Children's Medical Center Dallas

Dallas, Texas, 75207, United States

Location

University of Utah School of Medicine

Salt Lake City, Utah, 84132, United States

Location

Related Publications (1)

• 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.

  PMID: 31420846 DERIVED

Related Links

• Clinical Study Report (CSR) Synopsis - a results summary

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

nusinersen

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Biogen Study Medical Director
• Organization: Biogen

clinicaltrials@biogen.com

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 8, 2012
• First Posted: October 11, 2012
• Study Start: October 31, 2012
• Primary Completion: January 31, 2015
• Study Completion: January 31, 2015
• Last Updated: April 13, 2021
• Results First Posted: March 13, 2017

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share

Locations

US (4)