Gentamicin as an alternative to ceftriaxone in the treatment of gonorrhoea: the G-TOG non-inferiority RCT

Antibiotic treatment and resistance

Neisseria gonorrhoeae readily develops resistance to antibiotic regimens. Globally, there are now high levels of resistance against penicillins, sulphonamides, tetracyclines and quinolones, all of which are no longer recommended for routine use. 6 A real possibility of multidrug-resistant gonorrhoea and the lack of alternative treatment options has been highlighted. 7 Guidance from the British Association for Sexual Health and HIV (BASHH) recommends treating gonorrhoea with ceftriaxone (given with adjunctive azithromycin) and this currently cures > 95% of patients. 8 Recent surveillance data show a reduction in sensitivity to ceftriaxone with an upwards drift in the minimum inhibitory concentration (MIC); that is, the proportion of cases that remain highly sensitive to ceftriaxone has decreased over time. 3 Sporadic treatment failure of cephalosporins has been reported from a number of countries9–14 and a patient who failed dual therapy with ceftriaxone plus azithromycin has recently been documented in the UK. 15 The same reduction in antibiotic susceptibility was followed by widespread treatment failure within a few years for other antimicrobials (penicillin, tetracyclines and quinolones) used to treat gonorrhoea. An outbreak of azithromycin-resistant gonorrhoea has been reported in England since November 2014, further highlighting the need to identify other effective treatment regimens. 16 Despite this recent outbreak, azithromycin resistance remains uncommon in England and, overall, levels of azithromycin resistance have probably not increased over the past 3 years since the outbreak was first identified, although a change in laboratory procedures in 2015 makes direct comparisons over time difficult. Current national and international treatment guidelines continue to recommend dual antibiotic therapy, including azithromycin, for the treatment of gonorrhoea.

Primary objective

The primary objective was to determine whether or not gentamicin is an acceptable alternative to ceftriaxone in the treatment of gonorrhoea. This was addressed by determining whether or not the rate of microbiological clearance of N. gonorrhoeae in participants treated with gentamicin was non-inferior to the rate of clearance in participants treated with ceftriaxone.

Secondary objectives

The secondary objectives were to determine:

• whether or not a single intramuscular (i.m.) dose of gentamicin is safe and well tolerated

• whether or not a single i.m. dose of gentamicin is cost-effective for the NHS in comparison to ceftriaxone for the treatment of gonorrhoea

• the relationship between clinical effectiveness and the laboratory measurement of antibiotic effectiveness (the MIC required to inhibit growth of N. gonorrhoeae).

Recruiting centres

The trial was conducted in 14 sexual health clinics in England. Seven sites were originally planned to meet the recruitment target and a further seven sites were added during the trial. Sites were opened between September 2014 and February 2016, with participants being recruited from October 2014 to November 2016.

Identification of participants

Patients with a provisional (microscopy identification of Gram-negative cocci on a Gram stain of genital secretions) or confirmed (indicated by a positive NAAT) diagnosis of gonorrhoea were screened for the trial and approached by a member of the site research team to determine whether or not they were interested in participating. They were provided with a patient information sheet (PIS) and a verbal explanation of the trial and were given the opportunity to ask any questions that they might have. In addition, trial posters were on display in relevant areas of the clinic. These helped to introduce the trial and, if patients were interested, they could ask clinic staff for additional details. All participants gave written informed consent.

To avoid delaying treatment for a transmissible infection with serious sequelae, patients with either a provisional (on microscopy) or confirmed (on NAAT) diagnosis of untreated gonorrhoea were invited to participate and provide written consent at the same clinic visit.

Eligibility criteria

Patients were eligible for inclusion if they were aged 16–70 years and had a positive diagnosis in the previous 4 weeks of uncomplicated, untreated (i.e. they had not received any antibiotic in the previous 28 days that could have treated gonorrhoea, either partially or completely) genital, pharyngeal and/or rectal gonorrhoea. The exclusion criteria were having known concurrent STI(s) (excluding chlamydia); bacterial vaginosis and/or Trichomonas vaginalis infection; having contraindications or an allergy to gentamicin, ceftriaxone, azithromycin or lidocaine; being pregnant or breastfeeding; having complicated gonorrhoeal infection, for example pelvic inflammatory disease or epididymo-orchitis; weighing < 40 kg; and having used ceftriaxone, gentamicin or azithromycin in the preceding 28 days.

Assessment of feasibility

At 9 months after the start of recruitment, accrual was reviewed by the Trial Steering Committee (TSC) to determine whether or not the following feasibility criteria had been met for progression:

• Recruitment at 80% of target. If this was not achieved, the Trial Management Group (TMG) would implement effective and realistic strategies to increase recruitment and retention for the study to proceed.

• Percentage of completed follow-ups of > 50%.

If the study did proceed, an additional assessment of recruitment would be carried out.

On 22 June 2015, the trial received approval for progression, having met the feasibility criteria. At 9 months, 88% of target recruitment had been achieved, with follow-up of 74%. Recruitment was assessed regularly at monthly TMG meetings and at further TSC meetings.

Baseline visit

Demographic information and details of a participant’s sexual history and symptoms were collected during the baseline visit. Symptomatic and asymptomatic individuals were eligible for inclusion in the trial. For symptomatic participants, the baseline visit usually took place on the same day as diagnosis, which was based on the microscopy appearances of Gram-stained genital discharge. Asymptomatic participants were recalled to the clinic for treatment after a positive test result for gonorrhoea had been received; once they had given consent to participate in the trial, this second visit (the first following diagnosis) was considered as the baseline visit.

Each participant had swabs taken for NAAT and culture testing to determine the site(s) of infection. A urine sample could be taken in place of a NAAT urethral sample for men. A full sampling profile was required, taking account of a participant’s sex and sexual orientation, to reflect potential sites of exposure. This allowed the efficacy of treatment to be assessed at each infected site. When swabs or urine specimens were not part of routine clinical care or had not been taken already during the baseline clinic visit (e.g. symptomatic participants who had only swabs taken for routine care on the same day prior to consent), additional swabs were taken to complete the full sampling profile, as defined in Table 1.

All specimens collected were sent to local site laboratories for the identification of N. gonorrhoeae and results were reported back to the clinics in the usual manner. The results from the baseline visit informed subsequent testing of previously infected sites at the follow-up visit.

A number of licensed NAATs are available to detect N. gonorrhoeae, including the Hologic Aptima Combo 2^® (AC2) assay (Hologic, Inc., Marlborough, MA, USA). In centres where the AC2 assay was not used locally for testing, an additional set of swabs (or urine) was taken for the AC2 assay to be performed at Public Health England (PHE). These results were not reported back to the clinic but were reported in batches to the Nottingham Clinical Trials Unit (NCTU). The AC2 assay was, therefore, considered as the reference standard for the trial and the AC2 NAAT result was used as the primary outcome measure. The management of participants was based only on the results of local testing.

Additional blood samples were taken for future measurement of the pre-treatment immune response to gonococcal infection and for measurement of creatinine level.

Follow-up

Participants were asked to return to the clinic 2 weeks post treatment (which was also 2 weeks post randomisation) for a follow-up visit. Participants were reminded of their appointment using the individual clinics’ existing recall procedures, such as Short Message Service (SMS) and telephone reminders. During the follow-up visit, swabs (or urine) from previously infected sites were taken for NAAT and culture testing to assess the clearance of N. gonorrhoeae. A blood sample was taken to measure the post-treatment immune response and creatinine level. Each participant remained in the trial until this follow-up visit was completed. Participants were considered lost to follow-up if they had not returned for their follow-up appointment within 60 days of the baseline visit; this time point was chosen pragmatically to balance flexibility over when participants could return to the clinic against the potential increased risk of reinfection over a more prolonged time period. The recruitment flow diagram is shown in Figure 1.

FIGURE 1.

The G-TOG trial flow diagram. VAS, visual analogue scale. Reproduced from Brittain et al. 28 © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reproduced from Brittain et al. 28 © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

If follow-up test results at 2 weeks post treatment showed that a participant had gonorrhoea, he or she was offered further investigation and treatment in accordance with local clinic guidelines. This treatment was not considered to be part of the trial.

Randomisation

After providing consent, and after confirmation of eligibility, participants were registered in the trial using a secure web-based registration and randomisation system. Participants were randomised to receive either gentamicin or ceftriaxone by a member of the research team. Staff who performed randomisation had no role in administering trial treatments and remained blinded to the treatment allocation, thereby minimising the risk of selection bias through prediction of the allocation sequence.

Randomisation was based on a computer-generated pseudorandom code using permuted blocks of randomly varying size. The code was created by NCTU in accordance with standard operating procedures and held on a secure server. Randomisation was carried out in a 1 : 1 ratio, stratified by recruiting centre.

The web-based system generated a blinded prescription for G-TOG trial treatment, which required signature by the prescribing doctor. Site staff recorded only ‘G-TOG trial drug’ in the participants’ medical notes. The signed prescription was then passed to an injecting nurse who determined the actual treatment that a participant was randomised to and then administered the injection. The injecting nurse was the only member of the research team who was unblinded to treatment allocation.

Interventions

Participants were randomised to receive either 240 mg of gentamicin (intervention) or 500 mg of ceftriaxone (current standard treatment). Both treatments were administered from routine clinic stock as a single i.m. injection. Any European Union-licensed brands of gentamicin and ceftriaxone were permitted to be used.

The 240 mg of gentamicin was made up from three 2-ml (80-mg) vials, in accordance with the Summary of Product Characteristics (SmPC), and administered as a single 6-ml i.m. injection. For the ceftriaxone arm, 500 mg in a powder formulation was dissolved in 1% lidocaine, in accordance with the SmPC, and administered as a single 2-ml i.m. injection. In addition, all participants received a single oral dose of 1 g of azithromycin, which is currently given as standard treatment alongside ceftriaxone.

In previous trials, a 240-mg dose of gentamicin was most commonly used and the use of different doses has not demonstrated a significant dose–response effect across studies. 23,24 In vitro antimicrobial susceptibility testing also suggests that isolates remain sensitive to gentamicin. 27,29 The dose of ceftriaxone was chosen to be consistent with current UK gonorrhoea treatment guidelines. 30

Blinding

Nurses administering trial treatments were required to know each participant’s allocation as they prepared the drug for injection. Details of the nurses administering treatment at each centre were obtained during the trial set-up stage and access to the online randomisation system and treatment allocation was granted depending on the delegated role. All other staff at the recruiting centres remained blinded to treatment allocation.

Preparation and administration of trial treatments was undertaken in a separate area, away from the blinded research team and participants. In addition, nurses administering treatments were given guidance to provide standardised information to participants at the time of injection, which was the same regardless of treatment allocation, to prevent inadvertent unblinding. This two-step approach maintained blinding for members of the research team who were subsequently involved in the assessment of participants.

To ensure that assessment of outcome was not influenced by knowledge of the allocated treatment, nurses administering trial treatments were not permitted any role in the collection of outcome data.

End of the trial

Participants left the trial when they completed their 2-week follow-up visit.

Failure to receive the allocated treatment and withdrawal from follow-up were reported and reasons for withdrawal (if given) were documented. If a participant did not receive his or her allocated treatment but agreed to remain in the trial, outcome data collection continued in accordance with the protocol. 28 Participants were informed at the start of the trial that data collected up to the point of withdrawal would be retained and used in the final analysis.

Primary outcome

The primary outcome measure was clearance of N. gonorrhoeae at all infected sites, confirmed by a negative NAAT, at 2 weeks post treatment (as recommended by BASHH).

The NAAT is an automated laboratory test and, therefore, not subject to bias through knowledge of treatment allocation. Different licensed NAAT assays for the diagnosis of gonorrhoea are available from different manufacturers [e.g. AC2 NAAT; Becton, Dickinson and Company (BD) NAAT (BD, Franklin Lakes, NJ, USA); Cobas^® NAAT (Roche Diagnostics, Basel, Switzerland)]. Sexual health clinics participating in the G-TOG trial used either the AC2 NAAT or the BD NAAT; therefore, in order to ensure consistency and standardisation in diagnostic and follow-up tests, additional samples were taken from participants recruited at centres where the AC2 NAAT method was not used by the local laboratory. Testing of these additional samples by AC2 NAAT was performed by PHE. The results from the AC2 NAAT were used to assess clearance for the primary end point.

Secondary outcomes

The secondary outcomes were:

• clinical resolution of symptoms

• frequency of nausea/vomiting, hearing loss, dizziness and rash

• frequency of any other AEs reported by participants

• tolerability of injection as assessed by participants on a visual analogue scale (VAS)

• cost-effectiveness.

The relationship between clearance of N. gonorrhoeae and in vitro measurement of antibiotic MIC to inhibit N. gonorrhoeae growth was also assessed.

Effectiveness, tolerability and safety were assessed at the follow-up visit 2 weeks post treatment.

Protocol deviations

A protocol deviation was defined as an unanticipated or unintentional divergence or departure from the expected conduct of the trial, inconsistent with the protocol, consent document or other trial procedures. Protocol deviations were recorded by site staff. Protocol violations were defined as deviations that affected eligibility or outcome measures, as assessed by the TMG.

Trial oversight

A number of oversight groups monitored ongoing progress for the duration of the trial and also contributed to interpretation of findings. Roles and responsibilities were defined including the use of charters for the independent TSC and Data Monitoring Committee (DMC).

Risk assessment and safety monitoring

A risk assessment was conducted as part of protocol development; there was regular monitoring throughout the trial for new risks. The main risks to the trial were loss to follow-up in a young, sometimes transient, population and poor data collection owing to the very short time frame for trial participation of just 2 weeks. However, recruitment sites were well supported by NCTU in obtaining high-quality data and regular central monitoring checks were performed to identify any issues with data collection that could be followed up at individual site level. Data on AEs and SAEs were collected during the trial. As agreed by the sponsor, the Research Ethics Committee, the DMC and the TSC, the DMC was provided with a list of all AEs and SAEs, including any deaths, for review at each meeting.

Patient and public involvement

Twenty-four patients from three sexual health clinics (Birmingham, London and Manchester) commented on the trial design in June and July 2012. A further 25 patients in Birmingham reviewed a PIS for the trial in April 2013. Input was requested on the trial concept and design, whether or not patients with gonorrhoea would be likely to consent to take part in the proposed trial design and the clarity of the patient information provided. Patients’ main concerns following the initial consultation exercise were around the amount of time that participation would involve and whether or not the therapies being offered were safe. In response, the trial procedures were reviewed to optimise patient flow and the draft PIS was revised to expand the information on safety and AEs. Based on the revised patient information, 24 out of 25 patients in the second consultation exercise would have been happy to consider participation in the trial.

Two members of the public joined the TSC and provided input into the design and management of the trial. Specifically, they were invited to comment on all aspects of the trial design and conduct and to contribute to the design and review of documentation given to trial participants to ensure understanding and acceptability. This greatly benefited the research by helping to ensure that our material was acceptable and comprehensible, thus increasing our response rate and reducing the number of missing data. The public members of the TSC commented on the best way of sharing trial findings with the public and contributed as part of the research team to the interpretation of the trial findings. At each stage of the trial, the G-TOG trial team aimed to provide the PPI representatives with clear information in lay terms to allow them to participate in discussing the research, but not to bias their perspective towards that of the researchers/clinicians.

A lay summary of the trial findings, informed by our public members, will also be disseminated to participants who consented to receive the results.

Payments to participants

Participants were not paid to participate in the trial; however, at the end of their follow-up visit they were provided with a £15 voucher to compensate for the additional time associated with taking part in the trial.

Sample size

Based on a clearance rate of 96% for the ceftriaxone regimen, consistent with previous trials, it was estimated that a total sample size of 646 participants for analysis (323 in each group) would achieve 90% power at the 2.5% one-sided significance level to detect non-inferiority with a lower 95% confidence interval (CI) for the absolute risk difference of 5%. It was planned to randomise a total of 720 participants to allow for a loss to follow-up rate of ≤ 10%.

Analysis plan

A statistical analysis plan (SAP) was finalised before database lock and release of treatment codes to the statistician. All summaries and statistical analyses were conducted using Stata® version 13.1 (StataCorp LP, College Station, TX, USA).

Analysis data sets

Data derivations

Missing data

The primary analysis was performed on the ITT data set without imputation of missing data for clearance of N. gonorrhoeae at 2 weeks. When the baseline tests did not show any sites positive for N. gonorrhoeae or the baseline test results were missing, the results of positive pre-trial tests were used.

Sensitivity analyses of the primary outcome were performed on the ITT data set to check the robustness of the conclusions to missing outcome data. The pattern of missing data was explored overall and in each of the two treatment groups. When clearance at 2 weeks post treatment using the AC2 NAAT was missing, but there were data for the BD NAAT, the result of the BD NAAT was used for a sensitivity analysis.

Three imputation methods were applied when data for the clearance of N. gonorrhoeae (both the AC2 and the BD NAAT) at 2 weeks post treatment were missing:

1. multiple imputation using chained equations

2. assume that all missing data show clearance of N. gonorrhoeae

3. assume that all missing data show non-clearance of N. gonorrhoeae.

Table 2 outlines possible scenarios when a value for the primary outcome could be derived. Scenarios not included in this table resulted in missing primary outcome data.

Analysis of the primary outcome

The analysis of the primary outcome was modified from that specified in the protocol. This amendment was made before the database was locked and the treatment codes revealed.

The initial planned method of analysis was to use a general linear model for binary outcome adjusted by clinic site, with the primary efficacy parameter comparing gentamicin with ceftriaxone being the risk difference in the proportion of participants clear of infection at 2 weeks’ follow-up, along with the 95% CI. However, during the trial, additional centres were introduced, some of which could recruit only small numbers of participants. This meant that there was a chance that some centres would have no participants who had ‘failed’ treatment, making the inclusion of centre as a fixed effect inappropriate. Therefore, the primary approach to the between-group comparative analyses was modified to use generalised estimating equations (GEEs) for binary outcomes adjusted by recruiting centre as a random effect with robust standard errors. The GEE model used an identity link function to enable estimation of adjusted risk difference. The primary efficacy parameter comparing gentamicin with ceftriaxone was the risk difference in the proportion of participants clear of infection at all sites, determined by the AC2 NAAT at the 2-week follow-up, along with the 95% CI. Gentamicin was to be regarded as non-inferior if the lower 95% confidence limit for the risk difference (gentamicin group vs. ceftriaxone group) in confirmed clearance was ≥ –5 percentage points (i.e. closer to zero).

Sensitivity analyses for the primary outcome

In addition to the sensitivity analyses outlined in Missing data, we also investigated the treatment efficacy by performing the following sensitivity analyses:

• exclude participants who did not have any positive samples at baseline

• exclude participants who did not receive the allocated treatment

• exclude participants who did not have full baseline samples taken, that is, females and MSM should have had genital, rectal and pharyngeal samples taken and heterosexual men should have had genital samples taken.

It was planned that there would be an additional analysis further adjusting for baseline variables with a marked imbalance between treatment groups identified after the treatment codes were revealed. However, there were no marked imbalances considered likely to influence the results of the trial; therefore, this additional analysis was not appropriate.

Secondary outcomes

Data sets

The ITT data set was defined as ‘participants as randomised’, regardless of adherence to the allocated group and without imputation for missing data. There were 720 participants included in the ITT data set: 362 who were randomised to ceftriaxone and 358 who were randomised to gentamicin. All baseline summaries and summaries/analyses of efficacy data are based on this data set. Follow-up data were available for 624 participants: 322 in the ceftriaxone group and 302 in the gentamicin group.

The safety data set was defined as ‘all participants according to the treatment that they actually received’. It comprised 706 participants: 358 who received ceftriaxone and 348 who received gentamicin. The 14 participants who had not received ceftriaxone or gentamicin were excluded from this data set but the participants who did not receive azithromycin remained in this data set as they had received either ceftriaxone or gentamicin. This data set was used to summarise safety data at follow-up. Follow-up data were available for 618 participants: 320 who received ceftriaxone and 298 who received gentamicin.

Sensitivity analyses for the primary outcome

Sensitivity analyses for the primary outcome are presented in Table 16 and Figure 5. Although the adjusted risk differences varied between the different sensitivity analyses, all analyses performed were supportive of the primary analysis, with the lower 95% confidence limits of the 95% CIs all being < –5%.

FIGURE 5.

Sensitivity analyses for clearance of N. gonorrhoeae at 2 weeks post randomisation. The non-inferiority margin is –0.05.

Clearance of N. gonorrhoeae by infection site

Of the participants who had a genital infection, 98% in the ceftriaxone group and 94% in the gentamicin group were cleared at their follow-up visit (Table 17 and Figure 6). The adjusted risk difference was –4.4% (95% CI –8.7% to 0%). A greater proportion of participants with pharyngeal infection receiving ceftriaxone had clearance at their follow-up visit (96%) than participants receiving gentamicin (80%). The adjusted risk difference was –15.3% (95% CI –24.0% to –6.5%). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group showed clearance (98%) than patients in the gentamicin group (90%) (adjusted risk difference –7.8%, 95% CI –13.6% to –2.0%). Clearance at genital site by sex is also provided in Appendix 3, Table 34.

FIGURE 6.

Clearance of N. gonorrhoeae by infection site. The non-inferiority margin is –0.05.

Clinical resolution of symptoms

There was no evidence of any difference between the treatment groups in terms of resolution of symptoms (Table 18). The 95% CIs for the adjusted risk differences are wide for those cases when the number of participants experiencing some symptoms at baseline was small. For all 12 participants who had post-coital bleeding, this symptom had resolved at 2 weeks post randomisation. These data are therefore not included in Table 18. The complete summary data of symptoms at baseline and follow-up are included in Appendix 3, Table 35.

Frequency of nausea, vomiting, reduction in hearing, dizziness and rash

The frequencies of the expected side effects of gentamicin and ceftriaxone were summarised based on the safety data set. This data set excluded the 14 participants who did not receive either ceftriaxone or gentamicin. There were 358 participants who received ceftriaxone and 348 participants who received gentamicin included in the safety data set. Of these participants, follow-up data were available for 618 participants: 320 who had received ceftriaxone and 298 who had received gentamicin.

Other adverse events

Table 20 shows that the percentage of participants reporting other AEs at their follow-up visit was similar in both treatment groups: 15% (48/320) in the ceftriaxone group and 13% (38/298) in the gentamicin group, with the majority of AEs being mild. The most frequent class of AEs reported was gastrointestinal disorders: 14 participants reported these in the ceftriaxone group (4%) and 22 participants reported these in the gentamicin group (7%). The majority of these gastrointestinal disorders consisted of diarrhoea. Nervous system disorders were reported by 10 participants in the ceftriaxone group and three participants in the gentamicin group. The events that coded to nervous system disorders were headaches (six in the ceftriaxone group and one in the gentamicin group), dizziness (one in the ceftriaxone group and one in the gentamicin group), migraine (one in the ceftriaxone group), lethargy (one in the ceftriaxone group and one in the gentamicin group) and Bell’s palsy (one in the ceftriaxone group).

Five per cent of AEs in the ceftriaxone group and 6% in the gentamicin group were reported to be related to the trial medication. Three AEs (only one of which was related to the trial medication) were reported to be severe: one in the ceftriaxone group and two in the gentamicin group. These were ‘diarrhoea’, ‘grade 4 dizziness’ and ‘sickness’. Of these, the grade 4 dizziness was also classified as a SAE. All were resolved by the follow-up visit.

The SAE was grade 4 dizziness in a participant in the ceftriaxone group, which had occurred 4 days after randomisation. It was considered to be unrelated to the trial medication and was resolved before the follow-up visit.

A full list of AEs is provided in Appendix 3.

Creatinine level and estimated glomerular filtration rate

The percentage of participants who had an increase in creatinine level of > 30% was similar in both treatment groups: 3% (10/358) in the ceftriaxone group and 3% (9/348) in the gentamicin group (Table 21). The follow-up creatinine value for 9% (28/304) of participants in the ceftriaxone group and 13% (38/289) of participants in the gentamicin group exceeded the upper limit of normal, as defined by their local laboratory. Changes in eGFR between baseline and follow-up were similar in both arms (see Table 21).

TABLE 21 - Summary of creatinine levels and eGFR pre and post treatment

SD, standard deviation.

Defined as a change of > 30% from baseline.

There are specific lower and upper limits of normal values for each individual local site.

Creatinine levels and eGFR	Treatment group
	Ceftriaxone (N = 358)	Gentamicin (N = 348)
Creatinine level
At baseline (µmol/l)
Mean (SD)	78.7 (15.4)	78.3 (15.8)
N	341	329
At 2 weeks post treatment (µmol/l)
Mean (SD)	79.7 (14.4)	80.2 (15.6)
N	304	289
Change in creatinine level, n (%)
Number of participants who met clinically important change from baseline to 2 weeks post treatmenta	10 (3)	9 (3)
Number of participants who exceeded upper limit of normal value at 2 weeks post treatmentb	27 (7)	38 (11)
eGFR (ml/minute/1.73m2)
At baseline, mean (SD)	110.6 (18.2)	111.5 (17.7)
At 2 weeks post treatment, mean (SD)	109.2 (17.4)	108.7 (17.9)
Change in eGFR at 2 weeks post treatment, median (IQR)	–1.3 (–6.7 to 4.3)	–1.4 (–6.9 to 3.7)

The shift plots in Figures 7 and 8 demonstrate the shifts in creatinine level from baseline to visit 2. AEs relating to creatinine were reported for seven participants: five who had received ceftriaxone and two who had received gentamicin. All were mild and five out of the seven AEs were not thought to be related to trial medication. The grid lines represent the lowest of the lower bounds and highest of the upper bounds of normality between all of the local laboratories. The diagonal line represents the line of unity (no change).

FIGURE 7.

Shift plot of pre- and post-treatment creatinine levels in males.

FIGURE 8.

Shift plot of pre- and post-treatment creatinine levels in females.

Tolerability of injection

Minimum inhibitory concentrations

Gentamicin

Figure 9 shows the MIC distribution for gentamicin for the 367 participants for whom isolate data were available.

FIGURE 9.

Gentamicin overall MIC distribution (mg/l) at baseline (all participants with sample data).

Figure 10 shows the gentamicin MICs of isolates from participants who received gentamicin and achieved microbiological clearance (as defined by a negative AC2 NAAT at all previously infected sites, 2 weeks after treatment). Data were available for 149 participants. The proportion who had clearance of N. gonorrhoeae at all sites was 90%. All isolates from non-responders had a MIC of 4 mg/l.

FIGURE 10.

Distribution of gentamicin MIC (mg/l) for participants who received gentamicin, by clearance at 2 weeks post treatment.

Ceftriaxone

Figure 11 shows the MIC distribution for ceftriaxone for the 364 participants for whom isolate data were available. Fifty-nine participants (16%) harboured isolates with MIC values of ≤ 0.002 mg/l.

FIGURE 11.

Ceftriaxone overall MIC distribution (mg/l) at baseline (all participants with sample data).

Figure 12 shows the ceftriaxone MICs of isolates from participants who received ceftriaxone and achieved microbiological clearance (as defined by a negative AC2 NAAT at all previously infected sites, 2 weeks after treatment). Data were available for 170 participants. The proportion of these participants who had clearance of N. gonorrhoeae at all sites was 96%. The six non-responders had MICs ranging from ≤ 0.002 to 0.008 mg/l.

FIGURE 12.

Distribution of ceftriaxone MIC (mg/l) for participants who received ceftriaxone, by clearance at 2 weeks post treatment.

Azithromycin

Figure 13 shows the MIC distribution for azithromycin for the 357 participants for whom isolate data were available. The distribution of MICs ranged from 0.032 to 4 mg/l.

FIGURE 13.

Azithromycin overall MIC distribution (mg/l) at baseline (all participants with sample data).

Figure 14 shows the azithromycin MICs of isolates from participants who received azithromycin and achieved microbiological clearance (as defined by a negative AC2 NAAT at all previously infected sites, 2 weeks after treatment). Data were available for 305 participants. The proportion of these participants who had clearance of N. gonorrhoeae at all sites was 93%. The two non-respondents had MICs ranging from 0.064 to 1 mg/l.

FIGURE 14.

Distribution of azithromycin MIC (mg/l) for all participants, by clearance at 2 weeks post treatment.

Further plots showing the MIC distribution by infection site are available in Appendix 3.

Medications taken during the trial

A similar proportion of participants in both treatment arms took additional antibiotics in the period from randomisation to follow-up (Table 23).

Sexual behaviour and condom use during the trial

Tables 24 and 25 show the sexual behaviour of males and females, respectively, after receiving their trial medication. Out of 257 males in the ceftriaxone group and 251 males in the gentamicin group, 98 (38%) and 88 (35%), respectively, reported having had sex between receiving their randomised treatment and the 2-week follow-up. Of these, 40 males out of 98 (41%) and 37 males out of 88 (42%), respectively, never used a condom. Out of 65 females in the ceftriaxone group and 50 females in the gentamicin group, 20 (31%) and 16 (32%), respectively, reported having had sex between receiving trial treatment and the 2-week follow-up visit. Of these, 7 females out of 20 (35%) and 10 females out of 16 (63%) reported never using a condom. The risk of reinfection as a result of having sex in the follow-up period and the failure to use condoms in this period was therefore deemed similar in the two treatment groups.

Protocol deviations

Protocol deviations were reported in 121 out of 362 (33%) participants receiving ceftriaxone and 124 out of 358 (35%) participants receiving gentamicin; the majority of deviations were considered minor. There were only two major deviation categories: not receiving treatment according to randomisation and not fulfilling the eligibility criteria. Fourteen participants did not receive treatment according to randomisation and 20 deviations from the eligibility criteria were reported for 18 participants. These included participants being found to have contraindications to trial medication and having a disallowed concomitant disease. A list of the protocol deviations recorded on the deviation log can be found in Appendix 3.

Overview

A cost-effectiveness analysis (CEA) was undertaken from the perspective of the NHS. The main outcome considered was the clearance of gonorrhoea, as this was the primary outcome of the trial. A health-care perspective was deemed to be the most relevant as the RCT is concerned with the non-inferiority of gentamicin in the treatment of gonorrhoea; hence, the costs to the NHS associated with the two treatments need to be assessed. A within-trial economic evaluation was undertaken that reflected the objectives of the trial and the short follow-up period.

A simple decision tree was deemed to be the most suitable way of presenting the alternative patient pathways and synthesising the available data. The model was necessary in order to analyse alternative patient pathways, particularly in the sensitivity analyses, and collate available data. A decision-analytic model involves using mathematical relationships to set out the consequences that are associated with the different policy options under consideration. 38 This allows the costs and outcomes for each option to be evaluated, taking into account the probability of the consequences. Data on resource use and costs were collected prospectively via trial reporting mechanisms and additional data were sourced from the literature.

Model structure

A decision tree model was developed using TreeAge Pro 2016 (TreeAge Software, Inc., Williamstown, MA, USA). The structure was informed by the trial objectives and patient pathways were indicated by the clinical data. As shown in Figure 15, participants entered the model at the point of randomisation to receive the alternative treatment (gentamicin) or the standard treatment (ceftriaxone). Following the initial course of antibiotic treatment, participants either received additional NHS care [e.g. general practitioner (GP) visit] or did not access care. At 2 weeks post treatment, participants either were cleared of N. gonorrhoeae at all sites, confirmed by a negative NAAT, or were not cleared and required further treatment.

FIGURE 15.

Model structure.

If clearance of N. gonorrhoeae at all sites was not confirmed (at 2 weeks post treatment), participants were treated with a further course of antibiotics. For the purposes of the economic evaluation, the base-case analysis followed current guidelines and it was assumed that all participants who were not cleared of infection would be treated with a course of ceftriaxone. However, in the sensitivity analyses, alternative scenarios were also explored, including the use of alternative antibiotic treatments when participants were not cleared of the infection at all sites.

Clinical data

The primary outcome of the economic evaluation reflected the primary outcome of the trial – the clearance of N. gonorrhoeae at all infected sites (confirmed by a negative NAAT) at 2 weeks post treatment (Table 26). The primary approach to analysis was ITT without imputation of missing outcome data, as specified in the SAP. Data were also collected on whether or not participants required further NHS care following the initial treatment.

Treatment costs

Trial participants allocated to the gentamicin arm received 240 mg of gentamicin as a single i.m. injection. This was obtained from three 80-mg ampoules, with an estimated cost of £1 per ampoule [£3 overall, estimated using the British National Formulary (BNF)],39 as shown in Table 27. Participants allocated to the ceftriaxone arm received a 500-mg dose. Ceftriaxone was purchased in units of 1 g and mixed with 4 ml (1%) of lidocaine solution. Only half of the preparation was administered to the participant (half was discarded); we therefore included costs for one vial of 1 g of ceftriaxone powder (£1.10) per participant and two 2-ml lidocaine ampoules (£0.22 per ampoule). 39 Hence, the initial costs associated with gentamicin treatment were higher than those associated with the current standard treatment, ceftriaxone. Other equipment (such as syringes) would be required by both arms of the trial and so these costs were not included. In both trial arms, participants received a single oral dose of azithromycin, an initial consultation with a health-care professional and a follow-up visit. These costs were excluded from the analysis as they were incurred equally across the trial arms.

To check that there was no difference in the length of time required for delivery of the treatment therapy, a survey was undertaken with research nurses involved in the delivery of the two treatments. The survey aimed to check whether or not the delivery of the treatment and the length of the consultation were affected by the drug that was being administered. The survey received responses from 21 nurses who were administering injections. The majority of nurses (17 respondents, 81%) stated that there was no difference in the time taken to administer the two treatments. Just four nurses (19%) responded that there was a difference, all of whom stated that appointments to administer gentamicin were longer than those to administer ceftriaxone. The main reason given for the longer time needed to administer gentamicin was the increased pain associated with gentamicin injections (given as a reason by three of the nurses who felt that gentamicin took longer to administer). Two nurses stated that appointments to administer gentamicin took 0–5 minutes longer and two stated that an additional time of up to 10 minutes was needed. Given the survey results, for the base-case analysis additional time was not included to administer the gentamicin treatment; however, increased time was explored as part of the sensitivity analysis.

NHS resource use and costs incurred after initial treatment

NHS resource use by participants was collected during the trial at all participating sites using a form completed by a nurse/assessor. Data were collected on whether or not participants had visited their GP/nurse at their general practice, a GP out-of-hours service, health professionals at a sexual health clinic or an accident and emergency (A&E) department and on the use of other services. Data were also collected on whether or not participants were prescribed other medication (other than the trial treatment). In addition, details of any AEs and associated resource use were recorded. Unit cost estimates were applied to resource use data to generate individual-level cost estimates. The sources of unit costs included routine and published literature (e.g. Unit Costs of Health and Social Care 201640).

Resource use was similar across trial arms, with the main resources that were used relating to GP visits and sexual health centre visits (Table 28). No participants reported that they had been hospitalised during the trial or attended A&E.

Further treatment costs owing to non-clearance of infection

Within the trial, when infection was not cleared at all sites (as indicated by a NAAT), further treatment was given. Participants in the gentamicin arm were assumed to be treated with ceftriaxone (unless there was a contraindication for this treatment). Participants in the ceftriaxone arm were assumed to have been given a second course of ceftriaxone unless the culture demonstrated resistance to this treatment. For the purposes of the economic evaluation, it was assumed that in both trial arms, when infection was not cleared at 2 weeks post treatment, a sexual health clinic appointment would be needed and that a course of the standard treatment (ceftriaxone) would be given (Table 29). This was to reflect current guidelines;8 other scenarios were explored in the sensitivity analysis.

Analysis

The within-trial analysis took the form of a CEA, with results reported in terms of the cost per participant successfully treated (measured in terms of microbial clearance of N. gonorrhoeae at all infected sites, 2 weeks post treatment). As the trial was concerned with the immediate post-treatment period of 2 weeks, discounting was not undertaken. All costs are given in Great British pounds for 2015/16.

Sensitivity analysis

Both deterministic and probabilistic sensitivity analyses were undertaken to explore the uncertainty in the parameter estimates on the results produced by the model. 42 In the deterministic sensitivity analysis, one or more parameters were varied while keeping the others at their baseline value. Deterministic analysis can help to identify which values are important in leading to a particular decision and can help to identify threshold values. 43,44

A range of deterministic sensitivity analyses was carried out. First, the cost of the interventions was varied to reflect the purchase of different solutions/equipment based on prices reported in the BNF. 39 Second, the costs of additional treatment for those without clearance of N. gonorrhoeae was varied to take into account different scenarios for the development of AMR in gonorrhoea. The cost was increased to reflect a scenario in which two further treatments of ceftriaxone were given and two follow-up visits to a clinic. Third, the rates of clearance for gonorrhoea were varied to reflect different rates at different sites, using the lowest and highest 95% CIs reported in Table 17 for different sites. Fourth, the time taken to administer the gentamicin treatment was varied to reflect the responses of a minority of nurses in the survey who indicated that gentamicin injections took longer to administer. The cost of treatment was increased to take into account a scenario in which an additional 10 minutes would be needed to administer gentamicin than to administer ceftriaxone, assuming that the cost of the time of the nurse administering the treatment would be equivalent to that of a GP nurse. 40

A probabilistic sensitivity analysis (PSA) was also undertaken to allow uncertainty to be explored more comprehensively. A PSA involves varying all parameters simultaneously and sampling multiple sets of parameter values from defined probability distributions. A Monte Carlo simulation was used to sample from the distributions; this involved 1000 repeated random draws to analyse how variation in the parameters used in the model would affect the results. Beta distributions were used for binomial data and gamma distributions were used for costs, in line with recommendations for specifying distributions for parameters. 42

Antimicrobial resistance

The mechanisms leading to gentamicin resistance have not been fully elucidated but include reduced uptake into infected cells as a result of decreased cell membrane permeability to the antibiotic49 or modification of the drug by cellular enzymes, which reduce its activity. 50 For spectinomycin, which is in the same drug class of aminoglycosides and has a similar mechanism of action, mutations within 16S ribosomal ribonucleic acid that inhibit binding of the drug to the ribosome have been associated with high-level resistance. 51 In vitro measurement of the MIC for gentamicin in cultured isolates of N. gonorrhoeae provides a phenotypic assessment of antimicrobial susceptibility, but the ‘breakpoint’ MIC value, below which clinical cure occurs and above which treatment is ineffective, has not been established. It has been tentatively suggested that an isolate with a MIC of < 8 mg/l is susceptible, with a MIC of 8–16 mg/l is intermediate and with a MIC of > 16 mg/l is resistant. 29,52 The European Network for STI Surveillance found that 95% of isolates had gentamicin MICs in the range of 4–8 mg/l,27 using the agar dilution technique. Isolates of N. gonorrhoeae from participants in the G-TOG trial had a similar susceptibility profile, with 70% having a MIC of 4–8 mg/l using the Etest technique.

Previously proposed MIC ‘cut-offs’ points associated with AMR in N. gonorrhoeae for gentamicin, ceftriaxone and azithromycin are shown in Table 32.

The measurement of MICs requires a positive N. gonorrhoeae culture sample. Participants in the G-TOG trial had samples taken for culture at their baseline attendance and 2-week follow-up but culture is less sensitive than NAAT, particularly for extragenital sites, and, therefore, the data on in vitro susceptibility (using MICs) are limited to the subset of individuals who had a positive culture sample available. For genital infections, culture isolates were available for 356 out of 402 (88%) NAAT-positive samples at baseline; for rectal infections, this number was 146 out of 301 (47%) and for pharyngeal infections it was 88 out of 256 (34%).

Caution is, therefore, required in the interpretation of the antibiotic susceptibility profiles, which represent only a subgroup of the overall trial population, especially for those with pharyngeal and rectal infections. Overall, the culture-positive and culture-negative groups were similar with respect to age, sex and ethnicity, although there was a greater proportion of males among those with no culture result available (94% compared with 79% in the culture-positive group and 78% in the culture-negative group) and there were fewer white participants (59% compared with 66% and 74% in the culture-positive and culture-negative groups, respectively).

The extent of tissue penetration of different antimicrobials at the genital, rectal and pharyngeal sites is not known, nor is the extent of interindividual variation in tissue drug levels. This makes it difficult to interpret how the MIC values measured in vitro relate to the relative antibiotic susceptibility of gonococcal isolates in individual trial participants.

There did not appear to be any association between the in vitro gentamicin MIC and response to treatment.

The structurally similar antibiotic spectinomycin has been reported to be less effective for the treatment of pharyngeal gonorrhoea,55 probably because it fails to achieve bactericidal concentrations within the infected tissues for a sufficiently long time period to clear infection. 5 It is possible that this mechanism is also relevant for gentamicin.

Participants in both treatment groups received oral azithromycin and treatment failure was associated with a reduction in in vitro susceptibility (shift of the azithromycin MIC distribution to the right). Overall, treatment failure occurred in 14 out of 262 (5%) participants who had isolates with an azithromycin MIC of ≤ 0.5 mg/l compared with 2 out of 12 (17%) participants who had isolates with an azithromycin MIC of ≥ 1 mg/l.

In summary, we did not find that gentamicin MICs, as assessed by in vitro antimicrobial susceptibility testing, accurately predicted treatment failure. This suggests that in vitro laboratory assessment of MICs for gentamicin is not likely to be helpful in selecting those patients with gonorrhoea who can be successfully treated with gentamicin.

Reinfection

If a patient is reinfected after treatment, then their follow-up test for gonorrhoea will be positive even after successful initial therapy. If this occurs following sex with an existing infected partner, then it is likely that the same subtype of N. gonorrhoeae will be present at baseline and follow-up. If sexual contact was with a new partner, then the same subtype of N. gonorrhoeae could be present at follow-up (e.g. if this is a common subtype within the population) or a different subtype may occur.

Sexual contact following treatment for gonorrhoea was well balanced between the treatment groups: it was reported by 37% (118/322) of participants receiving ceftriaxone [15% (47/322) of whom reported not using condoms] and 34% (104/302) receiving gentamicin [16% (47/302) of whom reported not using condoms]. For both groups, a median of two episodes of sexual contact occurred in the interval between treatment and follow-up. There were similar clearance rates for participants who had and those who had not had sex following randomisation, and these rates appeared to be similar between treatment groups.

Reinfection of participants with gonorrhoea is, therefore, not likely to explain the difference in treatment success between participants receiving ceftriaxone and those receiving gentamicin.

Interval between treatment and follow-up assessment

Microbiological cure following treatment was assessed using NAAT and occurred at ≤ 21 days in 81% of participants in both treatment groups. The median time to assessment of cure did not differ between the two treatment groups (ceftriaxone 16 days, gentamicin 15 days). The median time to follow-up was 15 days from randomisation for those who were cleared of infection and 15.5 days for those who were not cleared of infection.

Persistence of bacterial nucleic acid following effective treatment, even in the absence of viable bacteria, has the potential to cause false-positive test results. Current UK national guidance is to assess cure by performing a NAAT 2 weeks after treatment, by which time a false-positive result is unlikely. 56–60 It has been suggested that pharyngeal infection may take longer to clear following treatment, with a greater possibility of a false-positive result 2 weeks after therapy. 61 The high treatment success rate at all anatomical sites in participants receiving ceftriaxone [genital 98% (151/154), pharyngeal 96% (108/113) and rectal 98% (134/137)] suggests that persistence of bacterial nucleic acid (in the absence of viable bacteria) leading to false-positive results did not occur frequently in the G-TOG trial participants. However, the pharmacodynamics of gentamicin for the treatment of pharyngeal gonorrhoea are largely unknown and it remains possible that the rate of bacterial clearance may be slower with gentamicin than with ceftriaxone.

Negative interaction between gentamicin and azithromycin

An antagonistic interaction between gentamicin and azithromycin could potentially reduce the efficacy of the combination of these two drugs. However, in vitro testing suggests that there is neither antagonism nor synergy when the two antibiotics are combined;62 furthermore, a recent trial using this combination demonstrated the potential for a high cure rate using dual therapy, at least in a subset of patients with genital infection diagnosed by culture. 25 An antagonistic interaction between gentamicin and azithromycin would, therefore, be an unlikely explanation for the difference in cure rates between ceftriaxone and gentamicin.

Protocol deviations

The proportion of participants reporting protocol deviations was similar between treatment groups and most deviations were considered to be minor. There was an imbalance in the proportion of participants who did not receive their randomised medication. However, it was considered unlikely that this was as a result of selection bias or knowledge of the treatment allocation. It is therefore believed that the protocol deviations did not affect the validity of the trial.

The role of azithromycin in the treatment of gonorrhoea

Participants in the G-TOG trial received dual treatment: 1 g of azithromycin combined with either ceftriaxone or gentamicin. Azithromycin has previously been shown to be effective for the treatment of gonorrhoea using a single dose of either 1 g or 2 g,65–68 although these previous studies used culture to diagnose infection and assess cure, which, as outlined in the previous section, is less sensitive than NAAT. Azithromycin resistance and treatment failure has subsequently been reported in a number of geographical locations. 69–73 In the UK, azithromycin-resistant N. gonorrhoeae has been detected intermittently since 2004,74,75 with an ongoing outbreak of high-level azithromycin-resistant isolates identified in England since 2014. 76 The Gonococcal Resistance to Antimicrobials Surveillance Programme reported that 10% of gonococcal isolates in England and Wales had a MIC of > 0.5 mg/l in 2015, indicating probable resistance. 3

In the G-TOG trial, participant treatment failure occurred in 6% of genital infections, 10% of rectal infections and 20% of pharyngeal infections in those who received gentamicin plus azithromycin, suggesting that oral azithromycin given as a 1-g dose may be suboptimal, particularly for extragenital gonorrhoea. The large majority of gonococcal isolates from participants in the G-TOG trial [290/305 (95%)] had azithromycin MICs within the non-resistant range (≤ 0.5 mg/l). Of the 15 isolates with a MIC of > 0.5 mg/l, two (13%) were from participants who had treatment failure. The majority of treatment failures overall [14/20 (70%)] occurred in participants who had isolates with a MIC of ≤ 0.25 mg/l. Sixty participants harboured an isolate with an azithromycin intermediate MIC of 0.5 mg/l, of whom four (7%) had treatment failure. Thus, we found in vitro azithromycin resistance was only partially predictive of treatment failure. The limited association between MIC and treatment efficacy has been reported by others. 77,78 It is possible that a higher dose of azithromycin (2 g), as was used in the Kirkcaldy et al. 25 study, would have been more effective, although without a direct comparative study this is speculative, especially for the treatment of pharyngeal gonorrhoea.

The use of a 1-g dose of azithromycin as monotherapy has also been reported to potentially induce resistance in N. gonorrhoeae, with a substantial increase in the MIC following treatment. 79,80

The use of a 2-g dose of azithromycin combined with gentamicin was associated with a high incidence of gastrointestinal side effects in the Kirkcaldy et al. 25 study, with nausea reported by 26% of participants and vomiting by 10%. In the G-TOG trial, the 1-g dose was better tolerated: 14% of participants reported nausea and 4% reported vomiting, which is consistent with previous studies. 68 An extended-release formulation of azithromycin is available that may reduce the incidence of side effects and improve tolerability but there are limited data directly comparing its AE profile with that of the immediate-release formulation. 81,82

The current UK and US gonorrhoea treatment guidelines recommend dual therapy with a regimen containing oral azithromycin as a 1-g single dose. 6 Our findings, which are the first to use the more sensitive NAATs to assess microbiological clearance, suggest that this component of treatment may be suboptimal, particularly for extragenital gonococcal infections.

Injection site pain

Participants receiving gentamicin reported more severe injection site pain than those receiving ceftriaxone (median VAS score 31.5 and 15.0, respectively), with resolution of pain occurring within a median of 1 hour for ceftriaxone and 1.5 hours for gentamicin. The site of injection and the needle gauge were not prespecified in the trial but would usually be the same for both antibiotics. Ceftriaxone is manufactured as a powder preparation that is reconstituted with lidocaine, resulting in an injection volume of approximately 2 ml for a 500-mg dose. 83 Gentamicin is manufactured as a solution: a 240-mg dose equates to an injection volume of 6 ml. 84 It is likely that this larger volume of injection led to participants who received gentamicin reporting more severe local site pain. In addition, the local anaesthetic effect of lidocaine in those receiving ceftriaxone is likely to have reduced the discomfort following injection.

Trial and data management: Nottingham Clinical Trials Unit

Lelia Duley, Professor of Clinical Trials Research; Alan Montgomery, Professor of Medical Statistics and Clinical Trials; Claire Brittan, Trial Manager to June 2016, then Senior Trial Manager to March 2017; Kirsty Sprange, Senior Trial Manager from March 2017; Margo Childs, Senior Trial Manager to March 2016; Trish Hepburn, Clinical Research Facilitator, Senior Statistician; Wei Tan, Medical Statistician; Sukhwinder Thandi, Trial Manager from June 2016; Garry Meakin, Trial Coordinator to September 2015; John Watson, Trial Administrator from December 15; Dan Simpkins, Senior Data Manager; Sarah Walker, Data Coordinator; Matt Foster, Data Administrator from April 2016; and Chris Rumsey, Information Technology (IT) Programmer.

Co-applicants

Jonathan Ross, Professor of Sexual Health and HIV, University Hospitals Birmingham NHS Foundation Trust; Christine Bowman, Consultant Physician in Genitourinary Medicine, Sheffield Teaching Hospitals NHS Foundation Trust; Stephanie Chisholm, Clinical Scientist, formerly of Public Health England; Michelle Cole, Health-care Scientist, Antimicrobial Resistance and Healthcare Associated Infections, National Infection Service, Public Health England; Lelia Duley, Professor of Clinical Trials Research, NCTU, University of Nottingham; Claudia Estcourt, Reader in Sexual Health and HIV, Barts and The London School of Medicine and Dentistry; Jan Harding, Research Co-ordinator in Sexual Health and HIV, University Hospitals Birmingham NHS Foundation Trust; Philip Hay, Reader, University of London; Louise Jackson, Research Fellow, University of Birmingham; Lucy Land, Reader in Nursing, Birmingham City University; Alan A Montgomery, Professor of Medical Statistics and Clinical Trials, NCTU, University of Nottingham; Rajul Patel, Senior Lecturer, University of Southampton; Gabriel Schembri, Consultant in Sexual Health and HIV Medicine/Research Lead, Central Manchester University Hospitals NHS Foundation Trust; John White, Consultant Physician in Sexual Health and HIV, Guy’s and St Thomas’ NHS Foundation Trust; and Janet Wilson, Consultant in Genitourinary Medicine, Leeds Teaching Hospitals NHS Trust.

Health economics

Louise Jackson and Tracy Roberts at the University of Birmingham provided health economics expertise to the trial.

Trial Management Group

Jonathan Ross, Professor of Sexual Health and HIV (chairperson); Lelia Duley, Professor of Clinical Trials Research; Alan A Montgomery, Professor of Medical Statistics and Clinical Trials; Clare Brittain, Trial Manager/Senior Trial Manager; Kirsty Sprange, Senior Trial Manager; Margo Childs, Senior Trial Manager; Trish Hepburn, Clinical Research Facilitator, Senior Statistician; Wei Tan, Medical Statistician; Tessa Lawrence, Sexual Health and HIV Research Manager; Sukhwinder Thandi, Trial Manager; Garry Meakin, Trial Co-ordinator; John Watson, Trial Administrator; and Jan Harding, Research Co-ordinator in Sexual Health and HIV.

Trial Steering Committee (independent members)

Professor Judith Stevenson (chairperson), Professor of Reproductive and Sexual Health, University College London; Professor John McLeod, Professor in Clinical Epidemiology and Primary Care, University of Bristol; Professor Andy Winter, Consultant in Sexual Health and HIV, NHS Greater Glasgow and Clyde; Mr David Roberts-Jones, Patient Representative; and Mr Matthew Keogh, Patient Representative.

Data Monitoring Committee (independent members)

Professor Chris Butler (chairperson), Professor of Primary Care, University of Oxford; Dr Mike Bradburn, Senior Statistician, University of Sheffield; Dr Danielle Mercey, Senior Clinical Lecturer, Farr Institute; and Professor Charles Lacey, Professor of Medicine, University of York.

Public Health England

Dr Colin Churchward and Mr Francesco Tripodo.

Sites

Presented in alphabetical order.

Search strategy

1. gonorrhoea.mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, an, ui]

2. gonorrhea.mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, an, ui]

3. Neisseria gonorrhoeae.mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, an, ui]

4. N gonorrhoeae.mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, an, ui]

5. 1 or 2 or 3 or 4

6. gentamicin.mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, an, ui]

7. gentamycin.mp. [mp = ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, nm, kf, px, rx, an, ui]

8. 6 or 7

9. 5 and 8

10. limit 9 to yr =‘2013-Current’

11. remove duplicates from 10