Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis Clinical Trial

Official title:

Phase II Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00355576
• Other study ID #: AAAB6334
• Secondary ID: ALSA ID#920
• Status: Completed
• Phase: Phase 2
• First received: July 21, 2006
• Last updated: January 31, 2011
• Start date: July 2006
• Est. completion date: May 2007

Study information

• Verified date: January 2011
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: May 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 85 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Celecoxib
Celecoxib 400 mg BID with creatine 10 g BID if randomized to the Celecoxib + Creatine study arm.
• Creatine
10 g BID for either study arm
• Minocycline
Minocycline 100 mg BID with creatine 10 g BID if randomized to the Minocycline + Creatine study arm

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	Medical College of Georgia	Augusta	Georgia
United States	University of Vermont	Burlington	Vermont
United States	University of Illinois	Chicago	Illinois
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of Kansas	Kansas City	Kansas
United States	UCLA	Los Angeles	California
United States	UMDNJ	New Brunswick	New Jersey
United States	Beth Israel	New York	New York
United States	Columbia University	New York	New York
United States	University of California Irvine	Orange	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Phoenix Neurological Associates	Phoenix	Arizona
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	California Pacific Medical Center	San Francisco	California
United States	Washington University	St. Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
Columbia University	ALS Association, Pfizer

Country where clinical trial is conducted

United States, 

References & Publications (3)

Cheung YK, Gordon PH, Levin B. Selecting promising ALS therapies in clinical trials. Neurology. 2006 Nov 28;67(10):1748-51. Review. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial.		Up to 6 months from the start of treatment	No
Secondary	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	Yes

External Links

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