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Safety, Tolerability, and Activity Study of ISIS SOD1Rx to Treat Familial Amyotrophic Lateral Sclerosis (ALS) Caused by SOD1 Gene Mutations (SOD-1)

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ClinicalTrials.gov Identifier: NCT01041222
Recruitment Status : Completed
First Posted : December 31, 2009
Last Update Posted : April 13, 2012
Sponsor:
Collaborators:
Muscular Dystrophy Association
ALS Association
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE December 30, 2009
First Posted Date  ICMJE December 31, 2009
Last Update Posted Date April 13, 2012
Study Start Date  ICMJE January 2010
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 30, 2009)
To evaluate the safety, tolerability, and pharmacokinetics of four dose levels of ISIS 333611 [ Time Frame: Safety analysis for dose escalation after Study Day 8 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01041222 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, and Activity Study of ISIS SOD1Rx to Treat Familial Amyotrophic Lateral Sclerosis (ALS) Caused by SOD1 Gene Mutations
Official Title  ICMJE A Phase 1, Double-Blind, Placebo-Controlled, Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of ISIS 333611 Administered Intrathecally to Patients With Familial Amyotrophic Lateral Sclerosis Due to Superoxide Dismutase 1 Gene Mutations
Brief Summary This study will test the safety, tolerability and pharmacokinetics of single doses of ISIS 333611 administered into the spinal canal as 12 hour infusions.
Detailed Description This study will test the safety, tolerability, and pharmacokinetics of single doses of ISIS 333611 administered as 12-hour intrathecal infusions. Four dose levels (0.15, 0.5, 1.5 and 3 mg) will be evaluated sequentially. The volume of the infusion is 0.25 mL/12 hours. Each dose level will be studied in a cohort of 8 patients where 6 are randomized to active treatment with ISIS 333611 and 2 are randomized to placebo.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Familial Amyotrophic Lateral Sclerosis
Intervention  ICMJE Drug: ISIS 333611
5 arms of 12 hour infusion: Arm 1 0.15 mg, Arm 2 0.5 mg, Arm 3 1.5 mg, Arm 4 3.0 mg, matching volume of placebo
Study Arms  ICMJE
  • Experimental: Arm 1
    0.15 mg ISIS 333611 continuous intrathecal infusion over 12 hours
    Intervention: Drug: ISIS 333611
  • Experimental: Arm 2
    0.5 mg ISIS 333611 continuous intrathecal infusion over 12 hours
    Intervention: Drug: ISIS 333611
  • Experimental: Arm 3
    1.5 mg ISIS 333611 continuous intrathecal infusion over 12 hours
    Intervention: Drug: ISIS 333611
  • Experimental: Arm 4
    3.0 mg ISIS 333611 continuous intrathecal infusion over 12 hours
    Intervention: Drug: ISIS 333611
  • Placebo Comparator: Placebo (phosphate buffered saline)
    Intervention: Drug: ISIS 333611
Publications * Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. doi: 10.1016/S1474-4422(13)70061-9. Epub 2013 Mar 29. Erratum in: Lancet Neurol. 2013 May;12(5):423.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 12, 2012)
33
Original Estimated Enrollment  ICMJE
 (submitted: December 30, 2009)
32
Actual Study Completion Date  ICMJE January 2012
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Clinical signs of weakness attributed to ALS.
  • Familial ALS with a documented SOD1 gene mutation.
  • Age 18 years or older.
  • Capable of providing informed consent and willing to comply with trial procedures and time commitments.
  • Vital capacity (VC) at least 50% predicted value for gender, height and age at screening and not using invasive respiratory support.
  • If taking riluzole, patients must be on stable dosage for at least 30 days prior to starting the study and expect to remain at that dosage until the end of the study.
  • Medically able to undergo temporary insertion of intrathecal catheter.
  • Normal test results for coagulation parameters.

Exclusion Criteria:

  • Treatment with another investigational drug for ALS (e.g. pyrimethamine, ceftriaxone, lithium, tamoxifen, arimoclomol, high dose creatine, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. No prior treatment with siRNA, cell transplant, or gene therapy is allowed.
  • Dosing in ISIS 333611-CS1 in a previous dose cohort within 60 days of screening.
  • Presence of any of the following clinical conditions:

    1. Drug abuse or alcoholism within one year of the Screening visit.
    2. Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic function, or active infectious disease.
    3. Documented history of HIV infection.
    4. Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the Screening Visit.
  • Any condition that may impact intrathecal infusion including:

    1. History of structural spinal disease including tumors and hyperplasia.
    2. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
    3. Clinically significant abnormalities in hematology or clinical chemistry parameters as assessed by the Site Investigator during the Screening visit.
    4. Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., severe degenerative arthritis, compromised nutritional state, peripheral neuropathy) that would interfere with the assessment of safety and efficacy of study material or device performance, or would compromise the ability of the patient to undergo study procedures.
    5. ALT or AST >/= 3 x ULN, unless discussed with and approved by the Medical Monitor.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01041222
Other Study ID Numbers  ICMJE ISIS 333611- CS1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ionis Pharmaceuticals, Inc.
Study Sponsor  ICMJE Ionis Pharmaceuticals, Inc.
Collaborators  ICMJE
  • Muscular Dystrophy Association
  • ALS Association
Investigators  ICMJE
Study Chair: Merit Cudkowicz, MD, MSc Massachusetts General Hospital
Study Chair: Timothy Miller, MD, PhD Washington University School of Medicine
PRS Account Ionis Pharmaceuticals, Inc.
Verification Date April 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP