Azithromycin vs. Placebo for the Clinical Outcome in Campylobacter concisus Diarrhoea in Adults: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial

Abstract

Campylobacter concisus has been associated with prolonged mild diarrhoea, but investigations regarding the efficacy of antimicrobial treatment have not been reported previously. We initiated a phase 3, single-centre, randomized, double-blinded, placebo-controlled study comparing the efficacy of 500 mg once-daily dose of azithromycin with a 500 mg once-daily dose of placebo for three days, for the treatment of C. concisus diarrhoea in adult patients with a follow-up period of ten days. If symptoms persisted at day ten, the patient was offered cross-over study treatment of three days and another ten-day follow-up period. The primary efficacy endpoint was the clinical response, defined as time to cessation of diarrhoea (<3 stools/day or reversal of accompanying symptoms). Our estimated sample size was 100 patients. We investigated a total of 10,036 diarrheic stool samples from 7,089 adult patients. Five-hundred and eighty-eight C. concisus positive patients were assessed for eligibility, of which 559 were excluded prior to randomization. The three main reasons for exclusion were duration of diarrhoea longer than 21 days (n = 124), previous antibiotic treatment (n = 113), and co-pathogens in stools (n = 87). Therefore, 24 patients completed the trial with either azithromycin (n = 12) or placebo (n = 12). Both groups presented symptoms of mild, prolonged diarrhoea with a mean duration of 18 days (95% CI: 16-19). One person in the azithromycin group and four from the placebo group chose to continue with crossover medication after the initial ten-day period. In the azithromycin group, there was a mean of seven days (95% CI: 5-9) to clinical cure and for the placebo group it was ten days (95% CI: 6-14) (OR-3 (95% CI: -7-1). We observed no differences in all examined outcomes between azithromycin treatment and placebo. However, due to unforeseen recruitment difficulties we did not reach our estimated sample size of 100 patients and statistical power to conclude on an effect of azithromycin treatment was not obtained.

Trial registration: Clinicaltrials.gov identifier: NCT01531218.

Fig 1. Flow-chart of subject inclusion.

Fig 2. Upon diagnosis of C. concisus in a stool sample the diarrheic patient was contacted by telephone, through their General Practitioner or physician (if hospitalized), by the principal-investigator (day 0).

If the patient still had diarrhoea the patient was offered to participate in the clinical trial. At day 1 the patient met the principal-investigator in an outpatient setting and was randomized to either azithromycin or placebo 500 mg once-daily dose for three days for the treatment of diarrhoea. Moreover, the patient was asked to deliver a blood sample (CRP and leukocytes) as well as a saliva sample. During the follow-up period of ten days the patient had to fill in a questionnaire on daily basis regarding diarrheic symptoms. At day ten the patient was contacted by telephone by the principal-investigator and if the patient stated ongoing diarrheic symptoms (no effect of study treatment; azithromycin or placebo) the patient was offered another ten-day study period and treatment with cross-over study medication (azithromycin or placebo), also double-blinded. Finally, the patient was asked to deliver a saliva sample as well as a stool sample for an ongoing diagnosis of C. concisus infection.