New Antibiotic Treatment Options for Uncomplicated Anogenital Gonorrhoea Infections - a Double-blind Randomized Controlled Non-inferiority Trial
Phase: PHASE3
Conditions: Gonorrhea
Sponsor: Public Health Service of Amsterdam

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ACADEMICAL MEDICAL CENTER (AMC) – PUBLIC HEALTH SERVICE (GGD) AMSTERDAM 
New antibiotic treatment 
options for 
uncomplicated 
anogenital gonorrhea    
(NABOGO trial) 
a double-blind randomized controlled non-
inferiority trial 
 
 
 
 
 
 
 
 
This document contains the protocol of a double-blind randomized controlled non-inferiority trial 
investigating registered antibiotics as new treatment options for uncomplicated anogenital gonorrhea. 
In this protocol the rationale and the study procedures are described in detail.  

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PROTOCOL TITLE: New antibiotic treatment options for uncomplicated anogenital gonorrhea 
infections – a double-blind randomized controlled non-inferiority trial 
Protocol ID 
NL60555.018.17  
MEC: 2017_092 
Short title 
NABOGO 
EudraCT number  
2017-000176-28 
Version 
4.1 
Date 
18-03-2019 
Study coordinator 
 
M.M. de Laat, MD, PhD student 
STI Outpatient Clinic, Public Health Service Amsterdam 
and Department of Dermatology, Academic Medical 
Center, University of Amsterdam 
Principal investigator 
 
Prof. dr. H.J.C. de Vries, MD 
Dermatologist, STI Outpatient Clinic, Public Health 
Service Amsterdam and Department of Dermatology, 
Academic Medical Center, University of Amsterdam  
Project members 
Dr. Anders Boyd 
Statistician, Department of Infectious Diseases, Public 
Health Service (GGD) Amsterdam 
Dr. Sylvia Bruisten 
Molecular microbiology, Department of Infectious 
Diseases, Public Health Service (GGD) Amsterdam 
Dr. A.P. van Dam, MD  
Medical Microbiology, Department Infectious Diseases, 
Public Health Service (GGD) Amsterdam  
Dr. A. Hogewoning, MD 
Dermatology, Department head, STI Outpatient clinic 
Public Health Service (GGD) Amsterdam 
Dr. M. Knol 
Senior epidemiologist, RIVM, National Institute for 
Public Health and the Environment, Centre for 
Infectious Disease Control Netherlands (CIb),  
Epidemiology and Surveillance Unit (EPI) 
Prof. dr. R.A.A. Mathot, MD 
Pharmacology, Department of pharmacology, 

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Academic Medical Center, University of Amsterdam 
Prof. dr. J.M. Prins, MD 
Internal Medicine and Infectious Diseases, Department 
head, Department of Internal Medicine, Academic 
Medical Center, University of Amsterdam 
Dr. M.F. Schim van der Loeff, MD 
Senior epidemiologist, Department research and 
prevention of infectious diseases, Public Health 
Service Amsterdam 
Dr. C.M. Wind, MD 
Dermatology Leiden University Medical Center 
Sponsor  
Academic Medical Center, Amsterdam 
Contractor 
Public Health Services, Amsterdam 
Funding source 
ZonMW, project number: 84801 5001 
Independent expert 
S. Keizer, medical doctor at TB control department, 
Department of Infectious Diseases, Public Health 
Service  Amsterdam 
Laboratory sites  
Public Health Laboratory, Department of Infectious 
Diseases, Public Health Service Amsterdam 
Pharmacy  
AMC Pharmacy 
Dr. E.M. Kemper, pharmacologist 

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PROTOCOL SIGNATURE SHEET 
Name 
Signature 
Date 
Department head: 
 
Prof. dr. R. Hoekzema, MD 
Dermatologist, Department 
head, Dermatology, Academic 
Medical Center Amsterdam 
 
Principal Investigator: 
 
Prof. dr. H.J.C. de Vries, MD 
Dermatologist, Department 
head, STI clinic, Public Health 
Services Amsterdam and 
Academic Medical Center 
Amsterdam 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ADJUSTMENTS 
1. 
INTRODUCTION AND RATIONALE ............................................................................................... 6 
2. 
OBJECTIVES .................................................................................................................................. 9 
3. 
STUDY DESIGN ............................................................................................................................ 10 
4. 
STUDY POPULATION .................................................................................................................. 16 
4.1 
Population (base)................................................................................................................... 16 
4.2 
Inclusion criteria ..................................................................................................................... 16 
4.3 
Exclusion criteria.................................................................................................................... 16 
4.4 
Sample size calculation……………………………………………………………………………19 
4.5 
Recruitment period ................................................................................................................ 19 
4.6 
Patient registration ................................................................................................................. 19 
5. 
TREATMENT OF SUBJECTS ....................................................................................................... 21 
5.1 
Investigational product/treatment .......................................................................................... 21 
5.2 
Use of co-intervention ............................................................................................................ 21 
5.3 
Escape medication ................................................................................................................ 21 
6. 
INVESTIGATIONAL PRODUCT .................................................................................................... 22 
6.1 
Name and description of investigational  product(s) ............................................................. 22 
6.2 
Summary of findings from non-clinical studies ...................................................................... 22 
6.3 
Summary of findings from clinical studies ............................................................................. 22 
6.4 
Summary of known and potential risks and benefits ............................................................. 22 
6.5 
Description and justification of route of administration and dosage ...................................... 23 
6.6 
Dosages, dosage modifications and method of administration ............................................. 23 
6.7 
Preparation and labelling of Investigational Medicinal Product ............................................. 25 
6.8 
Drug accountability ................................................................................................................ 25 
7. 
METHODS ..................................................................................................................................... 26 
7.1 
Study endpoints ..................................................................................................................... 26 
7.1.1 
Main study endpoint....................................................................................................... 26 
7.1.2 
Secondary study parameters/endpoints ........................................................................ 26 
7.2 
Randomization, blinding and treatment allocation ................................................................. 27 
7.3 
Study procedures................................................................................................................... 27 
7.4 
Withdrawal of individual subjects........................................................................................... 31 
7.5 
Replacement of individual subjects after withdrawal ............................................................. 31 
7.6 
Follow-up of subjects withdrawn from treatment ................................................................... 31 
7.7 
Premature termination of the study ....................................................................................... 31 
8. 
SAFETY REPORTING .................................................................................................................. 33 
8.2 
AEs, SAEs and SUSARs ....................................................................................................... 33 
8.2.1 
Adverse events (AEs) .................................................................................................... 33 
8.2.2 
Serious adverse events (SAEs) ..................................................................................... 33 
8.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ...................................... 33 
8.3 
Annual safety report .............................................................................................................. 34 
8.4 
Follow-up of adverse events .................................................................................................. 35 
8.5 
Data Safety Monitoring Board (DSMB) / Safety Committee .................................................. 35 

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9. 
STATISTICAL ANALYSIS ......................................................................................................... 36 
9.1 
Primary study parameters ..................................................................................................... 36 
9.2 
Secondary study parameters ................................................................................................. 37 
9.3 
Interim analysis ...................................................................................................................... 37 
10. 
ETHICAL CONSIDERATIONS .................................................................................................. 39 
10.1 
Regulation statement ............................................................................................................. 39 
10.2 
Recruitment and consent ....................................................................................................... 39 
10.3 
Objection by minors or incapacitated subjects (if applicable) ............................................... 39 
10.4 
Benefits and risks assessment, group relatedness ............................................................... 39 
10.5 
Compensation for injury ......................................................................................................... 40 
10.6 
Incentives ............................................................................................................................... 40 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ....................................... 41 
11.1 
Handling and storage of data and documents ....................................................................... 41 
11.2 
Monitoring and Quality Assurance......................................................................................... 41 
11.3 
Amendments .......................................................................................................................... 41 
11.4 
Annual progress report .......................................................................................................... 41 
11.5 
End of study report ................................................................................................................ 42 
11.6 
Public disclosure and publication policy ................................................................................ 42 
12. 
STRUCTURED RISK ANALYSIS .............................................................................................. 43 
12.1 
Potential issues of concern .................................................................................................... 43 
12.2 
Synthesis ............................................................................................................................... 47 
13. 
REFERENCES .......................................................................................................................... 48 

0 
 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
ABR 
ABR form, General Assessment and Registration form, is the application form that 
is required for submission to the accredited Ethics Committee (In Dutch, ABR = 
Algemene Beoordeling en Registratie) 
AMC 
AMR 
AE 
Academic Medical Center  
Antimicrobial Resistance 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DALY 
DSMB 
eGFR 
EMA 
Disability Adjusted Life Years 
Data Safety Monitoring Board 
estimated Glomerular Filtration Rate 
European Medicines Agency 
ESC 
Extended Spectrum Cephalosporin 
EudraCT 
European Drug Regulatory Affairs Clinical Trials  
FDA 
GCP 
HIV 
Food and Drug Administration 
Good Clinical Practice 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
IC 
IM 
Informed Consent 
Intramuscular(ly) 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
ITT 
IV 
METC  
Intention To Treat analysis 
Intravenous(ly) 
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
MIC 
MITT 
MSM 
NAAT 
Minimum Inhibitory Concentration 
Modified Intention To Treat analysis 
Men who have sex with men 
Nucleic Acid Amplification Test 

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1 
 
Ng 
NONMEM 
PP 
POC 
RCT 
(S)AE 
Neisseria gonorrhoeae 
Non-linear mixed effects modelling 
Per Protocol analysis  
Point-of-Care (test) 
Randomized Controlled Trial 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics  
Sponsor 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a funding source.  
STI 
SUSAR 
Sexually Transmitted Infection 
Suspected Unexpected Serious Adverse Reaction 
TOC 
Wbp 
Test of Cure 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WHO 
WMO 
World Health Organization 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 
 

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2 
 
SUMMARY 
Rationale: Antimicrobial resistance (AMR) to extended spectrum cephalosporins (ESC) in Neisseria 
gonorrhoeae (Ng) is a major public health concern. With no alternative options for the antimicrobial 
treatment of gonorrhea and only few new drugs in development, it is important to test existing 
antibiotics on their efficacy to treat gonorrhea.  
Objective: This project aims to identify new treatment modalities for uncomplicated gonorrhea using 
the registered drugs ertapenem, fosfomycin and gentamicin.  
Study design: A double-blind randomized controlled non-inferiority trial with three treatment arms.  
Study population: Patients with anogenital gonorrhea visiting the sexually transmitted infection (STI) 
outpatient clinic of the Public Health Services Amsterdam, aged 18 years and older, both female and 
male, with multiple ethnic backgrounds. The highest prevalence of gonorrhea is seen among men 
who have sex with men (MSM).  
For a substudy on the pharmacokinetics (PK) of the studied antibiotics, we aim to include 60 
volunteers who will be recruited from the STI clinic, the Public Health Service and the University of 
Amsterdam.  
Intervention: Patients will be randomly assigned to one of four treatment arms. They receive one of 
the following: ceftriaxone 500mg intramuscularly (IM), ertapenem 1000mg IM, gentamicin 5mg/kg IM 
with a maximum of 400mg (in two doses) supplemented with an oral placebo, or fosfomycin 6g oral 
suspension supplemented with an intramuscular placebo. Following the advice of the DSMB, we 
stopped administering fosfomycin and oral placebo to NABOGO participants on October 2, 2018.  
Main study endpoint: The bacterial eradication capacity of study antimicrobials at the included 
infection site using an RNA-based Nucleic Acid Amplification Test (NAAT) 7-14 days after treatment.  
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: With 78 million new cases of gonorrhea in adults aged 15-49 years, gonorrhea is the 
second most common bacterial STI worldwide. Persistent Ng infections may cause severe 
reproductive tract inflammation and irreversible damage resulting in infertility. Moreover, gonorrhea 
increases the risk of human immunodeficiency virus (HIV) transmission. If untreatable gonorrhea 
becomes a reality, an increase in both the burden of disease and costs for society will be observed.   
The drugs in this study are all widely-used antimicrobials. The most important side effects are 
gentamicin-associated nephro- and ototoxicity. However, limited research has been done on the 
safety of single dose intramuscular injection of gentamicin. We expect that single dose intramuscular 
injection will not harm young and healthy participants. For safety concerns regarding renal function 
after the administration of gentamicin, creatinine clearance will be monitored before and after 
treatment in participants of the main study. Patients with renal impairment are not eligible to take part 
in this study.  

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3 
 
The burden of participation in this study includes two intramuscular injections instead of one, which is 
due to the large required volume for injectable gentamicin (6-10 ml). A finger prick will be performed 
to draw blood for a point-of-care (POC) serum creatinine test, participants will be requested to return 
7-14 days after treatment for a test of cure and will be asked to keep a diary and abstain from sexual 
contact or condom use during the period between treatment and follow-up visit.  
We aim for 60 NABOGO participants (=gonorrhea patients) to provide one blood sample (obtained by 
vena punction) within 30-90 minutes after treatment administration to measure the plasma 
concentration of the administered antibiotic.  
Participants (n=60) of the PK substudy (= healthy volunteers) will receive either ceftriaxone 500mg IM 
(n=20), ertapenem 1000mg IM (n=20) or fosfomycin 6g PO (n=20) and will provide four blood 
samples within 24 hours after treatment administration to measure plasma concentration at different 
time points.  
 
 

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LIST OF MODIFICATIONS AMENDEMENT 3 
No 
Subject 
Previous 
situation/description 
Description of modifications 
Rationale 
C1  
No point of care 
measurement of 
creatinine in PK 
substudy with 
volunteers 
We planned to measure the 
creatinine serum levels with a 
point of care test to assess 
renal impairment in healthy 
volunteers.  
Severe renal impairment 
remains an exclusion criterion 
for volunteers participating in 
the PK substudy. However, we 
propose to evaluate renal 
impairment by medical history 
rather than by assessing 
creatinin serum level.   
A single dose of ceftriaxone 
500mg IM, ertapenem 
1000mg IM or fosfomycin 6g 
orally can safely be 
administered to persons with 
mild renal impairment (eGFR 
30-50 ml/min). In this healthy 
volunteer population we do 
not expect anybody to have 
severe renal impairment 
(eGFR <30 ml/min) without 
them knowing they have a 
health problem. We therefore 
propose to assess presence 
of severe renal impairment 
by a questionnaire rather 
than by creatinine serum 
level.  
Please note that in the main 
study with gonorrhoea 
patients, one third of whom 
are randomized to 
gentamicin, creatinine will be 
measured both before and 
one week after treatment 
administration. 
 
 
 
 

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5 
 
1. INTRODUCTION AND RATIONALE 
With 78 million new cases of gonorrhea in adults aged 15–49 years, gonorrhea is the second most 
common bacterial sexually transmitted infection (STI) worldwide [1]. Persistent infections may cause 
severe genital and reproductive tract inflammation and irreversible damage with infertility as a result. 
Moreover, gonorrhea increases the transmission of human immunodeficiency virus (HIV)[2]. The most 
recent global report of the World Health Organization (WHO) on antimicrobial resistance (AMR) 
published in 2014, specifically mentions treatment failures of gonorrhea due to resistance to extended 
spectrum cephalosporins (ESCs) in 10 countries. ESCs are the treatment of last resort for gonorrhea. 
Furthermore, decreased susceptibility to ESCs is reported in 36 countries including the Netherlands[3, 
4]. It is anticipated to be only a matter of time before gonococci with full resistance to the ESCs 
spread internationally. Consequently, gonorrhea may become untreatable unless new drugs become 
available or existing drugs that are presently not used for treatment of gonorrhea are tested for their 
efficacy in gonorrhea [5-7].  
The threat of untreatable gonorrhea is of global concern because there will be a major impact on 
disease control efforts due to prolonged infections, increased prevalence of serious complications, 
and also non-urogenital gonococcal diseases such as neonatal infections and disseminated 
gonococcal infections will become much more common. In addition, untreated gonorrhea is 
associated with an increased risk of acquisition and transmission of HIV infection[2]. Based on the 
2008 global estimates of incident gonococcal infections, the estimate for global disability adjusted life 
years (DALYs) due to gonorrhea is approximately 440,000[8]. Antimicrobial resistance in gonorrhea 
will further increase this burden and cost for society. Financial costs for health services and individual 
patients will increase[9]. 
This project aims to identify new treatment modalities for uncomplicated gonorrhea using the 
registered drugs: ertapenem, fosfomycin and gentamicin, which have not yet been proven clinically 
effective against gonorrhea. Although ertapenem is, like ceftriaxone, a beta-lactam antibiotic, so far 
Ng strains with resistance to ceftriaxone had much lower minimum inhibitory concentrations (MICs) for  
ertapenem. For this reason, ertapenem is very likely also an effective antibiotic against ESC-resistant 
strains. The efficacy of ertapenem in other extended spectrum β-lactamase (ESBL) producing gram-
negative bacteria’s is previously proven[10-12]. Both fosfomycin and gentamicin have modes of action 
very different from ceftriaxone, and their efficacy against gonorrhea will be unrelated to the strains’ 
susceptibility for ceftriaxone. Yuan et al. performed a randomized controlled trial (RCT) in which a 
three-dose regimen of 3 g fosfomycin was compared to dual regimen of ceftriaxone and azithromycin. 
In this trial, efficacy of both regimens for treatment of uncomplicated gonococcal urethritis in men was 
shown[13]. However, a non-inferior effectiveness of fosfomycin compared to ceftriaxone plus 
azithromycin could not be concluded. This study was limited by the small sample size and by the use 
of different test modalities for diagnosis (gram stain) and test of cure (culture and/or RNA-based 
Nucleic Acid Amplification Test (NAAT)). Gentamicin has been used for the treatment of gonorrhea in 
some developing countries for decades [14-16]. However, the effect had never been evaluated in an 
RCT. A two-arm dual therapeutic regimen trial is ongoing in the UK comparing gentamicin with 

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6 
 
ceftriaxone, plus azithromycin in both arms[17]. As mentioned by Kirkcaldy et al, a limitation of an 
RCT with dual therapeutic arms containing azithromycin is that it is not possible to evaluate the 
efficacy of the second antibiotic since high-dose azithromycin has demonstrated excellent efficacy 
against azithromycin susceptible gonorrhea as mono-therapy[18]. Besides, several studies have now 
conclusively shown that the formerly assumed synergistic effect of a combination of extended 
spectrum cephalosporin plus azithromycin in fact does not exist [19-23]. We will therefore compare 
mono-therapeutic regimes since this will allow a true evaluation of the eradicative capacity of each 
single antibiotic on gonorrhea.  
We propose a non-inferiority, double-blind randomized controlled trial to assess whether ertapenem 
1000mg, fosfomycin 6g and gentamicin 5mg/kg are good alternatives for the treatment of  
uncomplicated anogenital gonorrhea compared to the reference treatment in the Netherlands (500 mg 
ceftriaxone intramuscular (IM)).  
It is important to consider that the efficacy of an antimicrobial agent is dependent on the relationship 
between the MIC for the micro-organism and the exposure of the micro-organism to the agent in the 
patient. Therefore, we also aim to study the pharmacokinetic and pharmacodynamic properties of 
gentamicin, ertapenem and ceftriaxone (IM administered) and fosfomycin (orally administered). By 
combining pharmacokinetic data with antimicrobial susceptibility data (MIC) of circulating Neisseria 
Gonorrhoeae (Ng) strains, Monte Carlo simulations will be performed to predict treatment efficacy 
under various antimicrobial resistance prevalence conditions, both now and in the near future[24].  
The population pharmacokinetics of ceftriaxone, ertapenem and gentamicin have mainly been studied 
in hospitalized patients that received intravenous administrations of these antibiotics [25-31]. Musson 
et al.[32], however, studied pharmacokinetic parameters in healthy volunteers after the administration 
of ertapenem 1000mg intramuscularly without estimating the population pharmacokinetics. For the 
PKPD analysis of the studied antibiotics, it is important to have an estimation of the population 
pharmacokinetics after the administration of a single dose of ceftriaxone 500mg IM, ertapenem 
1000mg or gentamicin 5mg/kg IM in our substudy population. In the PK substudy, we plan to measure 
the plasma concentrations within 24 hours after administration of these intramuscular doses, and 
subsequently estimate the PK on population level by NONMEM analysis.  
Bergan et al.[33], and Wenzler et al.[34]  studied pharmacokinetics after oral administration of 3g and 
4g fosfomycin. Since saturated absorption or other unknown mechanisms might result in a non-linear 
increase in plasma concentration after administration of an increased dose, we also aim to study the 
population pharmacokinetics after oral administration of 6g fosfomycin in our population. We do not 
expect that volunteers and gonorrhea patients differ significantly regarding pharmacokinetic 
characteristics (renal and liver function, volume of distribution and level of proteins in blood plasma), 
in contrast to hospitalized patients in whom these characteristics may be strongly affected. Therefore 
we will study the population pharmacokinetics of ceftriaxone 500mg IM,  ertapenem 1000mg IM and 
fosfomycin 6g orally in volunteers without current gonorrhea or gonorrhea in the preceding two weeks 

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7 
 
(n=60), and we will study the population PK of ceftriaxone 500mg IM, ertapenem 1000mg IM and 
gentamicin 5mg/kg in NABOGO participants (n=60).  
As of October 2, 2018 the fosfomycin arm was dropped after the advice of the DSMB board based on 
an interim analysis performed by an independent statistician. The NABOGO trial is thus being 
continued as a three-armed RCT. The linking of pharmacokinetic and pharmacodynamic data of 
fosfomycin with clinical treatment outcomes will enable us to understand the main reasons for 
treatment failure and will allow us to recommend on future dosing regimens. The simulations based 
on both population pharmacokinetics and pharmacodynamics will be used to estimate the attainment 
rate of the pharmacodynamic target of the antibiotic for different concentrations; and eventually we 
may be able to predict promising dosing regimens.  
 
 

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8 
 
2. OBJ ECTIVES 
 
Primary objectives 
To evaluate whether ertapenem  and gentamicin are non-inferior to ceftriaxone in the treatment of 
uncomplicated anogenital gonorrhea in patients visiting the STI clinic of the Public Health Services in 
Amsterdam. Treatment effectiveness is determined by  the bacterial eradication capacity of the 
antibiotics, based on a test of cure (TOC) 7-14 days after treatment administration.  
 
Secondary objectives 
1. To determine the bacterial eradication capacity of the experimental treatment options (ertapenem  
and gentamicin) compared to the reference treatment (ceftriaxone) in uncomplicated anogenital 
gonococcal infections by molecular test of cure after 7-28 days.  
2. To determine the bacterial eradication capacity of experimental treatment options compared to the 
reference treatment at infection sites other than the included infection site (also including pharyngeal 
gonorrhea) by molecular test of cure after 7-28 days.  
3. To determine the type, frequency and severity of adverse events of the experimental treatment 
options compared to the reference treatment.  
4. To determine the time to disappearance of symptoms at the included infection site in the first 14  
days after treatment, for the experimental treatment compared to the reference treatment.  
5. To determine the clinical and demographic predictors for treatment failure (see chapter 7 for 
definition).  
6 
7. To determine the in vitro antimicrobial susceptibility (in MIC) of the experimental and reference 
treatment in all Ng strains collected at all infected anatomical sites of each participant at inclusion and 
in case of a positive test of cure, and to determine whether a relation exists between MIC and 
treatment outcome.  
8. To determine the population pharmacokinetics of a single dose of ceftriaxone 500mg IM, 
gentamicin 5mg/kg IM and ertapenem 1000mg IM, and fosfomycin 6g orally administered.  
 
 

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9 
 
3. STUDY DESIGN 
RCT 
A double-blind randomized controlled single center non-inferiority trial with two experimental arms and 
one reference arm. The expected duration of the study is 47 months, of which 27.4 months are 
needed for recruitment. The study will be conducted at the sexually transmitted infections (STI) 
outpatient clinic of the Public Health Service in Amsterdam.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* estimated numbers 
Figure 1. Flow chart of study design and sample size of total recruitment period (18th of September 
until the inclusion and follow-up of all 346 participants). 
 
 
Patients visiting STI Outpatient 
Clinic Amsterdam 
Meeting inclusion criteria  
Meeting exclusion criteria 
Reference therapy 
(n = 102)* 
Experimental arm 1 
(n = 102)* 
Experimental arm 2 
(n = 102)* 
Dropped arm 3 
(n = ±40)* 
Randomization  
(n = 346)* 
Post-randomisation exclusions based on 
negative baseline NAAT (n = 35)*  
Loss to follow-up (n = 35)* 
Protocol violations 
Per protocol population 
Modified Intention to treat population (n = 276)* 
Not meeting inclusion 
criteria 
Not meeting exclusion criteria 

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10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* estimated numbers 
Figure 2. Flow chart of study design and sample size period 1 (from the start of recruitment until the 
termination of one treatment arm (fosfomycin)). 
 
 
 
Patients visiting STI Outpatient 
Clinic Amsterdam 
Meeting inclusion criteria  
Meeting exclusion criteria 
Reference therapy 
(n = ±40)* 
Experimental arm 1 
(n = ±40)* 
Experimental arm 2 
(n = ±40)* 
Experimental arm 3 
(n = ±40)* 
Randomization  
(n = 154)* 
Post-randomisation exclusions based on 
negative baseline NAAT (n = 16)*  
Loss to follow-up (n = 16)* 
Protocol violations 
Per protocol population 
Intention to treat population (n = 122)* 
Not meeting inclusion 
criteria 
Not meeting exclusion criteria 

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11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* estimated numbers 
Figure 3. Flow chart of study design and sample size period 2 (from the termination of one treatment 
arm (fosfomycin) until the total required sample size is reached 1st of October 2018 until 3rd of 
February 2020*) 
 
 
 
 
 
 
 
Patients visiting STI Outpatient 
Clinic Amsterdam 
Meeting inclusion criteria  
Meeting exclusion criteria 
Reference therapy 
(n = 64)* 
Experimental arm 1 
(n = 64)* 
Experimental arm 2 
(n = 64)* 
Randomization  
(n =  (346-154=)192)* 
Post-randomisation exclusions based on 
negative baseline NAAT (n = 19)*  
Loss to follow-up (n = 19)* 
Protocol violations 
Per protocol population 
Modified intention to treat population (n = 154)* 
Not meeting inclusion 
criteria 
Not meeting exclusion criteria 

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12 
 
PK substudy 
To estimate the population pharmacokinetics of ceftriaxone 500mg IM, ertapenem 1000mg IM,  
fosfomycin 6g PO, and gentamicin 5mg/kg IM we will perform NONMEM based on blood plasma 
concentrations of these agents within 24hours after treatment administration. We experienced that it 
is not feasible for NABOGO participants to return 2-3 times within 24hours after treatment 
administration because they were not prepared for this. We decided to expand the population of the 
PK substudy with 60 healthy volunteers who did not receive antibiotics in the preceding 2 weeks. 
From this population we will obtain four blood samples to measure the plasma concentrations for 
ceftriaxone, ertapenem and fosfomycin at different time points within 24hours after treatment 
administration. Considering the known side effects of gentamicin (nephro- and ototoxicity) we decided 
not to expose healthy volunteers to gentamicin. Since gentamicin has a short Tmax, we aim to draw 
one blood sample in 60 NABOGO participants 30-90 minutes after treatment administration. Following 
the 1:1:1 randomization scheme, approximately 20 of these participants will have received 
gentamicin, 20 ertapenem and 20 ceftriaxone. With this we are able to estimate the population Cmax 
of gentamicin and at the same time compare the first plasma concentration for ceftriaxone and 
ertapenem in NABOGO participants and healthy volunteers.  
 
We aim to include 120 participants in the PK substudy in total. Of these, 60 participants will be 
gonorrhea patients and 60 participants will be healthy volunteers recruited at the STI clinic and at 
universities in Amsterdam.  
 
 

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13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4. Flow chart of study design and sample size of the PK substudy; healthy volunteers.  
NONMEM: Non-linear Mixed Effects Modeling. 
 
 
People visiting the STI Outpatient 
Clinic Amsterdam,  the Amsterdam 
University Medical Center or the 
University of Applied Sciences 
Amsterdam (HvA) 
Meeting inclusion criteria  
Meeting one or more exclusion criteria 
Not meeting inclusion 
criteria 
Meeting none of the  exclusion criteria 
Interested in participation 
Randomization  
(n = 60) 
Ceftriaxone administration 
(n = 20) 
Ertapenem administration 
(n = 20) 
Fosfomycin administration 
(n = 20) 
NONMEM 
NONMEM 
NONMEM 
Four return visits within 24h 
for blood sampling 
Four return visits within 24h 
for blood sampling 
Four return visits within 24h 
for blood sampling 
Measure blood plasma 
concentrations 
Measure blood plasma 
concentrations 
Measure blood plasma 
concentrations 

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14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
igure 5. Flow chart of study design and sample size of the PK substudy; gonorrhea patients.  
NONMEM: Non-linear Mixed Effects Modeling. 
 
 
 
 
 
 
 
 
 
NABOGO participants 
Interested in PK participation 
Randomization  
(n = 60) 
Blinded ceftriaxone 
administration (n = ±20)  
Blinded ertapenem 
administration (n = ±20)  
Blinded gentamicin  
administration (n = ±20)  
NONMEM 
NONMEM 
NONMEM 
One blood sample within 30-
90 minutes 
One blood sample within 30-
90 minutes 
One blood sample within 30-
90 minutes 
Measure blood plasma 
concentrations 
Measure blood plasma 
concentrations 
Measure blood plasma 
concentrations 

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15 
 
4. STUDY POPULATION 
 
4.1.1 Study population main study 
Patients visiting the STI Outpatient Clinic Amsterdam and having an uncomplicated anogenital Ng 
infection can be included in this study. At the STI clinic in Amsterdam we diagnosed 2230 new 
gonorrhea patients in 2016, or approximately 185 per month. Of these, 2033 patients were male and 
197 were female, ages ranged between 15 years and 73 years old with a variety in ethnic 
backgrounds. Of all gonorrhea cases 28.1% were coinfected with other bacterial STI. Of all 
anatomical infection sites, in 2016, the anorectal site was most frequently infected (1218 anorectal 
infections among MSM, 84 anorectal infections among females), followed by the pharyngeal infection 
site (1026 pharyngeal infections among MSM, 58 pharyngeal infections among females). The 
urogenital infection was the least infected site (476 urogenital infections among MSM, 144 urogenital 
infections among heterosexual males, 143 cervical/vaginal infections among females) at the STI clinic 
in Amsterdam [Annual report STI clinic Public Health Service (GGD) Amsterdam, 2016].  
4.1.2 Study population PK-substudy  
Attendees of the STI outpatient clinic Amsterdam and students of the Amsterdam University Medical 
Centre (AUMC) and the University of Applied Sciences Amserdam (HvA) will be approached in order 
to participate in the PK substudy  
 
4.2.1 Inclusion criteria main study 
In order to be eligible to participate in this study, a subject must meet all of the following criteria:  
- 
18 years or older 
- 
Anorectal, cervical/vaginal or urethral Ng infection, diagnosed by the following: 
o 
Ng-positive Gram-stained smear (intracellular Gram-negative diplococci and 
leukocytes) and/or 
o 
Positive for Ng by nucleic acid amplification test (NAAT) (Aptima Combo 2) and/or 
o 
Positive for Ng by culture 
- 
Provide samples from the included infection site for NAAT and direct culture immediately 
before treatment 
- 
Willing to abstain from anal, vaginal and oral sex until the test of cure (TOC)-visit, or use 
condoms during sex 
- 
Willing and able to return for a TOC-visit 7-14 days after treatment 
- 
Provide informed consent 
- 
Accept intramuscular injections 
 
4.2.2 Inclusion criteria PK substudy (healthy volunteers) 
In order to be eligible to participate in this study, a subject must meet all of the following criteria:  
- 
18 years or older 
- 
Provide informed consent 

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16 
 
 
 
4.3.1 Exclusion criteria main study 
A potential participant who meets any of the following criteria will be excluded from participation in this 
study 
 
Pre-randomisation: 
- 
Suspicion of a complicated Ng infection based on signs and/or symptoms indicating pelvic 
inflammatory disease (PID), epididymitis, prostatitis or gonococcal arthritis* 
- 
Another (sexually transmitted) infection or a suspicion of another infection for which systemic 
antimicrobial therapy is indicated 
- 
Pregnancy, having a wish to become pregnant or breastfeeding (tested at inclusion visit) 
- 
Not able to read/understand Dutch or English 
- 
HIV infection if: 
o 
Newly diagnosed HIV infection (upon the inclusion visit) and/or 
o 
CD4+ cell-count <200 cells/µL (as reported by the patient) 
- 
Known allergy or adverse reactions to ceftriaxone, ertapenemor gentamicin 
- 
Known renal impairment (based on estimated GFR using Cockroft and Gault formula using 
serum creatinin measured with a point-of-care (POC) test; cut off value renal impairment 
eGFR ≤ 50 ml/min) 
- 
Known liver cirrhosis (based on history) 
- 
Known congestive heart failure (based on history) 
- 
Known myasthenia gravis 
- 
Known hearing loss or balance disorder, confirmed by an ear-nose-throat (ENT)-doctor or for 
which an ENT doctor has been consulted and a diagnostic process is still in progress (based 
on history) 
- 
Concurrent use of any of the following medication:  
o 
systemic antibacterial antimicrobials other than nitrofurantoin or metronidazole 
o 
systemic immunosuppressive drugs 
o 
systemic valproic acid 
- 
Use of any antimicrobial therapy other than nitrofurantoin or metronidazole in the two weeks 
prior to study enrollment (based on history) 
- 
Previous enrollment in the study 
- 
Concurrent participation in other non-observational medical research* 
- 
Unlikely to adhere to the study protocol 
 
Post-randomisation: 
Exclusion of participants from the modified intention to treat analysis (mITT): 
- 
Negative result of Ng NAAT of sample collected on T0 (the day of treatment). This could be 
the case in the following situations: 

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17 
 
1. Negative NAAT in spite of positive gram stain. 
2. Positive NAAT on pre-study visit but spontaneous clearance of the infection in the time 
period between first test and return visit for treatment (=study inclusion visit). A novel 
sample for NAAT will be collected on the study inclusion visit just before administration of  
treatment; if these results are Ng-negative a participant will be excluded of mITT.  
- 
Loss to follow-up, i.e. no study visit TOC 7-14 days after treatment administration.  
 
Exclusion from per protocol analysis (PP):  
- 
Exclusion of mITT 
- 
Use of non-study related antibiotics after inclusion and prior to TOC visit 
- 
Condomless sexual contact with the primary anatomical gonorrhea site involved after 
inclusion and prior to TOC visit 
- 
Other protocol violations 
 
4.3.2 Exclusion criteria PK substudy (healthy volunteers) 
A potential participant who meets any of the following criteria will be excluded from participation in this 
study 
 
Pre-randomisation: 
- 
Pregnancy, having a wish to become pregnant or breastfeeding (tested at inclusion visit) 
- 
Not able to read/understand Dutch or English 
- 
Known allergy or adverse reactions to ceftriaxone, ertapenem, or fosfomycin. 
- 
Known renal impairment (based on history) 
- 
Known liver cirrhosis (based on history) 
- 
Concurrent use of any of the following medication:  
o 
systemic valproic acid 
o 
systemic metoclopramide 
- 
Use of any systemic antimicrobial therapy other than nitrofurantoin or metronidazole in the two 
weeks prior to study enrollment (based on history) 
- 
Concurrent participation in other non-observational medical research (apart from NABOGO RCT) 
- 
Unlikely to adhere to the study protocol 
 
 
 

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18 
 
4.4.1 Sample size calculation main study 
To calculate the required sample size for this non-inferiority trial we used the R function nBinomial of 
the “gsDesign“ package. This function computes sample size using the Farrington and Manning 
method for a trial to test the difference between two binomial event rates [35]. The following 
parameters were used in the calculation: 98% treatment success in control and experimental arms, 
10% non-inferiority δ-margin (a commonly used margin), and 90% power. Three hypothesis tests are 
considered in which proportion of treatment success are compared between each treatment arm and 
control. Significance of these tests will be determined using the stepwise Hochberg procedure and 
power will be based on a one-sided α-level at the first step of this procedure (α=0.025). This results in 
a sample size of 81 participants per treatment arm. Considering that 20% of participants will be 
excluded from analysis either due to loss-to-follow-up (10% participants not returning for TOC or 
exclusion criteria) or post hoc exclusion (10% due to false-positive gram stains and self-clearance), 
we require 102 included participants per treatment arm.  
 
4.2.2 Sample size calculation PK substudy 
In order to estimate the population pharmacokinetics, we will measure blood concentration of 
ceftriaxone, ertapenem and fosfomycin in 20 participants at 4 time points within 24h after 
administration for each of the three antibiotics, so 60 participants in total [36]. At the same time, we 
will measure the blood plasma concentration of ceftriaxone, ertapenem and gentamicin in 20 
participants at 1 time point within 90 minutes after administration for each of the three antibiotics 
remaining in the NABOGO trial. With the collected data reliable population pharmacokinetic-
pharmacodynamic models will be derived for Monte Carlo simulations.  
 
4.5. Recruitment duration 
At the STI clinic in Amsterdam we diagnosed 1667 new anogenital gonorrhea cases in 2016, which is 
approximately 138 per month. Assuming that 71.9% of them does not have a bacterial co-infection 
and will be eligible to participate in this trial and assuming that 30% of invited patients consent to 
participate and does not meet exclusion criteria, we may expect 30 inclusions per month. To allow for 
a slow inclusion of 25 per month, we will need a recruitment period of 408/25 = 16.3 months.  
 
The recruitment rate in the first 11 months of the trial was 2.8 participants per week. Since we need 
102 participants in each of the remaining three treatment arms (resulting in a total sample size of 
±346 participants), we expect that we need 124 weeks in total. Recruitment started on 18th of 
September 2017 and is expected to be completed on 3 of February 2020.  
 
4.6 Patient registration  
Inclusion of participants will be performed by research nurses and the research coordinator. After 
obtaining written informed consent, the research coordinator will keep the informed consent form. A 
study number will be generated at inclusion and stored on a coding list. All participants receive a 
‘study identification card’ with contact information of the study team and a personal study number of 

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19 
 
which should be kept by the participant. This ‘study identification card’ does not contain any personal 
information of the participant.  
 
 

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20 
 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational treatment 
Participants will be treated with one of the two experimental therapies (intramuscular gentamicin and 
ertapenem) or the reference therapy (intramuscular ceftriaxone). Participants and the treating health 
professional will be blinded for the treatment allocation. For blinding purposes, all participants receive 
two intramuscular injections (gentamicin will be administered in two intramuscular injections, when 
allocated to the ertapenem or ceftriaxone group participants will be given one intervention 
intramuscular injection and one placebo intramuscular injection). 
 
5.2 Use of co-intervention 
There will be no use of co-intervention. Nevertheless participants are asked to refrain from sexual 
intercourse or use condoms between treatment and follow-up visit in order to minimize the occurrence 
of re-infection.  
 
5.3 Escape medication 
In case of treatment failure (see chapter 8.1.1 for definition), patients will be treated with the current 
reference therapy in an increased dose, ceftriaxone 1000mg intramuscular, plus azithromycin 
1000mg orally. Ceftriaxone is currently still 100% effective in the Netherlands. However, it is possible 
that treatment failure occurs even after receiving ceftriaxone 500mg (as study therapy). Since Ng 
cultures are not always successful (positivity rate is approximately 80% in our laboratory) and thus we 
might not always have MIC values of the Ng strains, we choose to double the dose of ceftriaxone and 
to add azithromycin to the escape medication regime. Azithromycin is effective in the majority of Ng 
strains. If the Ng bacteria have been cultured from a case of treatment failure either at the day of 
inclusion and/or follow-up visit, and we know that the Ng strain is resistant to azithromycin and 
susceptible to ceftriaxone, the participant will receive ceftriaxone 1000mg only.  
 
 
 
 

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21 
 
6. INVESTIGATIONAL PRODUCT 
 
6.1 Names and description of investigational medicinal products 
There will be three arms consisting of experimental treatments and one control arm consisting of the 
current reference treatment.  
- 
Reference treatment: single dose ceftriaxone 500 mg IM, dissolved in 2 ml lidocaine 1% 
supplemented with 0.9% NaCl until 10 ml (2 x 5 ml). 
- 
Experimental arm 1: single dose ertapenem 1000 mg IM, dissolved in 3.2 ml lidocaine 1% 
supplemented with 0.9% NaCl until 10 ml (2 x 5 ml). 
- 
Experimental arm 2: gentamicin 5 mg/kg IM injection once (solution 40 mg/ml), if indicated 
supplemented with 0.9% NaCl until 10 ml (2 x 5 ml). Maximum gentamicin dose is 400 mg 
because this is diluted in 10ml which is the maximum volume for 2 intramuscular injections. 
- 
Experimental arm 3: fosfomycin 6 gram trometamol orally once (PK substudy only) 
- 
Placebo intramuscular injection: 5 ml or 10 ml (2 x 5 ml) 0.9% NaCl (when receiving oral therapy 
10 ml 0.9% NaCl will be administered, and when receiving ertapenem or ceftriaxone 5 ml 0.9% 
NaCl will be administered).  
 
6.2 Summary of findings from non-clinical studies 
See summary of product characteristics. 
 
6.3 Summary of findings from clinical studies 
See summary of product characteristics. 
 
6.4 Summary of known and potential risks and benefits 
Ceftriaxone 
Ceftriaxone is the standard therapy for Ng infections in the Netherlands. There is no resistance 
among Ng strains to ESCs reported in the Netherlands and ceftriaxone is well tolerated. Thus, in this 
trial ceftriaxone will not cause any additional risks in comparison to the general population with 
gonorrhea. Consequently there is no need for extra measures to reduce expected risks.  
Ertapenem 
Ertapenem is safely used for several indications worldwide both in intramuscular and intravenous 
form (for more detailed information see chapter 12.1) [37]. In Europe, ertapenem is not yet registered 
as intramuscular injection, however it is safely used intravenously [38]. We do not expect any harm 
from a single intramuscular dose in our young and relative healthy population. Because of the 
influence of ertapenem on the valproic acid plasma levels, patients using valproic acid are excluded 
from this trial.  
Fosfomycin 
Fosfomycin is safely used for several indications worldwide. The usual dose of oral fosfomycin in 
urinary tract infections is a single dose of 3g. Based on Monte Carlo simulations to predict effective 

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22 
 
treatment dosage, 6g is expected to be effective in gonococcal infections. Since intravenous doses 
are administered up to 24g in 2-3 doses per day, we do not expect toxicity from a 6g oral dose. A few 
clinical studies have been performed on (either intramuscular or oral) fosfomycin in patients with 
uncomplicated gonococcal urethritis, none of these studies reported any severe events [14, 30, 31]. 
Participants of this trial are assured not to take metoclopramide in the first 7 days. In case of the 
intake of metoclopramide on the day of inclusion or in case of the intention to take metoclopramide in 
the following days, patients are excluded from this study.  
Gentamicin 
Since gentamicin is widely used for different indications and earlier research on a single dose 
intramuscular injection of 240-280mg [18, 39-42] in patients with gonorrhea did not show any severe 
side effects, the hypothesis is that it is an efficient and safe product for this indication. There is limited 
knowledge on the prevalence of nephro- and ototoxicity as a result of a single dose gentamicin [43]. 
For this reason, renal function will be measured before treatment administration and people with an 
impaired renal function will be excluded from this study. Additionally, at the follow-up visit 7-14 days 
after treatment, renal function will again be tested in order to follow the effects of a single dose 
gentamicin on renal function. Also hearing problems and balance disorder will be evaluated before 
and after treatment.  
 
6.5 Description and justification of route of administration and dosage 
Ceftriaxone, ertapenem and gentamicin will be administered intramuscularly, as oral administration is 
not possible. Furthermore, intravenous administration is less comfortable for patients, not necessary 
and not possible at the STI outpatient clinic. In Europe, ertapenem is only registered for intravenous 
administration. In the United States of America (USA) ertapenem is approved by Food and Drug 
Administration (FDA) both for intravenous and intramuscular administration for various indications 
[37].  
For blinding purposes all participants receive two intramuscular injections.  
  
6.6 Dosages, dosage modifications and method of administration 
Dosages for ertapenem, fosfomycin and gentamicin are based on Monte Carlo simulations using 
pharmacokinetic information from literature [44-56], and MIC data of Ng strains isolated in Amsterdam 
Dosage of ceftriaxone is according to current Dutch STI guidelines [57]. 
Monte Carlo simulations of 5 mg/kg gentamicin (max 400 mg) IM demonstrated a median maximal 
concentration (Cmax) of 16 mg/L (95% CI: 8-22 mg/L (see figure 2). With a MIC of 1 the ratio 
Cmax/MIC is well above 10 which is considered a PD target for gentamicin. 

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23 
 
0
6
1 2
1 8
2 4
0
4
8
1 2
1 6
2 0
2 4
2 8
G e n ta m ic in  4 0 0  m g  im
tim e  (h )
g e n ta m ic in  c o n c  (m g /L )
 
Figure 6: Monte Carlo simulation of 5 mg/kg (max 400 mg) gentamicin IM  
 
Monte Carlo simulations of 1000 mg ertapenem IM resulted in unbound concentrations 9.6 hours 
above MIC in 100% of the patients with MIC up to 0.25 mg/L (Figure 3). This is well above the MIC90 
observed in our outpatient clinic (0.016 mg/L). 
 
0 .0 0 1
0 .0 1
0 .1
1
1 0
0
2 0
4 0
6 0
8 0
1 0 0
M IC  (m g /L )
%  p e rc n ta g e  p a tie n ts  9 .6  h o u r T > M IC
M IC 5 0
G G D
M IC 9 0
G G D
E rta p e n e m  1 0 0 0  m g  im
   
Figure 7: Monte Carlo simulation of 1000 mg ertapenem IM  
 

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24 
 
Monte Carlo simulations of 6 gram oral fosfomycin resulted in concentrations above an MIC of 10 
mg/L during an 8-hour period for 95% of the patients. Lopez Gracia reported a similar exposure after 
a single IM dose of 4 gram; in this study this dose produced 100% eradication [30]. 
0
6
1 2
1 8
2 4
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
F o s fo m y c in  6  g  p o
tim e  (h )
fo fs fo m y c in  c o n c  (m g /L )
 
 Figure 8: Monte Carlo simulation of 6 gram oral fosfomycin  
 
 
6.7 Preparation and labeling of Investigational Medicinal Product 
This study will be performed in a double-blind fashion. The patient, study nurse and the study 
coordinator will be blinded to treatment allocation.  
 
The medication will be prepared by an independent medical doctor or nurse from the STI clinic. When 
a patient is included in the study, this independent medical person performs the randomization and 
prepares the medication according to the allocated treatment arm. Subsequently, the blinded 
medication is delivered to the study coordinator or study nurse, who will administer the blinded 
medication to the participant. A list will be kept by the independent medical person with the participant 
study ID linked to the allocated study arm. Four to five medical doctors and nurses from the STI clinic 
will be trained to function as an independent treatment preparer.  
 
6.8 Drug accountability 
Ceftriaxone and gentamicin are registered at the European Medicines Agency (EMA) in this form and 
mode of administration and therefore will be available from any pharmacy. However, as stated before, 
ertapenem is only registered at the EMA for IV administration. The IV formulation is used for IM 
administration in the USA and this method is FDA approved for several indications. We will use the IV 
formulation likewise for IM administration. Batch numbers of medication used will be recorded. 
For intramuscular placebo we will use 0.9% NaCl.  
 

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25 
 
7. METHODS 
7.1 Study endpoints 
7.1.1 Primary endpoint 
Bacterial eradication of Ng infection at the included (anal or urogenital) infection site, based on a test 
of cure (TOC) using an RNA-based NAAT (Aptima Combo 2 assay) at the follow-up visit 7-14 days 
after treatment (T7).  Subsequently, the difference in treatment success rates between each 
investigational treatment and the reference treatment will be measured.  
Treatment success of anal, urethral, vaginal and pharyngeal infection sites is defined as a negative 
test of cure.  
Treatment failure of the anal, urethral and vaginal infection sites is defined as 1) a positive test of cure 
7-14 days after treatment, or 2) a positive test of cure less than 7 days after treatment in combination 
with persisting symptoms and/or a positive gram stain 3-6 days after treatment. 
Treatment failure of the pharyngeal infection site is defined as 1) a positive NAAT ≥ 14 days after 
treatment, or 2) a positive Ng culture ≥ 7 days after treatment.  
 
7.1.2. Secondary endpoints 
1. Bacterial eradication of Ng infection at the included (anal or urogenital) infection site, based on 
TOC using an RNA-based NAAT 7-28 days after treatment. 
2. Bacterial eradication of Ng infection at any infected site(s) (anal, urogenital and/or pharyngeal) not 
included in the primary endpoint analysis, based on a TOC using an RNA-based NAAT 7-28 days 
after treatment.  
3. Any adverse events (type, frequency and severity) occurring during 28 days following the start of 
treatment.  
4. In vitro MIC of all Ng strains for all study antimicrobials, determined by e-test on culture at 
inclusion (before treatment, T0) and at the TOC follow-up visit (T7). 
5. Clinical cure:  
a. Symptoms of Ng infection (such as pain, irritation/itch, redness, any discharge, bleeding, 
changed defecation pattern and/or swelling) from treatment to TOC visit (7-14 days). 
b. Time (in days) from the start of treatment to disappearance of symptoms of Ng infection. 
c. Signs of Ng infection (such as mucosal fragility, redness, discharge, bleeding and/or swelling) 
assessed at physical examination if indicated based on symptoms, at T0 and T7.  
6. Pharmacokinetic characteristics of study drugs in peripheral blood up to 24 hours after 
administration.  
 
 
 

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26 
 
 
7.2 Randomization, blinding and treatment allocation 
7.2.1 Randomization 
Participants will be randomized in a 1:1:1 ratio to the three treatment arms. Randomization will be 
performed using random permuted blocks assuring equal distribution to all treatment arms. The length 
of the blocks will be random to avoid any selection bias (3-9 participants per block). A computer 
randomization program ALEA, which is validated for use in GCP trials and will be provided by the 
AMC Clinical Research Unit, will be used to perform allocation.  
 
7.2.2 Blinding 
This study will be performed in a double-blind fashion. The patient, study nurse, the study coordinator 
and principal investigator will be blinded to treatment allocation.  
 
There will be an independent medication preparer available for randomization, treatment allocation, 
preparation and blinding of medication. When a patient is included in the study, the medication 
preparer performs the randomization and prepares the medication according to the allocated 
treatment arm. The independent medication preparer will deliver the blinded medication to the study 
coordinator or study nurse, who subsequently will administer the medication to the participant. A list 
will be kept by the independent medication preparer with the participant study ID linked to the 
allocated study arm. Medical doctors and nurses from the STI clinic will be trained to function as an 
independent treatment preparer.  
 
7.2.3 Treatment administration 
All participants receive two intramuscular injections of 5 ml in the upper outer quadrant of each 
gluteus maximus muscle.  
 
7.2.4 Indication for breaking the randomization code  
An AE that needs further treatment by a medical doctor could be an indication for breaking the 
randomization code in a particular participant. The appearance of a SAE that is determined to be 
related to the study treatment could also be an indication for deblinding the treatment allocation in a 
particular participant.   
 
7.3 Study procedures 
All participants will receive standard care including counseling, partner notification,  and diagnostics 
for other STIs if indicated.  
 
 
 

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27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 9. Flowchart of study procedures 
 
Persistence or worsening of symptoms after treatment 
Participants who contact the STI clinic in less than 7 days after treatment administration because of 
persistence or worsening of symptoms, will be evaluated by the study coordinator or the principal 
investigator. If indicated, a Gram stain will be repeated. If the Gram stain is negative, a watchful 
waiting policy will be followed regarding the Ng infection and the participant will be advised to come 
back at the follow-up visit 7 days after treatment administration. Further diagnostics can be initiated 
for other (suspected) diseases. When the repeated Gram stain is positive >48 h after treatment 
administration, samples will be collected for NAAT and culture, and the study physician decides 
whether to treat with escape medication or not, depending on the severity of complaints. Ng RNA may 
still be detectable within 7 days after treatment, even when the infection has been effectively treated 
[58]. This means that a positive NAAT within 7 days is not a reliable indicator for treatment failure. If 
escape medication is given and the NAAT is positive, this case will be considered as treatment failure 
in the intention to treat (mITT), but will be excluded from the per protocol analysis. When escape 
Gram-stain (complaints) 
STI consultation (no complaints) 
1. questionnaire and physical examination 
2. collect samples for Ng NAAT and culture 
3. finger prick (for POC serum creatinin test) 
4. randomization 
5. receive treatment (and placebo) 
6. receive diary and instruction for at home 
7. Optional: vena punction within 30-90 
minutes (PK substudy) 
collect samples for NAAT; wait for results 
T0 
Follow-up visit: 
- NAAT (TOC) and culture 
- POC serum creatinin test 
- evaluate symptoms 
- evaluate adverse events 
- physical examination if 
indicated 
Post randomization exclusion 
(self- clearance) 
Postrandomization 
exclusion (false positive) 
Final contact (per email) for evaluation by a digital questionnaire 
T30
T7 
1. questionnaire and physical examination 
2. repeat samples for Ng NAAT and culture 
3. finger prick (for POC serum creatinin test) 
4. randomization 
5. receive treatment (and placebo) 
6. receive diary and instruction for at home 
7. Optional: vena punction within 30-90 
minutes (PK substudy) 
Return for 
- NAAT and culture 
- treatment with escape 
medication 

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28 
 
medication is given and the culture is positive, this case will be treated as a treatment failure in both 
the mITT- and per protocol (PP) analysis.  
Questionnaire 
The following information will be obtained by a questionnaire at the day of inclusion and at the follow-
up visit at day 7-14: symptoms (pain, irritation/itch, redness, discharge, bleeding, and/or swelling, 
duration of symptoms), sexual behavior, and at the follow-up visit and by an e-questionnaire at day 30 
(a link to a secured digital questionnaire will be sent by email): any adverse events (in particular rash 
and hearing problems, vestibular problems or tinnitus).  The e-questionnaire at day 30 will also 
contain an evaluation of the experiences of participating in this trial.  
 
Diary 
All participants are requested to keep a diary to record the presence of complaints (either symptoms 
and adverse events), sexual activity and medication use.  
 
Physical examination 
Signs (mucosal fragility, redness, discharge, bleeding and/or swelling) at physical examination of the 
included infection site are scored by a study nurse, study physician or clinician during clinic visits at 
the day of inclusion (T0) and at the follow-up visit for TOC (T7) if indicated based on symptoms. 
 
Laboratory tests  
- 
Ng RNA-based NAAT (Aptima Combo 2 assay) 
The RNA-based NAAT is the test of first choice for test of cure because of its high specificity 
and superior sensitivity compared to bacterial culture[59]. It has been recently recommended 
to perform the test no sooner than 7 days after treatment [58]. 
o 
Men who have sex with men (MSM): anal and pharyngeal swabs and urine will be 
obtained at T0 and at T7, test of cure (TOC).  
o 
Females: anal, pharyngeal and vaginal swabs will be obtained at T0 and T7 (TOC) 
o 
Heterosexual men: urine will be obtained at T0 and T7 (TOC).  
In case of treatment failure another NAAT of the anatomical location(s) that were infected at 
T0 will be performed just before the administration of escape medication and 7-14 days later 
(a second TOC).  
 
- 
Ng culture  
o 
MSM: anal, pharyngeal and urethral swabs will be obtained at T0 and at T7 (TOC).  
o 
Females: anal, pharyngeal and vaginal swabs will be obtained at T0 and at T7 (TOC).  
o 
Heterosexual men: urethral swabs will be obtained at T0 and at T7 (TOC). 
In case of treatment failure additional cultures of the anatomical locations that were infected at 
T0 will be performed just before the administration of escape medication and 7-14 days later 
(a second TOC). 
 

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- 
Molecular typing 
In case of a Ng-positive culture at T0 and T7, strain identification of both the Ng strains will be 
performed by genotyping in order to identify whether these strains are genetically identical. 
 
- 
Minimal inhibitory concentrations 
MIC values of ceftriaxone, ertapenem, fosfomycin and gentamicin for all Ng strains by Etest. 
EUCAST certified breakpoints of MIC values for Neisseria gonorrhoeae do not exist for 
ertapenem, fosfomycin and gentamicin. For this reason, it is not possible to draw any 
conclusions on susceptibility/resistance before the analysis.  
 
- 
Creatinine and calculation of the estimated glomerular filtration rate (eGFR) 
Finger prick to collect a drop of blood (32 µL)  for a point-of-care serum creatinin test at T0 
and at T7 will be performed in order to test for renal impairment (an exclusion criterion and 
possible adverse event of gentamicin). Renal impairment is defined by a eGFR ≤50 ml/min 
(calculated with Cockroft-Gault).  
 
- 
Plasma concentration of antibiotics and albumin 
In participants of the substudy, a venapunction will be performed to collect 4,5 ml blood at 
four time points within 24 hours after treatment administration . In these blood samples the 
plasma concentration of the antibiotics and albumin (only in the first sample) will be 
measured. The maximal volume is 18 ml in total.  
 
Re-infections: to minimize the risk of re-infections  
All participants are requested to abstain from sexual intercourse until their TOC visit, or consistently 
use condoms, and report their behavior in a diary.  
 
Storage of bodily material 
According to routine procedures at the laboratory body material with negative test results will be 
destroyed after 2 weeks. Bodily material of positive test results will be stored until 5 years after the 
end of the trial, provided that consent is obtained.  
 
PK substudy 
1. Gonorrhea patients (also participants in main study) 
Each participant will be requested to participate in the PK substudy as well. If participants 
agree to provide one extra blood sample, a vena punction will be performed and maximum 
4.5mL blood will be drawn 30-90 minutes after the blinded treatment (ceftriaxone, ertapenem 
or gentamicin) administration.   
2. Healthy volunteers 
For this substudy participants will receive one of three antibiotics (ceftriaxone 500mg IM, 
ertapenem 1000mg IM, or fosfomycin 6g orally) at a pre-arranged moment and will return four 

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times within 24 hours in order to obtain one blood sample each timepoint. In total 18 ml blood 
will be obtained by venapuncture to measure the plasma concentration of the antibiotic, 
creatinine, ASAT, ALAT and albumin levels (the latter 4 values will only be measured in one 
blood sample).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 10. Flowchart of the PK substudy for healthy volunteers 
 
7.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason without any consequences.  
 
7.5 Replacement of individual subjects after withdrawal 
This longitudinal study has a relative short follow-up period. If patients are withdrawn from the study 
when recruitment is still ongoing, we will replace them by new inclusions until at least 346 patients are 
included.  
 
7.6 Follow-up of subjects withdrawn for treatment 
If subjects are withdrawn from the study, follow-up is still recommended in order to evaluate adverse 
events. Furthermore, patients will still be able to routinely visit the STI clinic.  
 
7.7 Premature termination of study 
Based on the scheduled interim analysis after the inclusion of one third of the total required sample 
size of the four-armed trial, the DSMB advised to discontinue with one treatment arm (fosfomycin). 
We thus continue this RCT with three arms (ceftriaxone, ertapenem and gentamicin), Other reasons 
Plan 4 appointments:  
1. First blood sample (15-60 minutes after AA) 
2. Second blood sample (60-180 minutes after AA)  
3. Third blood sample (3-7 hours after AA) 
4. Fourth blood sample (18-34 hours after AA) 
Healthy volunteer willing 
to participate in PK 
Sign two informed consent forms 
Check inclusion and exclusion criteria  
Randomization 
Antibiotic administration (oral suspension 
or intramuscular injection 

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to  stop a treatment arm would be situations in which any patient dies, any patient requires 
emergency surgery, or any patient suffers a permanent and irreversible disability, and it can be shown 
that this event was related to participation in this trial.  
 

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8. SAFETY REPORTING 
 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is 
sufficient ground that continuation of the study will jeopardize participant health or safety.  The 
sponsor will notify the accredited METC without undue delay of a temporary halt including the reason 
for such an action. The study will be suspended pending a further positive decision by the accredited 
METC. The investigator will take care that all participants are kept informed. 
 
8.2 AEs, SAEs and SUSARs 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a participant during the study, 
whether or not considered related to the trial procedure or the experimental intervention. All adverse 
events reported by the subject or observed by the investigators, meeting all of the following criteria 
will be recorded: 
- Severity: grade 3 and 4, or grade 1 and 2 lasting longer than 1 week, graded by the CTCAE 
(Common Terminology Criteria for Adverse Events, v4.03, June 2010). 
- Causality: there needs to be a reasonable suspicion of the AE being an effect of the medical 
treatment of uncomplicated anogenital gonorrhea.   
- Time window: between the moment of inclusion and the day 30 follow-up visit. 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that results in death or; 
- 
Is life threatening (at the time of the event); 
- 
Requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
Results in persistent or significant disability or incapacity; 
- 
Any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been, based upon appropriate 
judgment by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
Medically significant serious adverse events considered related to the investigational product by the 
investigator will be reported through the web portal ToetsingOnline to the accredited METC that 
approved the protocol within 7 days of first knowledge. Line-listings of all other SAEs will be reported 
in the annual safety report. 
 
8.2.3 Suspected unexpected serious adverse reactions 
Adverse reactions are all untoward and unintended responses to an investigational product related to 
any dose administered. 

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Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an undesirable 
reaction to the medicinal product under investigation, regardless of the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal ToetsingOnline  to the 
METC: 
 
SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 
SUSARs that have arisen in other clinical trials of the same sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects 
involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every 
half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine, 
accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as notification 
to the competent authority. 
The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the 
adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary 
report with another 8 days for completion of the report.  
8.3. Annual Safety report  
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout the 
clinical trial, a safety report to the accredited METC, competent authority, and competent authorities 
of the concerned Member States.  
This safety report consists of  
- a list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated 
summary table of all reported serious adverse reactions, ordered by organ system, per study; 
- a report concerning the safety of the subjects, consisting of a safety analysis and an evaluation of 
the balance between the efficacy and the harmfulness of the medicine under investigation; 
- a list of all medically non-significant serious adverse events and all serious adverse events 
considered unrelated to the investigational product.    
 
 

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8.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow-up may require additional tests or medical procedures as indicated, 
and/or referral to the general physician or a medical specialist may be required.  
 
8.5 Data safety monitoring board (DSMB) 
We expect the additional risks of participating in this study to be low-moderate. In case of moderate 
extra risks the use of a Data Safety Monitoring Board (DSMB) could be determined per study. In this 
study a DSMB will be installed to timely detect possible inefficacy of one or more experimental 
treatment arms. The included antimicrobials are widely used for other indications and there is ample 
experience with these drugs suggesting minimal safety risks. Nevertheless, if a SAE or important AE 
occurs, the investigators first evaluate whether a relation to the study medication is probable and 
whether deblinding is indicated. Subsequently, the investigators propose their plan to the DSMB who 
will eventually recommend on how to proceed. Detailed information on the DSMB procedures can be 
found in the DSMB-charter (K5).  
 
 

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9. STATISTICAL ANALYSIS 
9.1 Primary study parameters 
We will conduct two analyses on differently defined study populations.  
(1) modified ITT (mITT) analysis will include all patients randomized, apart from pre-specified 
exclusions (patients based on a microscopical gram result indicating gonorrhoea, but in whom 
gonorrhoea was not confirmed by NAAT or culture; and patients with  confirmed gonorrhoea, but in 
whom clearance of Ng prior to administering study treatment was confirmed by a negative NAAT at 
T0). In all mITT analyses, participants will be considered to have failed treatment if:   
- they were given escape medication within 7 days after treatment administration*; 
- if the result of the TOC NAAT between day 7 and 14 is positive 
* Exception: participants who were given escape medication within 7 days after treatment, but whose 
NAAT test result after initial study treatment was negative prior to escape medication will be regarded 
as treatment success.  
Participants are considered lost to follow-up in the analysis if there is no outcome assessment 7-14 
days post treatment. These participants will not be considered in the primary modified intention to 
treat analysis. To test the robustness of the analysis, we will conduct two sensitivity analyses as 
follows: i) considering the LTFU participants as treatment failures and ii) considering the LTFU 
participants as treatment successes.  
(2) PP analysis will only include patients who:  
- were considered in mITT analysis; 
- completed treatment; 
- did not receive unpermitted medication between time of treatment and time of outcome assessment; 
- did not report condomless sex with the primary anatomical gonorrhea site involved 
- had an outcome assessment between 7 and 14 days post-treatment; 
- had no protocol violations. 
If a single participant is infected with Neisseria gonorrhoeae at more than one anatomical site, only 
one site will be included in primary analysis. Because the prevalence of cervical infections is much 
lower than urethral or rectal infections, cervical infections will preferentially be included over rectal 
infections in the same patient. The order of inclusion will be: 1) cervical infections, 2) urethral 
infections and 3) anal infections. 
 
The difference in treatment success rates between each of the experimental treatments and the 
reference treatment will be calculated. The 97.5% confidence interval around this risk difference will 
be calculated using the R function ci.pd of the R “Epi” package. This package uses the Newcombe 
method to estimate the confidence intervals for the difference between independent proportions [60]. 
If the lower limit of the confidence interval around the risk difference between an experimental 
treatment and the control treatment does not exceed -10% (the predefined non-inferiority margin), the 

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experimental treatment will be declared non-inferior to the reference treatment. P-values will be 
estimated by the R “gsDesign” package. The Hochberg stepwise procedure will be used for three 
hypothesis tests. P-values for the three tests will be placed in order from lowest to highest. Sequential 
thresholds of one-tailed Type 1 error are applied to each respective test to determine significance: 
0.025, 0.0125 and 0.0083.  
We will perform a sensitivity analysis in which participants with a positive TOC based on a re-infection 
(proven by non-identical genetic type determined by genotyping) will be coded as treatment success 
instead of treatment failure.  
9.2 Secondary study parameters 
Secondary outcomes (eradication capacity of study drugs up to 28 days and eradication capacity of 
study drugs at different infection sites not included in primary objective) will be analyzed using 
equivalent methods as above.  
Analysis of adverse events to a particular medication will include all participants who received the 
medication. Adverse event analysis will be descriptive. Frequency counts and percentages of the 
prespecified main categories of AEs will be presented by treatment arm.  
In order to assess whether there are any differences in distributions of baseline covariates across 
treatment arms, demographic and clinical data at baseline will be compared between the four 
treatment groups.  
We will perform explorative analyses to assess determinants of treatment failure using univariable 
and multivariable logistic regression. Covariables to include in analysis are as follows: previous 
episodes of gonorrhea, HIV status, presence and duration of symptoms, age, gender and ethnicity. 
It is possible that non-inferiority for one or more treatments is not met in a specific patient stratum. 
Non-inferiority across sub-groups will be evaluated using a test for interaction developed by Wiens 
and Heyse [61].   
The population pharmacokinetics will be estimated for each study antibiotic based on the measured 
plasma antibiotic concentrations using non linear mixed effects modeling (NONMEM). The estimated 
population pharmacokinetic and antimicrobial susceptibility data of circulating Ng strains will be 
combined, and Monte Carlo simulations will be performed in order to predict treatment efficacy under 
various antimicrobial resistance prevalence conditions.  
9.3 Interim analysis 
A single planned interim analysis was performed by an independent statistician who informed the 
Data Safety Monitoring Board (DSMB) in order to timely reduce the risk of participants being exposed 
to a significantly less effective antimicrobial agent. After including one third of the total intended 
sample size, the proportion of treatment failures was calculated per treatment arm. The predefined 
stopping rule was:  40% or more of the participants in a given arm are not successfully treated (i.e. 
less than 60% have a negative TOC). The antimicrobial agent associated with this arm is considered 

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ineffective and the study arm will be discontinued. The steering committee considered this proportion 
of treatment failure as clinically unacceptable. When assuming a cure rate of 98% in the reference 
treatment, we calculated that with a number of 33 participants per treatment arm (approximately one-
third of the final number of participants per treatment arm), the 97.5% confidence interval (using the 
Newcombe method) around the risk difference between the experimental treatment (cure rate 60%) 
and the reference treatment (cure rate 98%) will be -56% to -14%. This would mean that the 
experimental treatment is significantly worse than the reference treatment with the upper limit under 
the non-inferiority margin of -10%.  
After discontinuation of the fosfomycin treatment arm, we will continue the blinding for the participants 
that were already included in the study before the termination of this/these arm(s). However, we deem 
it unethical to continue unnecessary exposure of participants to study procedures exclusively related 
to the terminated treatment arm. Therefore, we reveal to study staff and future participants which 
treatment armis terminated. This will allow us to adapt the protocol for the remaining treatment arms 
and therefore avoid continued unnecessary exposure of participants to procedures related to the 
terminated study arm.  
The outcome of the planned interim analysis resulted in the advice of the DSMB to discontinue the 
fosfomycin arm of this trial. Therefore we decided to stop the administration of fosfomycin 6g orally to 
NABOGO participants on October 2, 2018; also the oral placebo was no longer administered.  
If required, the DSMB will analyze safety of participants on an ad hoc basis and guide 
recommendation for continuation of the study or early termination because of clear harm to the 
participant. We will stop the study early if any patient dies, if any patient requires emergency surgery, 
or if any patient suffers a permanent and irreversible disability, and it can be shown that this event 
was related to participation in the clinical trial. 
 
 

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10. ETHICAL CONSIDERATIONS 
 
10.1 Regulation statement 
This project will be conducted according to the principles of the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, October 2013) and in accordance with the Medical Research Involving 
Human Subjects Act (WMO) of Dutch law.  
10.2 Recruitment and consent 
Recruitment will take place among gonorrhea patients visiting the STI outpatient clinic of the Public 
Health Service (GGD) in Amsterdam and will be performed by the local team of nurses and 
physicians. If a patient is interested in participation, further information will be given either by the 
research nurse or the study coordinator both verbally and in a written patient information brochure. 
Two main pathways in establishing the diagnosis of a Ng infection can be distinguished depending on 
the reason for consultation. As is shown in figure 7, part of the gonorrhea patients consulting the STI 
clinic have symptoms suggestive for gonorrhea. In these patients a gram stain is done immediately. If 
the gram stain is positive for gram negative diplococci (suggesting Neisseria gonorrhoeae) a 
preliminary diagnosis is established, and these patients are immediately treated for gonorrhea. 
Gonorrhea patients without symptoms have to wait 2-10 days for the results of the NAAT before they 
receive treatment. For the first group we offer a time period of 2 hours to read the patient information 
brochure and consider participation of the study. The latter group will receive a digital version of the 
patient information brochure, together with the gonorrhea diagnosis and the advice to make an 
appointment for treatment at the STI clinic. The latter patient group will have at least 24 hours to 
consider participation.  
Written informed consent will be obtained by the research nurse or the study coordinator. The patient 
information brochure, including the informed consent form, is attached to this document in the 
appendices (E1).  
Besides the STI outpatient clinic of the Public Health Service (GGD) in Amsterdam, volunteers for the 
PK substudy will also be recruited at the Amsterdam University Medical Centers (AUMC) and the 
University for Applied Sciences Amsterdam (HvA) using posters with the recruitment text. If a 
volunteer is interested in participating in this substudy we will give the person further information 
verbally and by a written participant information brochure with the informed consent attached. We also 
make an appointment for the inclusion visit. At this visit informed consent forms will be signed.   
10.3 Objection by minors or incapacitated subjects 
Not applicable.  
10.4 Benefits and risk assessments 
Considering the pattern of development of resistance to previous first line treatment regimens for 
gonorrhea and the emergence of Ng strains with decreased susceptibility or even resistance to ESC, 
it is expected that gonorrhea may become untreatable in the near future. For this reason, there is an 
urgent need to find alternative treatment options. Previous research suggests that ertapenem, 

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fosfomycin and gentamicin might be effective and safe options. However, this is not yet proven by 
well-designed and robust trials in uncomplicated anogenital gonorrhea cases. The most important risk 
for participants in this study is thus inefficacy of one of the treatment options, and therefore a delay in 
the administration of efficacious treatment. To minimize this risk, we have installed a DSMB to 
perform an interim analysis on treatment efficacy. Due to disproportional numbers of treatment failure 
in the fosfomycin arm, we have preliminary terminated this arm. Furthermore, there is always a risk of 
adverse events in medication trials. Since ceftriaxone, ertapenem  and gentamicin are registered and 
have been safely used for several indications for decades, we expect the risk of serious adverse 
events to be minimal. However, nephro- and ototoxicity are known side effects of gentamicin, in 
particular among patients receiving multiple (high) dosages  of gentamicin and among patients with 
renal impairment. Although the effects of a single dose of gentamicin have not been structurally 
investigated, we do expect this risk to be low in our relatively healthy study population receiving a 
single intramuscular dose. The consequences of nephro- and ototoxicity are considered serious, 
therefore we will examine the renal function (by performing a point-of-care serum creatinin test) and 
symptoms of ototoxicity (by questionnaire) before and after the admission of treatment. We will 
exclude patients with renal impairment defined as an eGFR ≤50 ml/min (Cockroft-Gault). A 
disadvantage of participation is the administration of an additional intramuscular injection. Albeit the 
risk of pain/bleeding/infection at injection site is very low, it is increased as a result of two IM injections 
instead of one. In conclusion, the most important benefit for anyone at risk for  STIs is the aim to 
assure treatment options for gonorrhea in the near future. A benefit for participants is a TOC (not 
otherwise done) and thus assurance of bacterial eradication. 
10.5 Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7 of the WMO. The sponsor 
(also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 
7 WMO). This insurance provides cover for damage to research subjects through injury or death 
caused by the study. The insurance applies to the damage that becomes apparent during the study or 
within 4 years after the end of the study. 
10.6 Incentives 
All 60 healthy volunteers that consent to participate in the PK substudy will receive a reimbursement 
of 100 euros to compensate for the 5 visits within 24 hours.  
All 60 gonorrhea participants that consent to participate in the PK substudy will receive a 
reimbursement of 20 euros to compensate for the extra visit 30-90 minutes after treatment 
administration. 
 
 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
11.1 Handling and storage of data and documents 
Clinical data and patient samples will be stored according to the standard procedures of the STI 
outpatient clinic. Electronic patient files are accessible to all medical personnel of the STI outpatient 
clinic with access and codes to the computer system. All data collected for the trial in particular [e.g. 
general medical history, in- and exclusion criteria (T0), adverse events and new medication use (T7)] 
will be directly entered in a digital database using a unique de-identified project ID, which is allocated 
to each participant at study inclusion. These data are thus not accessible for all medical personnel of 
the STI outpatient clinic, but only for the NABOGO research team. The data entry system has a 
detailed audit trail, tracking who modified the data and when they were modified. All research data will 
be stored for 15 years. The study coordinator will maintain a list linking study ID’s to electronic patient 
file identifiers. This list will be kept in a locked filing cabinet with restricted access. Information gained 
from the data collection and analysis of this trial will be available for inspection on request by the 
participating physicians, the METC, the DSMB, the monitoring board, the funder and the regulatory 
health authorities.  
11.2 Monitoring and Quality Assurance 
Monitoring of accuracy and quality of the research data and performance of the research is 
compulsory for this study. The CRU of the AMC will organize and perform the monitoring. A detailed 
monitoring plan will be composed in collaboration with the CRU.  
 
11.3 Amendments 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or to 
the protocol or any other supporting documentation, that is likely to affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. Non-
substantial amendments will not be notified to the accredited METC and the competent authority, but 
will be recorded and filed by the sponsor.  
11.4 Annual progress report 
The investigator will submit a summary of the progress of the trial to the accredited METC once a 
year. Information will be provided on the date of inclusion of the first subject, numbers of subjects 
included and numbers of subjects that have completed the trial, serious adverse events/ serious 
adverse reactions, other problems, and amendments.  

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11.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the study 
within a period of 90 days. The end of the study is defined as the last contact with the last patient (30 
days after the last participant has received treatment). The sponsor will notify the METC immediately 
of a temporary halt of the study, including the reason of such an action. In case the study is ended 
prematurely, the sponsor will notify the accredited METC and the competent authority within 15 days, 
including the reasons for the premature termination.  Within one year after the end of the study, the 
investigator will submit a final study report with the results of the study, including any 
publications/abstracts of the study, to the accredited METC and the Competent Authority.  
11.6 Public disclosure and publication policy 
This trial will be registered at clinicaltrials.gov and EudraCT. It is our intention to publish study 
outcomes in the most appropriate peer-reviewed scientific journals and at scientific congresses. Both 
the sponsor and the subsiding party support the intention to disclose the results of this trial. 
Authorship will follow the guidelines defined by the international Committee of Medical Journal 
Editors.  
 
 

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12. STRUCTURED RISK ANALYSIS 
12.1 Potential issues of concern 
Ertapenem 
a. Level of knowledge about mechanism of action 
The mechanism of action of ertapenem is well known. Ertapenem is one of the β-lactam 
antimicrobials, it is rapidly bactericidal and derives its activity from binding to specific penicillin binding 
proteins (PBP) and subsequent blocking of cell wall synthesis[38]. 
 
b. Previous exposure of human beings with the test product 
Ertapenem is widely used in patients with the following moderate to severe infections caused by 
susceptible bacteria: complicated intra-abdominal infections, complicated skin infections, community 
acquired pneumonia, complicated urinary tract infections, acute pelvic infections[38]. In Europe, 
ertapenem is only registered as intravenous treatment, however in the USA it is safely administered 
either intravenously and intramuscularly for the previously mentioned indications [37]. As far as we 
know, there are no clinical trials investigating the efficacy and safety of ertapenem in patients infected 
with Neisseria gonorrhoeae.   
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell 
material? 
Not applicable.  
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, 
pharmacology, repeated-dose toxicity, genotoxicity and toxicity to reproduction and development. 
Decreased neutrophil counts, however, occurred in rats that received high doses of ertapenem, which 
was not considered a significant safety issue. Long-term studies in animals have not been performed 
in order to evaluate the carcinogenic potential of ertapenem [38].  
e. Analysis of potential effect 
Previous research showed that ertapenem 1000mg is a safe, well tolerated and effective agent 
against urinary tract infections [62-66]. Based on PK/PD simulations using MIC values of Ng strains 
from the STI clinic in Amsterdam, we expect that ertapenem 1000mg single dose will be effective 
against gonorrhea as well (unpublished data, June 2014, correspondence with R.A.A. Mathot). The 
following serious adverse events are reported rarely: antibiotic-associated pseudomembranous colitis 
and  seizures (in elderly patients and those with pre-existing central nervous system disorders). 
Other, commonly reported (>1/100 - <1/10), adverse events are: diarrhoea, nausea, rash, headache, 
elevations in ALT, AST, alkaline phosphatase and platelet count. Of note, these data are based on 
patients using multiple doses of ertapenem, it is thus expected that the prevalence and severity of 
adverse events will be lower in our patients. The only explicit contra-indication is an anaphylactic 
reaction to any β-lactam antibacterial agent [38]. 

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f. Pharmacokinetic considerations 
Ertapenem is highly bound to plasma proteins. In healthy young adults the plasma half-life is 4 hours. 
There are inadequate data on the safety and efficacy of ertapenem in patients with advanced renal 
impairment to support a dose recommendation. Therefore, ertapenem should not be used in these 
patients [38].  
g. Study population 
The average population consulting the STI outpatient clinic in the city center of Amsterdam is young 
and has limited health concerns. A large proportion of this population is HIV positive, but in most of 
them this is well treated.  
h. Interaction with other products 
Co-administration of valproic acid with carbapenem agents may result in a decreased level of valproic 
acid falling below therapeutic range. This can lead to inadequate seizure control.  
 
i. Predictability of effect 
There are no markers available to predict the effect of ertapenem.  
j. Can effects be managed? 
In case of treatment failure, participants receive a doubled dose of ceftriaxone (1000mg) plus 
azithromycin 1000mg. Research subjects can always contact the STI outpatient clinic and the study 
coordinator in case of any questions or uncertainties. At the STI outpatient clinic a case with 
emergency medication (for instance, for anaphylactic reaction or seizures) is available. If necessary 
participants can be referred to a specialist in the hospital.  
Fosfomycin 
a. Level of knowledge about mechanism of action 
The mechanism of action of fosfomycin is well known. Fosfomycin is a fosfonic acid derivate which 
exhibits bactericidal activity by inhibiting cell wall synthesis through inhibition of fosfoenolpyruvate 
transferase. This enzyme is involved in the first phase of peptidoglycan synthesis in both Gram-
negative and Gram-positive bacteria. At the same time, fosfomycin inhibits adhesion of bacteria to the 
bladder mucosa and consequently prevents re-infection. Because of the distinctive mechanisms of 
fosfomycin, there is minimal cross-resistance with other antimicrobials [60-62].  
b. Previous exposure of human beings with the test product 
Fosfomycin-Trometamol is widely used in humans for the treatment of urinary tract infections and is a 
registered medicinal product at EMA. Three clinical studies have been performed to study the effect of 
fosfomycine in uncomplicated gonococcal urethritis. In these studies no severe adverse events were 
reported [14, 30, 63]. 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell 
material? 
Not applicable.  

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d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Oral fosfomycin is metabolized after absorption to the free acid fosfomycin, which will be eliminated in 
urine and faeces. It is mainly distributed to the kidneys, bladder wall, prostate and seminal vesicles. 
Preclinical data, based on conventional studies with single and repeated toxicity studies, genotoxicity 
studies and reproduction and development studies do not reveal any special risks for human beings.  
e. Analysis of potential effect 
Common adverse events of fosfomycin are mild and often self-limiting, including diarrhea, nausea, 
abdominal pain and headache. The only explicit contra-indication is an anaphylactic reaction to 
fosfomycin in the past [61, 64].  
f. Pharmacokinetic considerations 
The maximal plasma concentration is reached in 2 hours after intake. The half-life is 6 hours. 
fosfomycin is completely eliminated by the kidneys. Higher levels of fosfomycin concentration are 
found in urine than the MIC in peripheral blood samples after 24-48 hours[64].  
g. Study population 
The average population is young and has limited health concerns.  
h. Interaction with other products 
The serum concentration and urinary excretion of fosfomycin are decreased by co-administration of 
metoclopramide, but otherwise it has limited drug interactions[61]. A simultaneous intake with food 
delays fosfomycin absorption, following a decrease in peak plasma and urine [64]. 
i. Predictability of effect 
There are no markers available to predict the effect of fosfomycin. 
j. Can effects be managed? 
Research subjects can always contact the STI outpatient clinic and the study coordinator in case of 
any questions or uncertainties. At the STI outpatient clinic a case with emergency medication (for 
instance, for anaphylactic reaction or seizures) is available. If necessary participants can be referred 
to a specialist in the hospital.Gentamicin 
a. Level of knowledge about mechanism of action 
The mechanism of action of gentamicin is well known. Gentamicin is a bactericide antibiotic that 
inhibits the synthesis of proteins by binding to the 30S subunit of the bacterial ribosome. Gentamicin 
is known to be effective in a large amount of pathogen Gram-positive and Gram-negative bacteria 
[43]. 
b. Previous exposure of human beings with the test product 
Gentamicin is a widely used antibiotic for several indications and is a registered medicinal product at 
EMA. In different developing countries, gentamicin is being used for the treatment of gonorrhea for 
decades [14, 15, 67].  

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c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell 
material? 
Not applicable 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
After intramuscular admission, gentamicin is well distributed to body tissue and body fluids. However, 
low concentrations are found in cerebrospinal liquor, sputum and pleural and peritoneal fluids. 
Gentamicin passes both peritoneal and placental membranes. Preclinical safety research did not 
reveal any specific risks for human beings [43].  
e. Analysis of potential effect 
See 12.1b. Additionally, Felarca et al. found the adequate (efficient and safe) dose of gentamicin for 
the treatment of gonorrhea[39], subsequently several studies have been enrolled using a dose of 240-
280mg gentamicin IM with cure rates between 94-100%[18, 40-42]. Also, the susceptibility for 
gentamicin of Neisseria gonorrhoeae strains is widely investigated in Ng strains from different 
regions[14, 18, 42, 68-71].  Limited research on adverse events of gentamicin in patients with 
gonorrhea showed no nephrotoxicity and ototoxicity after a single dose intramuscular injection [39-42, 
72].  
f. Pharmacokinetic considerations 
Gentamicin is not metabolized in the human body and it is eliminated in its active form. In patients 
with a normal renal function, the half-life is between 2-3 hours. In patients with impaired renal 
function, the half-life is reduced based on the remaining renal function. Toxic dosages can cause 
renal impairment and/or neurological damage [43].  
g. Study population 
The average population consulting the STI outpatient clinic in the city center of Amsterdam is young 
and has limited health concerns. A high number of this population is HIV positive, but in most of them 
this is well treated. Therefore, we expect that the rate of participants with renal impairment or other 
chronic diseases will be low. However, because of the limited knowledge on adverse-events after one 
single dose of gentamicin, the renal function will be tested on forehand in all possible participants and 
people with renal impairment will be excluded from the study. Also pregnant women will be excluded 
from this study, since little is known on the effects of pregnancy [43].  
h. Interaction with other products 
There are no drug-interactions known with gentamicin. However, attention needs to be paid to 
nephro- and ototoxic medicines, because this effect could be increased when simultaneously using 
gentamicin [43]. For this reason, we will evaluate the renal function and we will exclude participants 
with renal impairment.  
i. Predictability of effect 
There are no markers in order to predict the effect of gentamicin.  

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j. Can effects be managed? 
In case of treatment failure, participants receive a doubled dose of ceftriaxone (1000mg) plus 
azithromycin 1000mg . Research subjects can always contact the STI outpatient clinic and the study 
coordinator in case of any questions or uncertainties. At the STI outpatient clinic a case with 
emergency medication (for instance, for anaphylactic reaction or seizures) is available. If necessary 
participants can be referred to a specialist in the hospital. 
12.2 Synthesis 
Ceftriaxone 
Ceftriaxone is the standard therapy for gonorrhea infections in the Netherlands, given the current 
efficacy-rate of 100% and the mild adverse events that are reported. For this reason, chapter 12.1 is 
not indicated for this product. Furthermore, in this trial Ceftriaxone will not cause any risks in 
comparison to the general population with gonorrhea. Consequently there is no need for extra 
measures to reduce expected risks.  
Ertapenem 
Ertapenem is safely used for several indications worldwide both in intramuscular and intravenous 
form. In Europe ertapenem is not yet registered as intramuscular injection, however it is safely used 
intravenously. We do not expect any harm from a single intramuscular dose in our young and 
relatively healthy population. Because of the influence of Ertapenem on the valproic acid plasma 
levels, patients using valproic acid are excluded from this trial.  
Fosfomycin 
Fosfomycin is safely used for several indications worldwide. A few clinical studies with (either 
intramuscular or oral) Fosfomycin have been performed in patients with uncomplicated gonococcal 
urethritis, none of these studies reported any severe events. Participants of this trial are assured not 
to take metoclopramide at the first 7 days. In case of the intake of metoclopramide on the day of 
inclusion or in case of the intention to take metoclopramide in the following days, patients are 
excluded from this study.  
Gentamicin 
Since a single intramuscular dose of gentamicin is used for gonorrhea in Malawi [14, 73] for decades 
and effectiveness is reported in different studies, we can expect that it is an efficient and safe product 
for this indication. Because of limited knowledge on the prevalence of nephro- and ototoxicity as a 
result of the single dose gentamicin, renal function will be measured before treatment is given and 
people with an impaired renal function will be excluded from this study. This is determined by a point-
of-care serum creatinin test before administration of treatment. Additionally, at the follow-up visit 7-14 
days after treatment, renal function will again be tested in order to evaluate the effects of a single 
dose gentamicin on renal function. Also deafness and balance disorder will be evaluated before and 
after treatment in order to look for ototoxicity after a single dose injection of gentamicin.  
 

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