Doxycycline Intervention for Bacterial STI ChemoprOphylaxis (DISCO)

Study Overview
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Brief Summary
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There is a growing epidemic of the bacterial sexually transmitted infections (STIs) syphilis, chlamydia and gonorrhea worldwide; similarly concerning trends have been noted in Canada, where increases of over 160% have been seen in bacterial STIs over the last decade. In Canada, gay, bisexual, and other men who have sex with men (gbMSM) - including those living with HIV - are disproportionately impacted by bacterial STIs5,6These dramatic increases in bacterial STIs, the potential development of serious complications including AMR, and waning effectiveness of the promotion of conventional STI prevention tools (e.g. condoms), signals the need for novel STI prevention strategies and tools to mitigate STI-related complications. A rigorous randomized controlled trial will be conducted to compare STI PrEP vs. STI PEP and definitively assess the efficacy, safety, antimicrobial resistance profiles and costs associated with doxycycline-based STI prevention.

Detailed Description
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With the rising rates of STIs among gbMSM populations in Canada, there is an urgent need for novel interventions to prevent significant sequelae (e.g. neurosyphilis) and onward transmission of untreated infections. Despite longstanding public health efforts to encourage conventional strategies of STI prevention, gbMSM continue to bear the burden of syphilis which poses synergistic effects in the transmission of HIV. This study will add to this field through providing the first methodologically rigorous, prospective multicentre, open-label randomized controlled trial (RCT) of doxycycline-based STI PrEP (daily 100mg doxycycline) versus STI PEP (200mg doxycycline after exposure event) for the prevention of bacterial STIs among gbMSM over 15 months (60 weeks) of follow-up with adequate power to address drug efficacy in the prevention of bacterial STIs. Beyond the determination of efficacy, our trial will provide insight to the unique challenges of medication adherence through assessing the acceptability, tolerability and safety of therapy with doxycycline. This study aims to provide health care providers one additional tool to address the burden of STIs in populations with an increased likelihood of infection.

Official Title
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A Randomized Trial of Doxycycline Chemoprophylaxis for the Prevention of Sexually Transmitted Infections in Gay, Bisexual and Other Men Who Have Sex With Men (gbMSM)

Conditions
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Bacterial Sexually Transmitted Diseases

Intervention / Treatment
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* Drug: Doxycycline Hyclate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males, ≥ 18 years of age; Any sexual activity (i.e. oral sex, insertive or receptive anal sex, with or without a condom) with more than one male partner in the preceding 12 months; Intention to remain sexually active with more than one male partner in the next 12 months; At least one prior episode of a previously diagnosed and adequately treated syphilis, gonorrhea or chlamydia infection within 12 months prior to screening. Exclusion Criteria: Known allergy to doxycycline or tetracyclines; Existing chronic or intermittent tetracycline or doxycycline use (e.g. for chronic osteomyelitis, acne). Use of medications which could lower doxycycline levels, including barbiturates, phenytoin and carbamazepine. Individuals currently using isotretinoin; Any individual capable of becoming pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization with a 1:1 ratio
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STI PrEP arm<br>doxycycline capsules 100mg orally daily for 12 months. Though the usual treatment dose of doxycycline is 100mg twice daily | Drug: Doxycycline Hyclate<br>* STI PrEP arm: doxycycline capsules 100mg orally daily for 12 months STI PEP arm: doxycycline 200mg orally once within 24-72 hours following each sexual encounter deemed at risk (i.e. condomless anal or oral sex), to a maximum of six pills (i.e. 600 mg total) per week<br>|
| Experimental: STI PEP arm<br>doxycycline 200mg orally once within 24-72 hours following each sexual encounter deemed at risk (i.e. condomless anal or oral sex), to a maximum of six pills (i.e. 600 mg total) per week | Drug: Doxycycline Hyclate<br>* STI PrEP arm: doxycycline capsules 100mg orally daily for 12 months STI PEP arm: doxycycline 200mg orally once within 24-72 hours following each sexual encounter deemed at risk (i.e. condomless anal or oral sex), to a maximum of six pills (i.e. 600 mg total) per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma doxycycyline levels to determine efficacy of doxycycline chemoprophylaxis | To determine the efficacy of doxycycline chemoprophylaxis in preventing incident bacterial STI cases (syphilis, gonorrhea, and/or chlamydia, including LGV) | 60 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of STIs over time | To describe frequency of syphilis, gonorrhea, and chlamydia incident infections among participants over the study period | 60 weeks | 
| Proportion of individuals reporting grade 3 or 4 adverse events in each study arm as assessed by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events | To determine the tolerability and safety of doxycycline chemoprophylaxis | 60 weeks | 
| Proportion of participants who report acceptability, community norms and partner attitudes of STI PrEP and PEP based on responses from questionnaires | To determine the acceptability of doxycycline chemoprophylaxis | 60 weeks | 
| Change in self-reported sexual activity defined as increases in condomless sexual acts and number of sexual partners based on responses from questionnaires | To evaluate the change in sexual behaviour reported by participants over the study period | 60 weeks | 
| Proportion of individuals with evidence of tetracycline class resistance in common flora (Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae) at 24 and 48 weeks. | To evaluate antimicrobial resistance in bacterial STIs and common commensal pathogens over study period | Over 48 weeks | 
| Proportion of cases with resistance to penicillins, tetracyclines or macrolides in syphilis, and tetracycline resistance in gonorrhea and chlamydia isolates taken from the anus, oral cavity or urethra. | To evaluate antimicrobial resistance in bacterial STIs and common commensal pathogens over study period | Over 48 weeks | 
| Proportion of individuals with adverse event-related study drug discontinuation in each study arm | To determine the tolerability and safety of doxycycline chemoprophylaxis | Over 60 weeks | 
| Rate of adherence to study treatment (STI PrEP vs. PEP) by participants. | To assess for superiority of doxycycline PrEP over PEP (if non-inferiority is shown) | Over 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sexually transmitted infections (STIs), Doxycycline, Pre-exposure prophylaxis (PrEP), Post-exposure prophylaxis (PEP), Gay, bisexual, men who have sex with other men (gbMSM)