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Effects of Riluzole on CNS Glutamate and Fatigue in Breast Cancer Survivors With High Inflammation

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ClinicalTrials.gov Identifier: NCT02796755
Recruitment Status : Recruiting
First Posted : June 13, 2016
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Andrew H Miller, Emory University

Brief Summary:
The goal of the proposed research is to determine whether riluzole, a drug that increases glutamate reuptake, will decrease CNS glutamate in breast cancer survivors with increased inflammation and fatigue. We will also determine whether decreasing glutamate with riluzole will reverse inflammation-related fatigue and other symptoms including cognitive dysfunction and decreased motivation. To accomplish these goals, we plan to conduct an 8 week, double-blind, randomized control trial of riluzole (100 mg/d) versus placebo in 40 breast cancer survivors (n=20 per group). All breast cancer survivors will have completed treatment within 1-3 years and have a fatigue level of ≥4 (on a 10 point scale) and a plasma c-reactive protein (CRP) concentration >3mg/L (indicative of high inflammation). Patients will undergo magnetic resonance spectroscopy (MRS) to measure CNS glutamate before and after 2 and 8 weeks of riluzole or placebo treatment. Fatigue and other behavioral assessments including measures of cognitive function and motivation will be conducted before and after treatment and correlated with the change in CNS glutamate.

Condition or disease Intervention/treatment Phase
Inflammation Fatigue Drug: Riluzole Drug: Placebo Phase 4

Detailed Description:

The primary objective of the proposed research is to provide the first data on the role of CNS glutamate and symptoms of fatigue in breast cancer patients using MRS and a medication that has been shown to lower CNS glutamate in animal models and human subjects. No previous study has examined the potential connection between increased inflammation, increased CNS glutamate and symptoms in breast cancer patients, although there is strong clinical and preclinical support for an important interrelationship among these variables. Identification of a significant relationship between increased CNS glutamate and symptoms will:

  • Enable the development of inflammatory biomarkers to identify patients with altered CNS glutamate.
  • Help focus future studies using glutamate stabilizing medications and glutamate antagonists on patients most likely to respond to glutamate-targeted therapies (personalization of trials and treatment).
  • Expand treatment studies to include synergistic or sequential targeting of inflammation and glutamate to reduce symptom burden in breast cancer patients.

This study will also serve as a foundation for efforts to link the impact of inflammatory cytokines and their relationship with increased CNS glutamate and behavior to a variety of cancers. Moreover, by testing novel treatment approaches (targeting glutamate), this study may ultimately improve the quality of life of breast cancer and other cancer patients.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Effects of Riluzole on CNS Glutamate and Fatigue in Breast Cancer Survivors With High Inflammation
Study Start Date : April 2016
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Riluzole

Arm Intervention/treatment
Experimental: Riluzole Arm
Participants will take a daily oral dose of 100 mg of riluzole (50 mg two times per day). Participants will be instructed to take the study medication on an empty stomach (1 hour before or 2 hours after meals).
Drug: Riluzole
Study participants randomized to this arm will take 100 mg/day of riluzole for 8 weeks.
Other Name: Rilutek

Placebo Comparator: Placebo Arm
Participants will take a daily oral dose of 100 mg of a placebo that appears identical to riluzole (50 mg two times per day). Participants will be instructed to take the study medication on an empty stomach (1 hour before or 2 hours after meals).
Drug: Placebo
Study participants randomized to this arm will take a placebo, that matches the appearance of 100 mg tablets of riluzole, daily for 8 weeks.




Primary Outcome Measures :
  1. Change in Central Nervous System (CNS) glutamate measured by Magnetic Resonance Spectroscopy (MRS) between riluzole and placebo arms [ Time Frame: Baseline 1 visit and at 1 and 8 weeks of treatment (8 weeks) ]
    Magnetic resonance spectroscopy (MRS) is a specialized technique associated with magnetic resonance imaging (MRI). MRS is a non-invasive way to obtain biochemical information about the tissues of the human body. Patients will undergo single voxel (3-dimensional volume X pixel) MRS to measure CNS glutamate before and after 1 and 8 weeks of riluzole or placebo treatment. Voxels will be placed in the right and left basal ganglia and the dorsal anterior cingulate cortex (dACC), well known targets of inflammatory cytokines on the brain, and cytokine effects on these brain regions have been associated with symptoms of fatigue and cognitive dysfunction as well as reduced motivation.


Secondary Outcome Measures :
  1. Change in score of the Multidimensional Fatigue Inventory (MFI) between riluzole and placebo arms [ Time Frame: Baseline 1 visit through end of treatment (up to 8 weeks) ]
    The Multidimensional Fatigue Inventory (MFI) is a 20-item scale used to evaluate the presence and severity of fatigue among subjects by self-reports. The MFI assesses 5 dimensions of fatigue, including general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Participants respond to fatigue related statements using a 5 point scale where 1 = "yes, that is true" and 5 = "no, that is not true".

  2. Change in score of the Promise-Fatigue Short Form (PROMIS) [ Time Frame: Baseline 1 visit through end of treatment (up to 8 weeks) ]
    PROMIS-Fatigue Short Form is a 7-item scale developed by the Patient-Reported Outcome Measurement Information System (PROMIS), a part of the NIH Roadmap Initiative which is focused on developing a publicly available resource of standardized, accurate, and efficient outcome measures of symptoms, distress, and functioning. The criterion for a minimally clinically important difference in patients with advanced-stage cancer is a 3 to 5 point difference in raw score.37 Recommendations for high priority research on cancer-related fatigue recommend use of the PROMIS fatigue scale to allow comparison of results across studies.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have completed surgery for Stage I-III breast cancer (lumpectomy or mastectomy) with or without neoadjuvant or adjuvant chemotherapy and with or without radiation.
  • Must be 1-5 years post-treatment for breast cancer
  • Must have a plasma c-reactive protein (CRP) level of >3mg/L
  • Must have a score of ≥4 (out of 10 points, 0 being no fatigue and 10 being severe, incapacitating fatigue) on a Single Item Screening Scale for Fatigue

Exclusion Criteria:

  • Presence of a medical condition that might represent a risk for riluzole treatment, including history of allergic reaction to riluzole and evidence of liver disease
  • Presence of a medical condition that might potentially confound the relationship among CNS glutamate, inflammation and behavior/cognition, including autoimmune or inflammatory disorders, chronic infectious diseases (e.g. HIV, hepatitis B or C), pregnancy, neurologic disorders (including a history of serious head trauma or seizures), liver disease (as manifested as an elevation in liver transaminases) and uncontrolled cardiovascular, metabolic, pulmonary or renal disease (as determined by medical history and laboratory testing)
  • Current or past history of schizophrenia
  • Individuals with bipolar disorder who have experienced a manic episode within 6 months of study entry, or at the discretion of the study doctor
  • Individuals receiving antidepressants, mood stabilizers, antipsychotic medications or benzodiazepines or drugs known to affect the immune system (e.g. glucocorticoids, methotrexate), or at the discretion of the study doctor
  • Individuals exhibiting signs of infection at the screening visit will be rescheduled to screen when symptoms have resolved

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): NCT02796755


Contacts
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Contact: Andrew H Miller, MD 404-727-8260 amill02@emory.edu
Contact: Bobbi Woolwine, LCSW 404-712-9620 bwoolwi@emory.edu

Locations
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United States, Georgia
Emory University Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Andrew H Miller, MD    404-727-8260    amill02@emory.edu   
Contact: Bobbi Woolwine, LCSW    404-712-9620    bwoolwi@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
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Principal Investigator: Andrew H Miller, MD Emory University

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Responsible Party: Andrew H Miller, MD, Emory University
ClinicalTrials.gov Identifier: NCT02796755     History of Changes
Other Study ID Numbers: IRB00086271
First Posted: June 13, 2016    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Andrew H Miller, Emory University:
Central Nervous System (CNS) Glutamate
Breast Cancer Treatment
Fatigue
Cognitive Dysfunction
Behavioral
Psychometrics
Imaging Technology
Magnetic Resonance Spectroscopy

Additional relevant MeSH terms:
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Breast Neoplasms
Inflammation
Fatigue
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Pathologic Processes
Signs and Symptoms
Riluzole
Anticonvulsants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents