Clinical trial NCT03891667: Disulfiram: A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease
Official title: Disulfiram ("Antabuse"): A Test of Symptom Reduction Among Patients With Previously Treated Lyme Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Fatigue
Quality of Life
Keywords: Lyme Disease
Post-treatment Lyme Disease Syndrome
Disulfiram
Chronic Lyme Disease
Lead sponsor: Research Foundation for Mental Hygiene, Inc.
Sponsor class: OTHER
Collaborators: name: FDC Foundation
First posted: 2019-03-27
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 follows a fixed-flexible schedule. Clinical judgment guides dosing increases, based on patient tolerance, side effects, and response.

Week 1: 250 mg every other day. Week 2: 250 mg daily (or continuation of lower dose based on clinical judgment).

Week 3: 250 mg alternating with 500 mg/daily (or continued lower dose based on clinical judgment) Week 4: 500 mg daily (or continued lower dose based on clinical judgment)

Week 5-8: 500 mg/daily (or continued lower dose based on clinical judgment) :

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Fatigue Severity Scale (FSS)
timeFrame: Change will be assessed over a 10 week interval
measure: Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)
timeFrame: Change will be assessed over a 10 week interval
Secondary outcomes:
measure: The Short Form (36) Health Survey (SF-36) Physical Component Summary (PCS)
timeFrame: Change will be assessed over a 10 week interval
measure: General Symptom Questionnaire (GSQ-30)- Assess Multisystemic Symptom Burden
timeFrame: Change will be assessed over a 10 week interval
measure: Patient-Reported Outcomes Measurement Information System (PROMIS-29) Symptom Summary Score on Sleep Disturbance, Pain, Anxiety, Depression, and Low Energy/Fatigue (SPADE)
timeFrame: Change will be assessed over a 10 week interval
measure: The Short Form (36) Health Survey (SF-36) Mental Component Summary (MCS)
timeFrame: Change will be assessed over a 10 week interval
Other outcomes:
Locations:
city: New York
country: United States
facility: Lyme Research Center New York State Psychiatric Institute
state: New York
Study officials:
affiliation: Columbia University
name: Brian A Fallon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Long TE. Repurposing Thiram and Disulfiram as Antibacterial Agents for Multidrug-Resistant Staphylococcus aureus Infections. Antimicrob Agents Chemother. 2017 Aug 24;61(9):e00898-17. doi: 10.1128/AAC.00898-17. Print 2017 Sep.
citation: Pothineni VR, Wagh D, Babar MM, Inayathullah M, Solow-Cordero D, Kim KM, Samineni AV, Parekh MB, Tayebi L, Rajadas J. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des Devel Ther. 2016 Apr 1;10:1307-22. doi: 10.2147/DDDT.S101486. eCollection 2016.
citation: Guerzoni S, Pellesi L, Pini LA, Caputo F. Drug-drug interactions in the treatment for alcohol use disorders: A comprehensive review. Pharmacol Res. 2018 Jul;133:65-76. doi: 10.1016/j.phrs.2018.04.024. Epub 2018 Apr 30.
citation: Liegner KB. Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases. Antibiotics (Basel). 2019 May 30;8(2):72. doi: 10.3390/antibiotics8020072.