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.

Brief Title

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

Brief Summary

Approximately 10-20% of patients experience ongoing symptoms despite having received standard<br /> antibiotic therapy for Lyme disease. Possible explanations for persistent symptoms include<br /> persistent infection and/or post-infectious causes. Recent in vitro studies indicate that<br /> disulfiram is effective at killing both the actively replicating and the more quiescent<br /> persister forms of Borrelia burgdorferi, the microbe that causes Lyme Disease. In this study,<br /> the investigators are examining the safety of disulfiram among patients with post-treatment<br /> Lyme disease symptoms. The investigators are also conducting a preliminary investigation<br /> 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.

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.

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.