Cefixime Plus Doxycycline Compared to Ceftriaxone Plus Azithromycin for Treatment of Gonorrhoea

Study Overview
=================
Brief Summary
-----------------
A non-inferiority, open-label, multicentre randomised controlled trial to compare two therapeutic regimens for the treatment of uncomplicated urogenital, rectal or pharyngeal gonorrhoea in men and women between 18 and 75 years of age. Patients were enrolled and treated from April 2021 to June 2022 at the Dermatovenerology Department, University Hospital Bulovka, Prague, Czech Republic and the Venereology Prague, Medicentrum Beroun, Prague, Czech Republic.

Detailed Description
-----------------
Non-inferiority, open-label, multicentre randomised clinical trial (RCT) compared two regimens for the treatment of uncomplicated urogenital, rectal or pharyngeal gonorrhoea in men and women between 18 and 65 years of age. Patients were enrolled and treated from April 2021 to June 2022 at the Dermatovenerology Department, University Hospital Bulovka, Prague, and the Venereology Prague, Medicentrum Beroun, Prague, Czech Republic. Laboratory testing The diagnosis of gonorrhoea and C. trachomatis infection was established from urogenital, rectal and pharyngeal swab specimens. Laboratory testing for inclusion in the study and at 3 weeks after initiation of treatment was performed using the Cobas 4800 CT/NG NAAT assay (Roche Diagnostics, Indianapolis, IN, USA). At test of cure visits 1 and 3 weeks after the initiation of treatment, swabs for cultivation of N. gonorrhoeae were also sampled and immediately inoculated onto non-selective and selective Modified Thayer-Martin agar plates. Inoculated agar plates were directly transferred to the hospital laboratory for incubation at 36°C in a humid 5% CO2-enriched atmosphere for 48 hours. Suspected gonococcal colonies were species verified using the biochemical NEISSERIAtest® (LACHEMA, Brno, Czech Republic) or the PolyViteX VCAT3® medium (Biomérieux, Marcy l'Etoile, France). Statistical analyses Sample size was based on assessing non-inferiority of the cefixime plus doxycycline arm compared to the ceftriaxone plus azithromycin arm with a one-sided 5% type I error rate. We estimated the sample size based on estimates from other gonorrhoea treatment studies and expert opinions. The target sample size of 152 participants (76 per group) was based on an assumed treatment failure of 0% in the ceftriaxone-azithromycin arm and 2% in the cefixime-doxycycline arm, which would provide at least 90% power for the comparison of the primary endpoint. Intention-to-treat (ITT) and per-protocol analyses were done; per protocol results are reported here and ITT results in the online supplement. The ITT population was composed of all randomised patients; the per-protocol population consisted of patients who were randomised, received the allocated regimen (for doxycycline, at least ≥85% (12/14) of the prescribed dose) underwent follow-up examinations, and abstained from any sexual activities, including protected intercourse, during the study period. For each study group, the proportion of patients with urogenital, rectal or pharyngeal gonorrhoea who achieved microbiological cure was calculated. The Clopper-Pearson exact method was used to estimate confidence intervals (CIs). We used chi-square tests (Pearson's or Fisher's test when less than five observations) for binomial outcome measures and Student's t test for continuous outcome measures, as appropriate.

Official Title
-----------------
Cefixime 800 mg Plus Doxycycline 100 mg b.i.d. for 7 Days Compared to Ceftriaxone 1 g Plus Azithromycin 2 g for Treatment of Urogenital, Rectal and Pharyngeal Gonorrhoea: A Randomised Controlled Trial

Conditions
-----------------
Gonorrhea

Intervention / Treatment
-----------------
* Drug: Cefixime
* Drug: Doxycyclin
* Drug: Ceftriaxon
* Drug: Azithromycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: uncomplicated urogenital, rectal or pharyngeal gonorrhoea diagnosed using the nucleic acid amplification test Exclusion Criteria: any antimicrobial treatment during the 4 weeks before study enrolment pregnancy or lactation autoimmune disease renal, hepatic or cardiac insufficiency immunosuppressive therapy allergy to cephalosporins, macrolides or doxycycline

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients were randomised to cefixime 800 mg single oral dose plus doxycycline 100 mg twice a day orally for 7 days or the comparator ceftriaxone 1 g single intramuscular dose plus azithromycin 2 g single oral dose with a computer-generated pseudo-random code using permuted block randomisation in a 1:1 ratio
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cefixime plus doxycycline<br>Single-dose cefixime 800 mg plus doxycycline 100 mg b.i.d. for 7 days | Drug: Cefixime<br>* Two 400 mg tablets will be administered orally to equal a 800 mg dose.<br>* Other names: Cefixime (ATC code J01DD08);Drug: Doxycyclin<br>* One 100 mg tablet will be administered orally twice a day for 7 days<br>* Other names: Doxyhexal (ATC code J01AA02);|
| Active Comparator: Ceftriaxone plus azithromycin<br>Single dose ceftriaxone 1 g plus single-dose azithromycin 2 g | Drug: Ceftriaxon<br>* Dose of 1 g intramuscular one time<br>* Other names: Ceftriaxone (ATC code J01DD04);Drug: Azithromycin<br>* Four 500 mg tablets will be administered orally to equal a 2 g dose.<br>* Other names: Sumamed (ATC code J01FA10);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with negative cultures 1 and 3 weeks and a negative NAAT 3 weeks (±3 days) after treatment initiation. | To assess the eradication rate of Neisseria gonorrhoeae by culture and NAAT following a single-dose cefixime 800 mg plus doxycycline 100 mg b.i.d. for 7 days compared to single-dose ceftriaxone 1 g plus single-dose azithromycin 2 g (Intent to Treat population). | One and three weeks (±3 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with clinical cure defined as disappearance of clinical symptoms and signs 1 week after treatment according to the clinical assessment of the patient by the physician. | To assess clinical cure (disapperance of clinical symptoms and sings) following a single-dose cefixime 800 mg plus doxycycline 100 mg b.i.d. for 7 days compared to single-dose ceftriaxone 1 g plus single-dose azithromycin 2 g (Intent to Treat population). | One week (±3 days) | 
| Occurrence of treatment-related severe adverse events in treatment groups | Adverse event frequency and severity will be compared between patients who received single-dose cefixime 800 mg plus doxycycline 100 mg b.i.d. for 7 days compared to single-dose ceftriaxone 1 g plus single-dose azithromycin 2 g | One and three weeks (±3 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neisseria gonorrhoeae, Cefixime, Azithromycin, Ceftriaxone, Doxycycline