An Open-label Safety, Tolerability and Dose-range Finding Study of Multiple Doses of ISIS SMNRx in Patient With Spinal Muscular Atrophy (SMNRx - CS2)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Isis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01703988
First received: October 8, 2012
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

This study will test the safety, tolerability, and pharmacokinetics of escalating doses of ISIS-SMNRx administered into the spinal fluid either two or three times over the duration of the trial, in patients with Spinal Muscular Atrophy.


Condition Intervention Phase
Spinal Muscular Atrophy
Drug: ISIS-SMNRx
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Spinal Muscular Atrophy

Resource links provided by NLM:


Further study details as provided by Isis Pharmaceuticals:

Primary Outcome Measures:
  • The number of participants with adverse events [ Time Frame: Patricipants will be followed for the duration of the study; an expected 36 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Plasma Pharmacokinetics (See clarification.) [ Time Frame: Plasma at 1, 2, 4, 6 and 20 hours after dosing ] [ Designated as safety issue: No ]
    • the maximal observed plasma drug concentration (Cmax)
    • the time to reach Cmax in plasma (Tmax)
    • the area under the plasma concentrations time curve from the time of the intrathecal dose to the last collected sample (20 hours after dosing)


Other Outcome Measures:
  • CSF Pharmacokinetics (See clarification.) [ Time Frame: CSF at Day 1, Day 29, and Day 85 ] [ Designated as safety issue: No ]
    - The observed CSF drug concentration


Estimated Enrollment: 32
Study Start Date: October 2012
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ISIS-SMNRx Dose level 1
Administered three times by intrathecal injection
Drug: ISIS-SMNRx
Single intrathecal injection for each dose
Experimental: ISIS-SMNRx: Dose level 2
Administered three times by intrathecal injection
Drug: ISIS-SMNRx
Single intrathecal injection for each dose
Experimental: ISIS-SMNRx: Dose level 3
Administered two times by intrathecal injection
Drug: ISIS-SMNRx
Single intrathecal injection for each dose
Experimental: Experimental: ISIS-SMNRx: Dose level 4
Administered three times by intrathecal injection
Drug: ISIS-SMNRx
Single intrathecal injection for each dose

Detailed Description:

This study will test the safety, tolerability, and pharmacokinetics of escalating doses of ISIS-SMNRx administered multiple times over the duration of the trial, as intrathecal injections. Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of 8 patients, where all patients will receive active drug.

  Eligibility

Ages Eligible for Study:   2 Years to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
  • Clinical signs attributable to Spinal Muscular Atrophy
  • Males and females 2 to 15 years of age
  • 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

Exclusion Criteria:

  • 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 Site Investigator
  • Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
  • Hospitalization for surgery (i.e. 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 CSF circulation
  • Presence of an implanted shunt for the drainage of CSF or an implanted CNS 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
  • Clinically significant abnormalities in hematology or clinical chemistry parameters
  • 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, etc.)that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01703988

Locations
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Texas
UT Southwestern Medical Center - Children's Medical Center Dallas
Dallas, Texas, United States, 75207
United States, Utah
University of Utah School of Medicine
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
Isis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Isis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01703988     History of Changes
Other Study ID Numbers: ISIS 396443 - CS2
Study First Received: October 8, 2012
Last Updated: April 4, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Isis Pharmaceuticals:
Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS 396443

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

ClinicalTrials.gov processed this record on October 22, 2014