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

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ClinicalTrials.gov Identifier: NCT03891667
Recruitment Status : Not yet recruiting
First Posted : March 27, 2019
Last Update Posted : April 2, 2019
Sponsor:
Collaborator:
FDC Foundation
Information provided by (Responsible Party):
Brian Fallon, Research Foundation for Mental Hygiene, Inc.

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.

Condition or disease Intervention/treatment Phase
Fatigue Quality of Life Drug: Disulfiram 500 MG Phase 1 Phase 2

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.

Our 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, our 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 daily disulfiram (56 days) and the other half will get a shorter duration of disulfiram for 4 weeks (28 days) 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 us regarding whether a larger definitive randomized trial should be conducted; it will also inform us regarding which treatment schedule is optimal.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
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 500mg Disulfiram daily for 8 weeks Treatment Group 2 - patients will receive 500 mg Disulfiram daily for 4 weeks followed by 4 weeks of placebo

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
Official Title: Disulfiram ("Antabuse"): A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Disulfiram

Arm Intervention/treatment
Experimental: 8 Week Disulfiram
Patients in this group receive 500 mg of disulfiram daily for 8 weeks
Drug: Disulfiram 500 MG
Patients will receive 2 250 mg capsules of disulfiram or 2 matching capsules of placebo.
Other Name: Antabuse

Active Comparator: 4 Week Disulfiram
Patients in this group receive 500 mg of disulfiram daily for 4 weeks followed by placebo capsules for 4 weeks.
Drug: Disulfiram 500 MG
Patients will receive 2 250 mg capsules of disulfiram or 2 matching capsules of placebo.
Other Name: Antabuse




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

• History of Lyme Disease diagnosis within the prior 8 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.

Ascertainment: photo of rash and/or documentation in the provider's medical record and lab test results.

• History of treatment for Lyme disease with the last 8 years

  • Documentation of prior treatment for Lyme Disease of at least 8 weeks of antibiotics (total adding all treatment courses) within the last 8 years; this meets or exceeds the Infectious Diseases Society of America (IDSA) recommended standards.

(We aim to recruit as many patients who have received between 2 and 6 months of prior antibiotic therapy for this episode of illness; for this study, at least half of the sample will need to meet this criterion. Duration of prior treatment will be less stringent for the remaining portion of the study sample, but no one can have received more than 2 years of prior antibiotic therapy for this episode of illness).

Ascertainment: Self-Report of patient and documentation of treatment brought by the participant (e.g., medical record note or pharmacy records).

• Partial Prior Response. History of at least partial response to prior antibiotic therapy for Lyme disease.

Ascertainment: self-report

• 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.

Ascertainment: Self-report

• 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.

    Ascertainment: Self-report, study clinician evaluation, study questionnaires

    • Current post-Lyme symptoms impair the patient's quality of life

    Ascertainment: Self-report

    • 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).

    Ascertainment: Self-report and Weekly study check-in

    • Between the ages 18-65

    Ascertainment: Self-report

    • Ability to read and speak English

    Ascertainment: Self-report

    Exclusion Criteria:

    • History of cardiovascular disease (e.g., coronary artery disease or heart failure).

    Ascertainment: Patient Report, EKG at Intake

    • 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.

    Ascertainment: self-report, MINI and LFTs (AST & ALT) & Bilirubin not greater than 2 times upper limit at intake.

    • History of Substance Use Disorder (e.g., alcohol abuse, multi-drug dependence) within the past 2 years

    Ascertainment: self-report and MINI interview

    • 4. History of habitual or excessive use as indicated by either of the following:
  1. Pre-screening history of greater than 5 alcoholic drinks/week on average during prior two months
  2. Alcohol use exceeds more than 4 drinks on any one day in the past year.

    Ascertainment: alcohol use questions in the screening questionnaire (self-report)

    • Evidence of current active tick-borne illness other than Lyme disease Ascertainment: self-report and review of provided medical records (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)

    Ascertainment: Patient Report and Blood-work

    • 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.

    Ascertainment: Patient Report and Urinalysis.

    • Inability to confirm abstinence from cannabis or CBD or THC-containing products Ascertainment: Patient Report and urinalysis at intake and at weeks 2 and 6 and patient-report.

    • Women who are breastfeeding, pregnant, or at risk of becoming pregnant during the course of the study.

    Ascertainment: a) current pregnancy will be assessed by self-report and by a pregnancy test given to all women post-menarche and pre-menopausal onsite); b) breastfeeding will be assessed by self-report; and c) if pregnancy is a risk, patients will be excluded if they plan to become pregnant during the course of this study or indicate an unwillingness to use an effective birth control method - these include double barrier methods (condom plus spermicide, or diaphragm plus spermicide), birth control, and abstinence.

    • Patients who are taking or plan to take warfarin, metronidazole, paraldehyde, phenytoin, theophylline, oral anticoagulants, or isoniazid

    Ascertainment: Patient report

    • A concurrent or recent illness that may better account for current fatigue

    Ascertainment: Review of history

    • Unwillingness to not take any new non-emergency medications during the course of this study without first reviewing with the study research physician

    Ascertainment: Patient Report

    • History of rubber-contact dermatitis or allergy to disulfiram or thiuram derivatives

    Ascertainment: patient report

    • Prior history of serious adverse reaction to disulfiram

    Ascertainment: Patient Report

    • Cognitive Impairment for patients over 60.

    Ascertainment: Patient's with scores of less than 24 on the Mini-Mental Status Exam will not be eligible for this study.


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): NCT03891667


Contacts
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Contact: Brian A Fallon, MD 646-774-8052 baf1@cumc.columbia.edu
Contact: Shannon Delaney, MD sld2158@cumc.columbia.edu

Sponsors and Collaborators
Research Foundation for Mental Hygiene, Inc.
FDC Foundation
Investigators
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Principal Investigator: Brian A Fallon, MD Columbia University

Additional Information:
Publications of Results:
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Responsible Party: Brian Fallon, Professor of Clinical Psychiatry, Research Foundation for Mental Hygiene, Inc.
ClinicalTrials.gov Identifier: NCT03891667     History of Changes
Other Study ID Numbers: 7755
First Posted: March 27, 2019    Key Record Dates
Last Update Posted: April 2, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There no current plan for sharing participant data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Brian Fallon, Research Foundation for Mental Hygiene, Inc.:
Lyme Disease
Post-treatment Lyme Disease Syndrome
Disulfiram
Chronic Lyme Disease

Additional relevant MeSH terms:
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Lyme Disease
Fatigue
Signs and Symptoms
Borrelia Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Tick-Borne Diseases
Spirochaetales Infections
Disulfiram
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action