New Antibiotic Treatment Options for Uncomplicated Anogenital Gonorrhoea infections

Antimicrobial resistant gonorrhoea is a growing worldwide problem. Resistance
and treatment failures to the last evidence-based treatment option,
ceftriaxone, have been reported In several European countries, including the
Netherlands. It is feared that ceftriaxone resistance will become widely
prevalent, making this last resort treatment obsolete, and gonorrhoea once
again an untreatable disease causing frequent and severe chronic complications.
In the short term, no new antibiotics are expected. Yet existing antibiotics
could form promising new treatment modalities, but
these need to be evaluated first in patients with gonorrhea. If there is
sufficient clinical efficacy, these agents can be considered
first line alternative options for the future treatment of ceftriaxone
resistant gonorrhoea.

On October 2, 2018, the fosfomycin treatment arm of the NABOGO trial was
dropped. From this moment, fosfomycin and oral placebo was not administered to
participants anymore. This decision was based on the advice of the Data Safety
Montoring Board (DSMB) following the predefined stopping rules after on a
pre-arranged interim analysis.

Primary objectives
To determine the bacterial eradication capacity of ertapenem, fosfomycine and
gentamicine compared to the reference treatment (ceftriaxone) in uncomplicated
anogenital gonococcal infections (at one included infection site) by molecular
test of cure 7-14 days after treatment.

Secondary objectives
1. To determine the bacterial eradication capacity of the experimental
treatment options (ertapenem, fosfomycine and gentamicine) 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 pharyngeal gonorrhoea) 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 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.
5. 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.
6. To determine the clinical and demographic predictors for treatment failure
(see chapter 7 for definition).
7. To determine the population pharmacokinetics of ceftriaxone, gentamicin and
ertapenem administered intramuscularly, and fosfomycin administered orally.

On October 2, 2018, the fosfomycin treatment arm of the NABOGO trial was
dropped. From this moment, fosfomycin and oral placebo was not administered to
participants anymore. This decision was based on the advice of the Data Safety
Montoring Board (DSMB) following the predefined stopping rules after on a
pre-arranged interim analysis.

A double-blind randomized non-inferiority trial with three experimental arms
and one reference arm.

The project consists of two parts:
1. Clinical- and microbiological efficacy and side effects of ertapenem,
gentamicin, and fosfomycin,
2. A Monte Carlo simulation model based on pharmacokinetic- and antimicrobial
susceptibility data of N. gonorrhoeae strains to
predict the future treatment failure rate under various antimicrobial
resistance prevalence conditions.

On October 2, 2018, the fosfomycin treatment arm of the NABOGO trial was
dropped. From this moment, fosfomycin and oral placebo was not administered to
participants anymore. This decision was based on the advice of the Data Safety
Montoring Board (DSMB) following the predefined stopping rules after on a
pre-arranged interim analysis.

- 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).
- Experimental arm 3: fosfomycin 6 gram trometamol oral once.
- Placebo intramuscular injection: 10 ml (2 x 5 ml) 0.9% NaCl.
- Placebo oral suspension: orange lemonade.

On October 2, 2018, the fosfomycin treatment arm of the NABOGO trial was
dropped. From this moment, fosfomycin and oral placebo was not administered to
participants anymore. This decision was based on the advice of the Data Safety
Montoring Board (DSMB) following the predefined stopping rules after on a
pre-arranged interim analysis.

Volunteers participating in the PK substudy will not receive gentamicin.

Considering the development pattern of resistance to previous first line
treatment regimes for gonorrhoea on one side and, the emergence of Ng-strains
with decreased susceptibility or even resistance to ESCs on the other side, it
is expected that gonorrhoea becomes untreatable in the near future. For this
reason, there is an urgent need to find alternative treatment options. Previous
research suggests that ertapenem, fosfomycin and gentamicin might be effective
and safe options. However, this is not yet proven by well-designed and robust
trials in uncomplicated anogenital gonorrhoea cases. The most important risk
for participants in this study is thus inefficacy of one of the treatment
options, and therefore treatment delay. To minimize this risk, we will install
a DSMB to perform an interim analysis on treatment efficacy. In the case of
disproportional numbers of treatment failure in one treatment arm, we will
preliminary terminate this arm. Furthermore, there is always a risk of adverse
events in medication trials. Since ceftriaxone, ertapenem, fosfomycin and
gentamicin are registered and 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 are
never structurally investigated, we do expect this risk to be low in our
relatively healthy study population receiving a single dose 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
creatinine test) and symptoms of ototoxicity (by questionnaire) before and
after the admission of treatment. We will exclude patients with renal
impairment defined by an eGFR<50mL/min (Cockroft-Gault). A disadvantage for
participation is the administration of an additional intramuscular injection
and an oral suspension. 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 participants, as well as for
anyone else at risk for STIs, is the aim to assure treatment options for
gonorrhoea in the near future. A benefit for participants in particular is a
TOC and thus assurance of bacterial eradication.

On October 2, 2018, the fosfomycin treatment arm of the NABOGO trial was
dropped. From this moment, fosfomycin and oral placebo was not administered to
participants anymore. This decision was based on the advice of the Data Safety
Montoring Board (DSMB) following the predefined stopping rules after on a
pre-arranged interim analysis.