Effectiveness Study of Human Papilloma Virus (HPV) Vaccines to Prevent Recurrence of Genital Warts

Study Overview
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Brief Summary
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Large genital warts are frequently diagnosed in general gynaecology and oncology clinics in South Africa. Medical and destructive therapy for small warts is generally very effective, however unique problems posed by large or extensive genital warts are not so easily solved and treatment of affected patients remains very challenging. Recurrences are common especially among immune-compromised women. This study will test whether giving the quadrivalent human papilloma virus (HPV) vaccine to women with extensive genital warts prior to surgical treatment will improve outcomes. Investigators hypothesize that pre-treatment with HPV vaccine can play a role in the control of both malignant and benign HPV disease in women with and without HIV infection through stimulation of the antibody response. In addition, HPV types and other associated diseases will be studied in women receiving HPV vaccine and placebo.

Detailed Description
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Patient selection: Female patients referred or presenting with genital warts at each site will be eligible and evaluated against the inclusion and exclusion criteria. Women who are clinically or severely immune-compromised will not be included into the study, but both HIV negative and HIV infected women will be included. Seventy-five women with large or recurrent genital warts will be recruited for this study from 2 sites in South Africa. Recruitment: Women with genital warts will be evaluated for inclusion into the study. Those who fit the inclusion criteria and are without any of the exclusion criteria will be fully informed and invited to participate. The first target will be to recruit the first seventy-five consecutive eligible patients who have signed written consent; recruitment for the study will be done for at least 24 months. First clinical visit: Evaluation genital lesions: On study entry tumour size and position will be documented graphically and photographically and viral typing from the vulva wart and cervix will be done using Roche Linear Array test. Evaluation immune status: HIV status and CD 4/CD 8 count will be recorded and tested and the serum will be collected for antibody testing. Cervical disease of clinical significance will be excluded or treatment offered if relevant. Randomization: Patients will be randomized to receive either quadrivalent HPV or Hepatitis B vaccine. Vaccination: The participants assigned to the test group will be administered quadrivalent HPV vaccine in three doses as recommended by the manufacturer. Participants assigned to the control group will receive Hepatitis B vaccine in three doses as recommended by the manufacturer. Follow-up clinical visits: week 8, week 16 and week 24: Evaluation genital lesions: Three follow up visits will be scheduled two months apart at which time the lesion size will be recorded. Evaluation immune status: After month 6 or the third visit, the serum will again be collected for antibody level testing. Treatment decision: According to the clinical response as measured at month six and onwards, locally destructive or surgical treatment will be allowed according to the preference of the clinician and as determined by clinical factors. Follow up after treatment: Follow up will be done at six monthly intervals. Evaluation genital lesions: At these visits lesion size will be determined and documented. HPV typing on the cervical and vulval lesions will be repeated at least once. Further treatment of warts: If needed, repeat surgery and/or local destruction will be allowed and documented. These will be around week 48 and week 72, or study exit Study exit: Participants will exit the study in week 72. In the absence of harm as determined at interim analysis or suggested by participant disease history, researchers will be unblinded for participant status at study exit and alternative vaccines will be offered to each of these women.

Official Title
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Prophylactic Vaccines as Therapy: Prevention of Recurrence of Extensive Genital Warts

Conditions
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Genital Warts

Intervention / Treatment
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* Biological: Quadrivalent HPV vaccine
* Biological: Hepatitis B vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patient > 16 years Presence of vulvo vaginal genital warts: largest tumour diameter > 3 cm OR Tumour on labia minora and labia majora OR bilateral > 1 cm each side OR Tumour in vagina/cervix as well as on vulva > 1 cm lesion each HIV negative or HIV infected and CD4 ≥ 300 cells/mm3 OR viral load controlled OR anti retro-viral (ARV) compliant > 6 months Exclusion Criteria: Pregnant of planned pregnancy within 6 months Not able to comprehend study method or not able to attend all study visits Previous HPV vaccination Active known opportunistic infection or malignancy including Pneumocystis pneumonia (PCP),Pulmonary tuberculosis (PTB), oesophageal Candida or Kaposi sarcoma or lymphoma Known allergy to vaccines or content of vaccine Previous radiation for genital warts

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Quadrivalent HPV vaccine<br>Three doses of 4 HPV vaccine is given at registered intervals. | Biological: Quadrivalent HPV vaccine<br>* Quadrivalent HPV vaccine doses administered intramuscular as 3 separate 0.5 ml doses at month 0, month 2 and month 6.<br>* Other names: q HPV vaccine;|
| Sham Comparator: Hepatitis B vaccine<br>Three doses of Hepatitis B vaccine is given at the same intervals as the quadrivalent HPV vaccine. | Biological: Hepatitis B vaccine<br>* Hepatitis B vaccine doses administered intramuscular as 3 separate 0.5 ml doses at month 0, month 2 and month 6.<br>* Other names: Hep B vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the maximum size of the genital wart lesion over the trial period (as measured in mm) |  | Baseline, week 8, 16, 24, 36, 48, 60, 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who acquire measurable levels of HPV type specific antibodies during the first 18 months of the trail as measured using a competitive Luminex immuno-assay (cLIA; reported in milli-Merck Units [mMU]/ml) |  | Week 36+ | 
| Number of participants who change from HPV 6 DNA positive in warts to negative at week 72 |  | Baseline, week 72 | 
| Number of participants who change from HPV 11 DNA positive in warts to negative at week 72 |  | Baseline, week 72 | 
| Number of participants who change from HPV 16 DNA positive at baseline to negative at week 60 |  | Baseline, week 60 | 
| Number of participants who change from HPV 18 DNA positive at baseline to negative at week 60 |  | Baseline, week 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genital warts, HPV types, HPV vaccine, Cervical cytology, Therapeutic vaccine, Quadrivalent HPV vaccine