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

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.

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.

Study Overview

• Status: Completed
• Conditions: Erythema Migrans; Post-Lyme Disease Symptoms
• Intervention / Treatment: Drug: doxycycline; Drug: cefuroxime axetil

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.

   1. We assumed that the outcomes in the two treatment groups will be comparable and that the patients could be combined for further analysis.
   2. 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.
   3. 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 Type: Interventional
• Enrollment (Actual): 544
• Phase: Phase 4

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Institute of Microbiology and Immunology, Medical Faculty, University of Ljubljana
  • Ljubljana, Slovenia, 1525
    • Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 14 Days	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	at 14 days post inclusion
Adverse Events	Number of patients reporting adverse events	at 14 days
Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 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	2 months
Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 6months	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	6 months
Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 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	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New or Increased Symptoms Since Erythema Migrans in Patients and Controls at 6 Months.	Comparison of the number patients and controls with new or increased symptoms since erythema migrans at 6 months.	6 months
New or Increased Symptoms Since Erythema Migrans in Patients Controls at 12 Months.	Comparison of the number of patients and controls with new or increased symptoms since erythema migrans at 12 months.	12 months
Selected Subjective Symptoms in Patients and Control Subjects	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.	Examination at 12 months

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Collaborators: 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 record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: June 28, 2010
• First Submitted That Met QC Criteria: December 18, 2011
• First Posted (Estimate): January 25, 2012

Study Record Updates

• Last Update Posted (Estimate): January 25, 2012
• Last Update Submitted That Met QC Criteria: December 18, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: doxycycline; erythema migrans; cefuroxime axetil; post-Lyme disease symptoms; background symptoms in general population
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Stomatognathic Diseases; Mouth Diseases; Vector Borne Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Skin Diseases, Infectious; Skin Manifestations; Skin Diseases, Bacterial; Tick-Borne Diseases; Borrelia Infections; Spirochaetales Infections; Tongue Diseases; Glossitis; Erythema; Lyme Disease; Erythema Chronicum Migrans; Glossitis, Benign Migratory; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline; Cefuroxime; Cefuroxime axetil
• Other Study ID Numbers: EM-DC