Cervical Cancer, Cervical Precancerous Lesions
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALProphylactic quadrivalent HPV vaccine Merck (Gardasil®)
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.
Sponsors
All India Institute of Medical Sciences
Cancer Foundation of India
Christian Fellowship Community Health Centre
German Cancer Research Center
Gujarat Cancer & Research Institute
Jehangir Clinical Development Centre
MNJ Institute of Oncology and Regional Cancer Center
Rajiv Gandhi Centre for Biotechnology
Nargis Datta Memorial Cancer Hospital
Tata Memorial Centre
Partha Basu
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
10 Years to 18 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points | Month 7 (for 3-dose and 2-dose groups), 12 (for 2 doses by default and single-dose groups), 18, 36, 48 | 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. |
| Frequency of Persistent HPV 16/18/6/11 Infection. | From date of marriage through to 7 years of follow-up | 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. |
| Frequency of HPV 16/18-associated Precancerous Lesions and Cancer. | Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Infection by Other Non-targeted High-risk HPV Types. | Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen | 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. |
| Frequency of Cervical Neoplasia Associated With Non-included HPV Types. | 15 years from the base-line date | 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. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3-dose The participants received three doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1, 60 and 180+.
Prophylactic quadrivalent HPV vaccine Merck (Gardasil®): 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. | 4,348 |
| 2-dose The participants received two doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1 and 180+.
Prophylactic quadrivalent HPV vaccine Merck (Gardasil®): 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. | 4,979 |
| 2 Doses by Default The participants received two doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1 and 60 by default (incomplete doses)
Prophylactic quadrivalent HPV vaccine Merck (Gardasil®): 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. | 3,452 |
| Single-dose The participants received one dose of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) by default (incomplete doses)
Prophylactic quadrivalent HPV vaccine Merck (Gardasil®): 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. | 4,950 |
| Unvaccinated A cohort of unvaccinated women | 4,646 |
| Total | 22,375 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Ongoing enrollment | 0 | 0 | 0 | 0 | 354 |
Baseline characteristics
| Characteristic | 3-dose | 2-dose | 2 Doses by Default | Single-dose | Unvaccinated | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 13.5 years STANDARD_DEVIATION 2.3 | 13.6 years STANDARD_DEVIATION 2.3 | 13.7 years STANDARD_DEVIATION 2.4 | 13.7 years STANDARD_DEVIATION 2.4 | 24.1 years STANDARD_DEVIATION 2.9 | 15.8 years STANDARD_DEVIATION 4.9 |
| Enrolment | 4348 Participants | 4979 Participants | 3452 Participants | 4950 Participants | 4646 Participants | 22375 Participants |
| Race and Ethnicity Not Collected | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 4348 Participants | 4979 Participants | 3452 Participants | 4950 Participants | 4646 Participants | 22375 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 30 / 4,348 | 22 / 4,979 | 38 / 3,452 | 45 / 4,950 | 9 / 4,646 |
| other Total, other adverse events | 637 / 4,348 | 614 / 4,979 | 614 / 3,452 | 296 / 4,950 | 0 / 4,646 |
| serious Total, serious adverse events | 125 / 4,348 | 135 / 4,979 | 292 / 3,452 | 356 / 4,950 | 0 / 4,646 |
Outcome results
Primary
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.
Time frame: Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen
Primary
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.
Time frame: From date of marriage through to 7 years of follow-up
Population: Participants with at least two cervical cell sample collections, that were collected at least 10 months apart.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3-dose | Frequency of Persistent HPV 16/18/6/11 Infection. | 1 Infections |
| 2-dose | Frequency of Persistent HPV 16/18/6/11 Infection. | 1 Infections |
| 2 Doses by Default | Frequency of Persistent HPV 16/18/6/11 Infection. | 4 Infections |
| Single-dose | Frequency of Persistent HPV 16/18/6/11 Infection. | 1 Infections |
| Unvaccinated | Frequency of Persistent HPV 16/18/6/11 Infection. | 32 Infections |
Primary
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.
Time frame: Month 7 (for 3-dose and 2-dose groups), 12 (for 2 doses by default and single-dose groups), 18, 36, 48
Population: Data used for this outcome are from a subset of participants that had their immunogeneicity samples tested in the laboratory. We are indicating the total of HPV 16 L1 antibodies of the HPV 16 L1 antiboties at month 7 for the 3-dose and 2-dose groups and at month 12 for the 2 doses by default and single-dose groups. No immunogeneity data was collected from the unvaccinated cohort as it was recruited adhoc to assess the HPV infections and CIN endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 3-dose | Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points | 5460 median flow intensities |
| 2-dose | Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points | 6125 median flow intensities |
| 2 Doses by Default | Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points | 437 median flow intensities |
| Single-dose | Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points | 106 median flow intensities |
Regression, Linear
Secondary
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.
Time frame: 15 years from the base-line date
Secondary
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.
Time frame: Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen