Lubricant Investigation in Men to Inhibit Transmission of HPV Infection

Study Overview
=================
Brief Summary
-----------------
The LIMIT-Study is a placebo-controlled, double-blinded randomized controlled trial designed to explore the efficacy of a carrageenan-based lubricant as a topical microbicide for preventing HPV acquisition. Individuals at high risk for infection (men who have sex with men, or MSM, and especially those with HIV) will be included in the trial. Participants will complete a self-administered baseline questionnaire during the enrollment visit, and follow-up questionnaires during all other six visits. The shorter follow-up questionnaires are intended to evaluate recent sexual behaviours and to corroborate the responses given during the baseline visit. These questionnaires will measure HPV risk factors, compliance, and monitor safety and tolerability of the gels. Between follow-up visits, participants will be asked to log into a secure web module at least once a week to answer questions on daily sexual activities, condom and study gel use, and adverse events. Individuals will be screened for eligibility over the telephone or in person and eligible men will attend an enrollment visit, where the nurse will obtain informed consent and instruct the participant on gel use. They will receive a one month's supply of gel and provide the first specimen. Random number sets will be assigned to the treatment and control gel. Each participant will be assigned an individual code, which will be used to match him to the study arm. Lastly, the nurse will provide details about HPV infection and advice about condom use and sexual health. HPV infection status will be measured using anal specimens at baseline (enrollment/time 0), and at all follow-up clinic visits (1, 2, 3, 6, 9 and 12 months).

Detailed Description
-----------------
Human papillomavirus (HPV) inhibitory compounds might be useful as topical microbicides for blocking the spread of HPV. Recent in-vitro and in-vivo laboratory studies have demonstrated the strong inhibitory properties of carrageenan (an inexpensive gelling agent that is non-toxic and safe in animals and humans) against all HPV types. So far, there has been no clinical trial designed to assess a carrageenan-based personal lubricant as a topical microbicide in the Men who have Sex with Men (MSM) population. Since the introduction of HAART therapy in 1996, there has been a paradoxical effect on the incidence of anal cancer, a disease caused by HPV. Whereas patients would formerly die of some other AIDS-related ailment, men undergoing HAART therapy now have increased longevity, thus allowing diseases with longer natural history such as anal cancer to develop. Low cluster of differentiation 4 (CD4) counts, high HPV incidence and longer duration of infection have contributed to elevating the risk of anal lesions and cancer among MSMs with HIV to nearly 80 times that of the general male population. Although HPV vaccination has been approved for males in Canada, it is exclusively prophylactic, i.e. it will only prevent HPV infection before exposure occurs. But considering that most MSMs will have already been exposed to the vaccine target types, its benefits in this population are limited. Furthermore, current vaccination only protects against two of the 14 oncogenic HPV types. The primary aim of the study is to evaluate the efficacy of carrageenan in reducing type-specific anal HPV incidence, i.e., in preventing infections by new HPV types in sexually active MSM. Secondary aims are: 1) to evaluate the efficacy of carrageenan in reducing type-specific anal HPV prevalence, i.e., in accelerating clearance of existing infections in sexually active MSM; 2) to compare the efficacy of carrageenan for type-specific prevention and clearance of anal HPV infections among MSM with and without HIV, i.e., to evaluate whether carrageenan is equally effective among these subgroups; and 3) to assess the safety and tolerability of the proposed gel and patient adherence to the intervention, i.e., the parameters important for future clinical use. To permit verification of the study's objectives with sufficient power at the end of the one-year follow-up period, we propose to recruit 380 subjects (110 HIV+ and 270 HIV-). We will be recruiting subjects living with HIV through 5 HIV/AIDS outpatient clinics in Montreal: Clinique Médicale du Quartier-Latin, Clinique L'Actuel, Clinique OPUS, Unité d'Hospitalisation de Recherche et d'Enseignement sur les Soins du SIDA (UHRESS) of the Centre Hospitalier de L'Université de Montréal (CHUM) and Chronic Viral Illnesses Service of McGill University Health Centre (MUHC). We will advertise at bars, sex and health clubs, in various media, and the abovementioned clinics-with the addition of the McGill University Student Health Services. MSMs with and without HIV will be recruited. For those with HIV, a chart review will be performed at enrollment to collect information on CD4+ count, viral load, HAART status, year of HIV diagnosis, and nadir CD4+ count. HIV testing will also be performed on MSMs without HIV to verify their status. Volunteer MSMs living in Montreal will be randomized to receive either a) treatment with carrageenan self-applied as an anal microbicide gel, or b) treatment with a placebo gel applied in the same way. Our specific primary aim is to evaluate the efficacy of carrageenan in reducing anal HPV incidence, i.e., in preventing new HPV infections in sexually active MSMs. Additional secondary aims include: to evaluate the efficacy of carrageenan in reducing anal HPV prevalence (i.e., in accelerating clearance of existing infections in sexually active MSMs), to evaluate if there is a difference in the efficacy of carrageenan for prevention and clearance of HPV infections between individuals living with and without HIV, and to evaluate patient adherence as measured by behavioural characteristics assessed by means of questionnaires. Participants will be randomized to either carrageenan or placebo gels by a variable block randomization algorithm and blinded intervention. Demographics, risk factor, and compliance information will be collected via computerized questionnaires at baseline (enrollment/ time 0), and 1, 2, 3, 6, 9 and 12 months post-enrollment. HPV DNA detection and genotyping of anal samples will be done at the same clinic visits by the PGMY polymerase chain reaction protocol. Measuring the efficacy of the intervention will be done by testing the null hypothesis of no difference in time to HPV infection (i.e., infection with an HPV type not present at baseline) between treatment groups with the log rank test. We will use a Cox proportional hazards regression model to estimate the hazard ratio and 95% confidence intervals of HPV infection for the treatment versus placebo group. We will also use survival analysis techniques to measure clearance of infections with HPV types present at enrollment according to the intervention. Our analyses will be conducted separately according to participant HIV status, and eventually pooled if results are found to be similar between groups. We will perform our analyses according to the intention-to-treat approach (i.e., including all participants who were randomized and received at least one-month's supply of gel), and the according-to-protocol approach (i.e., including only participants who complied with the protocol). Considering that HPV infection is responsible for 90% of anal cancer cases, as well as for much suffering due to genital warts, the potential for this microbicide-based approach in disease prevention cannot be overemphasized. Our team has extensive experience in studies of HPV epidemiology in Montreal and subject recruitment resources are already in place. (Full protocol available upon request)

Official Title
-----------------
A Randomized Controlled Trial of a Carrageenan-Containing Lubricant to Reduce Transmission of Human Papillomavirus Infection Among Men Who Have Sex With Men

Conditions
-----------------
Human Papillomavirus Infection

Intervention / Treatment
-----------------
* Other: Carrageenan-based gel
* Other: Control gel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men aged 18 or older, Men living in Montreal and plan to remain in the city for the next 12 months, Men who have had receptive anal sex with one or more men during the previous 3 months and intend to continue being sexually active for the duration of their involvement in the study, irrespective of whether their sexual partner will change, Men planning on having receptive anal sex with two or more men, but less than 50 DIFFERENT partners per year Men who understands French or English, Men willing to follow study instructions and comply with follow-ups for 12 months. Exclusion Criteria: Men must not be receiving treatment for anal or perianal condylomas or anal intraepithelial neoplasia lesions during the trial, Men must not have a known allergy or hypersensitivity to any of the ingredients in either gels.

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

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Carrageenan-containing gel
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carrageenan-based gel<br>The intervention to be administered is: a commercially available gel that contains carrageenan. water-based, latex-condom compatible, clear, odourless, tasteless, and have similar viscosity as the placebo gel. also packaged in a similar plastic bottle with a disk cap that can be operated with one finger, and must be applied prior to anal intercourse during the entire study period. Around 15 ml of the personal lubricant will be dispensed into the hand and applied directly to the genital, anal, and condom surfaces prior to and as needed during anal sex. When sexual activity ceases, the water-based formulation of the gel allows it to be easily removed with lukewarm water. | Other: Carrageenan-based gel<br>* Carrageenan is a non-toxic gelling agent safe in animals and humans as a potent HPV inhibitor. An anionic polymer derived from red algae, carrageenan has a long history of human use as a stabilizer and emulsifier in many industries. All three major classes of carrageenan act as extremely potent HPV inhibitors and block HPV infection by binding to the viral capsid, thus preventing attachment to the appropriate cell-surface heparan sulfate proteoglycans (HSPG) receptors.<br>|
| Placebo Comparator: Control gel<br>The intervention to be administered is: a commercially available gel that does not contain carrageenan. water-based, latex-condom compatible, clear, odourless, tasteless, and have similar viscosity as the carrageenan-containing gel. also packaged in a similar plastic bottle with a disk cap that can be operated with one finger, and must be applied prior to anal intercourse during the entire study period. Around 15 ml of the personal lubricant will be dispensed into the hand and applied directly to the genital, anal, and condom surfaces prior to and as needed during anal sex. When sexual activity ceases, the water-based formulation of the gel allows it to be easily removed with lukewarm water. | Other: Control gel<br>* A gel not containing carrageenan<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of a Newly Detected Anal Infection of a Specific HPV Type in a Man Who Was Negative for That HPV Type at Enrollment | Detection of 36 different HPV types will allow for the assessment of new HPV types even among those already infected. | One year follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance of Anal Type-specific HPV Infections Found at Baseline | Detection of 36 different HPV types will allow for the assessment of clearance of any HPV type or specific HPV types. | One year follow-up | 
| Patient Adherence, Measured Via Questionnaires and Review of Patient Adverse Event Reports. | Measured via questionnaires and review of patient adverse event reports. Adherence was defined as the number of times the gel was used during receptive anal intercourse divided by the number of receptive anal intercourse in the 7 days preceding each visit. Participants were considered adherent at a particular visit if they used the gel during receptive anal intercourse ≥ 50% of the time. This variable was analyzed at the visit level. Safety analyses are included in the adverse event reporting section. | One year follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Human papillomavirus, Carrageenan, Microbicide, Anal HPV infection