Erythema Migrans, Post-Lyme Disease Symptoms
Conditions
Keywords
erythema migrans, doxycycline, cefuroxime axetil, post-Lyme disease symptoms, background symptoms in general population
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.
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.
Interventions
DRUGdoxycycline
100 mg bid; 15 days
500 mg bid; 15 days
Sponsors
Slovenian Research Agency
University Medical Centre Ljubljana
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Adverse Events | at 14 days | Number of patients reporting adverse events |
| 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 |
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Slovenia
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 details
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)
Participants by arm
| Arm | Count |
|---|---|
| Doxycycline 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. | 145 |
| Cefuroxime Axetil 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. | 140 |
| Controls 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. | 259 |
| Total | 544 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 29 | 26 | 35 |
Baseline characteristics
| Characteristic | Cefuroxime Axetil | Doxycycline | Controls | Total |
|---|---|---|---|---|
| Age Continuous | 51.5 years FULL_RANGE 14.9 | 54 years FULL_RANGE 14.6 | 52 years | 52.5 years FULL_RANGE 14.9 |
| Region of Enrollment Slovenia | 140 participants | 145 participants | 259 participants | 544.0 participants |
| Sex: Female, Male Female | 77 Participants | 84 Participants | 125 Participants | 286.0 Participants |
| Sex: Female, Male Male | 63 Participants | 61 Participants | 134 Participants | 258.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 145 | 21 / 140 | 0 / 259 |
| serious Total, serious adverse events | 0 / 145 | 0 / 140 | 0 / 259 |
Outcome results
Primary
Adverse Events
Number of patients reporting adverse events
Time frame: at 14 days
Population: All participants who followed the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | Adverse Events | 22 participants |
| Cefuroxime Axetil | Adverse Events | 23 participants |
Primary
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
Time frame: 12 months
Population: all participants who followed the protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 12 Months | 3 participants |
| Cefuroxime Axetil | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 12 Months | 4 participants |
Primary
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
Time frame: at 14 days post inclusion
Population: All participants who followed the protocol were eligible for analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 14 Days | 30 participants |
| Cefuroxime Axetil | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 14 Days | 27 participants |
Primary
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
Time frame: 2 months
Population: all participants who followed the protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 2 Months | 19 participants |
| Cefuroxime Axetil | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 2 Months | 14 participants |
Primary
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
Time frame: 6 months
Population: all participants who followed the protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 6months | 5 participants |
| Cefuroxime Axetil | Objective Lyme Disease Manifestations and Post-Lyme Disease Symptoms at 6months | 6 participants |
Secondary
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.
Time frame: 6 months
Population: all participants who followed the protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | New or Increased Symptoms Since Erythema Migrans in Patients and Controls at 6 Months. | 9 participants |
| Cefuroxime Axetil | New or Increased Symptoms Since Erythema Migrans in Patients and Controls at 6 Months. | 16 participants |
Secondary
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.
Time frame: 12 months
Population: all participants who followed the protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | New or Increased Symptoms Since Erythema Migrans in Patients Controls at 12 Months. | 5 participants |
| Cefuroxime Axetil | New or Increased Symptoms Since Erythema Migrans in Patients Controls at 12 Months. | 21 participants |
Secondary
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.
Time frame: Examination at 12 months
Population: all participants who followed the protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxycycline | Selected Subjective Symptoms in Patients and Control Subjects | 178 participants |
| Cefuroxime Axetil | Selected Subjective Symptoms in Patients and Control Subjects | 181 participants |