Therapy in Amyotrophic Lateral Sclerosis (TAME)

Study Overview
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Brief Summary
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The purpose of this study is to determine if memantine at up to 20 mg twice a day 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 serum biomarkers can be used both as a diagnostic and a prognostic marker in patients with ALS. Funding Source: FDA - Orphan Products Development (OPD)

Detailed Description
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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 twice a day 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 cerebrospinal fluid (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 twice a day, in a double blind, placebo controlled, randomized trial of 90 patients with ALS to determine if a therapy of memantine, especially in combination with riluzole, can slow disease progression compared to treatment with riluzole alone or no treatment. Participants who experience treatment related adverse events may undergo dose reduction or discontinuation. 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 (NPI-Q). Finally the investigators will examine specific validated protein serum biomarkers 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.

Official Title
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Phase 2B Study of Memantine for the Treatment of Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis, Frontal Temporal Dementia

Intervention / Treatment
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* Drug: Memantine
* Drug: Placebo (for Memantine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-85 Male or Female Clinically definite, probable, probable lab-supported, or possible ALS by El Escorial criteria ALSFRS-R > 25 Must be willing to undergo longitudinal blood draws for biomarker analysis Availability and willingness to complete the study Capable of providing informed consent and complying with trial procedures If patients are taking riluzole and/or Radicava, they must be a on a stable dose for at least thirty days prior to the baseline. Exclusion Criteria: Patients with forced vital capacity (FVC) ≤ 60% History of liver disease Severe renal failure History of intolerance to memantine Onset of weakness 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 investigational medications. If the patient was previously on investigational medications, a 30-day washout period is required before the baseline visit. Non-trial medications are not cause for exclusion. Unwillingness to provide consent Remote Inclusion Criteria: Age 18-85 Male or Female Clinically definite, probable, probable lab-supported, or possible ALS by El Escorial criteria ALSFRS-R > 25 Must be willing to undergo longitudinal blood draws for biomarker analysis. This may be foregone during the screening visit Availability and willingness to complete the study Capable of providing informed consent and complying with trial procedures If patients are taking riluzole and/or Radicava, they must be a on a stable dose for at least thirty days prior to the baseline Documentation of not clinically significant liver enzymes within the previous 6 months Remote Exclusion Criteria: Patients with FVC ≤ 60%* History of liver disease Severe renal failure History of intolerance to memantine Onset of weakness 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 investigational medications. If the patient was previously on investigational medications, a 30-day washout period is required before the baseline visit. Non-trial medications are not cause for exclusion. Unwillingness to provide consent Since FVC cannot be captured during a remote screening visit, and acceptable FVC performed within the previous 90 days is acceptable. If an FVC is not available within the previous 90 days, the subject may be enrolled if the local site PI believes the subject has no significant shortness of breath or respiratory issues.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Memantine<br>Up to 20 mg memantine taken by mouth twice a day for 36 weeks | Drug: Memantine<br>* All randomized patients will be instructed to take one tablet once a day for the first two weeks from a blinded bottle that contains 10 mg tablets or matching placebo. At week three, patients will be instructed to take one tablet twice a day from the 10 mg bottle or matching placebo. At week five, patients will be instructed to take one tablet in the morning and two tablets in the evening from the 10 mg bottle or matching placebo. At week seven patients will be instructed to take two tablets twice a day from the 10 mg bottle or matching placebo.<br>* Other names: Namenda;|
| Placebo Comparator: Placebo<br>Up to 2 placebo tablets taken by mouth twice a day for 36 weeks | Drug: Placebo (for Memantine)<br>* All randomized patients will be instructed to take one tablet once a day for the first two weeks from a blinded bottle that contains 10 mg tablets or matching placebo. At week three, patients will be instructed to take one tablet twice a day from the 10 mg bottle or matching placebo. At week five, patients will be instructed to take one tablet in the morning and two tablets in the evening from the 10 mg bottle or matching placebo. At week seven patients will be instructed to take two tablets twice a day from the 10 mg bottle or matching placebo.<br>* Other names: Sugar pill manufactured to mimic memantine 10 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Comparison for Efficacy Will be Based on a Linear Mixed Effects (LME) Model Fit to the ALSFRS-R Data for the Patients Followed Over 36 Weeks. | The primary outcome measure will be disease progression as measured by the Amyotrophic Lateral Sclerosis 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. The ALSFRS-R is a 12 question rating scale used to determine each participant's assessment of their capability and independence in daily activities. Possible values are from 0 to 48; higher score means better outcome. | During 36 weeks of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, FTD, Tau, pNF-H/C3