Zoliflodacin in Uncomplicated Gonorrhoea

Study Overview
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Brief Summary
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This trial is 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 intra-muscular 500 mg dose of ceftriaxone and a single 1 g oral dose of azithromycin for the treatment of uncomplicated gonorrhoea.

Official Title
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A Multi-center, Randomized, Open-label, Non Inferiority Trial to Evaluate the Efficacy and Safety of a Single, Oral Dose of Zoliflodacin Compared to a Combination of a Single Intramuscular Dose of Ceftriaxone and a Single Oral Dose of Azithromycin in the Treatment of Patients With Uncomplicated Gonorrhoea

Conditions
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Gonorrhea

Intervention / Treatment
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* Drug: zoliflodacin
* Drug: ceftriaxone
* Drug: azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 12 years old (if enrolment of minors is in agreement with local regulations and thics guidance) Weight ≥ 35 kg 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 test/gentian violet stain in the past 14 days prior to screening OR Unprotected sexual contact with an individual reported to be infected with NG in the past 14 days prior to screening (confirmation by a positive NAAT, Gram stain or methylene blue test/ gentian violet stain or culture) For females of child-bearing potential, a negative urine pregnancy test at screening For females of child bearing potential, use of highly effective contraception for at least 28 days prior to screening and during at least 28 days after treatment. Females on oral contraceptives must also use a barrier contraception method during participation in the study. For males with a female partner of child-bearing age, willingness to delay conception for 28 days after treatment Willingness to comply with trial protocol Willingness to undergo HIV testing Willingness to abstain from sexual intercourse or use condoms for vaginal, anal and oral sex until end of trial visit 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: Confirmed or suspected complicated or disseminated gonorrhoea Pregnant or breastfeeding women Known concomitant infection which would require immediate additional systemic antibiotics with activity against NG (e.g. CT infection) Use of any systemic or intravaginal antibiotics with activity against NG within 30 days prior to screening Use of systemic corticoid drugs or other immunosuppressive therapy within 30 days prior to screening Use of moderate or strong CYP3A4 inducers (e.g. efavirenz, rifampicin, carbamazepine, phenobarbital) within 30 days or five half-lives of the drug, whichever is greater, prior to screening Cytotoxic or radiation therapy within 30 days prior to screening 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 History of urogenital sex-reassignment surgery Immunosuppression as evidenced by medical history, clinical examination or a recent (≤ 1 month) CD4 count <200 cells/μL Know clinically relevant cardiac pro-arrhythmic conditions such as cardiac arrhythmia, congenital or documented QT prolongation Known history of severe allergy to cephalosporin, penicillin, monobactams, carbapenems or macrolide antibiotics Known or suspected allergies or hypersensitivities to lidocaine, methylparaben, lactose or any of the components of the study drugs (refer to the zoliflodacin IB and SmPC for the comparators treatments) 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 History of alcohol or drug abuse within 12 months prior to screening which would compromise trial participation in the judgment of the investigator Severe medical or psychiatric condition which, 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 Individuals whom, in the judgement of the investigator, are unlikely or unable to comply with this trial protocol Previous randomisation in this clinical trial. Use of moderate or strong CYP3A4 inhibitors within 30 days or five half-lives of the drug, whichever is greater, prior to screening

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single dose of Zoliflodacin or comparators combination in single dose: ceftriaxone and azithromycin
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zoliflodacin<br>Participant in this arm will receive a single dose of zoliflodacin. | Drug: zoliflodacin<br>* Dose: 3g, oral administration<br>|
| Active Comparator: ceftriaxone and azithromycin combination<br>Participant in this arm will receive a single dose of comparators combination (ceftriaxone and azithromycin). | Drug: ceftriaxone<br>* Dose: 500mg, Intra-Muscular (IM) administration<br>Drug: azithromycin<br>* Dose: 1g, oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of a single dose of zoliflodacin will be assessed compared to a combination of a single dose of ceftriaxone and azithromycin. | Microbiological cure as determined by culture at urethral or cervical sites at test of cure visit. | Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of a single dose of zoliflodacin will be assessed compared to a combination a single dose of ceftriaxone and azithromycin. | Adverse events will be assessed. | Day 6 and Day 30 | 
| Microbiological cure rate of pharyngeal gonorrhoea will be determined after administration of a single dose of zoliflodacin compared to a combination of a single dose of ceftriaxone and azithromycin. | Proportion of participants with microbiological cure as determined by culture at pharyngeal sites at test of cure visit. | Day 6 | 
| Microbiological cure rate of rectal gonorrhoea will be determined after administration of a single dose of zoliflodacin compared to a combination of a single dose of ceftriaxone and azithromycin. | Proportion of participants with microbiological cure as determined by culture at rectal sites at test of cure visit. | Day 6 | 
| The clinical cure rate of symptomatic gonorrhoea in male participants will be determined after administration of a single dose of zoliflodacin compared to a combination of single dose of ceftriaxone and azithromycin. | Proportion of male participants with clinical cure at test of cure visit. | Day 6 | 
| Microbiological cure rate of urogenital gonorrhoea will be determined among women and men respectively, after administration of a single dose of zoliflodacin compared to a combination of a single dose of ceftriaxone and azithromycin. | Proportion of female and male participants respectively with microbiological cure as determined by culture at cervical or urethral site at test of cure visit. | Day 6 | 
| Microbiological cure rate of Neisseria gonorrhoeae (NG) at urogenital sites will be determined. | Proportion of participants with microbiological cure as determined by culture at urethral or cervical sites at the test of cure visit and for whom the baseline antimicrobial susceptibility profile indicated pre-existing resistance to antibiotics commonly used for Neisseria gonorrhoeae (NG) treatment. | Day 6 | 
| Antimicrobial susceptibility profile will be determined of gonococcal strains isolated from participants with uncomplicated gonorrhoea at baseline and the test of cure visit. | Antimicrobial susceptibility profile of gonococcal strains isolated at baseline and at test of cure visit. | Day 6 | 
| The eradication rate of NG nucleic acid will be determined from urogenital rectal, pharyngeal specimens after administration of a single dose of zoliflodacin compared to a combination of a single dose of ceftriaxone and azithromycin. | Proportion of participants with a negative NG NAAT from urethral or cervical, oropharyngeal and rectal sites at test of cure visit. | Day 6 | 
| The plasma concentration will be evaluated (included Area Under the Curve (AUC) over 36 hours) after a single dose of zoliflodacin. | Five PK timepoints post-treatment will be assessed. | Day 2 |