Riluzole in Mild Alzheimer's Disease

NCT01703117 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: GCO 18-0623APE-0792
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 2

Brief Summary

Cognitive aging is a major source of disability in an increasingly aging population. The paucity of effective treatments for cognitive aging disorders, and most importantly in Alzheimer's disease instigates a need for further research into novel therapeutic possibilities. Alzheimer's disease is the most common neurodegenerative disorder and its prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders and in particular in Alzheimer's disease has been shown to cause significant cerebral damage. Early effective therapeutic intervention in Alzheimer's disease is critical in order to prevent or at least slow down neuropathological progression that will lead to widespread irreversible neuronal loss and significant cognitive dysfunction. Riluzole, a glutamate modulator agent, will be tested in mild Alzheimer's disease patients. Cognitive functional changes along with two established in vivo biomarkers, namely, Magnetic Resonance Spectroscopy (MRS) and Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) will be evaluated.

Conditions

Alzheimer's Disease

Keywords

Alzheimer's Disease; Dementia

Outcome Measures

Primary Outcomes (2)

• Imaging Biomarkers FDG-PET SUVR in Regions of Interest

  Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.

  Change from baseline to 6 months

• Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS

  N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.

  Changes from baseline to 6 months

Secondary Outcomes (4)

• Glutamate Levels Measured Through 1H MRS

  Change from baseline to 6 months

• Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)

  baseline to 6 months

• Neuropsychiatry Inventory - NPI

  baseline to 6 months

• ADCS Activities of Daily Living

  baseline to 6 months

Study Arms (2)

age matched cohort 50-95 years old

EXPERIMENTAL

20-22 subjects between the ages of 50-95 will receive riluzole

Drug: Riluzole

24 subjects between 50-95 years old

PLACEBO COMPARATOR

20-22 subjects between 50-95 will receive placebo

Drug: Placebo

Interventions

Riluzole DRUG

20-22 subjects between the ages of 60-85 will receive study drug.

Also known as: no other names

age matched cohort 50-95 years old

Placebo DRUG

20-22 subjects between the ages of 60-85 will receive placebo

Also known as: no other names

24 subjects between 50-95 years old

Eligibility Criteria

• Age: 50 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female; 50 - 95 years old with mild Alzheimer's disease determined after neurological and neuropsychological evaluation following the National Institute on Aging - Alzheimer's disease Association criteria that recently revisited the NINCDS-ADRDA criteria. For mild Alzheimer's disease, Clinical Dementia Ratings Scale (CDR) should be 0.5 or 1 and Mini Mental State Examination (MMSS) between 19 and 27.
• Must be fluent in English
• The subject will appoint or have previously appointed a health care proxy specifically designated for research consent and that this be documented.

You may not qualify if:

• Severe Alzheimer's disease and other dementias as determined by neuropsychological testing and neurological evaluation.
• Previous riluzole treatment.
• MRI contraindication (severe claustrophobia, metal implants, shunts, pacemaker, joint implants, metal valves).
• Currently taking medications that either have evidence of glutamatergic activity or has previous MRS evidence of effects on brain glutamate levels at the discretion of the PI such as memantine, lamotrigine, lithium, opiates, bupropion, psychostimulants such as amphetamines and methylphenidate, tricyclic antidepressants, benzodiazepines and any other drug that the investigators judge might interfere with the study. (subjects on those medications may still be included in the study however only the values of NAA from MRS will be utilized and not the glutamate measurements).
• Currently a user of the following illicit drugs: cocaine, methylenedioxymethamphetamine (MDMA) ("ecstasy"), heroin and other opioids or has a history of drug or alcohol abuse within the past 5 years.
• Serum creatinine \>1.5 times the upper limit of normal.
• Abnormal liver function test (greater than 2 times the upper limit of normal for alanine aminotransferase (ALT) or aspartate aminotransferase (AST); or bilirubin \>1.5 times the upper limit of normal.
• History of brain disease including Parkinson's Disease, severe brain trauma, seizures, history of stroke, clinically significant lacunar infarct in a region important for cognition or multiple lacunes or a cortical infarct or focal lesions of clinical significance, multiple sclerosis, mental retardation, normal pressure hydrocephalus, central nervous system (CNS) tumor, Huntington's disease, subdural hematoma or other serious neurological disorder.
• Uncontrolled diabetes mellitus (Hba1c higher than 7) or chronically uncontrolled hypertension.
• Subject must not be taking Namenda® (memantine) for 6-weeks prior to study entrance.
• Currently taking any concomitant hepatotoxic drugs such as allopurinol, methyldopa and sulfasalazine.
• Any unstable serious co-existing medical condition(s) including but not limited to myocardial infarction, coronary artery disease requiring coronary bypass surgery, unstable angina, clinically evident congestive heart failure within 6 months prior to the screening visit.
• Current smoker or user of nicotine-containing products, such as chewing tobacco, nicotine patch or gum for the past 2 months.
• Current untreated major depression defined by Geriatric Depression Scale \> 20.
• Participation in any investigational or marketed drug or device trial within 30 days prior to the screening visit.

Sponsors & Collaborators

• Icahn School of Medicine at Mount Sinai: lead
• Rockefeller University: collaborator

Study Sites (2)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

The Rockefeller University

New York, New York, 10065, United States

Location

Related Publications (1)

• Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, Andrews RD, Lukic AS, Lee J, Hampilos N, Shafiian N, Sano M, David Mozley P, Fillit H, McEwen BS, Shungu DC, Pereira AC. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease. Brain. 2021 Dec 31;144(12):3742-3755. doi: 10.1093/brain/awab222.

  PMID: 34145880 RESULT

MeSH Terms

Conditions

Alzheimer Disease; Dementia

Interventions

Riluzole

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Benzothiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

1.Sample size was relatively small, and results require replication in larger-sample studies. 2.lack of amyloid characterization. 3.MRS is unable to differentiate neurotransmitter or vesicular and metabolic pools of glutamate. Longitudinal MRS measurements can be subject to technical variability and head motion. 4. the study was not powered for neuropsychological outcome and clinical changes must be viewed only as directional/exploratory.

Results Point of Contact

• Title: Dr. Ana Pereira
• Organization: Icahn School of Medicine at Mount Sinai

ana.pereira@mssm.edu

212-241-6984

Study Officials

• Ana Pereira, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator; Assistant Professor of Neurology and Neuroscience

Study Record Dates

• First Submitted: October 4, 2012
• First Posted: October 10, 2012
• Study Start: November 1, 2013
• Primary Completion: May 26, 2020
• Study Completion: May 26, 2020
• Last Updated: September 22, 2021
• Results First Posted: September 22, 2021

Record last verified: 2021-07

Locations

US (2)