A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue
- Registration Number
- NCT04141696
- Lead Sponsor
- National Institute of Nursing Research (NINR)
- Brief Summary
Background:
Many people experience fatigue as a side effect of their illnesses and treatments. There are no medicines to treat fatigue, but a drug called ketamine has reduced fatigue in depressed people. Researchers hope that ketamine, compared to a drug called midazolam, can reduce fatigue in people with illnesses.
Objective:
To test whether ketamine reduces fatigue in cancer survivors and people with chronic illness.
Eligibility:
Adults between the ages of 18 and 70 who have fatigue and are cancer survivors or have been diagnosed with a chronic illness such as chronic fatigue syndrome and lupus.
Design:
Participants will be screened with a physical exam, medical history, blood and urine tests, questions about their fatigue, and breathalyzer test.
During phase 1, participants will complete rating their fatigue using questionnaires. They will be provided thinking, memory, and motivation tests. They will also take a handgrip test. For this study, the participant will have an IV, which a needle guides a thin plastic tube (intravenous or IV line) into an arm in their vein. An IV will be required for two of the visits. They will get a single dose of either ketamine or midazolam through an IV line over 40 minutes. Participants must be accompanied by a responsible friend/family/colleague to take them home after getting the study drug.
Participants will have follow-up visits where they repeat the above tests. They will also have follow-up phone calls.
Phase 2 is the same as phase 1, but participants get the other study drug.
The study lasts 1 month. Each phase lasts 2 weeks. Participants will have 6-8 total NIH visits. For the whole study, they will wear a device on their wrists that records physical activity.
Drug side effects can include vivid dreams, seeing colors, perceiving time as moving slower or faster than normal, dizziness, headache, restlessness, nausea, or vomiting, among others.
- Detailed 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 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 visual analogue scale (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: physical activity count, skeletal muscle strength, motivation score, cognitive function test scores before 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 10
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Ketamine then midazolam administration Ketamine Participants receive ketamine 0.5 mg/kg intravenous infusion over 40 minutes followed by a two week washout period then receive midazolam 0.045 mg/kg intravenous infusion over 40 minutes followed by two weeks of observation. Midazolam then ketamine administration Midazolam Participants receive midazolam 0.045 mg/kg intravenous infusion over 40 minutes followed by a two week washout period then receive ketamine 0.5 mg/kg intravenous infusion over 40 minutes followed by two weeks of observation. Ketamine then midazolam administration Midazolam Participants receive ketamine 0.5 mg/kg intravenous infusion over 40 minutes followed by a two week washout period then receive midazolam 0.045 mg/kg intravenous infusion over 40 minutes followed by two weeks of observation. Midazolam then ketamine administration Ketamine Participants receive midazolam 0.045 mg/kg intravenous infusion over 40 minutes followed by a two week washout period then receive ketamine 0.5 mg/kg intravenous infusion over 40 minutes followed by two weeks of observation.
- Primary Outcome Measures
Name Time Method Percentage Change in Self-reported Fatigue Visual Analog Scale (VAS) Scale Baseline to three days post infusion for each study arm Percentage change in self-reported Fatigue Visual Analog Scale (VAS) after a single intravenous dose of the study drug. The Fatigue VAS is a 0-100 mm scale widely used to assess fatigue in patients with chronic illness. Higher score indicates worse fatigue. Change in fatigue VAS scores measured as comparison of fatigue VAS scores collected at the first visit (baseline) and three days post infusion of study drug during each treatment arm (Ketamine, active comparator). Analysis is measured as the difference between day three score minus the baseline score, divided by the baseline score.
- Secondary Outcome Measures
Name Time Method Percentage Change in Self-reported Fatigue Visual Analog Scale (VAS) Scale - Day 7 Up to 7 days post infusion for each study drug Percentage change in self-reported Fatigue Visual Analog Scale (VAS) after a single intravenous dose of the study drug. The Fatigue VAS is a 0-100 mm scale widely used to assess fatigue in patients with chronic illness. Higher score indicates worse fatigue. Change in fatigue VAS scores measured as comparison of fatigue VAS scores collected at the first visit (baseline) and seven days post infusion for each treatment arm (Ketamine, active comparator). Analysis is measured as the percentage change in day seven score minus the baseline score, divided by the baseline score.
Areas Under the Curve (AUC) for Percentage Changes in Self-reported Fatigue VAS Score - Through Day 7 Up to 7 days post infusion for each study drug Percentage change in self-reported Fatigue Visual Analog Scale (VAS) after a single intravenous dose of the study drug. The Fatigue VAS is a 0-100 mm scale widely used to assess fatigue in patients with chronic illness. Higher score indicates worse fatigue. Change in fatigue VAS scores measured as comparison of fatigue VAS scores collected at the first visit (baseline), and then 40, 80, 120, 230 minutes, and 1, 3, and 7 days post infusion for each treatment arm (Ketamine, active comparator). Analysis is measured as the areas under the curve.
Mean Physical Activity Count Using Actigraphy Day 7 post infusion Mean physical activity count using actigraphy. Participants wore a portable device to monitor activity levels at day seven post infusion for each study drug. Analysis is measured as the mean of physical activity count on day seven post infusion for each treatment arm.
Fatigue Level Measured by Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale Day 7 post infusion The Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale is a 13-item questionnaire that measures level of fatigue symptoms. Each item is rated on a scale of 0 (not al all) to 4 (very much) with total score ranging from 0 to 52. Lower score indicates greater fatigue. The Fatigue subscale was used to assess participant's level of fatigue at day seven post infusion for each study arm analyzed as the mean score.
Patient Reported Outcome Measurement Information System (PROMIS) - Anxiety Domain Day 7 post infusion The Patient Reported Outcome Measurement Information System (PROMIS) profile is a self-reported questionnaire assessing quality of life in various domains. The anxiety domain is scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. Higher scores indicate more anxiety. Participants completed the computerized adaptive test version of PROMIS anxiety subscale on day seven post infusion and analyzed as mean score.
Patient Reported Outcome Measurement Information System (PROMIS) - Depression Domain Day 7 post infusion The Patient Reported Outcome Measurement Information System (PROMIS) profile is a self-reported questionnaire assessing quality of life in various domains. The depression domain is scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. Higher score indicates worsening depression. Participants completed the computerized adaptive test version of PROMIS depression subscale on day seven post infusion and analyzed as mean score.
Patient Reported Outcome Measurement Information System (PROMIS) - Fatigue Domain Day 7 post infusion The Patient Reported Outcome Measurement Information System (PROMIS) profile is a self-reported questionnaire assessing quality of life in various domains. The fatigue domain is scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. Higher score indicates worsening fatigue. Participants completed the computerized adaptive test version of PROMIS fatigue subscale on day seven post infusion and analyzed as mean score.
Patient Reported Outcome Measurement Information System (PROMIS) - Sleep Disturbance Domain Day 7 post infusion The Patient Reported Outcome Measurement Information System (PROMIS) profile is a self-reported questionnaire assessing quality of life in various domains. The Sleep Disturbance domain is scored on a 5-point Likert scale and converted into standardized T-scores with a mean of 50 and a standard deviation of 10 based on a US general population. Higher scores indicate worsening sleep disturbance being measured. Participants completed the computerized adaptive test version of PROMIS sleep disturbance subscale on day seven post infusion and analyzed as mean score.
Fatigue Level Measured by Fatigue Visual Analogue Scale Day 7 post infusion The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. The Fatigue VAS is a 0-100 mm scale with 0 (no fatigue at all) to 100 (extreme fatigue). Higher score indicates worsening fatigue. Fatigue VAS score collected from all participants on day seven post infusion for each treatment arm and analyzed as mean score.
Measure of Depression Using the Hamilton Rating Scale for Depression (HAM-D) Day 7 post infusion Hamilton Depression (HAM-D) utilizes a 21-item, clinician-rated paper questionnaire that measures the severity of depressive symptoms of the participants in the past week prior to the interview though only the first 17 items are used in scoring. Depending on the item, it is scored between 0 (not present) and 4 (severe) points using either a three-point or a five-point scale and summed up to obtain the total score. The HAM-D comprises 17 items, of which 9 are evaluated on a five-point scale (0-4) and 8-on a three-point scale (0-2). The total score range from 0 to the maximum score 52 on a 17-item scale, with higher scores indicating more serious depression. Total scores of 0-7 are considered as normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. Data was collected from all participants on day seven post infusion for each treatment arm and analyzed as mean score.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States