Clinical trial NCT01207739: Persistent Lyme Empiric Antibiotic Study Europe
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Lyme Disease
Borrelia Infection
Keywords: Prolonged antibiotic treatment in Lyme disease
Doxycycline
Clarithromycin
Hydroxychloroquine
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Sint Maartenskliniek
name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2010-09-23
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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).

Primary outcomes:
measure: Global score 36-item Short-form General Health Survey (SF 36)
timeFrame: Week 14
Secondary outcomes:
measure: Subscales 36-item Short-form General Health Survey (SF 36)
timeFrame: weeks 0, 14, 26, 40 and 52
measure: Actometer recording during 14 days (objective physical activity)
timeFrame: weeks 0, 14 and 40
measure: Measurements of neuropsychological impairment
timeFrame: weeks 0, 14, 26 and 40
measure: Economic evaluation: Questionaire EQ-5D, health consumption and productivity of labour
timeFrame: weeks 0, 14, 26, 40 and 52
measure: Fatigue subscale of Checklist Individual Strength (CIS)
timeFrame: weeks 0, 14, 26, 40 and 52
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Nijmegen
country: Netherlands
facility: Sint Maartenskliniek
Study officials:
affiliation: Radboud University Medical Center
name: Bart-Jan Kullberg, Prof., M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: van Middendorp H, Berende A, Vos FJ, Ter Hofstede HHM, Kullberg BJ, Evers AWM. Expectancies as predictors of symptom improvement after antimicrobial therapy for persistent symptoms attributed to Lyme disease. Clin Rheumatol. 2021 Oct;40(10):4295-4308. doi: 10.1007/s10067-021-05760-1. Epub 2021 May 24.
citation: Berende A, Agelink van Rentergem J, Evers AWM, Ter Hofstede HJM, Vos FJ, Kullberg BJ, Kessels RPC. Cognitive impairments in patients with persistent symptoms attributed to Lyme disease. BMC Infect Dis. 2019 Oct 7;19(1):833. doi: 10.1186/s12879-019-4452-y.
citation: Berende A, Ter Hofstede HJM, Vos FJ, Vogelaar ML, van Middendorp H, Evers AWM, Kessels RPC, Kullberg BJ. Effect of prolonged antibiotic treatment on cognition in patients with Lyme borreliosis. Neurology. 2019 Mar 26;92(13):e1447-e1455. doi: 10.1212/WNL.0000000000007186. Epub 2019 Feb 22.