Top

Zoliflodacin Trial

A multi-center, randomized, open-label, noninferiority 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.

Rationale

There is growing concerns over progressive antimicrobial resistance and the development pipeline for uncomplicated gonorrhoea remains relatively empty with only two new chemical entities (NCE) currently in development: zoliflodacin and gepotidacin. Zoliflodacin (AZD0914) has shown extremely good activity against a large collection of isolates (standard and clinical), from different geographical origins, including multi-drug resistant (MDR) and extremely drug resistant (XDR) strains. Zoliflodacin has proven to be an excellent clinical candidate both in terms of efficacy and safety. The drug is well tolerated, can be administered orally and has shown high rates of cure for urethral, cervical and rectal gonococcal infection in phase II. In summary, zoliflodacin is a new promising option to address the risk posed by the threat of drug-resistant gonorrhoea. The purpose of this phase III multi-center, randomized, open-label, non-inferiority trial is to confirm the efficacy and safety outcomes observed in the phase II trial and to generate the necessary evidence to support a marketing authorization application in the USA, the European Union (EU), South Africa and Thailand.

Primary Objectives

To assess the efficacy of a single, oral, 3g 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 urogenital gonorrhoea

Study population

Sexually-active, HIV-uninfected adolescents (<18 years old at time of enrolment)

Zoliflodacin Abstract

Oral zoliflodacin is non-inferior to a combination of ceftriaxone and azithromycin for treatment of uncomplicated urogenital gonorrhoea: results of a large global Phase 3 randomised controlled trial

Alison Luckey, Helen Broadhurst, Pierre Daram, Sinead Delany-Moretlwe, Henry J.C. de Vries, Rossaphorn Kittiyaowamarn, Drew Lewis, John P Mueller, Seamus O’Brien, Mary-Ann Richardson, Subasree Srinivasan, Stephanie N. Taylor, Magnus Unemo, Edward Hook for the zoliflodacin Phase 3 trial group.ESCMID Global 2024.Barcelona, Spain. 29-30 April 2024.

Background: Developing new treatments for multidrug-resistant Neisseria gonorrhoeae is a critical public health priority. The spiropyrimidinetrione, zoliflodacin, is a first-in-class oral bacterial topoisomerase inhibitor with potent in vitro activity against N. gonorrhoeae, including multidrug-resistant strains. A global pivotal Phase 3 clinical trial, enabled through a public-private partnership, evaluated the efficacy and safety of zoliflodacin in the treatment of uncomplicated gonorrhoea.

Methods: A randomised controlled (sponsor-blinded) non-inferiority trial was conducted in South Africa, Thailand, the USA, the Netherlands and Belgium. A single, oral 3 g dose of zoliflodacin was compared to a combination of a single dose each of intramuscular ceftriaxone 500 mg and oral azithromycin 1 g (2:1 randomisation), in participants ≥12 years of age with uncomplicated urogenital gonorrhoea. The primary endpoint was microbiological cure, determined by culture from urethral/cervical site at test-of-cure (Day 6 ±2) in the microbiological intention to treat (micro-ITT) population. The pre-defined non-inferiority margin was 12.0%. Safety was assessed in all patients who received treatment.

Results: Of the 930 randomised participants analysed, the mean age (standard deviation) was 29.7 (9.42) years, 87.6% were male, 55.3% were Black or African American and 21.4% had a positive HIV status. Of the randomised population, 744 (80.0%) were included in the micro-ITT (urogenital) population, of which 506 received zoliflodacin and 238 comparator treatment. Non-inferiority of zoliflodacin to the comparator was demonstrated with a difference in urogenital microbiological cure rate of 5.31% (95%CI; 1.38%, 8.65%) (Table 1). Cure rates at extragenital sites were comparable between treatment arms (secondary endpoints). Zoliflodacin 3 g was generally well tolerated and adverse events were comparable between treatment arms. No deaths or other serious adverse events were reported.

Conclusion: A single oral 3 g dose of zoliflodacin is non-inferior to a combination of ceftriaxone and azithromycin for treatment of urogenital uncomplicated gonorrhoea. Zoliflodacin was generally well tolerated. Given the public health threat of global transmission of ceftriaxone-resistant N. gonorrhoeae, this is a positive milestone in the development of new treatments for uncomplicated gonorrhoea.

Media Coverage:

  1. GARDP Press Release, 01 November 2023: Positive results announced in largest pivotal phase 3 trial of a first-in-class oral antibiotic to treat uncomplicated gonorrhoea.
  2. Press Release, 02 November 2023: New Gonorrhoea Treatment Shows Positive Results in Trial Sponsored by Non-Profit Partnership

Latest Update:

June 2024

For more about Zoliflodacin trial please email rhicomms@wrhi.ac.za

Stay up to date

Get updates on news, resources, events and happenings from Wits RHI.