Symptomatic Management of Lyme Arthritis

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.

Study Overview

• Status: Recruiting
• Conditions: Arthritis; Lyme Disease; Lyme Arthritis
• Intervention / Treatment: Drug: Naproxen; Drug: Acetaminophen

Detailed Description

Specific Aims:

1. Demonstrate feasibility to ensure adequate patient enrollment and symptomatic follow-up of patients with Lyme arthritis.
2. 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.

1. Quantification of antibiotic-refractory Lyme arthritis in our population
2. 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)
3. Assess side effects of patients with Lyme arthritis placed on scheduled NSAIDs versus those not placed on scheduled NSAIDs
4. 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 Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Desiree NW Neville, MD; Phone Number: 412-692-7692; Email: desiree.neville@chp.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
      • Contact: Neville, MD; Email: desiree.neville@chp.edu
      • Principal Investigator: Desiree Neville, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the degree of joint pain determined by serial visual analog scale for pain via text surveys	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	days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded
Change in the degree of joint redness determined by serial visual analog scale for joint redness via text surveys	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	days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded
Change in degree of joint movement determined by serial visual analog scale for joint movement via text surveys	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	days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded
Change in degree of overall function determined by serial visual analog scale for overall function via text surveys	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	days 1, 3, 7, 10, 14, 21, 28, 60 the VAS score will be collected, time to symptom resolution will be recorded
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.	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in medication compliance as determined by question in serial text survey	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	days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)
Development of medication side effects as determined by question in serial text survey	survey asks parents to describe any medication side effects they feel their child has had - descriptive outcome only	days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)
Other medications taken as determined by question in serial text survey	Parents are asked to list any medications in addition to their study drug and antibiotic that their child has taken- descriptive outcome only	days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)
Fever as determined by question in serial text survey	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	days 1, 3, 7, 10, 14, 21, 28, 60 (collected until symptom resolution)

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Desiree Neville, MD
• Investigators: Principal Investigator: Desiree NW Neville, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 15, 2019
• First Submitted That Met QC Criteria: July 26, 2019
• First Posted (Actual): July 30, 2019

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Arthritis; Lyme; Lyme Arthritis; Lyme Disease; NSAID
• Additional Relevant MeSH Terms: Infections; Joint Diseases; Musculoskeletal Diseases; Vector Borne Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Tick-Borne Diseases; Borrelia Infections; Spirochaetales Infections; Arthritis; Lyme Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Gout Suppressants; Acetaminophen; Naproxen
• Other Study ID Numbers: PRO18110151

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No