Memantine Therapy in Amyotrophic Lateral Sclerosis (TAME)

Phase IIA Open Label Trial of Memantine in Combination With Riluzole (Customary Care) for the Treatment of ALS

Tau, a protein in the cerebrospinal fluid CSF is believed to be elevated in amyotrophic lateral sclerosis (ALS) patients. The investigators believe that Tau is truly a marker of increased neuronal death from any disease process. It is been shown that Memantine can inhibit and reverse the abnormal hyperphosphorylation of Tau and therefore the investigators are looking at the efficacy of Memantine at 10 mg twice a day (BID) to see if disease progression correlates with possible changes in Tau in ALS patients based on ALS Functional Rating Scale (ALSFRS) scores.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Memantine

Detailed Description

We have been very interested in the role of developing a more active anti-excitotoxic cocktail for patients with ALS. As part of this interest we have been investigating potential markers for disease progression. One of our candidate markers has been the presence of elevated levels of TAU in the CSF of patients with ALS. While the presence of Tau was originally described as being used for adjunctive diagnostic testing in patients with Alzheimer's disease it has become clear that many neurodegenerative diseases possess elevated levels of Tau in the CSF. Therefore Tau is truly a marker of increased neuronal death from any disease process.

While levels of Tau have not been studied in depth in ALS, there was one report in 2003 which showed that 70% of ALS patients have elevated levels of Tau in their CSF (Sussmuth et al). We have also collected a series of 24 patients with clinically definite ALS and found that 22 of them had elevated levels of Tau at the time of diagnosis.

We have been intrigued by the findings that Memantine, an NMDA receptor antagonist, can inhibit and reverse the abnormal hyperphosphorylation of Tau which leads to sequestration of the normal Tau microtubules as well as microtubule associated protein 1 (MAP-1) and MAP-2. Further, Memantine has been shown to block the disassembly of microtubules which follows the hyperphosphorylation if Tau (Li et al., 2004).

We have submitted for presentation to the International Motor Neuron Disease meeting in 2005 the data on two anecdotal cases of patients with ALS. These two patients were diagnosed with ALS on clinical and electrophysiological data and they were found to have elevated levels of Tau in their CSF at the time of diagnosis. Both patients were treated with Riluzole, as standard therapy, and with Memantine 10 mg BID for 6 months. After 6 months their disease course was clearly very slow. A repeat analysis of their CSF showed that levels of Tau had returned to normal.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Phoenix Neurological Associates, LTD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Age 18-85
2. Male or Female
3. Clinically definite ALS by El Escorial criteria
4. Elevated levels of Tau in CSF

Exclusion Criteria:

1. Patients with FVC below 1.5 L or who require respiratory assistance
2. History of liver disease
3. Severe renal failure
4. History of intolerance to Riluzole or Memantine
5. Any other co morbid condition which would make completion of trial unlikely
6. If female, pregnant or breast-feeding; or, if of childbearing age, an unwillingness to use birth control.
7. Taking any trial medications. Non-trial medications are not cause for exclusion.
8. Unwillingness to provide consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ACTIVE	Drug: Memantine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Standardized assessment of ALS disease progression through the ALS Functional Rating Scale (ALSFRS) and compare the levels of Tau at baseline, 6 and 12 months	18 months

Secondary Outcome Measures

Outcome Measure
Change in muscle strength as measured by quantitative dynamometry (baseline vs 18 months)

Collaborators and Investigators

• Sponsor: Phoenix Neurological Associates, LTD
• Collaborators: Forest Laboratories

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: November 20, 2009
• First Submitted That Met QC Criteria: November 23, 2009
• First Posted (Estimate): November 25, 2009

Study Record Updates

• Last Update Posted (Estimate): November 25, 2009
• Last Update Submitted That Met QC Criteria: November 23, 2009
• Last Verified: November 1, 2009

More Information

Terms related to this study

• Keywords: ALS
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Memantine
• Other Study ID Numbers: Memantine in ALS