Trial of Two Versus Three Doses of Human Papillomavirus (HPV) Vaccine in India

Study Overview
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Brief Summary
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The primary study hypothesis wasthat a two-dose human papillomavirus (HPV) vaccine regimen would offer similar immunogenicity and protection as that of a three-dose regimen to girls against persistent HPV infection and cervical neoplasia caused by HPV types included in the vaccine. The Government of India stopped vaccination in all the HPV vaccine trials in the country in April 2010 due to reasons not related to this study.

Detailed Description
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The suspension of vaccination resulted in girls receiving 3 doses (days 1, 60 and ≥180), receiving 2 doses (days 1 and ≥180), receiving 2 doses at days 1 and 60 due to incomplete treatment (by default), and receiving one dose by default. A first age and site-matched cohort of unvaccinated married women was recruited, starting in May 2012 to serve as the unvaccinated control group of women for the analysis of HPV incidence and persistence outcomes. A second age and site-matched (age and site matched to the vaccinated women undergoing screening) cohort of unvaccinated married women is being recruited starting in June 2017 and is to be used in addition to the first unvaccinated cohort for the assessment of the cervical neoplasia outcome.

Official Title
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Randomised Trial of Two Versus Three Doses of Human Papillomavirus (HPV) Vaccine in India

Conditions
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Cervical Cancer, Cervical Precancerous Lesions

Intervention / Treatment
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* Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Apparently healthy, ambulant girls aged 10 - 18 years Unmarried girls Girls with intact uterus Resident in the villages chosen for the study Exclusion Criteria: Girls with any severe and/or debilitating illness Past history of allergy to any medication

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3-dose<br>The participants received three doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1, 60 and 180+. | Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®)<br>* The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.<br>* Other names: Gardasil®;|
| Experimental: 2-dose<br>The participants received two doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1 and 180+. | Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®)<br>* The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.<br>* Other names: Gardasil®;|
| Experimental: 2 doses by default<br>The participants received two doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1 and 60 by default (incomplete doses) | Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®)<br>* The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.<br>* Other names: Gardasil®;|
| Experimental: Single-dose<br>The participants received one dose of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) by default (incomplete doses) | Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®)<br>* The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.<br>* Other names: Gardasil®;|
| No Intervention: Unvaccinated<br>A cohort of unvaccinated women | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points | Samples were treated with EDTA and analysed with Luminex (Austin, TX, USA) based multiplex serology to assess the concentration of binding antibodies against the major capsid protein L1 as mean median fluorescence intensity (MFI). MFI values as a measure of antibody concentration quantified by use of HPV multiplex serology are directly comparable with optical densities measured with ELISA. | Month 7 (for 3-dose and 2-dose groups), 12 (for 2 doses by default and single-dose groups), 18, 36, 48 | 
| Frequency of Persistent HPV 16/18/6/11 Infection. | The first cervical cell samples were collected from women 18 months after married or 6 months after the first delivery. After that, 3 extra annual collections were obtained. The HPV genotyping method involved HPV-type-specific E7 PCR bead-based multiplex genotyping. The multiplex HPV-type-specific E7 PCR uses HPV type-specific primers targeting the E7 region for the detection of 19 high-risk or probable high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68a, 68b, 70, 73, and 82), and two low-risk HPV types (6 and 11), with detection limits ranging from ten to 1000 copies of the viral genome. | From date of marriage through to 7 years of follow-up | 
| Frequency of HPV 16/18-associated Precancerous Lesions and Cancer. | Pathology Panel diagnosis of: CIN 2, CIN 3 (including squamous carcinoma in situ), adenocarcinoma in situ, invasive squamous cervical carcinoma, or invasive adenocarcinoma of the cervix and detection of HPV 16 and/or HPV 18 by PCR in the same biopsy tissue sample. | Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Infection by Other Non-targeted High-risk HPV Types. | The HPV genotyping method involved HPV-type-specific E7 PCR bead-based multiplex genotyping. The multiplex HPV-type-specific E7 PCR uses HPV type-specific primers targeting the E7 region for the detection of 19 high-risk or probable high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68a, 68b, 70, 73, and 82), and two low-risk HPV types (6 and 11), with detection limits ranging from ten to 1000 copies of the viral genome. | Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen | 
| Frequency of Cervical Neoplasia Associated With Non-included HPV Types. | Pathology Panel diagnosis of: CIN 2, CIN 3 (including squamous carcinoma in situ), adenocarcinoma in situ, invasive squamous cervical carcinoma, or invasive adenocarcinoma of the cervix and detection of other non vaccine included HPV types by PCR in the same biopsy tissue sample. | 15 years from the base-line date |