A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue

Summary

Participation Requirements

Description

Purpose: The purpose of the study is to investigate the anti-fatigue effects of ketamine in individuals with chronic illness. Background: Although the underlying mechanisms of fatigue have been studied in several disease conditions, the etiology, mechanisms, and risk factors remain elusive and this ...

Purpose: The purpose of the study is to investigate the anti-fatigue effects of ketamine in individuals with chronic illness. Background: Although the underlying mechanisms of fatigue have been studied in several disease conditions, the etiology, mechanisms, and risk factors remain elusive and this symptom remains poorly managed. Fatigue is conceptualized as a multidimensional symptom which incorporates temporal, sensory, cognitive/mental, affective/emotional, behavioral, and physiological dimensions. It is described as a common, chronic, and disabling symptom in individuals with Sjogren s syndrome and those with systemic lupus erythematosus. We recently observed that upregulation of glutamate receptors (e.g.,GRM5) can predict individuals who will develop chronic fatigue one year after completing cancer therapy, suggesting that fatigue may share common glutamatergic markers with depression. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and has been reported to have rapid anti-depressant effects, and we recently found that it also has rapid anti-fatigue effects. Evidence suggest that severe fatigue in diverse medical conditions is driven by similar biological mechanisms, hence identifying a potential anti-fatigue agent in one medical condition may be a valuable anti-fatigue therapy for other fatiguing conditions. Population for Study: This proof-of-concept study will enroll 59 individuals (target n of completers = 50) with chronic fatigue. Key Inclusion/Exclusion Criteria: Participants must have a fatigue visual analog scale (VAS) score of greater than or equal to 50 mm (on a 0-100 mm horizontal scale). The greater than or equal to 50 mm fatigue VAS score is considered clinically important fatigue cutoff score for patients with chronic illness, and also captures the effectivity outcome of a previous pharmacologic intervention for fatigue. The participants must not have any progressive or unstable conditions or be taking medications that cause fatigue. Methodology: This is a phase II, randomized, double-blind (study team and participants), active comparator-controlled, cross-over trial. After determining eligibility during the screening visit, the participant will be randomized to determine the sequence of study drug/active comparator to take during each phase. Main Study Events / Estimates of Duration and Time Commitments: The study has two periods, and each period is approximately two weeks long (total of four weeks). The study (both periods, excluding the screening visit) will require eight NIH outpatient visits and three phone calls. Primary and Representative Secondary Outcomes: The primary outcome measure of the study is the change in self-reported fatigue VAS score before and three days after receiving ketamine or active comparator (midazolam). A 20% decrease in fatigue VAS score three days after ketamine treatment will be considered the primary indicator of efficacy in this study. The secondary outcomes of this study include: symptoms, physical activity count, skeletal muscle strength, motivation score, cognitive function test scores, changes in gene expression or protein levels of pro-inflammatory markers (e.g., lymphotoxin, IFNy, TNF alpha) typically seen in fatigue, and neurometabolite (e.g., BDNF) levels and mitochondrial markers (e.g., glucose transporte) and after a dose of ketamine or active comparator. General Analytic Plans: A linear mixed model with restricted maximum likelihood estimation will be used to examine changes in fatigue symptoms over the course of the trial where all participants with at least a pre-dose and one post-dose measure will be included. Within-subjects factors will include time with pre-dose and all other points. The interaction between time and ketamine treatment will be included along with the fixed intercept. Multiple test corrections (e.g., Bonferroni post hoc tests) will be used to examine differences between levels of significant effects. The primary outcome measure of the study is the change in fatigue score as measured by the self-reported fatigue instrument.

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