Clinical trial NCT00047723: Minocycline to Treat Amyotrophic Lateral Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS
amyotrophic lateral sclerosis
minocycline
Lead sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
Sponsor class: NIH
First posted: 2002-10-17
Enrollment: 400
Sex: ALL
Minimum age (years): 21
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to test the safety, tolerability, and effectiveness of minocycline compared to placebo in patients with amyotrophic lateral sclerosis (ALS).

Detailed description: ALS is a progressive neurodegenerative disorder without cure or known treatment that significantly improves function. Loss of motor neurons in the brain and spinal cord of ALS patients causes the progressive symptoms. Laboratory studies have linked inducible nitric oxide synthase (iNOS) and caspase enzyme activation to motor nerve cell death in ALS. Minocycline-a medication currently approved by the FDA for treatment of bacterial infections-is a tetracycline antibiotic with high central nervous system penetration when taken orally. The drug inhibits the activity of iNOS and caspase enzymes.

Minocycline has been tested and shown to protect nerve cells in many scientific experiments. It reduces cell death and prolongs survival in animal models of ALS, stroke, trauma, Huntington's disease, and Parkinson's disease. It has been shown to be beneficial in many different animal experiments of ALS, conducted in Europe, Canada and the United States.

Minocycline has been tested in 2 preliminary human trials and has been shown to be safe in patients with ALS. It has been well tolerated in conjunction with riluzole (Rilutek), the only currently FDA-approved medication for ALS.

This trial is the final important step in determining whether minocycline improves the course of ALS. The principle objective of this clinical trial is to determine whether minocycline slows disease progression and helps maintain function in patients with ALS. This multi-center placebo-controlled study will select patients early in the course of ALS, when a neuroprotective therapy may be most beneficial. The study will measure change in function (as detected by ALSFRS-R scores), strength, pulmonary function, survival, and quality of life. Participants will undergo monthly outpatient evaluations and analysis of laboratory and adverse events. This is a 13-month study.

Eligibility criteria: To be eligible for enrollment in this study, subjects must meet the following eligibility criteria within fourteen days prior to randomization:

Inclusion criteria:

* A clinical diagnosis of laboratory-supported probable, probable or definite ALS, according to modified EL Escorial criteria.
* FVC greater or equal to 75% of predicted.
* Onset of weakness within 3 years prior to enrollment.
* If patients are receiving riluzole they must be on a stable dose for at least the past thirty days.
* Women of childbearing age must be non-lactating and surgically sterile or using an effective method of birth control and have a negative pregnancy test (adequate birth control includes use of intra-uterine device or oral contraceptives plus a barrier method, e.g. condom, diaphragm).
* Willing and able to give signed informed consent that has been approved by your Institutional Review Board (IRB).

Exclusion criteria:

* Requirement for tracheotomy ventilation (or non-invasive ventilation \> 23 hours/day).
* Diagnosis of other neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, etc).
* FVC \< 75% of predicted.
* A clinically significant history of unstable medical illness (unstable angina, advanced cancer, etc) over the last 30 days.
* History of renal disease (screening creatinine greater than 1.5).
* History of liver disease (screening alanine aminotransferase greater than 3 times the upper limit of normal).
* History of hematologic disease (screening white blood cell count less than 3,800/mm3).
* History of system lupus erythematosis (or screening ANA of 1:160 or greater).
* Treatment with any medications that may cause lupus-like symptoms within 4 weeks of baseline visit (e.g. procainamide, hydralazine).
* History of vestibular disease (excluding benign position vertigo).
* Pregnancy or lactation.
* Allergy to tetracycline antibiotics.
* Use of minocycline within thirty days of enrollment (baseline visit).
* Use of anti-epileptic medications other than gabapentin.
* Limited mental capacity rendering the subject unable to provide written informed consent or comply with evaluation procedures.
* History of recent alcohol or drug abuse or noncompliance with treatment or other experimental protocols.
* Use of any investigational drug within the past 30 days (Creatine, Vioxx, Celebrex, Topiramate).
* Women with the potential to become pregnant who are not practicing effective birth control.

Primary outcomes:
measure: Change in function as detected by the ALS Functional Rating Scale (ALSFRS-R) in patients taking minocycline compared to those taking placebo.
Secondary outcomes:
measure: Changes in manual muscle testing (MMT), forced vital capacity (FVC, percent predicted), quality of life (QOL) and survival
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Los Angeles
country: United States
facility: University of California Department of Neurology
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Denver
country: United States
facility: Univ. of Colorado Health Sciences Center
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Minneapolis
country: United States
facility: Hennepin County Med Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: New Brunswick
country: United States
facility: UMDNJ/Robert Wood Johnson Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Columbia Unversity, Eleanor and Lou Gehrig MDA/ALS Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston- Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cleveland
country: United States
facility: Metro Health Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine, Hahnemann Campus
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Sciences Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
Study officials:
affiliation: Associate Medical Director, Eleanor and Lou Gehrig MDA/ALS Center, Columbia University Medical Center
name: Paul H. Gordon, M.D.,
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R; Western ALS Study Group. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007 Dec;6(12):1045-53. doi: 10.1016/S1474-4422(07)70270-3. Epub 2007 Nov 5.