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 Purpose:

This study will test the safety, tolerability and pharmacokinetics of single doses of ISIS 333611 administered into the spinal canal as 12 hour infusions.

Study Status:

Not recruiting


Familial Amyotrophic Lateral Sclerosis

Study Type:


Type of Intervention:


Intervention Name:

ISIS 333611



Phase 1

Study Chair(s)/Principal Investigator(s):

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

Clinicaltrials.gov ID:


Neals Affiliated?


Coordinating Center Contact Information

Massachusetts General Hospital

149 13th Street
Charlestown, Massachusetts, 02129 United States

Full Study Summary:

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 Sponsor:

Ionis Pharmaceuticals, Inc.

Participant Duration:

Total enrollment time for this study is about 8 weeks. The screening visit will last approximately 2-4 hours. During the treatment phase of the study, you will be admitted to the hospital for the temporary intrathecal infusion procedure for about two days. After the treatment phase, there is a 4 week follow up period with two in-clinic visits (each visit is about 2-3 hours) and one telephone contact/visit (about 30 minutes).

Estimated Enrollment:


Estimated Study Start Date:

12 / 31 / 2009

Estimated Study Completion Date:

01 / 01 / 2012

Posting Last Modified Date:

04 / 13 / 2012

Date Study Added to neals.org:

12 / 31 / 2009

Minimum Age:

18 Years

Maximum Age:


Can participants use Riluzole?


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.

Johns Hopkins University

Baltimore, Maryland 21287
United States

Massachusetts General Hospital-East, Neurology Clinical Trials Unit

Charlestown, Massachusetts 02129
United States

Washington University School of Medicine

St. Louis, Missouri 63110
United States

Methodist Neurological Institute

Houston, Texas 77030
United States