Multi-centered Double Blind, Placebo Controlled Study Evaluating the Safety and Efficacy of Memantine at 20 mg BID in Patients With ALS Currently Taking Riluzole
The purpose of this study is to determine if memantine at 20 mg BID when used in conjunction with riluzole, can slow down the disease progression of patients with ALS including potentially improving their neuropsychiatric changes, as well as determine if CSF protein biomarkers can be used both as a diagnostic and a prognostic marker in patients with ALS.
Disease:Amyotrophic Lateral Sclerosis (ALS), Familial ALS, Sporadic ALS
Study Type:Interventional Trial
Study Category:Drug Trial
Study Status:Active, not yet recruiting
Study Chair(s)/Principal Investigator(s):
Richard D Barohn, MD (University of Kansas)
Clinicaltrials.gov ID (11 digit #):NCT02118727
Coordinating Center Contact InformationUniversity of Kansas
Full Study Summary:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 30,000 Americans each year. Of these 30,000 Americans, it has been suggested that up to 50% will experience cognitive and behavioral changes in the form of frontotemporal dysfunction and up to 40% will meet criteria for frontotemporal dementia (FTD). Riluzole the only FDA approved agent for ALS extends a patient's lifespan by 2-3 months, and there are no proven therapies for the cognitive changes associated with ALS. More effective therapy for this universally fatal disease is desperately needed.
Results from an open label pilot trial of 20 patients treated with memantine at 10 mg BID suggested that treatment with the combination of memantine and riluzole slowed ALS disease progression. This trial also showed that levels of specific protein biomarkers in the CSF at baseline correlated with the rate of disease progression. A concurrent phase II study performed by Dr Carvalho, found no effect with similar dosing; however, the study was limited in terms of power. Comments on previous failed drug trials in ALS have raised the concern that many ALS trials study a potential therapeutic agent at only a single dose and thus may miss the potential efficacy of non FDA approved doses; therefore, this proposed study will test a higher dose of memantine, 20 mg BID, in a double blind, placebo controlled, randomized trial of 90 patients with ALS to determine if a combination therapy of memantine with riluzole can slow disease progression compared to treatment with riluzole alone. The primary outcome measure will be the rate of disease progression as measured by the ALS Functional Rating Scale- Revised (ALSFRS-R). In addition the investigators will examine the cognitive deficits seen in ALS patients measured by the ALS Cognitive Behavioral Screen (ALS-CBS) and the Neuropsychiatric Inventory Questionnaire (NIP-Q). Finally the investigators will examine specific validated protein biomarkers found in the cerebrospinal fluid to determine if there is a correlation between the levels of these biomarkers and the rate of disease progression. In particular the investigators will measure the ratio of phosphorylated heavy neurofilament to Complement 3 to see if this ratio is predictive of disease progression and if the levels change during therapy with memantine.
This project will offer unique insights into this untreatable disease. If this study confirms earlier results and suggests that memantine, when used in conjunction with riluzole, significantly slows down the progression of the disease, as well as ameliorates cognitive deficits in patients with fronto-temporal dysfunction, it will set the groundwork for conducting a larger phase III trial.
Study Sponsor:FDA OOPD
36 weeks of treatment
Estimated Study Start Date:03/31/2016
Estimated Study Completion Date:09/30/2019
Posting Last Modified Date:11/02/2016
Date Study Added to alsconsortium.org:08/18/2015
Primary Outcome Measures:
-Disease progression as measured by the number of points lost on the ALS Functional Rating-Scale-Revised (ALSFRS-R) [ Time Frame: During 36 weeks of therapy ] [ Designated as safety issue: No ]
-The primary outcome measure will be disease progression as measured by the number of points lost on the ALS Functional Rating Scale- Revised (ALSFRS-R) during the 36 weeks of therapy. The patient's rate of progression on active therapy during the 36 week treatment arm will be compared to the rate of progression of the placebo arm. Disease progression in numerous ALS clinical trials has been measured using the ALSFRS-R which is a 12 question rating scale used to determine each participant's assessment of their capability and independence in daily activities. The ALSFRS-R can be administered with high inter-rater reliability and test-retest reliability in person or over the phone. The advantages of using such a measurement to determine disease progression are that the categories are relevant to ALS, it is a sensitive and reliable tool, and the rate of decline correlates strongly with survival
Secondary Outcome Measures:
-Measuring the levels of Tau, pNFH and the pNFH/C3 ratio in CSF and blood [ Time Frame: 36 weeks of treatment ] [ Designated as safety issue: No ]
-Preliminary data have demonstrated that there are elevated levels of tau and phosphorylated neurofilament heavy chain (pNF-H) in the CSF of patients with ALS as compared to healthy controls suggesting that these proteins could also be used for measuring a patient's disease progression. Recently published data have also shown a high sensitivity and specificity for the ratio of pNFH/C3 in the CSF for diagnosing ALS. These combinations of biomarkers could be markers for axonal injury and neuronal cell death.
Other Outcome Measures:
-Slowing of behavioral decline in those with FTD characteristics based on the NPI-Q and the ALS-CBS [ Time Frame: the course of 36 weeks of treatment ] [ Designated as safety issue: No ]
-It is demonstrated that up to half of patients with ALS may develop cognitive impairment during the course of the disease and up to 40% of ALS patients develop FTD. The ALS Cognitive Behavioral Screen (ALS-CBS™) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), are two neuropsychological batteries that are validated, brief practical measures that will be administered. Previous data has shown that memantine can slow the progression of behavioral and cognitive decline in other neurodegenerative diseases, such as Alzheimer's, Parkinson's and Lewy Body Disease, that there may be potential for a positive effect in patients with ALS. These scales should be great indicators of not only the diagnosis frototemporal dysfunction and even FTD, but also whether memantine can have any positive effect upon the progression of these changes.
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Time since Symptom Onset:
Time since Diagnosis:<36 months
Can participants use Riluzole?Yes
Male or Female
Clinically definite or probable ALS by El Escorial criteria
ALS-FRS > 25
On stable dose of Rilutek 50 mg bid for at least 30 days prior to screening
Capable of providing informed consent and complying with trial procedures
Patients with FVC below 60%
History of liver disease
Severe renal failure
History of intolerance to Riluzole or memantine
Evidence of motor neuron disease for greater than 3 years
Any other co-morbid condition which would make completion of the trial unlikely
If female, pregnant or breast-feeding; or, if of childbearing age, an unwillingness to use birth control.
Taking any trial medications. Non-trial medications are not cause for exclusion.
Unwillingness to provide consent
Site Contact Information
California Pacific Medical Center
San Francisco, California 94775
Department of Neurology Washington University of Medicine
Duke ALS Clinic
Durham, North Carolina 27705
Mayo Clinic Department of Neurology
Jacksonville, Florida 32224
Phoenix Neurological Associates
Phoenix, Arizona 85018
Orange County, California 92868
University of Kansas Medical Center
Kansas City, Kansas 66160
University of Pittsburgh
Pittsburgh, Pennsylvania 15213
University of Washington