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

NCT01041222 | Completed Phase 1 DMC

• 1 other identifier: ISIS 333611- CS1
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 4

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.

Conditions

Familial Amyotrophic Lateral Sclerosis

Keywords

Familial ALS; ALS; SOD1 Protein; ISIS 333611; SOD1Rx

Outcome Measures

Primary Outcomes (1)

• To evaluate the safety, tolerability, and pharmacokinetics of four dose levels of ISIS 333611

  Safety analysis for dose escalation after Study Day 8

Study Arms (5)

Arm 1

EXPERIMENTAL

0.15 mg ISIS 333611 continuous intrathecal infusion over 12 hours

Drug: ISIS 333611

Arm 2

EXPERIMENTAL

0.5 mg ISIS 333611 continuous intrathecal infusion over 12 hours

Drug: ISIS 333611

Arm 3

EXPERIMENTAL

1.5 mg ISIS 333611 continuous intrathecal infusion over 12 hours

Drug: ISIS 333611

Arm 4

EXPERIMENTAL

3.0 mg ISIS 333611 continuous intrathecal infusion over 12 hours

Drug: ISIS 333611

Placebo (phosphate buffered saline)

PLACEBO COMPARATOR

Drug: ISIS 333611

Interventions

ISIS 333611 DRUG

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

Arm 1; Arm 2; Arm 3; Arm 4; Placebo (phosphate buffered saline)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• Drug abuse or alcoholism within one year of the Screening visit.
• Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic function, or active infectious disease.
• Documented history of HIV infection.
• 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:
• History of structural spinal disease including tumors and hyperplasia.
• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
• Clinically significant abnormalities in hematology or clinical chemistry parameters as assessed by the Site Investigator during the Screening visit.
• 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.
• ALT or AST \>/= 3 x ULN, unless discussed with and approved by the Medical Monitor.

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead
• Muscular Dystrophy Association: collaborator
• ALS Association: collaborator

Study Sites (4)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital-East, Neurology Clinical Trials Unit

Charlestown, Massachusetts, 02129, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Methodist Neurological Institute

Houston, Texas, 77030, United States

Location

Related Publications (1)

• 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.

  PMID: 23541756 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Merit Cudkowicz, MD, MSc

  Massachusetts General Hospital

  STUDY CHAIR

• Timothy Miller, MD, PhD

  Washington University School of Medicine

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2009
• First Posted: December 31, 2009
• Study Start: January 1, 2010
• Primary Completion: December 1, 2011
• Study Completion: January 1, 2012
• Last Updated: April 13, 2012

Record last verified: 2012-04

Locations

US (4)