Therapy in Amyotrophic Lateral Sclerosis (TAME)

NCT ID: NCT02118727

Last Updated: 2022-11-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 89 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-07
• Study Completion Date: 2021-07-22

Brief Summary

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

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.

Conditions

Amyotrophic Lateral Sclerosis; Frontal Temporal Dementia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Memantine

Up to 20 mg memantine taken by mouth twice a day for 36 weeks

Group Type: ACTIVE_COMPARATOR

Memantine

Intervention Type: DRUG

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.

Placebo

Up to 2 placebo tablets taken by mouth twice a day for 36 weeks

Group Type: PLACEBO_COMPARATOR

Placebo (for Memantine)

Intervention Type: DRUG

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.

Interventions

Memantine

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.

Intervention Type: DRUG

Placebo (for Memantine)

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.

Intervention Type: DRUG

Other Intervention Names

Namenda; Sugar pill manufactured to mimic memantine 10 mg

Eligibility Criteria

Inclusion Criteria

1. Age 18-85

2. Male or Female

3. Clinically definite, probable, probable lab-supported, or possible ALS by El Escorial criteria

4. ALSFRS-R > 25

5. Must be willing to undergo longitudinal blood draws for biomarker analysis

6. Availability and willingness to complete the study

7. Capable of providing informed consent and complying with trial procedures

8. 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.

1. Age 18-85

2. Male or Female

3. Clinically definite, probable, probable lab-supported, or possible ALS by El Escorial criteria

4. ALSFRS-R > 25

5. Must be willing to undergo longitudinal blood draws for biomarker analysis. This may be foregone during the screening visit

6. Availability and willingness to complete the study

7. Capable of providing informed consent and complying with trial procedures

8. 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

9. Documentation of not clinically significant liver enzymes within the previous 6 months

Exclusion Criteria

1. Patients with forced vital capacity (FVC) ≤ 60%

2. History of liver disease

3. Severe renal failure

4. History of intolerance to memantine

5. Onset of weakness 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 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.

9. Unwillingness to provide consent

1. Patients with FVC ≤ 60%*

2. History of liver disease

3. Severe renal failure

4. History of intolerance to memantine

5. Onset of weakness 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 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.

9. 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Missouri-Columbia

OTHER

Sponsor Role: collaborator

University of Kansas Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Richard J. Barohn, MD

Executive Vice Chancellor for Health Affairs

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard J Barohn, MD

Role: PRINCIPAL_INVESTIGATOR

University of Missouri Health Care

Locations

Phoenix Neurological Associates

Phoenix, Arizona, United States

UC Irvine

Irvine, California, United States

University of Florida

Jacksonville, Florida, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Kansas School of Medicine - Wichita

Wichita, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

University of Missouri

Columbia, Missouri, United States

CoxHealth

Springfield, Missouri, United States

Providence Health Sciences

Portland, Oregon, United States

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States

Austin Neuromuscular Center

Austin, Texas, United States

Nerve & Muscle Center of Texas

Houston, Texas, United States

University of Washington

Seattle, Washington, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

FDA

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

TAME-ALS FD003937-01

Identifier Type: -

Identifier Source: org_study_id