Comparison of Doxycycline and Cefuroxime Axetil for Treatment of Erythema Migrans: Clinical and Microbiological Outcome

• Sponsor: University Medical Centre Ljubljana (Other)
• Overall Status: Completed
• CT.gov ID: NCT01518192
• Collaborator: Slovenian Research Agency (Other)
• Enrollment: 544
• Locations: 2
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 272
• Patients Per Site Per Month: 8.8

Study Details

Study Description

Brief Summary

Background:

• While doxycycline is a standard antibiotic for treatment of erythema migrans in Europe as well as in the USA, the effectiveness of cefuroxime axetil in the treatment of adult patients with erythema migrans has been assessed only in the USA where the causative agent of Lyme disease is Borrelia burgdorferi, but not in Europe where the main etiologic agents are B. afzelii and B. garinii.

• Controversy exists over the significance and even the existence of post-Lyme disease symptoms because of the high rate of similar background symptoms in the general population.

Purpose:

The two main purposes of this European, prospective clinical trial in which doxycycline and cefuroxime axetil are compared in the treatment of adult patients with erythema migrans and which included a control group to address the significance of post-Lyme disease symptoms are:

• To assess and compare the effectiveness of doxycycline and cefuroxime axetil in the treatment of erythema migrans using clinical and bacteriological criteria (noninferiority testing approach), and

• to compare the frequency of post-Lyme disease symptoms in adult patients treated for EM with antibiotics and the frequency of similar symptoms in control subjects without Lyme disease.

Condition or Disease	Intervention/Treatment	Phase
Erythema Migrans; Post-Lyme Disease Symptoms	Drug: doxycycline; Drug: cefuroxime axetil	Phase 4

Detailed Description

Sample size

Decisions were based on the following:

1. Number of patients with erythema migrans treated with doxycycline and cefuroxime axetil was determined assuming no difference in treatment outcome will be detected (non-inferiority testing).

2. The decision for a larger sample sizes than needed for 1. was done with the intention to evaluate the secondary outcome measure, i.e., to assess the difference between the frequency of new or increased symptoms in patients treated for early Lyme disease and the occurrence of the same symptoms in control subjects.

3. We assumed that the outcomes in the two treatment groups will be comparable and that the patients could be combined for further analysis.

4. To obtain a control group from the same geographical area, each patient was asked if she or he had a family member or friend who was within 5 years of her or his age and who was without a history of Lyme borreliosis. These persons were approached by a short written explanation of the investigation, containing also a request for their participation. We assumed that we will be able to get a corresponding control person not for all but for approximately 80-90% of patients.

5. Under the assumption that approximately 15% of an estimated 200 patients would have new or increased symptoms at >6 months after enrollment into the study, a control group of 165 subjects would be sufficient to detect a >10 percentage point lower rate of new or increased symptoms in controls compared with patients at the 0.05 level (2-sided) with >90% power. To comply with drop outs at different time points we assessed that 280 patients and 230 controls should be included at baseline.

Study Design

• Study Type: Interventional
• Actual Enrollment: 544 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Risk Factors for Failure of Erythema Migrans Treatment - Comparison of Doxycycline and Cefuroxime Axetil for Treatment of Adult Patients With Erythema Migrans: Clinical and Microbiological Outcome.
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1Doxycycline	Drug: doxycycline; 100 mg bid; 15 days
Active Comparator: 2 Cefuroxime axetil	Drug: cefuroxime axetil; 500 mg bid; 15 days

Outcome Measures

Primary Outcome Measures

1. Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 14 Days [at 14 days post inclusion]

   Number of patients with objective manifestations of Lyme disease(persistence of erythema migrans or any of the extracutaneous-cardiac, nervous or skeletal-Lyme disease manifestations)and/or with post-Lyme disease symptoms in patients treated for solitary erythema migrans at 14 days post inclusion

2. Adverse Events [at 14 days]

   Number of patients reporting adverse events

3. Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 2 Months [2 months]

   Number of patients with objective Lyme disease manifestations and/or post-Lyme disease symptoms in patients treated for solitary erythema migrans at 2 months post inclusion

4. Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 6months [6 months]

   Number of patients with objective Lyme disease manifestations and/or post-Lyme disease symptoms in patients treated for solitary erythema migrans at 6 months post inclusion

5. Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 12 Months [12 months]

   Number of patients with objective Lyme disease manifestations and/or post-Lyme disease symptoms in patients treated for solitary erythema migrans at 12 months post inclusion

Secondary Outcome Measures

1. New or Increased Symptoms Since Erythema Migrans in Patients and Controls at 6 Months. [6 months]

   Comparison of the number patients and controls with new or increased symptoms since erythema migrans at 6 months.

2. New or Increased Symptoms Since Erythema Migrans in Patients Controls at 12 Months. [12 months]

   Comparison of the number of patients and controls with new or increased symptoms since erythema migrans at 12 months.

3. Selected Subjective Symptoms in Patients and Control Subjects [Examination at 12 months]

   Comparison of the number of patients and controls with selected 8 symptoms (fatigue, arthralgias, myalgias, headache, paresthesias, dizziness, irritability, or nausea) within the preceding week, irrespective of whether they were new or increased since erythema migrans.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• patients 15 or more years old

• with typical erythema migrans

• evaluated between 6/06 and 9/06

• evaluated at the Lyme Disease Outpatient Clinic, University Medical Center Ljubljana, Slovenia.

Exclusion Criteria:

• history of Lyme disease in the past

• pregnancy

• lactation

• immunocompromising condition

• history of a serious adverse reaction to a beta-lactam or tetracycline drug

• receiving an antibiotic with known anti-borrelial activity within 10 days

• multiple erythema migrans lesions or an extracutaneous manifestation of Lyme disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institute of Microbiology and Immunology, Medical Faculty, University of Ljubljana	Ljubljana		Slovenia	1000
2	Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia	Ljubljana		Slovenia	1525

Sponsors and Collaborators

• University Medical Centre Ljubljana
• Slovenian Research Agency

Investigators

• Principal Investigator: Daša Cerar, MD, Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
• Study Chair: Franc Strle, MD, Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Franc Strle, M.D., PhD, University Medical Centre Ljubljana
• ClinicalTrials.gov Identifier: NCT01518192
• Other Study ID Numbers: EM-DC
• First Posted: Jan 25, 2012
• Last Update Posted: Jan 25, 2012
• Last Verified: Dec 1, 2011

• Keywords provided by Franc Strle, M.D., PhD, University Medical Centre Ljubljana: erythema migrans; doxycycline; cefuroxime axetil; post-Lyme disease symptoms; background symptoms in general population
• Additional relevant MeSH terms: Lyme Disease; Erythema Chronicum Migrans; Glossitis, Benign Migratory; Erythema; Doxycycline; Cefuroxime; Cefuroxime axetil

Study Results

Participant Flow

Recruitment Details	Adult patients with typical erythema migrans, examined in the period from June to September 2006 at Lyme Disease Outpatient Clinic, University Medical Center Ljubljana, Slovenia
Pre-assignment Detail	113/398 patients were ineligible due to: receiving antibiotic with known anti-borrelial activity (73) multiple erythema migrans (16) history of Lyme disease (12) immunocompromising condition (4) serious adverse reaction to study drugs (3) pregnancy or lactation (4) erythema migrans accompanied by meningitis (1)

Arm/Group Title	Doxycycline	Cefuroxime Axetil	Controls
Arm/Group Description	Patients were assigned to receive a 15-day oral treatment with doxycycline 100 mg twice daily. At baseline and at 14 days, 2, 6, and 12 months thereafter, patients were interviewed and examined. At baseline, a skin biopsy specimen was cultured; this procedure was repeated 2-3 months later in patients with a positive culture.	Patients were assigned to receive a 15-day oral treatment with cefuroxime axetil 500 mg twice daily. At baseline and at 14 days, 2, 6, and 12 months thereafter, patients were interviewed and examined. At baseline, a skin biopsy specimen was cultured; this procedure was repeated 2-3 months later in patients with a positive culture.	patients' family members or friends without a history of Lyme disease
Period Title: Overall Study
STARTED	145	140	259
COMPLETED	116	114	224
NOT COMPLETED	29	26	35

Baseline Characteristics

Arm/Group Title	Doxycycline	Cefuroxime Axetil	Controls	Total
Arm/Group Description	Patients were assigned to receive a 15-day oral treatment with either doxycycline 100 mg or cefuroxime axetil 500 mg twice daily, by alternating treatment regimens each week. Evaluations: At baseline and at 14 days, 2, 6, and 12 months thereafter, patients were interviewed and examined. At baseline, a skin biopsy specimen was cultured as previously described; this procedure was repeated 2-3 months later in patients with a positive culture.	Patients were assigned to receive a 15-day oral treatment with either doxycycline 100 mg or cefuroxime axetil 500 mg twice daily, by alternating treatment regimens each week. Evaluations: At baseline and at 14 days, 2, 6, and 12 months thereafter, patients were interviewed and examined. At baseline, a skin biopsy specimen was cultured as previously described; this procedure was repeated 2-3 months later in patients with a positive culture.	To obtain a control group from the same geographical area, each patient was asked if he/she had a family member or friend who was within 5 years of his/her age and had no history of Lyme disease (two of the potential control subjects were excluded due to this reason), and was not pregnant, lactating or immunocompromised.	Total of all reporting groups
Overall Participants	145	140	259	544
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54 (14.6)	51.5 (14.9)	52	52.5 (14.9)
Sex: Female, Male (Count of Participants)
Female	84 57.9%	77 55%	125 48.3%	286.0 52.6%
Male	61 42.1%	63 45%	134 51.7%	258.0 47.4%
Region of Enrollment (participants) [Number]
Slovenia	145 100%	140 100%	259 100%	544.0 100%

Outcome Measures

1. Primary Outcome

Title	Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 14 Days
Description	Number of patients with objective manifestations of Lyme disease(persistence of erythema migrans or any of the extracutaneous-cardiac, nervous or skeletal-Lyme disease manifestations)and/or with post-Lyme disease symptoms in patients treated for solitary erythema migrans at 14 days post inclusion
Time Frame	at 14 days post inclusion

Outcome Measure Data

Analysis Population Description

All participants who followed the protocol were eligible for analysis

Arm/Group Title	Doxycycline	Cefuroxime Axetil
Arm/Group Description	doxycycline 100 mg twice daily for 15 days	cefuroxime axetil 500 mg twice daily for 15 days
Measure Participants	145	140
Number [participants]	30 20.7%	27 19.3%

2. Secondary Outcome

Title	New or Increased Symptoms Since Erythema Migrans in Patients and Controls at 6 Months.
Description	Comparison of the number patients and controls with new or increased symptoms since erythema migrans at 6 months.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

all participants who followed the protocol

Arm/Group Title	Patients	Controls
Arm/Group Description	patients with new or increased symptoms since erythema migrans at 6 months post inclusion	controls with new or increased symptoms since enrollment at 6 months post inclusion
Measure Participants	194	236
Number [participants]	9 6.2%	16 11.4%

3. Primary Outcome

Title	Adverse Events
Description	Number of patients reporting adverse events
Time Frame	at 14 days

Outcome Measure Data

Analysis Population Description

All participants who followed the protocol.

Arm/Group Title	Doxycycline	Cefuroxime Axetil
Arm/Group Description	doxycycline 100 mg twice daily for 15 days	cefuroxime axetil 500 mg twice daily for 15 days
Measure Participants	145	140
Number [participants]	22 15.2%	23 16.4%

4. Primary Outcome

Title	Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 2 Months
Description	Number of patients with objective Lyme disease manifestations and/or post-Lyme disease symptoms in patients treated for solitary erythema migrans at 2 months post inclusion
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

all participants who followed the protocol

Arm/Group Title	Doxycycline	Cefuroxime Axetil
Arm/Group Description	doxycycline 100 mg twice daily for 15 days	cefuroxime axetil 500 mg twice daily for 15 days
Measure Participants	136	134
Number [participants]	19 13.1%	14 10%

5. Primary Outcome

Title	Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 6months
Description	Number of patients with objective Lyme disease manifestations and/or post-Lyme disease symptoms in patients treated for solitary erythema migrans at 6 months post inclusion
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

all participants who followed the protocol

Arm/Group Title	Doxycycline	Cefuroximew Axetil
Arm/Group Description	doxycycline 100 mg twice daily for 15 days	cefuroxime axetil 500 mg twice daily for 15 days
Measure Participants	102	93
Number [participants]	5 3.4%	6 4.3%

6. Primary Outcome

Title	Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 12 Months
Description	Number of patients with objective Lyme disease manifestations and/or post-Lyme disease symptoms in patients treated for solitary erythema migrans at 12 months post inclusion
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

all participants who followed the protocol

Arm/Group Title	Doxycycline	Cefuroxime Axetil
Arm/Group Description	doxycycline 100 mg twice daily for 15 days	cefuroxime axetil 500 mg twice daily for 15 days
Measure Participants	116	114
Number [participants]	3 2.1%	4 2.9%

7. Secondary Outcome

Title	New or Increased Symptoms Since Erythema Migrans in Patients Controls at 12 Months.
Description	Comparison of the number of patients and controls with new or increased symptoms since erythema migrans at 12 months.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

all participants who followed the protocol

Arm/Group Title	Patients	Controls
Arm/Group Description	patients with new or increased symptoms since erythema migrans at 12 months post inclusion	controls with new or increased symptoms since erythema migrans at 12 months post inclusion
Measure Participants	230	224
Number [participants]	5 3.4%	21 15%

8. Secondary Outcome

Title	Selected Subjective Symptoms in Patients and Control Subjects
Description	Comparison of the number of patients and controls with selected 8 symptoms (fatigue, arthralgias, myalgias, headache, paresthesias, dizziness, irritability, or nausea) within the preceding week, irrespective of whether they were new or increased since erythema migrans.
Time Frame	Examination at 12 months

Outcome Measure Data

Analysis Population Description

all participants who followed the protocol

Arm/Group Title	Patients	Controls
Arm/Group Description	patients with selected subjective symptoms at 12 months post inclusion	controls with selected subjective symptoms at 12 months post inclusion
Measure Participants	230	224
Number [participants]	178 122.8%	181 129.3%

Adverse Events

Time Frame	2 months
Arm/Group Title	Doxycycline		Cefuroxime Axetil		Controls
Arm/Group Description	Patients were assigned to receive a 15-day oral treatment with doxycycline 100 mg twice daily. At baseline and at 14 days, 2, 6, and 12 months thereafter, patients were interviewed and examined. At baseline, a skin biopsy specimen was cultured; this procedure was repeated 2-3 months later in patients with a positive culture.		Patients were assigned to receive a 15-day oral treatment with cefuroxime axetil 500 mg twice daily. At baseline and at 14 days, 2, 6, and 12 months thereafter, patients were interviewed and examined. At baseline, a skin biopsy specimen was cultured; this procedure was repeated 2-3 months later in patients with a positive culture.		patients' family members or friends without a history of Lyme disease
All Cause Mortality
	Doxycycline		Cefuroxime Axetil		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Doxycycline		Cefuroxime Axetil		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/145 (0%)		0/140 (0%)		0/259 (0%)
Other (Not Including Serious) Adverse Events
	Doxycycline		Cefuroxime Axetil		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/145 (14.5%)		21/140 (15%)		0/259 (0%)
Gastrointestinal disorders
Gastrointestinal symptoms	20/145 (13.8%)	20	21/140 (15%)	21	0/259 (0%)	0
General disorders
Photosensitivity	1/145 (0.7%)	1	0/140 (0%)	0	0/259 (0%)	0

Limitations/Caveats

Medical explanation besides Lyme disease of the symptoms in patients was based on history and physical examination, therefore some other medical explanations might have been missed. With regard to controls this was even more likely.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.