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Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Celecoxib
Creatine
Minocycline
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic Lateral Sclerosis, Celecoxib, Creatine, Minocycline, Combination, Selection, ALS, Motor Neuron Disease

Eligibility Criteria

21 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Phoenix Neurological Associates
  • UCLA
  • University of California Irvine
  • California Pacific Medical Center
  • Mayo Clinic Florida
  • Medical College of Georgia
  • University of Illinois
  • University of Kansas
  • Mayo Clinic Rochester
  • Washington University
  • UMDNJ
  • University of New Mexico
  • Beth Israel
  • Columbia University
  • Duke University
  • Oregon Health and Science University
  • University of Pennsylvania
  • UT Southwestern Medical Center
  • University of Vermont

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Minocycline + Creatine

Celecoxib + Creatine

Arm Description

Minocycline 100 mg BID and Creatine 10 g BID

Celecoxib 400 mg BID and Creatine 10 g BID

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
July 21, 2006
Last Updated
January 31, 2011
Sponsor
Columbia University
Collaborators
ALS Association, Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT00355576
Brief Title
Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis
Official Title
Phase II Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
January 2011
Overall Recruitment Status
Completed
Study Start Date
July 2006 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
May 2007 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Columbia University
Collaborators
ALS Association, Pfizer

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
Amyotrophic Lateral Sclerosis, Celecoxib, Creatine, Minocycline, Combination, Selection, ALS, Motor Neuron Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
86 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Minocycline + Creatine
Arm Type
Experimental
Arm Description
Minocycline 100 mg BID and Creatine 10 g BID
Arm Title
Celecoxib + Creatine
Arm Type
Experimental
Arm Description
Celecoxib 400 mg BID and Creatine 10 g BID
Intervention Type
Drug
Intervention Name(s)
Celecoxib
Intervention Description
Celecoxib 400 mg BID with creatine 10 g BID if randomized to the Celecoxib + Creatine study arm.
Intervention Type
Drug
Intervention Name(s)
Creatine
Intervention Description
10 g BID for either study arm
Intervention Type
Drug
Intervention Name(s)
Minocycline
Intervention Description
Minocycline 100 mg BID with creatine 10 g BID if randomized to the Minocycline + Creatine study arm
Primary Outcome Measure Information:
Title
ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial.
Time Frame
Up to 6 months from the start of treatment
Secondary Outcome Measure Information:
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul H Gordon, MD
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Phoenix Neurological Associates
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85006
Country
United States
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California Irvine
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Medical College of Georgia
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
University of Illinois
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Kansas
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Mayo Clinic Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
UMDNJ
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Facility Name
Beth Israel
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97201
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
University of Vermont
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05405
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
14720207
Citation
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.
Results Reference
background
PubMed Identifier
12557297
Citation
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.
Results Reference
background
PubMed Identifier
17130405
Citation
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.
Results Reference
background
Links:
URL
http://www.columbiaals.org
Description
Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University website
URL
http://www.alsa.org
Description
ALS Association Website

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Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

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