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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.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Familial Amyotrophic Lateral Sclerosis Drug: ISIS 333611 Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : January 2010
Actual Primary Completion Date : December 2011
Actual Study Completion Date : January 2012

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm 1
0.15 mg ISIS 333611 continuous intrathecal infusion over 12 hours
 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
Experimental: Arm 2
0.5 mg ISIS 333611 continuous intrathecal infusion over 12 hours
 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
Experimental: Arm 3
1.5 mg ISIS 333611 continuous intrathecal infusion over 12 hours
 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
Experimental: Arm 4
3.0 mg ISIS 333611 continuous intrathecal infusion over 12 hours
 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
Placebo Comparator: Placebo (phosphate buffered saline) 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


Outcome Measures
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Primary Outcome Measures :
  1. 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 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01041222


Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital-East, Neurology Clinical Trials Unit
Charlestown, Massachusetts, United States, 02129
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, Texas
Methodist Neurological Institute
Houston, Texas, United States, 77030
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
Muscular Dystrophy Association
ALS Association
Investigators
Study Chair: Merit Cudkowicz, MD, MSc Massachusetts General Hospital
Study Chair: Timothy Miller, MD, PhD Washington University School of Medicine
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01041222     History of Changes
Other Study ID Numbers: ISIS 333611- CS1
First Posted: December 31, 2009    Key Record Dates
Last Update Posted: April 13, 2012
Last Verified: April 2012

Keywords provided by Ionis Pharmaceuticals, Inc.:
Familial ALS
ALS
SOD1 Protein
ISIS 333611
SOD1Rx

Additional relevant MeSH terms:
Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
 TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Superoxide Dismutase
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs