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

• Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 14 Days [ Time Frame: at 14 days post inclusion ] [ Designated as safety issue: No ]
  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
  
  
• Adverse Events [ Time Frame: at 14 days ] [ Designated as safety issue: Yes ]
  Number of patients reporting adverse events
  
  
• Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 2 Months [ Time Frame: 2 months ] [ Designated as safety issue: No ]
  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
  
  
• Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 6months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  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
  
  
• Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  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
  
  

• New or Increased Symptoms Since Erythema Migrans in Patients and Controls at 6 Months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Comparison of the number patients and controls with new or increased symptoms since erythema migrans at 6 months.
  
  
• New or Increased Symptoms Since Erythema Migrans in Patients Controls at 12 Months. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Comparison of the number of patients and controls with new or increased symptoms since erythema migrans at 12 months.
  
  
• Selected Subjective Symptoms in Patients and Control Subjects [ Time Frame: Examination at 12 months ] [ Designated as safety issue: No ]
  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.
  
  

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.