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Therapy in Amyotrophic Lateral Sclerosis With Memantine at 20 mg BID (TAME) (TAME)

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ClinicalTrials.gov Identifier: NCT02118727
Recruitment Status : Recruiting
First Posted : April 21, 2014
Last Update Posted : November 8, 2018
Sponsor:
Information provided by (Responsible Party):
Richard Barohn, MD, University of Kansas Medical Center

Brief Summary:

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.

Funding Source-FDA OOPD


Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Frontal Temporal Dementia Drug: Memantine Drug: Placebo (for Memantine) Phase 2

Detailed Description:

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 7, 2018
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : October 2022


Arm Intervention/treatment
Active Comparator: Memantine
20mg taken by mouth every day BID for 32 weeks
Drug: Memantine
All randomized patients will be instructed to take one tablet once a day for the first week from a blinded bottle that contains 10 mg tablets or matching placebo. At week two, patients will be instructed to take one tablet twice a day from the 10 mg bottle or matching placebo. At week three, patients will be instructed to take two tablets in the morning from the 10 mg bottle and one tablet from the 10 mg bottle or the matching placebo bottle in the evening. At week four patients will be instructed to take two pills twice a day from the 10 mg bottle or matching placebo.
Other Name: Namenda

Placebo Comparator: Placebo
Placebo (for Memantine) taken by mouth everyday BID for 32 weeks
Drug: Placebo (for Memantine)
All randomized patients will be instructed to take one tablet once a day for the first week from a blinded bottle that contains 10 mg tablets or matching placebo. At week two, patients will be instructed to take one tablet twice a day from the 10 mg bottle or matching placebo. At week three, patients will be instructed to take two tablets in the morning from the 10 mg bottle and one tablet from the 10 mg bottle or the matching placebo bottle in the evening. At week four patients will be instructed to take two pills twice a day from the 10 mg bottle or matching placebo.
Other Name: Sugar Pill manufactured to mimic Memantine 20 mg




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. Measuring the levels of Tau, pNFH and the pNFH/C3 ratio in CSF and blood [ Time Frame: 36 weeks of treatment ]
    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:
  1. 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 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-85
  2. Male or Female
  3. Clinically definite or probable ALS by El Escorial criteria
  4. ALS-FRS > 25
  5. On stable dose of Rilutek 50 mg bid for at least 30 days prior to screening
  6. Capable of providing informed consent and complying with trial procedures

Exclusion Criteria:

  1. Patients with FVC below 60%
  2. History of liver disease
  3. Severe renal failure
  4. History of intolerance to Riluzole or memantine
  5. Evidence of motor neuron disease for greater than 3 years
  6. Any other co-morbid condition which would make completion of the trial unlikely
  7. If female, pregnant or breast-feeding; or, if of childbearing age, an unwillingness to use birth control.
  8. Taking any trial medications. Non-trial medications are not cause for exclusion.
  9. Unwillingness to provide consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02118727


Contacts
Contact: Sherri Anderson (913) 945-9936 sanderson10@kumc.edu
Contact: Andrew Heim (913) 945-9926 aheim2@kumc.edu

Locations
United States, Arizona
Phoenix Neurological Associates Not yet recruiting
Phoenix, Arizona, United States, 85018
Contact: Angelina Cooper         
Principal Investigator: Todd D Levine, MD         
United States, California
UC Irvine Not yet recruiting
Irvine, California, United States, 92868
Contact: Veronica Martin, CCRC    714-456-7760    vero@uci.edu   
Contact: Veena Mathew    714-456-2864    vmathew@uci.edu   
Principal Investigator: Tahseen Mozaffar, MD         
United States, Kansas
University of Kansas Medical Center Recruiting
Kansas City, Kansas, United States, 66160
Contact: Sherri Anderson    913-945-9936    sanderson10@kumc.edu   
Contact: Andrew Heim    913-945-9926    aheim2@kumc.edu   
Principal Investigator: Richard J Barohn, MD         
University of Kansas School of Medicine - Wichita Not yet recruiting
Wichita, Kansas, United States, 67214
Contact: Trish Steele    316-293-3805    tsteele5@kumc.edu   
Principal Investigator: Tiffany Schwasinger-Schmidt, MD         
United States, Washington
University of Washington Not yet recruiting
Seattle, Washington, United States, 98195
Contact: Sharon Downing       sdowning@uw.edu   
Contact: Susan Strom, sstrom@uw.edu         
Principal Investigator: Michael Weiss, MD         
Sponsors and Collaborators
University of Kansas Medical Center
Investigators
Principal Investigator: Richard D Barohn, MD University of Kansas Medical Center

Responsible Party: Richard Barohn, MD, Gertrude and Dewey Ziegler Professor of Neurology and Chair, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT02118727     History of Changes
Other Study ID Numbers: TAME-ALS FD003937-01
FDA ( Other Grant/Funding Number: R01FD003937 )
First Posted: April 21, 2014    Key Record Dates
Last Update Posted: November 8, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Richard Barohn, MD, University of Kansas Medical Center:
ALS
FTD
Tau
pNF-H/C3

Additional relevant MeSH terms:
Sclerosis
Dementia
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Neuromuscular Diseases
Spinal Cord Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Memantine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents