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

  • STATUS
    Recruiting
  • End date
    Dec 29, 2023
  • participants needed
    59
  • sponsor
    National Institute of Nursing Research (NINR)
Updated on 16 August 2021
cancer
midazolam

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.

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 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.

Details
Condition Fatigue, tired, fatigued, lack of energy
Treatment Ketamine, Midazolam
Clinical Study IdentifierNCT04141696
SponsorNational Institute of Nursing Research (NINR)
Last Modified on16 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Have chronic, persistent fatigue for at least 6 months
Intensity greater than or equal to 50 mm using fatigue VAS (on a 0-100 mm horizontal fatigue scale)
Chronicity greater than or equal to six months total in the past year using the first item of the revised Piper Fatigue Scale
Be a cancer survivor with a documented medical report of completing primary cancer treatment > 6 months ago (except hormone and vaccine therapies) OR diagnosed as having ME/CFS with clinical documentation that patient meets the 2015 IOM Diagnostic Criteria
Able to provide written informed consent
Able to have an accompanying responsible adult for drug infusion study visits
18-70 years of age at the time of signing the informed consent form
Participants may be NIH employees/staff (see below for some exclusion)
For individuals of childbearing potential; must use at least one of the following highly effective birth control methods for the duration of the study
Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Depot/implantable hormone (e.g., Depo-provera , Implanon)
Bilateral tubal occlusion/ligation
Individuals of non-childbearing potential; as defined by the following criteria
Postmenopausal defined as 12 months of spontaneous amenorrhea or follicle-stimulating hormone (FSH) serum level > 40mIU/mL;. appropriate documentation is required
Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure
Has a congenital condition resulting in no uterus. OR
Is sterile
Has documentation confirming vasectomy
EXCLUSION CRITIERIA
Total body irradiation or cranial irradiation for cancer
Has a diagnosis of progressive or unstable disease to any body system causing clinically significant fatigue (e.g., class IV congestive heart failure, end-stage r disease, liver failure, stage IV chronic obstructive pulmonary disease) including patients with active systemic infections (e.g., human immunodeficiency virus (HIV), active hepatitis, COVID-19 - screened using NIH Clinical Center questionnaire)
Individuals with comorbid conditions other than clinically stable cardiovascular, metabolic conditions, and rheumatologic/systemic autoimmune diseases
Current or past psychiatric disorders including medically documented depression with psychosis, bipolar disorder, schizophrenia
Clinically documented post-traumatic stress syndrome and/or traumatic brain injury because of the high risk for ketamine to exacerbate symptoms including hallucinations
Categorized as a high-risk drinker (>=5 drinks/day and >=15 drinks/week for men, >=4 drinks/day and >=8 drinks/week for women). ("Dietary Guidelines for Americans 2015-2020," U.S. Department of Health and Human Services and U.S. Department of Agriculture)
Detectable alcohol content >1 mg/dL using urine alcohol test
Current substance use disorder within the last five years as diagnosed on the Structured Clinical Interview for DSM-5 (SCID-5) or positive urine toxicology results at enrollment
Participants with clinical hypothyroidism or hyperthyroidism defined by abnormal thyroid stimulating hormone TSH
Poorly controlled hypertension as judged by the Principal Investigator and confirmed by repeat assessment during the screening period (SBP >160 and DBP > 100 in all readings)
Any medical condition causing impairment in mobility (e.g., stroke with residual neuromuscular weakness). This may prohibit the assessment of study outcomes, such as physical activity
Any change in dose of regularly scheduled medication or initiation of a new medication (excluding PRN medications) within four weeks prior to signing the informed consent form and throughout the entire duration of the study
Taking concomitant medication known to interact with ketamine and/or midazolam 14 days prior to study drug administration and during the study. The medications are shown
below
LIST OF PSYCHIATRIC MEDICATIONS ALLOWED AND NOT ALLOWED DURING THE STUDY
Drug class: Antidepressants
Episodic Use(as needed): No; Chronic Use:No
Restrictions: SSRI, SNRI, and serotonin modulators, including Buproprion are allowed if on low maintenance doses, and no history of seizure if taking SNRI
Drug class: Antipsychotics
\--- Episodic Use(as needed): No; Chronic Use:No
Drug class: Anxiolytics
\--- Episodic Use(as needed): No; Chronic Use:No
Drug class: Mood Stabilizers
\--- Episodic Use(as needed): No; Chronic Use:No
Drug class: Psychotropic drugs not otherwise specified (including herbal products)
Episodic Use(as needed): No; Chronic Use:No
Restrictions: No drugs with psychomotor effects or with anxiolytic, stimulant, antipsychotic, or sedative properties are allowed
Drug class: Sedatives/Hypnotics
Drug class: Analgesics
LIST OF NON-PSYCHIATRIC MEDICATIONS ALLOWED AND NOT ALLOWED DURING THE STUDY
Episodic Use(as needed): Yes; Chronic Use:No
Restrictions: Non-narcotic analgesics only
Drug class: Anorexics (sibuteramine)
Drug class: Antacids
\--- Episodic Use(as needed): No; Chronic Use:No
\--- Episodic Use(as needed): Yes; Chronic Use:Yes
Drug class: Antianginal Agents
Drug class: Antiarrhythmics
\--- Episodic Use(as needed): No; Chronic Use:No
Drug class: Antiasthma Agents
\--- Episodic Use(as needed): No; Chronic Use:No
Episodic Use(as needed): Yes; Chronic Use:Yes
Drug class: Antibiotics
Restrictions: Systemic corticosteroids are not allowed if taking more than > 10 mg /day of prednisone or glucocorticoid equivalent
Episodic Use(as needed): Yes; Chronic Use:No
Except erythromycin (see P450-3A4 enzyme inhibitors below)
Drug class: Anticholinergics
Drug class: Anticoagulants
\--- Episodic Use(as needed): No; Chronic Use:No
Drug class: Anticonvulsants
\--- Episodic Use(as needed): No; Chronic Use:No
Episodic Use(as needed): No; Chronic Use:No
Restrictions: Carbamazepine, phenytoin, and oxcarbazepine are 3A4 inducers and significantly decrease perampanel levels. Topiramate may increase perampanel levels up to 20%
Drug class: Antidiarrheal Preparations
\--- Episodic Use(as needed): Yes; Chronic Use:No
Drug class: Analgesics-Systemic
Drug class: Analgesics-Topical
\--- Episodic Use(as needed): No; Chronic Use:No
\--- Episodic Use(as needed): Yes; Chronic Use:Yes
Drug class: Antihistamines-Nonsedating
\--- Episodic Use(as needed): Yes; Chronic Use:Yes
Drug class: Antihistamines-Sedating
\--- Episodic Use(as needed): N; Chronic Use:No
Drug class: Antihypertensives
Episodic Use(as needed): Yes; Chronic Use:Y
Restrictions: Non-narcotic analgesics only
Drug class: Anti-inflammatory Drugs
Episodic Use(as needed): Yes; Chronic Use:Y(a)
Drug class: Antinauseants
Restrictions: Systemic corticosteroids are not allowed if taking more than > 10 mg /day of prednisone or glucocorticoid equivalent
\--- Episodic Use(as needed): Yes; Chronic Use:Yes
Drug class: Antineoplastics
Drug class: Antiobesity
Restrictions: Agents used in low maintenance doses as immunosuppressive agents (not as antineoplastics) such as Azathioprine, Methotrexate, Mycophenolate mofetil, and Belimumab are allowed
Drug class: Antivirals
Episodic Use(as needed): No; Chronic Use:No
\--- Episodic Use(as needed): No; Chronic Use:No
Restrictions: Except for treatment of HSV with agents without CNS activity e.g. acyclovir, ganciclovir, famciclovir, valacyclovir
Drug class: Cough/Cold Preparations
Episodic Use(as needed): Yes; Chronic Use:No
Restrictions: Dextromethorphan preps- N/N, Guaifenesin - Y/Y, Pseudoephedrine- N/N
Drug class: Diuretics
Episodic Use(as needed): Yes; Chronic Use:Y(b)
Restrictions: Non-narcotic analgesics only
Drug class: H2-Blockers/ PPI
Episodic Use(as needed): Yes; Chronic Use:Y(b)
Restrictions: Except cimetidine (see P450-3A4 enzyme inhibitors below)
Drug class: Hormones
Episodic Use(as needed): N; Chronic Use:Y(b)
Restrictions: Only thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy are allowed
Drug class: Hypoglycemic Agents
Episodic Use(as needed): No; Chronic Use:Yes(b)
Restrictions: Only oral hypoglycemic agents are allowed
Drug class: Antihyperlipidemics
\--- Episodic Use(as needed): No; Chronic Use:No(b)
Drug class: Insulin
Drug class: Laxatives
\--- Episodic Use(as needed): Yes; Chronic Use:Yes
\--- Episodic Use(as needed): No; Chronic Use:No
Drug class: Muscle Relaxants
Drug class: P450-3A4 enzyme inhibitors
Episodic Use(as needed): No; Chronic Use:No
\--- Episodic Use(as needed): No; Chronic Use:No
Restrictions: Including cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole (topical ketoconazole allowed)
Drug class: Protease Inhibitor
Episodic Use(as needed): No; Chronic Use:No
Episodic Use(as needed): No; Chronic Use:No
Restrictions: Including Saquinavir
a Allowed only if being taken prior to enrolling in the study
Episodic Use(as needed): No; Chronic Use:No
b Allowed only if being taken for at least 2 months prior to enrolling in the
study and the dose has been stable for at least 1 month
Some medications in the above table may be indicated for exclusionary conditions; therefore, it would be unlikely that participants meeting inclusion will be taking them
\. Medical diagnosis of sleep disorder requiring medical intervention such
as obstructive sleep apnea that increase risks of sedation
\. Medically diagnosed acute narrow-angle glaucoma
\. Allergic to ketamine, benzodiazepines, flumazenil
\. Medically diagnosed kidney disease(except for chronic stable kidney
\. With poor IV access
disease with eGFR>45)
\. NINR employees or subordinates, relatives, and/or co-workers of NINR
employees/staff or study investigators
\. Pregnant or lactating individuals
\. Ongoing medical condition that is deemed by the Principal Investigator to
interfere with the conduct or assessments of the study or safety of the
participant
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