Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lyme Disease; Borrelia Infection	Drug: Doxycycline; Drug: Clarithromycin and hydroxychloroquine; Drug: Placebo	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	280 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	September 2010
Actual Primary Completion Date :	October 2013
Actual Study Completion Date :	October 2014

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Doxycycline	Drug: Doxycycline; 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; Other Names: Doxycycline disper; CASnr 564-25-0 (doxycycline); 17086-28-1 (doxycycline monohydraat)
Active Comparator: Clarithromycin and hydroxychloroquine	Drug: Clarithromycin and hydroxychloroquine; 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; Other Names: Clarithromycine Mylan, RVG 32619; CASnr 81103-11-9; Hydroxychloroquine; Plaquenil, RVG 00853; CASnr 118-42-3 (hydroxychloroquine); 737-36-4 (hydroxychloroquine sulfate)
Placebo Comparator: Placebo	Drug: Placebo; After open-label i.v. ceftriaxone 2000 mg qd via a peripheral i.v. catheter: 12 weeks' course of double placebo b.i.d.

Outcome Measures

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Primary Outcome Measures :

1. Global score 36-item Short-form General Health Survey (SF 36) [ Time Frame: Week 14 ]
   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.

Secondary Outcome Measures :

1. Subscales 36-item Short-form General Health Survey (SF 36) [ Time Frame: weeks 0, 14, 26, 40 and 52 ]
   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).
2. Actometer recording during 14 days (objective physical activity) [ Time Frame: weeks 0, 14 and 40 ]
3. Measurements of neuropsychological impairment [ Time Frame: weeks 0, 14, 26 and 40 ]
4. Economic evaluation: Questionaire EQ-5D, health consumption and productivity of labour [ Time Frame: weeks 0, 14, 26, 40 and 52 ]
   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).
5. Fatigue subscale of Checklist Individual Strength (CIS) [ Time Frame: weeks 0, 14, 26, 40 and 52 ]
   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).

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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).

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Netherlands, 6500 HB
Sint Maartenskliniek
Nijmegen, Netherlands, 6522 JV

Sponsors and Collaborators

Radboud University

Sint Maartenskliniek

ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

Principal Investigator:	Bart-Jan Kullberg, Prof., M.D.	Radboud University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Berende A, ter Hofstede HJ, Vos FJ, van Middendorp H, Vogelaar ML, Tromp M, van den Hoogen FH, Donders AR, Evers AW, Kullberg BJ. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med. 2016 Mar 31;374(13):1209-20. doi: 10.1056/NEJMoa1505425.

Other Publications:

Berende A, ter Hofstede HJ, Donders AR, van Middendorp H, Kessels RP, Adang EM, Vos FJ, Evers AW, Kullberg BJ. Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)--design of a randomized controlled trial of prolonged antibiotic treatment in patients with persistent symptoms attributed to Lyme borreliosis. BMC Infect Dis. 2014 Oct 16;14:543. doi: 10.1186/s12879-014-0543-y.

Responsible Party:	Radboud University
ClinicalTrials.gov Identifier:	NCT01207739 History of Changes
Other Study ID Numbers:	PLEASE; NL-27344.091.09 ( Other Grant/Funding Number: ZonMW ); 2009-010939-40 ( EudraCT Number )
First Posted:	September 23, 2010
Last Update Posted:	September 8, 2016
Last Verified:	September 2016

Keywords provided by Radboud University:

Prolonged antibiotic treatment in Lyme disease; Doxycycline; Clarithromycin; Hydroxychloroquine

Additional relevant MeSH terms:

Lyme Disease; Borrelia Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Tick-Borne Diseases; Spirochaetales Infections; Anti-Bacterial Agents; Clarithromycin; Doxycycline; Ceftriaxone; Antibiotics, Antitubercular; Hydroxychloroquine	Anti-Infective Agents; Antitubercular Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Antirheumatic Agents