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

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ClinicalTrials.gov Identifier: NCT04141696
Recruitment Status : Recruiting
First Posted : October 28, 2019
Last Update Posted : August 6, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Nursing Research (NINR) )

Tracking Information
First Submitted Date  ICMJE October 25, 2019
First Posted Date  ICMJE October 28, 2019
Last Update Posted Date August 6, 2021
Actual Study Start Date  ICMJE July 26, 2021
Estimated Primary Completion Date December 29, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 11, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 25, 2019)
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 placebo change in self-reported fatigue VAS score before and 3 daysafter 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 thisstudy.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 3, 2021)
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2019)
  • 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 24hours, at 7 days, and at 14 days). ]
    cognition; skeletal muscle strength; motivation
  • Change in gene expression or protein levels of pro-inflammatorymarkers 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 24hours, at 7 days, and at 14 days). ]
    change in gene expression or protein levels of pro inflammatory markers levels and bioenergetic markers
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue
Official Title  ICMJE A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Fatigue
Intervention  ICMJE
  • Drug: Ketamine
    Given intravenously over 40 minutes
  • Drug: Midazolam
    Given intravenously over 40 minutes
Study Arms  ICMJE
  • Experimental: Ketamine
    Given intravenously over 40 minutes
    Intervention: Drug: Ketamine
  • Active Comparator: Midazolam (Placebo)
    Given intravenously over 40 minutes
    Intervention: Drug: Midazolam
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 25, 2019)
59
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 29, 2023
Estimated Primary Completion Date December 29, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Angela Wang, R.N. (301) 841-5085 tzu-fang.wang@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04141696
Other Study ID Numbers  ICMJE 200003
20-NR-0003
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Nursing Research (NINR) )
Study Sponsor  ICMJE National Institute of Nursing Research (NINR)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Leorey N Saligan, C.R.N.P. National Institute of Nursing Research (NINR)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date August 2, 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP