Symptomatic Management of Lyme Arthritis

Sponsor

Desiree Neville, MD (Other)

Overall Status

Recruiting

CT.gov ID

NCT04038346

Collaborator

(none)

300

Enrollment

Location

Arms

Anticipated Duration (Months)

4.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Lyme arthritis resolves with appropriate antimicrobial treatment in a majority of patients, but 10-20% of patients develop antibiotic-refractory Lyme arthritis with prolonged arthritis symptoms and treatment courses. Excessive up-regulation of the inflammatory process has been shown in patients with antibiotic-refractory Lyme arthritis. The over-expressed pro-inflammatory cell mediators are downstream of NSAID inhibition, which would suggest initial inflammatory inhibition may be beneficial in these patients. While NSAIDs are known to reduce pro-inflammatory cell mediators early in the course of inflammation, research has shown that there are other cytokines that play a role in the healing after inflammation that are also inhibited by NSAIDs, and that NSAID use can delay healing.

It is not known if scheduled NSAID therapy will reduce, increase, or have no effect on the occurrence of refractory Lyme arthritis cases. The hypothesis of the study is that prescribing scheduled NSAIDs at the time of diagnosis of Lyme arthritis can prevent the development of the excessive inflammatory phase and decrease the number of patients with antibiotic-refractory Lyme arthritis, or at least decrease the duration of persistent Lyme arthritis symptoms.

The pilot study design randomizes patients to scheduled NSAIDs, scheduled acetaminophen, or scheduled NSAIDs x 1 week than acetaminophen. Primary outcomes are duration of arthritis symptoms, number of refractory cases, side effects and compliance.

Condition or Disease	Intervention/Treatment	Phase
Lyme Arthritis Lyme Disease Arthritis	Drug: Naproxen Drug: Acetaminophen	Phase 3

Detailed Description

Specific Aims:

Demonstrate feasibility to ensure adequate patient enrollment and symptomatic follow-up of patients with Lyme arthritis.
Develop pilot data necessary for sample size and power calculations:

The purpose of the research study is to evaluate whether there is symptomatic benefit of schedule NSAID therapy in patients with Lyme arthritis diagnosis.

Quantification of antibiotic-refractory Lyme arthritis in our population
Symptomatic outcomes of patients with Lyme arthritis on scheduled NSAIDs versus those not placed on scheduled NSAIDs (duration to resolution and number of patients with resistant arthritis)
Assess side effects of patients with Lyme arthritis placed on scheduled NSAIDs versus those not placed on scheduled NSAIDs
Assess changes in resources (follow-up visits, further prescriptions) required for patients taking scheduled NSAIDs versus not taking scheduled NSAIDs

Background:

Lyme disease is the systemic tick-borne disease caused by Borrelia burgdorferi infection, and is endemic to an expanding portion of the United States. Lyme arthritis is a common presentation of Lyme disease. While Lyme arthritis resolves with appropriate antimicrobial treatment in a majority of patients, 10-20% of patients develop antibiotic-refractory Lyme arthritis with prolonged inflammatory arthritis. Research suggests excessive up-regulation of the inflammatory process in patients with prolonged symptoms. The over-expressed pro- inflammatory cell mediators are downstream of NSAID inhibition, which would suggest NSAIDs may be beneficial in these patients. In fact, there is data that NSAIDs and/or disease-modifying anti-rheumatic drugs (DMARDs) may be beneficial in refractory Lyme arthritis cases, once diagnosed as refractory.

The hypothesis of the study is that prescribing scheduled NSAIDs at the time of diagnosis can prevent the development of the excessive inflammatory phase and decrease the number of patients with antibiotic-refractory Lyme arthritis, or at least decrease the duration of persistent Lyme arthritis symptoms. There are no known methods to identify patients who will develop antibiotic-refractory Lyme arthritis. This work is important to delineate optimal timing and duration of NSAIDs given the research that shows the anti- inflammatory effects during healing can potentially delay recovery.

Significance:

While antibiotic-refractory Lyme arthritis has been studied at a microbiologic/cytokine level as well as evaluated in terms of treatment once patients have been deemed antibiotic refractory, to our knowledge there are no published studies evaluating prevention.

With no literature looking at the question of NSAIDs for the prevention of antibiotic- refractory Lyme arthritis, this pilot study is needed to adequately calculate sample size and power calculations for a large-scale multicenter study. There is anecdotal data from the Rheumatology and Infectious Disease departments at the UPMC Children's Hospital of Pittsburgh that early scheduled NSAIDs may decrease refractory cases, but there has been no formal evaluation into this question. Retrospective evaluation is challenging since the medications in question (NSAIDs) are over the counter, and clinicians may recommend scheduled or intermittent NSAID therapy without documentation, and certainly without prescriptions in the medical record. Many patients with refractory Lyme arthritis are placed on NSAIDs, but given the question of delayed healing with inhibition of prostaglandins during the healing phase of inflammation, the question of whether NSAIDs are beneficial in patients to prevent refractory arthritis is worthwhile rather than the current process of variable NSAID prescription.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective, randomized, controlled, non blindedProspective, randomized, controlled, non blinded

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Symptomatic Management of Lyme Arthritis

Actual Study Start Date :

Oct 1, 2019

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NSAID Naproxen at weight based standard dose given bid daily until symptoms resolve	Drug: Naproxen Patients will be randomized to an NSAID (naproxen) Other Names: naprosyn, aleve, anaprox
Active Comparator: Acetaminophen Acetaminophen at weight based standard dose given qid until symptoms resolve	Drug: Acetaminophen Patients will be randomized to acetaminophen Other Names: tylenol
Experimental: NSAID first, then Acetaminophen Naproxen at weight based standard dose given bid for one week, then acetaminophen at weight based standard dose given qid until symptoms resolve	Drug: Naproxen Patients will be randomized to an NSAID (naproxen) Other Names: naprosyn, aleve, anaprox Drug: Acetaminophen Patients will be randomized to acetaminophen Other Names: tylenol
No Intervention: Standard Care Symptom observation only

Outcome Measures

Primary Outcome Measures

Change in the degree of joint pain determined by serial visual analog scale for pain via text surveys [days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded]
0-100 scale (no pain to worst pain - higher score, worse outcome), slide bar in text survey, VAS score rate of change will be compared between treatment arms, and time to normalization
Change in the degree of joint redness determined by serial visual analog scale for joint redness via text surveys [days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded]
0-100 scale (no redness to maximal redness- higher score, worse outcome), slide bar in text survey, VAS score rate of change will be compared between treatment arms, and time to normalization
Change in degree of joint movement determined by serial visual analog scale for joint movement via text surveys [days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded]
0-100 scale (no joint movement to normal joint movement- higher score, better outcome), slide bar in text survey, VAS score rate of change will be compared between treatment arms, and time to normalization
Change in degree of overall function determined by serial visual analog scale for overall function via text surveys [days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded]
0-100 scale (severely impaired function to normal function- higher score, better outcome), slide bar in text survey, VAS score rate of change will be compared between treatment arms, and time to normalization
Time to complete symptom resolution as collected by a yes/no question on the text survey and a branching question asking the date that the symptoms were completely resolved. [The branching question will appear on their text survey at any of the time points (days 1, 3, 7, 10, 14, 21, 28, 60) once they enter "yes" to symptoms completely resolved.]
If patient answers yes to symptoms completely resolved, they will receive a branching question to input the date. Time from diagnosis to symptom resolution will be compared between the treatment groups.

Secondary Outcome Measures

Change in medication compliance as determined by question in serial text survey [days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)]
Parents enter number of days patient has taken the medication in the past day as well as per day since the last survey in two questions on the text survey with their response being a drop down number list on the text survey- medication compliance will be compared to the number of doses that would be full compliance for that treatment arm
Development of medication side effects as determined by question in serial text survey [days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)]
survey asks parents to describe any medication side effects they feel their child has had - descriptive outcome only
Other medications taken as determined by question in serial text survey [days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)]
Parents are asked to list any medications in addition to their study drug and antibiotic that their child has taken- descriptive outcome only
Fever as determined by question in serial text survey [days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)]
Parents are asked if their child had fever in the 24 hours prior to taking the text survey, duration of fever compared between treatment arms

Other Outcome Measures

Need for further care as determined by medical record review as number of visits in the system for Lyme arthritis symptoms [30 days, 60 days, 120 days, 1 year]
Mean repeat medical visits for Lyme arthritis will be compared between treatment arms based on medical record review

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Arthritis
Undergoing Lyme disease testing (Lyme test positive)

Exclusion Criteria:

Patients will be secondarily withdrawn from analysis and instructed to stop study medication if their Lyme test is negative.

Underlying diagnosis of rheumatoid or recurrent arthritis Already on scheduled NSAIDs

Anything that restricts the prescription of naproxen or acetaminophen:

Hypersensitivity to naproxen (for example: anaphylactic reactions, serious skin reactions) or any component of the formulation; history of aspirin induced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs, underlying kidney or liver impairment
Already taking daily NSAIDs (naproxen or ibuprofen) or daily acetaminophen
Hypersensitivity to acetaminophen or any component of the formulation; severe liver impairment or severe active liver disease