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.


Background: The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment.

Methods: In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease--either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi--to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed.

Results: Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin-hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, -2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, -1.6 to 3.3] in the clarithromycin-hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P<0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event occurred during the 12-week randomized phase.

Conclusions: In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment. (Funded by the Netherlands Organization for Health Research and Development ZonMw; PLEASE ClinicalTrials.gov number, NCT01207739.).

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / adverse effects
  • Antimalarials / administration & dosage*
  • Antimalarials / adverse effects
  • Clarithromycin / administration & dosage*
  • Double-Blind Method
  • Doxycycline / administration & dosage*
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hydroxychloroquine / administration & dosage*
  • Infusions, Intravenous
  • Intention to Treat Analysis
  • Lyme Disease / drug therapy*
  • Male
  • Middle Aged
  • Quality of Life


  • Anti-Bacterial Agents
  • Antimalarials
  • Hydroxychloroquine
  • Clarithromycin
  • Doxycycline

Associated data

  • ClinicalTrials.gov/NCT01207739