Disulfiram: A Test of Symptom Reduction Among Patients Wi... | NCT03891667

NCT03891667

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
FDC Foundation	OTHER

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
8 Week Disulfiram	Experimental	Patients in this group receive disulfiram for 8 weeks. The dosing schedule is fixed-flexible, starting at 250 mg every other day at week 1, 250 mg daily for week 2, 250 mg alternating with 500 mg for week 3, and 500 mg daily for week 4 to week 8. Dose increases are based on clinical judgment guided by patient tolerance, response, body weight, and side effects.	Drug: Disulfiram
4 Week Disulfiram	Active Comparator	Patients in this group receive disulfiram for 4 weeks followed by placebo capsules for 4 weeks. The dosing schedule is fixed-flexible, starting at 250 mg every other day at week 1, 250 mg daily for week 2, 250 mg alternating with 500 mg during week 3, and 500 mg daily during week 4. Placebo capsules are given during weeks 5-8. Dose increases are based on clinical judgment guided by patient tolerance, response, body weight, and side effects.	Drug: Disulfiram

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Disulfiram	Drug	Patients will receive disulfiram for 4 weeks followed by placebo for 4 weeks or disulfiram for 8 weeks.	4 Week Disulfiram 8 Week Disulfiram

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Fatigue Severity Scale (FSS)	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. A responder on the FSS is an individual whose FSS total score has decreased by 0.7 its when compared baseline to week 10 (or last observation carried forward); 0.7 refers to the minimally clinical significant difference (MCID) in change over time. We report the number of participants who reached a meaningful reduction in fatigue (equal or more than MCID).	Change will be assessed over a 10 week interval
Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)	The Q-LES-Q - SF is a self-reported questionnaire, with 16 items evaluating 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, 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. Meaningful improvement on the Q-LES-Q to is a change score between baseline and week 10 (or last observation carried forward) of at least 6.8 points; 6.8 refers to the minimally clinical significant difference (MCID) where a score equal to or greater than 6.8 points represents an improved quality of file. We report # with meaningful improvement.	Change will be assessed over a 10 week interval

Secondary Outcomes

Measure	Description	Time Frame
The Short Form (36) Health Survey (SF-36) Physical Component Summary (PCS)	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. We calculate the Physical Component Summary (PCS) (representing physical functioning) which represent the items in the SF-36 representing physical functioning (Ware, 2000); as in the sub scales, lower scores indicate greater disability.The norm-based estimate has a mean of 50 and a standard deviation of 10. We report the magnitude of the score change from baseline to week 10 (or the last observation carried forward (LOCF); negative change scores indicate improvement.

Eligibility Module

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.

Name	Affiliation	Role
Brian A Fallon, MD	Columbia University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Lyme Research Center New York State Psychiatric Institute		New York	New York	10032	United States

PubMed Identifier	Type	Citation	Retractions
28674046	Background	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.
27103785	Background	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.

Label	URL
NIH website review of disulfiram's risk of liver toxicity	View source

Arm/Group Information

ID	Title	Description
FG000	8 Week Disulfiram	Patients in this group receive disulfiram for 8 weeks. The dosing schedule is fixed-flexible, starting at 250 mg every other day at week 1, 250 mg daily for week 2, 250 mg alternating with 500 mg for week 3, and 500 mg daily for week 4 to week 8. Dose increases are based on clinical judgment guided by patient tolerance, response, body weight, and side effects. Disulfiram: Patients will receive disulfiram for 4 weeks followed by placebo for 4 weeks or disulfiram for 8 weeks.
FG001	4 Week Disulfiram	Patients in this group receive disulfiram for 4 weeks followed by placebo capsules for 4 weeks. The dosing schedule is fixed-flexible, starting at 250 mg every other day at week 1, 250 mg daily for week 2, 250 mg alternating with 500 mg during week 3, and 500 mg daily during week 4. Placebo capsules are given during weeks 5-8. Dose increases are based on clinical judgment guided by patient tolerance, response, body weight, and side effects. Disulfiram: Patients will receive disulfiram for 4 weeks followed by placebo for 4 weeks or disulfiram for 8 weeks.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	8 Week Disulfiram	Patients in this group receive disulfiram for 8 weeks. The dosing schedule is fixed-flexible, starting at 250 mg every other day at week 1, 250 mg daily for week 2, 250 mg alternating with 500 mg for week 3, and 500 mg daily for week 4 to week 8. Dose increases are based on clinical judgment guided by patient tolerance, response, body weight, and side effects. Disulfiram: Patients will receive disulfiram for 4 weeks followed by placebo for 4 weeks or disulfiram for 8 weeks.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Fatigue Severity Scale (FSS)

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. A responder on the FSS is an individual whose FSS total score has decreased by 0.7 its when compared baseline to week 10 (or last observation carried forward); 0.7 refers to the minimally clinical significant difference (MCID) in change over time. We report the number of participants who reached a meaningful reduction in fatigue (equal or more than MCID).

We conduct an intent to treat analysis which covers all enrolled and randomized patients who received study drug.

Posted

Count of Participants

Participants

Change will be assessed over a 10 week interval

ID	Title	Description
OG000	8 Week Disulfiram

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	8 Week Disulfiram	Patients in this group receive disulfiram for 8 weeks. The dosing schedule is fixed-flexible, starting at 250 mg every other day at week 1, 250 mg daily for week 2, 250 mg alternating with 500 mg for week 3, and 500 mg daily for week 4 to week 8. Dose increases are based on clinical judgment guided by patient tolerance, response, body weight, and side effects. Disulfiram: Patients will receive disulfiram for 8 weeks .

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
ER visit	Immune system disorders		Non-systematic Assessment	10 days after ending disulfiram treatment early (due to headaches), an episode of throat tightness nausea and light-headedness occurred. The patient (hx of asthma) went to ER and was treated for emerging possible anaphylaxis and recovered.

ID	Term
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D016905	Gram-Negative Bacterial Infections
D001424	Bacterial Infections

ID	Term
D004050	Ditiocarb
D013859	Thiocarbamates
D002219	Carbamates
D000144	Acids, Acyclic

ID	Term
D005221	Fatigue
D008193	Lyme Disease
D000077342	Post-Lyme Disease Syndrome