Efficacy of Doxycycline Monohydrate in Reducing Bacterial STIs in MSM and TGW with HIV: A Randomized, Double-Blind, Placebo-Controlled Cross-Over Trial

The primary objective of this study is to evaluate the efficacy of **doxycycline** post-exposure prophylaxis (doxyPEP) in reducing the incidence rate of symptomatic **Neisseria gonorrhoeae** (NG), **Chlamydia trachomatis** (CT), and all **Treponema pallidum** (TP) infections among men who have sex with men (MSM) and transgender women (TGW) living with HIV in Belgium. This is clinically relevant as it addresses the prevention of bacterial sexually transmitted infections (STIs) in a high-risk population, potentially reducing morbidity and transmission rates.

Secondary objectives include assessing differences between study arms in:

• Antimicrobial consumption (tetracycline, macrolide, cephalosporin, penicillin)
• Antimicrobial susceptibility of commensal **Neisseria spp.** and **E. coli**
• Gut resistome/microbiome
• Incidence of symptomatic NG, CT, and TP infections
• Incidence of all NG, CT, and TP infections
• Tetracycline resistance among NG isolates

The clinical trial focuses on a **population** of men who have sex with men (MSM) and transgender women (TGW) living with HIV in Belgium. Participants are aged 18 years or older and were assigned male sex at birth. The study population is exclusively male, with no female subjects included. Participants must have an undetectable viral load for at least six months and have experienced at least one bacterial sexually transmitted infection in the past 24 months or have had five or more sexual partners in the previous six months. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The study aims to assess the incidence rate of symptomatic **Neisseria gonorrhoeae**, **Chlamydia trachomatis**, and **Treponema pallidum** infections while using doxyPEP compared to a placebo. Participants are expected to adhere to study procedures and provide informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **double-blind**, multi-center, randomized, placebo-controlled cross-over study to evaluate the efficacy of doxycycline post-exposure prophylaxis (doxyPEP) in reducing the incidence of **bacterial sexually transmitted infections** (STIs) among men who have sex with men (MSM) and transgender women (TGW) living with HIV in Belgium. The trial aims to determine if there is a difference in the incidence rate of symptomatic **Neisseria gonorrhoeae**, **Chlamydia trachomatis**, and all **Treponema pallidum** infections between participants using doxyPEP and those receiving a placebo. The study is expected to commence recruitment on June 1, 2025, and conclude by May 31, 2027, with a maximum treatment period of 180 days for each participant.

Participants will be randomly assigned to receive either doxycycline EG 100 mg tablets or placebo capsules, both administered orally. The trial will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, HIV status, and history of bacterial STIs or multiple sexual partners. Follow-up visits will be scheduled to monitor the incidence of STIs and assess any adverse effects. The end-of-study visit will evaluate the overall health status and collect final data on STI incidence. Participants are expected to be involved in the study for the entire duration unless they meet conditions for early termination, such as withdrawal of consent or non-compliance with study procedures.

The primary endpoint is the incidence rate ratio of symptomatic NG, CT, and TP infections between the doxyPEP and placebo arms. Secondary endpoints include the rate ratio of various antibiotics, microbiota diversity, and the abundance of resistance genes. The study is categorized as low-intervention and is conducted under the authorization of relevant regulatory bodies, ensuring adherence to ethical standards and scientific rigor throughout the trial process.

The clinical trial involves the administration of **Doxycycline EG 100 mg tablets** as the experimental medication. The active substance in these tablets is **doxycycline monohydrate**, a chemical compound classified under the ATC code J01AA02. The pharmaceutical form of the medication is a tablet, and it is administered orally. Participants will receive a maximum daily dose of 200 mg, with the total dose not exceeding 20,571 mg over the course of the study. The treatment period is set for a maximum of 180 days. For blinding purposes, the commercially available Doxycycline 100 mg tablets will be supplied as over-encapsulated tablets. Compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** control group. The placebo is presented in the form of capsules designed to mimic the appearance of the Doxycycline capsules. These placebo capsules are empty HPMC capsules, known as Vcaps Plus, colored Swedish orange, and filled with microcrystalline cellulose. The placebo is administered orally, following the same dosing schedule as the experimental medication, to ensure blinding and maintain the integrity of the study design. Participant adherence to the placebo regimen will be monitored in a manner consistent with the experimental group.

The efficacy of the clinical trial will be assessed by evaluating the **incidence rate ratio** of symptomatic infections caused by *Neisseria gonorrhoeae* (NG), *Chlamydia trachomatis* (CT), and all *Treponema pallidum* (TP) infections among men who have sex with men (MSM) and transgender women (TGW) living with HIV in Belgium. The primary endpoint focuses on comparing these incidence rates between participants using doxyPEP and those receiving a placebo. Secondary endpoints include the rate ratio of antibiotic classes such as tetracyclines, macrolides, cephalosporins, and penicillins, as well as the minimum inhibitory concentration (MIC) distribution of doxycycline, cefixime, and ciprofloxacin for commensal *Neisseria* species and *E. coli*.

Additional secondary endpoints involve assessing microbiota diversity, richness, and the abundance of specific bacterial families, including Bifidobacteria, Fusobacterium, Lactobacillaceae, Enterobacteriaceae, and Bacteroidaceae. The abundance of resistance genes for tetracyclines and other antimicrobial classes will also be evaluated. The trial will further analyze the incidence rate ratios of both symptomatic and all infections of NG, CT, and TP in the doxyPEP versus placebo arms, as well as the tetracycline MIC distribution of NG isolates. These efficacy parameters will be measured and analyzed throughout the trial duration, with specific timepoints and methods not detailed in the provided data.