Lyme DiseasePhase 4PLEASENCT01207739
Persistent Lyme Empiric Antibiotic Study Europe
A Phase 4 study testing Doxycycline and Clarithromycin and hydroxychloroquine in people with Lyme Disease and Borrelia Infection, run by Radboud University Medical Center at 2 sites in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lyme Disease, Borrelia Infection
- What is being tested?
- Doxycycline and Clarithromycin and hydroxychloroquine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 280 participants
- Where
- 2 sitesNetherlands
- Study dates
- Sep 2010to Oct 2014
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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).
Trial locations and contacts
2 sites in 1 country.
Netherlands2 sites
Radboud University Nijmegen Medical Centre
Nijmegen, 6500 HB
Sint Maartenskliniek
Nijmegen, 6522 JV
About this study
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
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.
- Conditions
- Lyme Disease, Borrelia Infection
- Being tested
- Doxycycline, Clarithromycin and hydroxychloroquine, Placebo
- Keywords
- Prolonged antibiotic treatment in Lyme disease, Doxycycline, Clarithromycin, Hydroxychloroquine
- Medical subject headings
- Lyme Disease, Borrelia Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DoxycyclineDrug
Also called Doxycycline disper, CASnr 564-25-0 (doxycycline); 17086-28-1 (doxycycline monohydraat)
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
Clarithromycin and hydroxychloroquineDrug
Also called Clarithromycine Mylan, RVG 32619, CASnr 81103-11-9, Hydroxychloroquine; Plaquenil, RVG 00853, CASnr 118-42-3 (hydroxychloroquine); 737-36-4 (hydroxychloroquine sulfate)
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
PlaceboDrug
After open-label i.v. ceftriaxone 2000 mg qd via a peripheral i.v. catheter: 12 weeks' course of double placebo b.i.d.
| Study group | Role | What they receive |
|---|---|---|
| Doxycycline | Active comparator | Not described Receives: Drug: Doxycycline |
| Clarithromycin and hydroxychloroquine | Active comparator | Not described Receives: Drug: Clarithromycin and hydroxychloroquine |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Week 14
Secondary outcomes (5)
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).
Measured: weeks 0, 14, 26, 40 and 52
Actometer recording during 14 days (objective physical activity)
Measured: weeks 0, 14 and 40
Measurements of neuropsychological impairment
Measured: 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).
Measured: 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).
Measured: weeks 0, 14, 26, 40 and 52
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2010 (estimated)
- Study startSep 2010
- Primary completionOct 2013
- Study completionOct 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Lyme DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 280 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Sint Maartenskliniek, ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Sponsor
- Investigators
- Bart-Jan Kullberg, Prof., M.D., Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01207739
- Sponsor's protocol ID
- PLEASE
- Other IDs
- NL-27344.091.09, 2009-010939-40, 2009
- Acronym
- PLEASE
- Status last verified
- Sep 2016
- First submitted
- 22 Sep 2010
- Last updated
- 8 Sep 2016
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 25318999Berende 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.
PubMed 27028911van 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.
PubMed 34031759Berende 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.
PubMed 31590634Berende 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.
PubMed 30796143
Study at a glance
From the registry record, last updated by the sponsor on 8 Sep 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01207739
- Acronym / sponsor ID
- PLEASE / PLEASE
- Conditions
- Lyme Disease, Borrelia Infection
- Keywords
- Prolonged antibiotic treatment in Lyme disease, Doxycycline, Clarithromycin, Hydroxychloroquine
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 280 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Collaborators
- Sint Maartenskliniek, ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- Sep 2010
- Primary completion
- Oct 2013 (actual)
- Study completion
- Oct 2014 (actual)
- First posted
- 23 Sep 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Doxycycline | Active comparator | Drug: Doxycycline |
| Clarithromycin and hydroxychloroquine | Active comparator | Drug: Clarithromycin and hydroxychloroquine |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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:
- Subjects must sign a written informed consent form.
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DoxycyclineAlso: Doxycycline disper, CASnr 564-25-0 (doxycycline); 17086-28-1 (doxycycline monohydraat)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 | Drug | Doxycycline |
| Clarithromycin and hydroxychloroquineAlso: Clarithromycine Mylan, RVG 32619, CASnr 81103-11-9, Hydroxychloroquine; Plaquenil, RVG 00853, CASnr 118-42-3 (hydroxychloroquine); 737-36-4 (hydroxychloroquine sulfate)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 | Drug | Clarithromycin and hydroxychloroquine |
| PlaceboAfter open-label i.v. ceftriaxone 2000 mg qd via a peripheral i.v. catheter: 12 weeks' course of double placebo b.i.d. | Drug | Placebo |
Primary outcome
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.
5 secondary outcomes
Subscales 36-item Short-form General Health Survey (SF 36)
Time frame: weeks 0, 14, 26, 40 and 52
Actometer recording during 14 days (objective physical activity)
Time frame: weeks 0, 14 and 40
Measurements of neuropsychological impairment
Time frame: weeks 0, 14, 26 and 40
Economic evaluation: Questionaire EQ-5D, health consumption and productivity of labour
Time frame: weeks 0, 14, 26, 40 and 52
Fatigue subscale of Checklist Individual Strength (CIS)
Time frame: weeks 0, 14, 26, 40 and 52
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Sep 2016.
- Background: PubMed 25318999Berende 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.
- Results publication: PubMed 27028911Berende 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.
- Derived from this study: PubMed 34031759van 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.
- Derived from this study: PubMed 31590634Berende 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.
- Derived from this study: PubMed 30796143Berende 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bart-Jan Kullberg, Prof., M.D. principal investigator
Radboud University Medical Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Doxycycline and Clarithromycin and hydroxychloroquine in people with Lyme Disease and Borrelia Infection, run by Radboud University Medical Center at 2 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Global score 36-item Short-form General Health Survey (SF 36) (time frame: Week 14). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01207739, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Sep 2016; AzTrials last refreshed its copy on 29 Oct 2026.