Clinical trial NCT03294395: New AntiBiotic Treatment Options for Uncomplicated Anogenital GOnorrhoea
Official title: New Antibiotic Treatment Options for Uncomplicated Anogenital Gonorrhoea Infections - a Double-blind Randomized Controlled Non-inferiority Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gonorrhea
Keywords: Antimicrobial resistance
Antibiotics
Fosfomycin
Ertapenem
Gentamicin
Neisseria Gonorrhoeae
Lead sponsor: Public Health Service of Amsterdam
Sponsor class: OTHER_GOV
Collaborators: name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
First posted: 2017-09-27
Enrollment: 346
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A double-blind randomized clinical trial with non-inferiority design

\*since October 2018 one study arm (fosfomycin) has been dropped. In a subset of these participants the plasma concentration of ceftriaxone, ertapenem and gentamicin is measured.

An open-label randomized substudy evaluating the pharmacokinetics of ceftriaxone ertapenem and fosfomycin in 60 healthy volunteers (this number is in addition to the 346 NABOGO participants with gonorrhea)
Primary purpose: TREATMENT

Brief summary: This study evaluates the efficacy of three experimental antibiotics in the treatment of uncomplicated anogenital gonorrhoea. Participants will be randomized to one of four study arms and will receive either one of the three experimental antibiotics (ertapenem, fosfomycin and gentamicin) or the current standard antibiotic (ceftriaxone). Both the study team and the participant are blinded to the administered treatment. This enables the investigators to compare the eradication capacity and safety of the experimental antibiotics with the standard treatment.

\*Following the advise of the DSMB based on a planned interim analysis, in October 2018 one study arm (fosfomycin 6g PO) was dropped and the randomized clinical trial was continued with three treatment arms (ceftriaxone 500mg IM, ertapenem 1000mg IM and gentamicin 5mg/kg IM) and without the oral placebo.

Detailed description: Antimicrobial resistance (AMR) to extended spectrum cephalosporins (ESC) among Neisseria gonorrhoeae (Ng) is a major public health concern. With no alternative antimicrobial treatment options for gonorrhoea and only a few new drugs in the development pipeline, it is important to test existing antibiotics for their efficacy in gonorrhoea treatment. This project aims to identify new treatment modalities for uncomplicated gonorrhoea using the registered drugs ertapenem, fosfomycin and gentamicin. This trial is a double blind randomized clinical non-inferiority trial with four treatment arms. 108 participants are randomly assigned to each study arm . Participants will receive either ceftriaxone 500mg intramuscularly (IM) or ertapenem 1000mg IM or gentamicin 5mg/kg IM with a maximum of 400mg (in two doses) supplemented with an oral placebo, or receive fosfomycin 6g oral suspension supplemented with an intramuscular placebo. The bacterial eradication capacity of the study antimicrobials at the included infection site is measured 7-14 days after treatment, using an RNA-based Nucleic Acid Amplification Test (NAAT).

\*Following the advise of the DSMB based on a planned interim analysis, in October 2018 one study arm (fosfomycin 6g PO) was dropped and the randomized clinical trial was continued with three treatment arms (ceftriaxone 500mg IM, ertapenem 1000mg IM and gentamicin 5mg/kg IM) and without the oral placebo.

Eligibility criteria: Inclusion criteria main study

* 18 years or older
* Anorectal, cervical/vaginal or urethral Ng infection, diagnosed by the following:

  * Ng-positive Gram-stained smear (intracellular Gram-negative diplococci and leukocytes) and/or
  * Positive for Ng by nucleic acid amplification test (NAAT) (Aptima Combo 2) and/or
  * 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

Exclusion criteria main 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:

  * Newly diagnosed HIV infection (upon the inclusion visit) and/or
  * 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:

  * systemic antibacterial antimicrobials other than nitrofurantoin or metronidazole
  * systemic immunosuppressive drugs
  * 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:

  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

Inclusion criteria PK substudy (healthy volunteers):

* 18 years or older
* Provide informed consent

Exclusion criteria PK substudy (healthy volunteers)

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 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)
* Concurrent use of any of the following medication:

  * systemic valproic acid
  * 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

Primary outcomes:
measure: Proportion of participants with treatment success in each study arm for the included anatomic infection
timeFrame: 7-14 days after treatment
Secondary outcomes:
measure: Proportion of participants with treatment success in each study arm at all anatomical infection sites
timeFrame: 7-28 days after treatment
measure: Incidence of treatment-emergent adverse events
timeFrame: until 30 days after treatment
measure: Antimicrobial susceptibility of Ng-strains to study antibiotics
timeFrame: Day 0 (before treatment) - 28 (after treatment)
measure: Blood plasma concentration of ceftriaxone, ertapenem and gentamicin in a subset of 60 NABOGO participants
timeFrame: within 24 hours after treatment administration
measure: Duration of symptoms after treatment
timeFrame: 1-30 days after treatment
measure: Clinical and demographic predictors for treatment failure
timeFrame: until 7-14 days after treatment
measure: Blood plasma concentration of ceftriaxone, ertapenem and fosfomycin in 60 healthy volunteers
timeFrame: 24 hours
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Public Health Service
state: Noord Holland
Study officials:
affiliation: Public Health Service of Amsterdam
name: Henry JC de Vries, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Vries HJC, de Laat M, Jongen VW, Heijman T, Wind CM, Boyd A, de Korne-Elenbaas J, van Dam AP, Schim van der Loeff MF; NABOGO steering group. Efficacy of ertapenem, gentamicin, fosfomycin, and ceftriaxone for the treatment of anogenital gonorrhoea (NABOGO): a randomised, non-inferiority trial. Lancet Infect Dis. 2022 May;22(5):706-717. doi: 10.1016/S1473-3099(21)00625-3. Epub 2022 Jan 19.