To assess the efficacy of a single, oral, 3 grams (g) dose of zoliflodacin compared to a combination of a singleintramuscular (IM) 500 milligram (mg) dose of ceftriaxone and a single 1 g oral dose of azithromycin for the treatment ofuncomplicated…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Microbiological cure as determined by culture at urethral or cervical sites at
TOC (day 6 ±2)
Secondary outcome
Secondary endpoints
* Incidence, severity, causality, and seriousness of treatment-emergent adverse
events and the evaluation of changes from baseline in safety laboratory test
results and physical examinations
* Proportion of participants with microbiological cure as determined by culture
at pharyngeal sites at TOC (day 6 ±2)
* Proportion of participants with microbiological cure as determined by culture
at rectal sites at TOC (day 6 ±2)
* Proportion of male participants with clinical cure at TOC (day 6 ±2)
* Proportion of female and male participants respectively with microbiological
cure as determined by culture at cervical or urethral site at TOC (day 6 ±2)
* Proportion of participants with microbiological cure as determined by culture
at urethral or cervical sites at TOC and for whom the baseline antimicrobial
susceptibility profile indicated pre-existing resistance to antibiotics
commonly used for NG treatment (including to ceftriaxone alone, to azithromycin
alone, and to both)
* Antimicrobial susceptibility profile of gonococcal strains isolated at
baseline and at TOC (day 6 ±2)
* Proportion of participants with a negative NG nucleic acid amplification test
(NAAT) from urethral or cervical sites at TOC (day 6 ±2)
* Proportion of participants with a negative NG NAAT from oropharyngeal sites
at TOC (day 6 ±2)
* Proportion of participants with a negative NG NAAT from rectal sites at TOC
(day 6 ±2)
Background summary
Bacterial sexually transmitted infections (STI) are a major public health
concern globally, affecting over 357 million people every year. Neisseria
gonorrhoeae (NG), the etiological agent of gonorrhoea, is estimated to have
caused 78 million infections in 2012. The Western Pacific and African regions
have the highest incidence of gonococcal infections worldwide, with 89 and 50
cases per 100*000 population respectively. Rates of male urethral discharge
(UD), which is primarily due to NG or Chlamydia trachomatis (CT), are also
highest for these two regions, amounting to 567 per 100*000 in Africa and 141
per 100*000 in the Western Pacific. In high income countries (HIC), gonorrhoea
is also raising significant concerns. In the
United States of America (USA) it is the second most frequently reported
notifiable infectious diseases, with about 400*000 infections reported per
year. NG has been included as one of three organisms presenting an urgent
threat due to progressive antimicrobial resistance by the US Centers for
Disease Control and Prevention (US CDC). Gonorrhoea affects both men and women.
In men, infections commonly manifest as
urethritis. Symptoms develop in 75% of the men within four to eight days of
genital infection and in 80 to 90% within two weeks. UD is the most frequent
presenting symptom and is often undistinguishable from non-gonococcal
urethritis (e.g. CT infections). Acute unilateral epididymitis can be a
complication of gonococcal infection, although it is more common with CT
infections. In women, gonococcal infections are often (>=50% of the cases)
asymptomatic. Genital infections, in particular cervical infections, are the
most common infections. When symptomatic, cervical infection typically
manifests as mucopurulent discharge. If left untreated, NG infections can
ascend to involve the uterus and fallopian tubes.
Gonorrhoea is associated with significant morbidity and if not treated
appropriately, can have serious consequences on reproductive health. Pelvic
inflammatory disease (PID), ectopic pregnancies, abortions, neonatal
conjunctivitis and blindness are among the possible complications. Studies have
also shown that gonorrhoea enhances the transmission of human immunodeficiency
virus (HIV) by three to five fold.
Most individuals with gonorrhoea are managed in the community, and clinical
management is often empiric and syndromic: treatment is based on the presence
of easily recognized signs (e.g. urethral or vaginal discharge), and the
provision of antibiotics that deal with the majority
of, or the most serious, organisms responsible for the syndrome. Extended
spectrum cephalosporins (ESC) constitute the mainstay of gonorrhoea treatment.
However, with increasing resistance to ESC emerging globally, and in particular
to cefixime, several countries have now switched from ESC monotherapy to a dual
therapy that includes an injectable ESC - ceftriaxone- and azithromycin
(10,11), the underlying, unproven, assumption being that a dual therapy would
slow down resistance emergence.
Over the past few years, the World Health Organization (WHO) and others have
raised concerns over the spread of gonococcal antimicrobial resistance (AMR),
warning that infections due to NG may soon become untreatable. Reports of
treatment failures with ESC and azithromycin monotherapy have multiplied over
the past few years, and clinical failures to dual therapy have been reported.
Despite this, the drug development
pipeline for NG remains insufficient. In 2012, the WHO launched a global action
plan to control the spread and impact of antimicrobial resistance in NG.
Identifying new treatment options for multi-drug resistant (MDR) gonorrhoea is
a key element of the WHO global action plan, and has long been called for by
clinicians and microbiologists.
Zoliflodacin (ETX0914) belongs to a new class of antibiotics that inhibit
bacterial deoxyribonucleic acid (DNA) replication. It shows in vitro
antibacterial activity against several Gram-positive pathogens such as
Staphylococcus spp. and Streptococcus spp. as well as fastidious Gram-negative
pathogens such as Haemophilus influenzae, Moraxella catarrhalis and NG. Minimum
inhibitory concentration required to inhibit the growth of 90% of organisms
(MIC90) values for NG range from 0.125 to 0.25 microgram (µg)/millilitre (mL).
A complete program of both oral and intravenous (IV) toxicity studies was
performed in the rat and dog. Data collected included clinical observations,
body weight changes, food
consumption, clinical pathology and histopathology. Also completed was a
battery of genetic toxicology studies and single dose safety pharmacology
studies to assess cardiovascular, central nervous system, renal, respiratory
and gastrointestinal endpoints. Detailed results of
these pre-clinical evaluations are summarized in the investigator brochure
(IB). Studies performed in the Staphylococcus aureus (S. aureus) neutropenic
thigh model indicated that the ratio between the area under the
concentration-time curve (AUC) and the MIC was the driver of log kill. Those
studies also supported a predicted efficacious mean AUC in humans of 49
µg*hour(h)/mL. Overall the preclinical data supported progression to phase I
trials.
Zoliflodacin is being developed as an oral, single dose treatment. Final data
is available from five clinical trials : a phase I single-ascending dose (SAD)
trial, a phase I absorption, distribution, metabolism, excretion (ADME) trial,
a phase II trial involving participants with confirmed urogenital gonococcal
infection (clinicaltrials.gov NCT02257918), a phase I relative bioavailability
(rBA) trial (clinicaltrials.gov NCT03404167) and a phase I food effect trial
with healthy volunteers to assess the effect of food on the PK characteristics
of a newly developed formulation (clinicaltrials.gov NCT03718806). The SAD and
ADME trials showed that zoliflodacin was well tolerated at all doses tested
(200 mg- 4*000 mg). In phase 1
clinical trials, the most common adverse events (AEs) were dysgeusia, corrected
QT interval (QTc) change from baseline and headache.
In the phase II, 96% (95%CI: 88-100%) cure rates were observed with both the 2
g and the 3 g doses in the microbiological intent-to-treat (micro ITT)
population at the urogenital site (55 out of 57 and 54 out of 56 participants
respectively) compared to 100% (95% CI:88-100) in the
comparator arm of ceftriaxone 500 mg IM. All participants with concomitant
rectal infections were cured with either dose of zoliflodacin, while for those
with concurrent oropharyngeal infections, cure rates were lower (2 g 50%
[95%CI: 16-84]; 3 g 82% [95%CI: 48- 98]) compared to 100% (95%CI: 40-100) for
ceftriaxone. The small number of participants with concurrent oropharyngeal
infections included in the phase II (8 participants in the 2 g arm, 11
participants in the 3 g arm and 4 in the ceftriaxone arm) however precludes any
firm conclusion about efficacy at this site. In the phase II, the safety
profile of zoliflodacin was generally similar to ceftriaxone; the most common
adverse events (excluding infection-related
AEs) were diarrhoea, headache, and nausea. The drug was overall generally well
tolerated.
Study objective
To assess the efficacy of a single, oral, 3 grams (g) dose of zoliflodacin
compared to a combination of a single
intramuscular (IM) 500 milligram (mg) dose of ceftriaxone and a single 1 g oral
dose of azithromycin for the treatment of
uncomplicated urogenital gonorrhoea
To evaluate the plasma PK of a single, oral, 3 g dose of zoliflodacin:
• in human immunodeficiency virus (HIV) negative adult participants (>= 18 years
old) and HIV positive adult participants with uncomplicated gonorrhoea
• in HIV negative adolescent participants (>= 12 and < 18 years old) with
uncomplicated gonorrhoea
Study design
This trial will be a multi-center, open label, randomized controlled,
non-inferiority phase III trial evaluating the safety and efficacy of a 3 g
oral dose of zoliflodacin compared to a combination of a single IM 500 mg dose
of ceftriaxone and a single 1 g oral dose of azithromycin for the treatment of
uncomplicated gonorrhoea. Participants will present to the clinic for
assessment of eligibility after informed consent is signed on Day 1. Should
eligibility be confirmed, they will be randomised to either the zoliflodacin
group or the ceftriaxone/azithromycin combination group, undergo baseline
assessments and dosed with the trial treatment on the same day.
The randomization sequence will be obtained by computer-generated random
numbers and provided to each trial site through a web-based randomization
system. Trial participants will be assigned to receive either zoliflodacin or a
ceftriaxone/azithromycin combination in a 2:1
allocation ratio. Unequal randomization has been chosen to increase the number
of individuals from which safety data is gathered. Randomisation will be
performed using random permutated blocks of 3, 6, and 9 by site with
stratification by sex at birth.
Those participants who are assigned to the zoliflodacin group and who will also
have consented to be enrolled in the PK sub-study will undergo blood sampling
on Day 1 and return to the clinic on Day 2 for further blood sampling. Sites
staff will call participants on Day 3 for safety monitoring purposes and to
enquire about sex behaviour since the previous clinic visit. Participants will
return to the clinic on Day 6 for the TOC visit, involving safety and efficacy
assessments (primary endpoint for the trial will be assessed at the TOC visit).
Those participants that will a posteriori have been diagnosed with a CT
infection via NAAT at baseline and who were randomised to the zoliflodacin arm
will then be treated for the CT infection as per standard of care. Participants
will be asked to return to the clinic for the end of trial visit on Day 30 for
final safety and efficacy assessments.Participants will be asked to return to
the clinic for a follow up visit on Day 30 for final safety and efficacy
assessments.
Intervention
Reference treatment: Combination of a single dose ceftriaxone 500 mg IM,
dissolved in lidocaine 1% and a single oral 1 g dose of azithromycin
Studiemedication: Single oral 3 g dose of zoliflodacin granules as oral
suspension
Study burden and risks
The study medication may be less effective than the current standard treatment:
treatment failure. In that case, the study participants will receive the
standard treatment (7-14 days after the study of medication).
In the phase II, the safety profile of zoliflodacin was generally similar to
ceftriaxone; the most common adverse events (excluding infection-related
AEs) were diarrhoea, headache, and nausea. The drug was overall generally well
tolerated.
The effect of zoliflodacin administration has not been studied in pregnant
women. Therefore, all eligible women of reproductive age must not be pregnant
and have a negative pregnancy test before they can be included in the trial.
GARDP have received preliminary results from recent Physiologically Based
Pharmacokinetic (PBPK) modelling which provides estimation of exposure in
subjects in various conditions, including when taking strong CYP3A4 inhibitors.
GARDP have evaluated these data with respect to the potential for risk of QTc
prolongation in certain situations. Pending full assessment of the data, GARDP
are taking a conservative step with this protocol amendment by excluding from
the trial participants taking strong or moderate CYP3A4 inhibitors. As a
consequence, it is expected only a minority of HIV positive participants will
be eligible.
Chemin Camille Vidart 15
Geneva 1202
CH
Chemin Camille Vidart 15
Geneva 1202
CH
Listed location countries
Age
Inclusion criteria
1. >= 12 years old (if enrolment of minors is in agreement with local
regulations and ethics guidance, for Dutch site 16 years and older will be
maintained)
2. >= 35 kilogram (kg)
3. Signs and symptoms consistent with urethral or cervical gonorrhoea
OR
Urethral or cervical uncomplicated gonorrhoea as determined by either a
positive culture or NAAT or Gram stain or methylene blue/gentian violet stain
in the past 14 days prior to screening
OR
Unprotected sexual contact with an individual confirmed to be infected with NG
in the past 14 days prior to screening (positive NAAT, Gram stain, methylene
blue/gentian violet stain or culture)
4. For females of child-bearing potential, a negative urine pregnancy test at
screening
5.For females of child bearing potential, use of highly effective method of
contraception at the time of IMP administration on Day 1 (see Appendix 1:
contraception methods considered as highly effective and required duration) and
until at least 28 days after treatment. Females on oral contraceptives must
also use a barrier contraception method during participatien in the study.
6. For males with a female partner of child-bearing age, willingness to delay
conception during the trial and for 28 days after treatment
7. Willingness to comply with trial protocol
8. For participants in the PK sub-study: Willingness to undergo HIV testing
9. Willingness to abstain from sexual intercourse or use condoms for vaginal,
anal and oral sex from enrollment until end of trial (EOT) visit
10. Willingness and ability to give written informed consent or be consented by
a legal representative, or provide assent and parental consent (for minors, as
appropriate)
Exclusion criteria
1. Confirmed or suspected complicated or disseminated gonorrhoea
2. Pregnant or breastfeeding females
3. Known concomitant infection which would require immediate additional
systemic antibiotics with activity against NG
4. Use of any systemic or intravaginal antibiotics with activity against NG
within 30 days prior to screening
5. Use of systemic corticoid drugs or other immunosuppressive therapy within 30
days prior to screening
6. Use of moderate or strong CYP3A4 inducers (e.g. efavirenz, rifampicin,
carbamazepine, phenobarbital) within 30 days or five halflives of the drug,
whichever is greater, prior to screening
7. Cytotoxic or radiation therapy within 30 days prior to screening
8. Known chronic renal, hepatic, hematologic impairment or other condition
interfering with the absorption, distribution or elimination of the drug, based
on medical history and physical examination
9. History of urogenital sex-reassignment surgery
10. Immunosuppression as evidence by medical history, clinical examination or a
recent (<=1 month) CD4 count below 200
cells/microliter (µL)
11. Known clinically relevant cardiac pro-arrhythmic conditions such ascardiac
arrhythmia, congenital or documented QT prolongation
12. Known history of severe allergy to cephalosporin, penicillin, monobactams,
carbapenems or macrolide antibiotics
13. Known or suspected allergies or hypersensitivities to lidocaine,
methylparaben, lactose or any of the components of the study drugs (refer to
the zoliflodacin investigator brochure (IB) and ummaries of product
characteristics (SmPC) for the comparator treatments)
14. Receipt or planned receipt of an investigational product in a clinical
trial within 30 days or five half-lives of the drug, whichever is greater prior
to screening until end of participation to this clinical trial
15. History of alcohol or drug abuse in the 12 months prior to screening which
would compromise trial participation in the judgement of the investigator
16. Severe medical or psychiatric condition that, in the opinion of the
investigator, may increase the risk associated with trial participation or may
interfere with the interpretation of trial results or affect the individual's
ability to provide informed consent
17. Individuals whom, in the judgement of the investigator, are unlikely or
unable to comply with this trial protocol
18. Previous randomisation in this clinical trial
19. Use of moderate or strong CYP3A4 inhibitors within 30 days or five
half-lives of the drug, whichever is greater, prior to screening
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-000990-22-NL |
| CCMO | NL70051.018.19 |