Official Title: “Phase II Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Historical Control, Parallel Assignment, Safety/Efficacy Study

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.

Intervention(s) in this Clinical Trial

• Drug: celecoxib
• Drug: creatine
• Drug: minocycline

Primary Measures

• ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial.

Secondary Measures

• Forced Vital Capacity, Quality of Life, Timed Get Up and Go performed monthly. Survival and measures of safety throughout the trial.

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 21 Years

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Columbia University

Overall Clinical Trial Officials and Contacts

Paul H Gordon, MD Principal Investigator Columbia University  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00355576

Study ID Number: AAAB6334

ClinicalTrials.gov Identifier: NCT00355576

Health Authority: United States: Food and Drug Administration

Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University website

ALS Association Website