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Disulfiram: A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease

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: NCT03891667
Recruitment Status : Recruiting
First Posted : March 27, 2019
Last Update Posted : October 30, 2019
Sponsor:
Collaborator:
FDC Foundation
Information provided by (Responsible Party):
Brian A Fallon, Research Foundation for Mental Hygiene, Inc.

Tracking Information
First Submitted Date  ICMJE March 25, 2019
First Posted Date  ICMJE March 27, 2019
Last Update Posted Date October 30, 2019
Actual Study Start Date  ICMJE July 31, 2019
Estimated Primary Completion Date March 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
  • Fatigue Severity Scale (FSS) [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated self-report measure of fatigue. This measure consists of 11 items inquiring about the severity of fatigue in different situations during the past week. Scores for each item range from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement. Higher scores indicate higher levels of fatigue.
  • Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) [ Time Frame: Change will be assessed over a 10 week interval ]
    TThe Q-LES-Q - SF is a self-reported questionnaire, with 16 items, that evaluates overall enjoyment and satisfaction with physical health, mood, work, household and leisure activities, social and family relationships, daily functioning, sexual life, economic status, overall well-being and medications. Responses are scored on a 5-point scale ('not at all or never' to 'frequently or all the time'), where higher scores indicate better enjoyment and satisfaction with life (possible range 14-70). Fourteen summated items create the total Q-LES-Q - SF score. Two last items, about medications and overall life satisfaction, are considered independently.
Original Primary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Fatigue Severity Scale [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated self-report measure of fatigue
  • Quality of Life and Satisfaction Questionnaire (Q-LES-Q) Short Form [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated self report measure of quality of life
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
  • The Short Form (36) Health Survey (SF-36) [ Time Frame: Change will be assessed over a 10 week interval ]
    The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. The 8 scales are-vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning mental health. Each scale is directly transformed into a 0-100 scale, the lower the score the more disability and the higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
  • General Symptom Questionnaire (GSQ-30)- Assess multisystemic symptom burden [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated 30 item self-report measure of symptom burden. The measure asks participants to rate how bothered they have been with a particular symptom over a 2-week time frame. Responses are made on 5-point Likert scale ranging from "not at all" to "very much" (scored 0-4); and the total score ranges from 0-120. Higher scores indicate more symptom severity.
  • PROMIS-29 [ Time Frame: Change will be assessed over a 10 week interval ]
    The PROMIS-29 psychometrically validated 29 item self-report measure of 7 domains. These 7 domains are- Depression, Anxiety, Physical Function, Pain Interference, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities. The questions are ranked on a 5-point Likert Scale. There is also one 11-point rating scale for pain intensity. Norm-based scores have been calculated for each domain on the PROMIS measure. High scores represent more of the domain being measured. Thus, on symptom oriented domains of PROMIS-29 (anxiety, depression, fatigue, pain interference, and sleep disturbance), higher scores represent worse symptomatology. On the function oriented domains (physical functioning and social role) higher scores represent better functioning.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Short Form-36 [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated scale of physical and mental functioning
  • General Symptom Questionnaire (GSQ-30) [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated 30 item self-report measure of symptom burden
  • PROMIS-29 [ Time Frame: Change will be assessed over a 10 week interval ]
    This is a psychometrically validated 29 item self-report measure of 7 domains
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Disulfiram: A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease
Official Title  ICMJE Disulfiram ("Antabuse"): A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease
Brief Summary Approximately 10-20% of patients experience ongoing symptoms despite having received standard antibiotic therapy for Lyme disease. Possible explanations for persistent symptoms include persistent infection and/or post-infectious causes. Recent in vitro studies indicate that disulfiram is effective at killing both the actively replicating and the more quiescent persister forms of Borrelia burgdorferi, the microbe that causes Lyme Disease. In this study, the investigators are examining the safety of disulfiram among patients with post-treatment Lyme disease symptoms. The investigators are also conducting a preliminary investigation regarding the relative benefit of 4 vs 8 weeks of treatment with disulfiram.
Detailed Description

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common tick-borne illness in the United States. Typically, after being bitten by an infected tick, patients will notice an expanding rash and flu-like symptoms. Most patients recover fully after initial treatment with antibiotics such as doxycycline or amoxicillin. Some patients, however, do not recover fully or their symptoms return within a few months after having completed antibiotic treatment. Common persistent symptoms include fatigue, joint pain, muscle pain, numbness, tingling, burning pains, and changes in mood, memory or mental clarity. These symptoms can last months to years after treatment and, when accompanied by functional impairment, are collectively referred to by the academic community as "Post Treatment Lyme Disease Syndrome (PTLDS)". Patients however typically refer to this constellation of persistent symptoms as "Chronic Lyme Disease".

There are several possible explanations for why patients may have persistent symptoms, including persistent infection and post-infectious changes triggered by the prior infection.

Scientists recently discovered that disulfiram is effective in the lab setting at killing the microbes that cause Lyme disease. Disulfiram is more commonly known as "Antabuse". It is an FDA-approved compound used to assist alcoholics in resisting alcohol consumption. Most remarkable is that disulfiram was effective at killing not only the actively replicating Lyme bacteria (ie, the ones that are typically killed by several antibiotics) but also the relatively dormant or quiescent Lyme bacteria (these are called "drug-tolerant persisters") - these latter spirochetes are the ones that may account for the development of chronic Lyme disease symptoms.

This initial pilot study will focus on patients with persistent symptoms despite having received the standard antibiotic therapy (or more) for Lyme disease. Because no one has yet studied the safety of disulfiram for patients with a history of Lyme disease and because the investigators do not know the optimal treatment duration for disulfiram, the initial effort will have the primary aims of assessing safety and determining whether a longer course of daily treatment is more effective than a shorter course of daily treatment.

The investigators propose therefore a small 14-week randomized placebo-controlled pilot study enrolling 24 patients with persistent symptoms despite prior antibiotic treatment for Lyme disease (known as Post-treatment Lyme Disease Syndrome). Among the 24 disulfiram-treated patients, half will get 8 weeks of disulfiram and the other half will get a shorter duration of disulfiram for 4 weeks followed by 4 weeks of matching placebo. After week 8, patients will be off pills for 2 weeks for the primary week 10 evaluation and then for another 4 weeks for the week 14 follow-up evaluation. This will be a double-blinded study; neither physician nor patient will know which treatment group the patient is assigned to.

With this initial study, the investigators will be able to evaluate the side effects, tolerability and initial signs of the effectiveness of disulfiram in reducing symptoms among the 24 patients assessed. The results of this study will guide the investigators regarding whether a larger definitive randomized trial should be conducted and which treatment schedule is optimal.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Patients will be randomly assigned to one of two groups:

Treatment Group I- patients will receive Disulfiram for 8 weeks

Treatment Group 2 - patients will receive Disulfiram for 4 weeks followed by 4 weeks of placebo.

The dosing starts at 250 mg on day 1, none on day 2, 250 mg on day 3, none on day 4, and then 250 mg x 3 days. If tolerated, the dose is then increased to 500 mg/day.

Primary outcome is at week 10. Patients will be reassessed at week 14.

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
This is a placebo-controlled study using matching capsules for disulfiram and placebo. Neither the participant, the care provider, nor the investigator will know the randomized assignment. The research pharmacy and a researcher not involved with this study will keep the code regarding group assignment.
Primary Purpose: Treatment
Condition  ICMJE
  • Fatigue
  • Quality of Life
Intervention  ICMJE Drug: Disulfiram 500 MG
Patients will receive 2 250 mg capsules of disulfiram or 2 matching capsules of placebo.
Other Name: Antabuse
Study Arms  ICMJE
  • Experimental: 8 Week Disulfiram
    Patients in this group receive disulfiram for 8 weeks. The dosing starts at 250 mg on day 1, none on day 2, 250 mg on day 3, none on day 4, and then 250 mg x 3 days. If tolerated, the dose is then increased to 500 mg/day.
    Intervention: Drug: Disulfiram 500 MG
  • Active Comparator: 4 Week Disulfiram
    Patients in this group receive disulfiram for 4 weeks followed by placebo capsules for 4 weeks. The dosing of disulfiram starts at 250 mg on day 1, none on day 2, 250 mg on day 3, none on day 4, and then 250 mg x 3 days. If tolerated, the dose is then increased to 500 mg/day.
    Intervention: Drug: Disulfiram 500 MG
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: March 25, 2019)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2021
Estimated Primary Completion Date March 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • History of Lyme Disease diagnosis within the prior 16 years History of prior diagnosis of Lyme disease that met the Centers for Disease Control (CDC) surveillance criteria case definition

    • For erythema migrans (EM) rash, this has to be health-care provider diagnosed;
    • For later stages of Lyme disease, this requires a diagnosis of LD by a health-care provider and laboratory testing that confirms a positive result historically.
  • History of treatment for Lyme disease that consists of at least 5 weeks of antibiotics (total adding all treatment courses) within the last 16 years.
  • Partial Prior Response. History of at least partial response to prior antibiotic therapy for Lyme disease.
  • Antibiotic-free interval. Willingness to be off of other antibiotics during the course of this study and for at least 3 months prior to study randomization and during the 14 weeks of this study.
  • Current moderate to severe fatigue. The following criteria need to be met:

    1. at least moderate intensity at study screening and at intake (a score of 4 or more on the Fatigue Severity Scale)
    2. triggered or perpetuated by Lyme disease and persisting for at least 6 months after treatment
    3. is not better attributed to another independent medical or psychiatric condition
    4. current episode of Lyme disease-related fatigue is relatively persistent and has not had an intervening interval of 8 months without fatigue since diagnosis of Lyme disease.
  • Current post-Lyme symptoms impair the patient's quality of life
  • Keeping other current treatments stable- Patients can stay on other non-antibiotic medications as long as these medications have been stable for the 3 months prior to study onset and the dosage regimen does not change during the course of this study (unless the latter is medically or psychiatrically indicated).
  • Between the ages 18-65
  • Ability to read and speak English

Exclusion Criteria:

  • History of cardiovascular disease (e.g., coronary artery disease or heart failure).
  • History of seizure disorder, abnormal EEGs, traumatic brain injury, renal disease (e.g. nephritis), liver disease (e.g., hepatitis, CIRRHOSIS), diabetes mellitus, hypothyroidism and/or psychosis. Patients with a history of large fiber neuropathy (EMG/NCS documented) will also be excluded.
  • History of Substance Use Disorder (e.g., alcohol abuse, multi-drug dependence) within the past 2 years
  • History in the last 6 months of heavy alcohol use which is defined as binge drinking more than 5 days in a one-month period. A binge-drinking episode refers to the consumption of 5 or more drinks for men or 4 or more drinks for women in a 2-hour period.
  • Evidence of current active tick-borne illness other than Lyme disease. (Note: patients with evidence of positive antibodies for another TBI will be eligible unless there is evidence that this other TBI is currently active (eg., elevated LFTS (AST & ALT not greater than 2 times upper limit), low platelets, low WBC, high fevers)
  • Unwillingness to confirm that he/she will abstain from alcohol and products that may contain alcohol (including sauces, cough syrup, vinegar, backrub products, aftershave lotions) during the month prior to randomization, during the course of this study, and for 6 weeks after the last dose of study medication.
  • Inability to confirm abstinence from cannabis or CBD or THC-containing products
  • Women who are breastfeeding, pregnant, or at risk of becoming pregnant during the course of the study.
  • Patients who are taking or plan to take warfarin, metronidazole, paraldehyde, phenytoin, theophylline, oral anticoagulants, or isoniazid
  • A concurrent or recent illness that may better account for current fatigue
  • Unwillingness to not take any new non-emergency medications during the course of this study without first reviewing with the study research physician
  • History of rubber-contact dermatitis or allergy to disulfiram or thiuram derivatives
  • Prior history of serious adverse reaction to disulfiram
  • Cognitive Impairment for patients over 60.
  • Suicidal acts in the last 6 months or current suicidal thoughts with intent or plan or history of bipolar disorder.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Brian A Fallon, MD 646-774-8052 baf1@cumc.columbia.edu
Contact: Shannon Delaney, MD sld2158@cumc.columbia.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03891667
Other Study ID Numbers  ICMJE 7755
Has Data Monitoring Committee No
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
Plan to Share IPD: No
Plan Description: There no current plan for sharing participant data.
Responsible Party Brian A Fallon, Research Foundation for Mental Hygiene, Inc.
Study Sponsor  ICMJE Research Foundation for Mental Hygiene, Inc.
Collaborators  ICMJE FDC Foundation
Investigators  ICMJE
Principal Investigator: Brian A Fallon, MD Columbia University
PRS Account Research Foundation for Mental Hygiene, Inc.
Verification Date October 2019

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