Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

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 Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Creatine; Drug: Minocycline; Drug: Celecoxib

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.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Phoenix Neurological Associates
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
    • Orange, California, United States, 92868
      • University of California Irvine
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Illinois
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • UMDNJ
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10003
      • Beth Israel
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Oregon
    • Portland, Oregon, United States, 97201
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • University of Pennsylvania
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Pfizer; ALS Association
• Investigators: Principal Investigator: Paul H Gordon, MD, Columbia University

Publications and helpful links

General 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. doi: 10.1046/j.1471-4159.2003.02160.x.
• 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. doi: 10.1002/ana.10476.
• Cheung YK, Gordon PH, Levin B. Selecting promising ALS therapies in clinical trials. Neurology. 2006 Nov 28;67(10):1748-51. doi: 10.1212/01.wnl.0000244464.73221.13.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: July 1, 2006
• Study Completion (Actual): May 1, 2007

Study Registration Dates

• First Submitted: July 21, 2006
• First Submitted That Met QC Criteria: July 21, 2006
• First Posted (Estimate): July 24, 2006

Study Record Updates

• Last Update Posted (Estimate): February 1, 2011
• Last Update Submitted That Met QC Criteria: January 31, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; ALS; Motor Neuron Disease; Celecoxib; Combination; Creatine; Minocycline; Selection
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Anti-Bacterial Agents; Cyclooxygenase 2 Inhibitors; Celecoxib; Minocycline
• Other Study ID Numbers: AAAB6334; ALSA ID#920 (Other Identifier: CUMC)