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

• Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborators: Muscular Dystrophy Association; ALS Association
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Study Description

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

Arms and Interventions

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

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

Locations

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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

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Study Chair:	Merit Cudkowicz, MD, MSc	Massachusetts General Hospital
Study Chair:	Timothy Miller, MD, PhD	Washington University School of Medicine

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT01041222 History of Changes
Other Study ID Numbers:	ISIS 333611- CS1
First Posted:	December 31, 2009
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:

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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