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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04141696
Recruitment Status : Recruiting
First Posted : October 28, 2019
Last Update Posted : January 3, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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.


Condition or disease Intervention/treatment Phase
Fatigue Drug: Ketamine Drug: Midazolam Phase 1 Phase 2

Show Show detailed description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue
Actual Study Start Date : July 26, 2021
Estimated Primary Completion Date : December 29, 2023
Estimated Study Completion Date : December 29, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fatigue

Arm Intervention/treatment
Experimental: Ketamine
Given intravenously over 40 minutes
Drug: Ketamine
Given intravenously over 40 minutes

Active Comparator: Midazolam (Placebo)
Given intravenously over 40 minutes
Drug: Midazolam
Given intravenously over 40 minutes




Primary Outcome Measures :
  1. change in self-reported fatigue score [ Time Frame: before and 3 days after receiving Ketamine or active placebo ]
    The primary outcome measure of the study is the percentage change in self-reported fatigue VAS score before and 3 days after receiving Ketamine or active placebo for each individual study participant. A 20% change in fatigue VAS score 3 days after Ketamine treatment will be considered indication of efficacy in this study.


Secondary Outcome Measures :
  1. cognition; skeletal muscle strength; motivation [ Time Frame: before and after a dose of Ketamine or active placebo at multiple time points (at +40 min, at +80 min, at +120 min, at +230 min, at 24 hours, at 7 days, and at 14 days). ]
    cognition; skeletal muscle strength; motivation

  2. change in gene expression or protein levels of pro-inflammatory markers levels and bioenergetic markers [ Time Frame: before and after a dose of Ketamine or active placebo at multiple time points (at +40 min, at +80 min, at +120 min, at +230 min, at 24 hours, at 7 days, and at 14 days). ]
    change in gene expression or protein levels of pro-inflammatory markers levels and bioenergetic markers



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

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): NCT04141696


Contacts
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Contact: Angela (Tzu-fang) Wang, R.N. (301) 841-5085 tzu-fang.wang@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Nursing Research (NINR)
Investigators
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Principal Investigator: Leorey N Saligan, C.R.N.P. National Institute of Nursing Research (NINR)
Additional Information:
Publications:
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Responsible Party: National Institute of Nursing Research (NINR)
ClinicalTrials.gov Identifier: NCT04141696    
Other Study ID Numbers: 200003
20-NR-0003
First Posted: October 28, 2019    Key Record Dates
Last Update Posted: January 3, 2022
Last Verified: November 29, 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Nursing Research (NINR) ):
Anesthetics
Signs and Symptoms
Midazolam
Physiological Effects of Drugs
Additional relevant MeSH terms:
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Fatigue
Midazolam
Ketamine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adjuvants, Anesthesia
Hypnotics and Sedatives
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
GABA Modulators
GABA Agents