Persistent Lyme Empiric Antibiotic Study Europe

Study Overview
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Brief Summary
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The purpose of the study is to establish whether prolonged antibiotic treatment of patients diagnosed with proven or presumed PLD (as endorsed by the international ILADS guidelines) leads to better patient outcome than short-term treatment as endorsed by the Dutch CBO guidelines.

Official Title
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Persistent Lyme Empiric Antibiotic Study Europe. A Prospective, Randomised Study Comparing Two Prolonged Oral Antibiotic Strategies After Initial Intravenous Ceftriaxone Therapy for Patients With Symptoms of Proven or Possible Persistent Lyme Disease

Conditions
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Lyme Disease, Borrelia Infection

Intervention / Treatment
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* Drug: Doxycycline
* Drug: Clarithromycin and hydroxychloroquine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or non-pregnant, non-lactating females who are 18 years or older. Women of child-bearing potential must agree to use contraception methods other than oral contraceptives during the study therapy period, since failure of oral contraceptives due to long-term antibiotic use has been described and doxycycline might be teratogenic. Patients with presumed or proven PLD. In this study, clinical suspicion of PLD is defined as complaints of musculoskeletal pain, arthritis or arthralgia, neuralgia or sensory disturbances (such as paresthesias or dysesthesias), neuropsychological or cognitive disorders, and persistent fatigue, that are: temporally related to an episode of erythema migrans or otherwise proven symptomatic Lyme disease (defined as within 4 months after erythema migrans as assessed by a physician, or positive biopsy, PCR, culture, intrathecal B. burgdorferi antibodies), OR accompanied by a positive B. burgdorferi IgG or IgM immunoblot (as defined by strict criteria in line with the European Union Concerted Action on Lyme Borreliosis (EUCALB)), regardless of prior ELISA IgG/IgM screening results. Subjects must sign a written informed consent form. Exclusion Criteria: Subjects with a known history of allergy or intolerance to tetracyclines, macrolides, hydroxychloroquine or ceftriaxone. Subjects who have had more than 5 days of antimicrobial therapy with activity against B. burgdorferi within the previous 4 weeks. Subjects with a presumed diagnosis of neuroborreliosis (CSF pleocytosis or intrathecal antibody production) for which intravenous antimicrobial therapy is required. Subjects with a known diagnosis of HIV-seropositivity or other immune disorders. (No HIV serologic testing is required for the study). Subjects with positive syphilis serology or signs of other spirochetal diseases. Subjects with moderate or severe liver disease defined as alkaline phosphatase, ALAT, or ASAT greater than 3 times upper limit of normal. Subjects who are receiving and cannot discontinue cisapride, astemizole, terfenadine, barbiturates, phenytoin, or carbamazepine (The concentrations of these drugs may increase during clarithromycin therapy and/or lead to reduced availability of doxycycline). Subjects who are currently enrolled on other investigational drug trials or receiving investigational agents. Subjects who have been previously randomized into this study. Severe physical or psychiatric co-morbidity that interferes with participation in the study protocol, including previous medical diagnosis of rheumatic conditions, chronic fatigue syndrome or chronic pain conditions as well as insufficient command of the Dutch language. Co-morbidity that could (partially) account for the symptoms of the subject (e.g. vitamin B12 deficiency, anemia, hypothyroidism).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Doxycycline<br> | Drug: Doxycycline<br>* After open-label i.v. ceftriaxone 2000 mg qd via a peripheral i.v. catheter: oral Doxycycline 100 mg combined with a placebo b.i.d. for 12 weeks<br>* Other names: CASnr 564-25-0 (doxycycline); 17086-28-1 (doxycycline monohydraat);|
| Active Comparator: Clarithromycin and hydroxychloroquine<br> | Drug: Clarithromycin and hydroxychloroquine<br>* After open-label i.v. ceftriaxone 2000 mg qd via a peripheral i.v. catheter: clarithromycin 500 mg combined with hydroxychloroquine 200 mg b.i.d. for 12 weeks<br>* Other names: CASnr 118-42-3 (hydroxychloroquine); 737-36-4 (hydroxychloroquine sulfate);|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* After open-label i.v. ceftriaxone 2000 mg qd via a peripheral i.v. catheter: 12 weeks' course of double placebo b.i.d.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global score 36-item Short-form General Health Survey (SF 36) | Because different operationalizations of the term 'Global score 36-item Short-form General Health Survey (SF 36)' exist, the primary outcome measure is specified here as the 'physical component summary score' (PCS) of the RAND-36 Health Status Inventory (RAND SF-36, Hays 1998), which is similar to the Medical Outcomes Study (MOS) 36-item Short-Form General Health Survey (SF-36). The PCS is also known as the physical health composite score (PHC). This specification has been communicated to the local Ethics Committee on March 1, 2011, and was approved on April 6, 2011. | Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subscales 36-item Short-form General Health Survey (SF 36) | After the last comprehensive outcome assessment at week 40, patients are surveyed by post-study questionnaires at week 52 (protocol version 3.8; dated July 17, 2009; final Ethics Committee approval April 29, 2010). | weeks 0, 14, 26, 40 and 52 | 
| Actometer recording during 14 days (objective physical activity) |  | weeks 0, 14 and 40 | 
| Measurements of neuropsychological impairment |  | weeks 0, 14, 26 and 40 | 
| Economic evaluation: Questionaire EQ-5D, health consumption and productivity of labour | After the last comprehensive outcome assessment at week 40, patients are surveyed by post-study questionnaires at week 52 (protocol version 3.8; dated July 17, 2009; final Ethics Committee approval April 29, 2010). | weeks 0, 14, 26, 40 and 52 | 
| Fatigue subscale of Checklist Individual Strength (CIS) | After the last comprehensive outcome assessment at week 40, patients are surveyed by post-study questionnaires at week 52 (protocol version 3.8; dated July 17, 2009; final Ethics Committee approval April 29, 2010). | weeks 0, 14, 26, 40 and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prolonged antibiotic treatment in Lyme disease, Doxycycline, Clarithromycin, Hydroxychloroquine