A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue
A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue
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.
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.
-  INCLUSION CRITERIA:

 1. Have chronic, persistent fatigue for at least 6 months;

 1. Intensity greater than or equal to 50 mm using fatigue VAS (on a 0-100 mm
 horizontal fatigue scale).

 2. Chronicity greater than or equal to six months total in the past year using
 the first item of the revised Piper Fatigue Scale.

 2. 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;

 3. Able to provide written informed consent;

 4. Able to have an accompanying responsible adult for drug infusion study visits;

 5. 18-70 years of age at the time of signing the informed consent form;

 6. Participants may be NIH employees/staff (see below for some exclusion);

 7. 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.

 8. 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:

 1. Total body irradiation or cranial irradiation for cancer;

 2. 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);

 3. Individuals with comorbid conditions other than clinically stable cardiovascular,
 metabolic conditions, and rheumatologic/systemic autoimmune diseases;

 4. Current or past psychiatric disorders including medically documented depression with
 psychosis, bipolar disorder, schizophrenia;

 5. Clinically documented post-traumatic stress syndrome and/or traumatic brain injury
 because of the high risk for ketamine to exacerbate symptoms including hallucinations;

 6. 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);

 7. Detectable alcohol content >1 mg/dL using urine alcohol test;

 8. 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;

 9. Participants with clinical hypothyroidism or hyperthyroidism defined by abnormal
 thyroid stimulating hormone TSH;

 10. 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);

 11. 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;

 12. 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;

 13. 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;

 -  Episodic Use(as needed): No; Chronic Use:No

 -  LIST OF NON-PSYCHIATRIC MEDICATIONS ALLOWED AND NOT ALLOWED DURING THE STUDY*

 -  Drug class: Analgesics;

 -  Episodic Use(as needed): Yes; Chronic Use:No;

 -  Restrictions: Non-narcotic analgesics only

 -  Drug class: Anorexics (sibuteramine);

 --- Episodic Use(as needed): No; Chronic Use:No

 -  Drug class: Antacids;

 --- Episodic Use(as needed): Yes; Chronic Use:Yes;

 -  Drug class: Antianginal Agents;

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Antiarrhythmics;

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Antiasthma Agents;

 -  Episodic Use(as needed): Yes; Chronic Use:Yes

 -  Restrictions: Systemic corticosteroids are not allowed if taking more
 than > 10 mg /day of prednisone or glucocorticoid equivalent.

 -  Drug class: Antibiotics;

 -  Episodic Use(as needed): Yes; Chronic Use:No;

 -  Except erythromycin (see P450-3A4 enzyme inhibitors below)

 -  Drug class: Anticholinergics;

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Anticoagulants;

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Anticonvulsants;

 -  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;

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Analgesics-Topical;

 --- 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);

 -  Restrictions: Systemic corticosteroids are not allowed if taking more
 than > 10 mg /day of prednisone or glucocorticoid equivalent.

 -  Drug class: Antinauseants;

 --- Episodic Use(as needed): Yes; Chronic Use:Yes;

 -  Drug class: Antineoplastics;

 -  Episodic Use(as needed): No; Chronic Use:No;

 -  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: Antiobesity;

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Antivirals;

 -  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

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: Laxatives

 --- Episodic Use(as needed): Yes; Chronic Use:Yes;

 -  Drug class: Muscle Relaxants

 --- Episodic Use(as needed): No; Chronic Use:No;

 -  Drug class: P450-3A4 enzyme inhibitors

 -  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;

 -  Restrictions: Including Saquinavir

 a Allowed only if being taken prior to enrolling in the study.

 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.

 14. Medical diagnosis of sleep disorder requiring medical intervention such as obstructive
 sleep apnea that increase risks of sedation;

 15. Medically diagnosed kidney disease(except for chronic stable kidney disease with
 eGFR>45);

 16. Medically diagnosed acute narrow-angle glaucoma;

 17. Allergic to ketamine, benzodiazepines, flumazenil;

 18. With poor IV access;

 19. NINR employees or subordinates, relatives, and/or co-workers of NINR employees/staff
 or study investigators;

 20. Pregnant or lactating individuals.

 21. 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.