Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Celecoxib
* Drug: Creatine
* Drug: Minocycline


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Minocycline + Creatine<br>Minocycline 100 mg BID and Creatine 10 g BID | Drug: Creatine<br>* 10 g BID for either study arm<br>Drug: Minocycline<br>* Minocycline 100 mg BID with creatine 10 g BID if randomized to the Minocycline + Creatine study arm<br>|
| Experimental: Celecoxib + Creatine<br>Celecoxib 400 mg BID and Creatine 10 g BID | Drug: Celecoxib<br>* Celecoxib 400 mg BID with creatine 10 g BID if randomized to the Celecoxib + Creatine study arm.<br>Drug: Creatine<br>* 10 g BID for either study arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial. |  | Up to 6 months from the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Vital Capacity, Quality of Life, Timed Get Up and Go performed monthly. Survival and measures of safety throughout the trial. |  | Up to 6 months from the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Celecoxib, Amyotrophic Lateral Sclerosis, Creatine, Minocycline, Combination, Selection, ALS, Motor Neuron Disease