Title: A randomised controlled trial to compare the clinical effectiveness and safety of gentamicin and ceftriaxone in the treatment of gonorrhoea
Funder: Department of Health (England)

Abstract: Design:A multi-centre parallel group blinded randomised controlled trial with equal allocation [1:1].Setting:The trial will take place in sexual health outpatient clinics in Birmingham Leeds London (3 centres) Manchester Sheffield and Southampton. Target Population:Men and women aged 16-70 with a diagnosis of genital pharyngeal or rectal gonorrhoea.Eligibility Criteria:Inclusion • men and women aged 16-70 • diagnosis of untreated genital pharyngeal or rectal gonorrhoea based on a positive gram stained smear on microscopy or positive nucleic acid amplification test (NAAT)• written informed consentExclusion• concurrent bacterial sexually transmitted infection (except for chlamydia)• known contra-indications or allergy to gentamicin ceftriaxone or azithromycin• pregnancy or breastfeeding• complicated gonorrhoea infections e.g. pelvic inflammatory disease epididymo-orchitis• need for concurrent additional antibiotic therapy• weight less than 40kg• received ceftriaxone or gentamicin within the preceding 28 daysHealth Technologies being assessed:Ceftriaxone is the current accepted therapy for gonorrhoea and recommended in the British Association for Sexual Health and HIV guidelines (www.bashh.org). Azithromycin is given with ceftriaxone to provide antimicrobial cover for Chlamydia trachomatis which occurs as a co-infection in 30% of patients with gonorrhoea and to also provide additional antimicrobial activity against N. gonorrhoeae. Azithromycin is not recommended as monotherapy for gonorrhoea due to the risk of resistance rapidly developing and poor tolerability of the higher dose required (2g).The health technology being assessed is gentamicin in comparison to ceftriaxone for the treatment of gonorrhoea. Participants will be randomised to receive either a single intramuscular injection of gentamicin (240mg) OR single intramuscular injection of ceftriaxone (500mg). Additionally both groups will receive a single oral dose of azithromycin (1g). Participants will be blinded to which therapy they receive. Measurement of costs and outcomes:The primary outcome measure is clearance of N. gonorrhoeae at the infected site confirmed by a negative nucleic acid amplification test two weeks post treatment (as recommended by the British Association for Sexual Health and HIV). Secondary outcomes are clinical resolution of symptoms frequency of adverse events and tolerability of therapy. Laboratory assessment of antibiotic resistance will be performed by measuring minimum inhibitory concentrations (MICs) to assess what concentration of antibiotic is required to completely inhibit bacterial growth. Isolate MICs will be measured using the serial agar dilution method.The economic analysis will compare the costs associated with the current standard treatment ceftriaxone with those of the proposed alternative treatment gentamicin in the treatment of gonorrhoea. Given that the primary objective of the trial is to determine non-inferiority of gentamicin the economic analysis will focus on establishing whether the use of gentamicin rather than ceftriaxone is cost-neutral in the treatment of gonorrhoea. Sample size:Based on an efficacy rate of 96% for the ceftriaxone regimen which is consistent with previous treatment trials a total sample size of 646 (323 in each group) will achieve 90% power to detect non-inferiority with lower confidence interval of 5% using a one-sided binomial test for non-inferiority. The significance level is 0.0250. To allow for a loss to follow up rate of up to 10% the study will recruit a total of 718 patients. A 5% lower confidence interval was acceptable to 17 of 24 sexual health patients whose opinion was sought and provides a realistic recruitment target.Project timetable including recruitment rate:Months -6-0: the first 6 months will be dedicated to the trial set-up including negotiating contracts producing all study documentation and materials developing randomisation and database systems confirmation of sites and gaining the regulatory and ethics approvals.Months 1-10: Gaining R&D approvals initiation and training of sites. Recruitment will start in month 3 and continue for 26 months. Recruitment will be 1-2 patients per week at each of the eight sites. The recruitment estimate is based on the current number of gonorrhoea diagnoses at study sites (3100 per annum) 80% of patients fulfilling eligibility criteria and 30% recruitment rate based on patient feedback. Attendance for routine clinical follow up is 85% and we estimate this will be increased to 90% in the trial based on the use of text/phone reminders and support of research staff.Month 11: feasibility assessment using data from 8 months of staged patient recruitment with 1 month for analysis and reporting. Feasibility will be assessed by reviewing the number of patients completing follow up against target:- >90%: continue trial- 65-90%: review recruitment and retention procedures to identify underlying problems and put in place strategies to address these. Review in 6 months- 35-65%: review recruitment and retention procedures to identify underlying problems and put in place strategies to address these. Review in 2 months and terminate trial if recruitment trajectory does not indicate that full recruitment will occur within scheduled recruitment period.- <35%: terminate the trialMonth 11-28: recruitment will continue Month 29-30: All participants will be followed up in the trial for between 2 and 4 weeks from entry into the trial Month 31-36: the final 6 months will be dedicated to data cleaning site closure data analysis writing up and dissemination of the resultsExpertise in TeamThe investigators have experience as chief and principle investigators in previous and ongoing clinical studies and trials including the evaluation of non-invasive testing for sexually transmitted infections therapies for genital warts and antibiotic treatment of pelvic inflammatory disease. The clinical trials unit has helped develop this application and will provide expertise in planning obtaining relevant approvals recruitment monitoring data management analysis and reporting. The team also includes expertise in laboratory testing for sexually transmitted bacterial infections and the performance of economic evaluations for sexually transmitted infections.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION