Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis
Information source: Columbia University
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Amyotrophic Lateral Sclerosis
Intervention: celecoxib (Drug); creatine (Drug); minocycline (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: Columbia University Official(s) and/or principal investigator(s):
Paul H Gordon, MD, Principal Investigator, Affiliation: Columbia University
Summary
The objective of this study is to compare two combinations of drugs, minocycline and creatine
or celecoxib and creatine, in a phase II trial designed to determine which combination is
more effective for ALS.
Clinical Details
Official title: Phase II Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis
Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Historical Control, Parallel Assignment, Safety/Efficacy Study
Primary outcome: ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial.
Secondary outcome: Forced Vital Capacity, Quality of Life, Timed Get Up and Go performed monthly. Survival and measures of safety throughout the trial.
Detailed description:
Excess free radicals, energy mishandling, excitotoxicity, activation of cell death pathways
and inflammation likely all contribute to neurodegeneration in ALS. Past trials may have been
negative in part because they tested single agents, usually influencing only one mechanism of
cell death. Combinations of agents that affect different and multiple mechanisms of
neurodegeneration may be necessary to reach meaningful outcomes in trials of ALS.
This trial has several unique features. First, it compares the neuroprotective potential of
two combinations of agents that impact multiple mechanisms of cell death. The combinations of
minocycline/creatine and celecoxib/creatine are the only agents that have had additive
effects in the mouse model of ALS, reducing neurodegeneration and prolonging survival more
than individual agents alone. Second, it uses an important new phase II selection trial
design to determine which combination is superior. Not only does this trial test combination
therapy, but there is no placebo, so everyone who enrolls in the trial will receive active
treatment.
Minocycline, creatine and celecoxib have been tested individually and have been shown to be
safe in patients with ALS. This will be the first time human trials will be conducted with
combinations of minocycline/creatine and celecoxib/creatine.
We will compare combinations of drugs in a phase II trial design to determine which
combination is superior. If successful, this trial will lead directly to a phase III trial of
the selected combination. If the design is found useful, this trial will lead to larger phase
II selection trials assessing greater numbers of agents simultaneously, thereby improving the
efficiency of drug screening in ALS.
Eligibility
Minimum age: 21 Years.
Maximum age: 85 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- A clinical diagnosis of possible, laboratory-supported probable, probable or definite
ALS, according to modified EL Escorial criteria
- FVC greater or equal to 60% at the screening visit
- Symptom onset within 5 years
- 21 to 85 years of age
- If patients are taking riluzole, they must be on a stable dose for at least the past
thirty days
- A woman of childbearing age, must be nonlactating and surgically sterile or using an
effective method of birth control (barrier method) and have a negative pregnancy test
- Able to maintain adequate hydration levels defined as 6-8 cups (8ounces/cup) of water
or a non-caffeinated beverage per day
- Willing and able to give signed informed consent that has been approved by an
Institutional Review Board (IRB)
Exclusion Criteria:
- Tracheotomy and mechanical ventilation
- Diagnosis of other neurodegenerative diseases (Parkinson's disease, Alzheimer's
disease, etc)
- Unstable medical illness (coronary artery disease, advanced cancer, active esophageal
or gastroduodenal ulcers, etc) in the last one year
- Systemic Lupus Erythematosis
- FVC < 60%
- Pregnancy or lactation
- Allergy to minocycline, tetracyclines, celecoxib, sulfonamides, NSAIDS, or creatine
- History of congestive heart failure
- Renal disease [baseline Cr > 1. 5 (men) or 1. 2 (women)]
- History of significant hepatic disease (baseline AST/ALT or bilirubin > 1. 5x normal)
- Use of an investigational agent within thirty days of enrollment
- First degree relative with ALS or gene identified familial ALS
- Inability or unwillingness to maintain adequate daily hydration (defined above)
- Limited mental capacity such that the patient cannot provide written informed consent
or comply with evaluation procedures.
- History of recent alcohol or drug abuse or noncompliance with treatment or other
experimental protocols.
Locations and Contacts
Phoenix Neurological Associates, Phoenix, Arizona 85006, United States
California Pacific Medical Center, San Francisco, California 94115, United States
UCLA, Los Angeles, California 90095, United States
University of California Irvine, Orange, California 92868, United States
Mayo Clinic Florida, Jacksonville, Florida 32224, United States
Medical College of Georgia, Augusta, Georgia 30912, United States
University of Illinois, Chicago, Illinois 60637, United States
University of Kansas, Kansas City, Kansas 66160, United States
Mayo Clinic Rochester, Rochester, Minnesota 55905, United States
Washington University, St. Louis, Missouri 63110, United States
UMDNJ, New Brunswick, New Jersey 08901, United States
University of New Mexico, Albuquerque, New Mexico 87131, United States
Beth Israel, New York, New York 10003, United States
Columbia University, New York, New York 10032, United States
Duke University, Durham, North Carolina 27705, United States
Oregon Health and Science University, Portland, Oregon 97201, United States
University of Pennsylvania, Philadelphia, Pennsylvania 19107, United States
UT Southwestern Medical Center, Dallas, Texas 75390, United States
University of Vermont, Burlington, Vermont 05405, United States
Additional Information
Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University website ALS Association Website
Related publications: Klivenyi P, Kiaei M, Gardian G, Calingasan NY, Beal MF. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2004 Feb;88(3):576-82. Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003 Feb;53(2):267-70. Cheung YK, Gordon PH, Levin B. Selecting promising ALS therapies in clinical trials. Neurology. 2006 Nov 28;67(10):1748-51. Review.
Starting date: July 2006
Ending date: May 2007
Last updated: December 11, 2007
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