Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis - Full Text View

Sponsor:	Columbia University
Collaborators:	ALS Association Pfizer
Information provided by:	Columbia University
ClinicalTrials.gov Identifier:	NCT00355576

Purpose

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.

Condition	Intervention	Phase
Amyotrophic Lateral Sclerosis	Drug: Celecoxib Drug: Creatine Drug: Minocycline	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Phase II Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

Resource links provided by NLM:

Genetics Home Reference related topics: amyotrophic lateral sclerosis

MedlinePlus related topics: Amyotrophic Lateral Sclerosis

Drug Information available for: Creatine Minocycline Minocycline hydrochloride Celecoxib Creatine monohydrate

U.S. FDA Resources

Further study details as provided by Columbia University:

Primary Outcome Measures:

ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial. [ Time Frame: Up to 6 months from the start of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Forced Vital Capacity, Quality of Life, Timed Get Up and Go performed monthly. Survival and measures of safety throughout the trial. [ Time Frame: Up to 6 months from the start of treatment ] [ Designated as safety issue: Yes ]

Enrollment:	86
Study Start Date:	July 2006
Study Completion Date:	May 2007

Arms	Assigned Interventions
Experimental: Minocycline + Creatine Minocycline 100 mg BID and Creatine 10 g BID	Drug: Creatine 10 g BID for either study arm Other Name: Creatine Drug: Minocycline Minocycline 100 mg BID with creatine 10 g BID if randomized to the Minocycline + Creatine study arm Other Name: Minocycline
Experimental: Celecoxib + Creatine Celecoxib 400 mg BID and Creatine 10 g BID	Drug: Celecoxib Celecoxib 400 mg BID with creatine 10 g BID if randomized to the Celecoxib + Creatine study arm. Other Name: Celecoxib Drug: Creatine 10 g BID for either study arm Other Name: Creatine

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

Ages Eligible for Study:	21 Years to 85 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00355576

Show 19 Study Locations

Sponsors and Collaborators

Columbia University

ALS Association

Pfizer

Investigators

Principal Investigator:

Paul H Gordon, MD

Columbia University

More Information

Additional Information:

Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University website This link exits the ClinicalTrials.gov site

ALS Association Website This link exits the ClinicalTrials.gov site

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.

Responsible Party:	Paul H. Gordon, Columbia University Medical Center
ClinicalTrials.gov Identifier:	NCT00355576 History of Changes
Other Study ID Numbers:	AAAB6334, ALSA ID#920
Study First Received:	July 21, 2006
Last Updated:	January 31, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Columbia University:

Amyotrophic Lateral Sclerosis
Celecoxib
Creatine
Minocycline

Combination
Selection
ALS
Motor Neuron Disease

Additional relevant MeSH terms:

Amyotrophic Lateral Sclerosis
Sclerosis
Motor Neuron Disease
Spinal Cord Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
TDP-43 Proteinopathies
Neuromuscular Diseases
Proteostasis Deficiencies
Metabolic Diseases
Pathologic Processes
Minocycline
Celecoxib
Anti-Bacterial Agents

Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on February 09, 2012