Clinical trial NCT00355576: Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis
Official title: Phase II Combination Therapy Selection Trial in Amyotrophic Lateral Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic Lateral Sclerosis
Celecoxib
Creatine
Minocycline
Combination
Selection
ALS
Motor Neuron Disease
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: ALS Association
name: Pfizer
First posted: 2006-07-24
Enrollment: 86
Sex: ALL
Minimum age (years): 21
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: ALS Functional Rating Scale Revised (ALSFRS-R) completed monthly during trial.
timeFrame: Up to 6 months from the start of treatment
Secondary outcomes:
measure: Forced Vital Capacity, Quality of Life, Timed Get Up and Go performed monthly. Survival and measures of safety throughout the trial.
timeFrame: Up to 6 months from the start of treatment
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Neurological Associates
state: Arizona
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: New Brunswick
country: United States
facility: UMDNJ
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Beth Israel
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
Study officials:
affiliation: Columbia University
name: Paul H Gordon, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.