Clinical trial NCT02864550: Oral Doxycycline for the Prevention of Syphilis in Men Who Have Sex with Men (DaDHS)
Official title: A Randomized, Placebo-controlled Trial of Oral Doxycycline for the Prevention of Syphilis in HIV-positive Men Who Have Sex with Men (MSM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Syphilis
Sexually Transmitted Infections
Keywords: Men who have sex with men
Human immunodeficiency virus
Doxycycline
Tetracycline
Lead sponsor: British Columbia Centre for Disease Control
Sponsor class: OTHER_GOV
First posted: 2016-08-12
Enrollment: 52
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Syphilis is a sexually transmitted infection (STI) disproportionately affecting gay, bisexual and other men who have sex with men (gbMSM), with the potential for significant sequelae - particularly in those who are Human Immunodeficiency Virus (HIV)-positive. Rising rates of this STI have prompted a search for novel prevention solutions. A recent pilot study of daily doxycycline prophylaxis demonstrated promise as a novel STI prevention tool. This innovative approach to STI prevention has solid clinical precedent, both from the HIV pre-exposure prophylaxis (PrEP) literature, as well as doxycycline's use as prophylaxis for other infections. The overarching goal of this project is to determine whether the daily use of doxycycline is an efficacious and acceptable intervention for syphilis prevention in high-risk, HIV-positive gbMSM.

Detailed description: Syphilis disproportionately impacts gbMSM:

Syphilis remains an important cause of morbidity in gbMSM. Up to 75% of early syphilis infections occur in gbMSM - a population with syphilis rates nearly 10-fold higher than in those who are HIV negative. In Canada's urban centres, 2/3 of syphilis cases are in HIV-positive gbMSM, and re-infection remains high. HIV co-infection with syphilis has important implications for HIV management. Syphilis may increase HIV viral load levels in virologically suppressed individuals, and genital ulcers increase the risk of HIV transmission and acquisition.

The era of novel, biomedical prevention technologies:

Significant advancements have shaped the past two decades of HIV care. Antiretroviral therapy (ART) has substantially reduced HIV-associated morbidity and mortality and extended life expectancy to near-normal levels. With reduced morbidity and mortality associated with HIV, gbMSM may also be changing their sexual behaviours. Seroadaptive strategies, such as serosorting (selecting sexual partners of the same serostatus) and seropositioning (selecting a sexual position to minimize the risk of HIV transmission) are common among gbMSM. While this may be mitigating the risk of HIV transmission or acquisition, there is evidence to suggest that decreasing condom use may contribute to a rise in syphilis and other bacterial STIs in high-risk populations. Further, new evidence has emerged demonstrating the efficacy of HIV PrEP in preventing HIV acquisition. The combination use of tenofovir/emtricitabine was shown in the Pre-exposure Prophylaxis Initiative (iPREX) trial to reduce the risk of HIV acquisition by 44% in HIV-negative gbMSM when taken daily as PrEP. Among those with detectable drug levels, the risk reduction was \> 90%.

A role for PrEP in other STIs? The exciting developments in HIV prevention have encouraged investigators to expand this strategy to the prevention of other STIs, a modality previously shown to be acceptable to gbMSM. A recent pilot study randomized participants to receive either the antimicrobial doxycycline daily or a monetary incentive to remain STI-free throughout the study period. After 48 weeks, those receiving doxycycline were significantly less likely to be diagnosed with any STI (odds ratio: 0.27; 95% confidence interval: 0.09-0.83). Though there was also a trend toward benefit for doxycycline in specifically preventing syphilis, significance was not achieved for this outcome.

The first large-scale syphilis PrEP study:

Given the rising rates of syphilis and its disproportionate impact on HIV-positive gbMSM, there is an urgent need to replicate this study on a broader scale. This proposed study will contribute to this field by being - to the investigators' knowledge - the first large-scale, methodologically rigorous trial of syphilis PrEP, and has the potential to provide a completely novel and innovative tool to the syphilis prevention armamentarium. It will provide insight on whether daily doxycycline is an efficacious PrEP intervention for the prevention of syphilis and other bacterial STIs, as well as shedding light on issues relating to its feasibility as a prevention tool, including its safety, tolerability, how well individuals adhere to it, and its impact on the development of antimicrobial resistance. These outcomes are directly in line with the planned outputs of this study, and have the potential to drastically shift how people think about and manage syphilis and other STI prevention in gbMSM.

Primary objective

1. To assess feasibility of using daily doxycycline PrEP, as defined by:

   a. Evaluation of feasibility of recruitment for a larger study i. Proportion of participants approached for study who are eligible and agree to participate.

   b. Adherence to 24 and 48 weeks of study drug (doxycycline or placebo) i. Determine proportion of individuals with \>95% adherence to study drug over 24 and 48 weeks ii. Proportion of individuals in the doxycycline arm with therapeutic doxycycline plasma level at each study visit.

   c. Tolerability of doxycycline i. Comparison of grade 3 or 4 adverse events in those receiving doxycycline vs. placebo ii. Comparison of the proportion of individuals with adverse event-related discontinuation of study drug in each arm

   2.2 Secondary objectives
2. To evaluate antimicrobial resistance over time.

   a. Change in proportion of participants with evidence of tetracycline class resistance in common flora, namely Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae from baseline to 24 and 48 weeks.
3. To evaluate changes in sexual activity reported by study participants over the study period.
4. To compare syphilis incidence between those in the doxycycline vs. placebo arms.
5. To describe frequency of other STIs diagnosed in study participants over the study period.

   Exploratory objectives will include:
6. To changes in the rectal microbiome of study participants from baseline to 24 and 48 weeks after initiation of doxycycline.

Eligibility criteria: The inclusion criteria for this study are as follows:

1. Males, ≥ 18 years of age at baseline;
2. Self-reported MSM status;
3. Self-report condomless anal sex with a man within the last 6 months;
4. Laboratory documentation of HIV-1 infection;
5. Prior diagnosis of early/infectious syphilis (i.e. primary, secondary or early latent) within preceding 36 months (defined on the basis of a new positive serum rapid plasma reagin (RPR) test, or ≥2-dilution rise in titre if previous syphilis, or positive darkfield microscopy result or T. pallidum direct fluorescent antibody test or PCR from a primary lesion);
6. Able to provide informed consent.

The exclusion criteria for this study are as follows:

1. Known allergy or intolerance to doxycycline or tetracyclines;
2. A known diagnosis of myasthenia gravis;
3. Use of medications which could lower doxycycline levels, including barbiturates, phenytoin and carbamazepine;
4. Individuals using isotretinoin;
5. Any individual capable of getting pregnant.

Primary outcomes:
measure: To assess the proportion of participants who are eligible and consent to participate amongst those approached.
timeFrame: 15 months
measure: To assess the proportion of participants reporting > 95% adherence to study drug, according to self-report and pill counts.
timeFrame: 15 months
measure: To assess the proportion of individuals with therapeutic doxycycline drug level (defined at ≥ 1000 ng/mL) at each study time point.
timeFrame: 15 months
measure: To assess the proportion of individuals reporting grade 3 or 4 adverse events in each study arm.
timeFrame: 15 months
measure: Proportion of individuals with adverse event-related study drug discontinuation in each study arm.
timeFrame: 15 months
Secondary outcomes:
measure: To assess the proportion of individuals with evidence of tetracycline class resistance in common flora (Staphylococcus aureus, Streptococcus pyogene and Streptococcus pneumoniae)
timeFrame: At 6 and 12 months
measure: To assess the changes in sexual risk behaviour will be calculated by comparing risk parameters (i.e. number partners, number of anal sexual encounters that were condomless) from pre-PrEP initiation to the study period.
timeFrame: 15 months
measure: To assess the incidence of early syphilis infection
timeFrame: 15 months
measure: To assess the incidence of gonorrhea or chlamydia infection
timeFrame: 15 months
Other outcomes:
measure: To assess changes in the bacterial populations found in the rectal microbiome.
timeFrame: 15 months
Locations:
city: Vancouver
country: Canada
facility: British Columbia Centre for Disease Control
state: British Columbia
Study officials:
affiliation: BC Centre for Disease Control
name: Troy Grennan, MD
role: PRINCIPAL_INVESTIGATOR
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