Comparing One or Two Doses of the Human Papillomavirus Vaccine for the Prevention of Human Papillomavirus Infection, ESCUDDO Study

Study Overview
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Brief Summary
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This phase IV trial investigates whether one dose of a human papillomavirus vaccine works as well as two doses in preventing human papillomavirus (HPV) infection. Certain types of HPV cause almost all cases of cervical cancer. Vaccines that protect against infection with these types of human papillomavirus may reduce the risk of cervical cancer. Both Gardasil-9 and Cervarix protect against HPV 16 and 18, which cause 70% of all cervical cancers. However, HPV vaccination rates are too low, especially in countries with very high rates of cervical cancer. HPV vaccines are expensive-many countries cannot afford them-more than one dose is needed, and giving multiple doses is difficult. Researchers want to find out if one dose prevents HPV infection. If it does, more people might get the vaccine.

Detailed Description
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PRIMARY OBJECTIVES: I. For each vaccine separately, to evaluate non-inferiority of one compared to two vaccination doses in the prevention of new HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination. II. For each vaccine separately, to evaluate one dose of HPV vaccination compared to no vaccination in the protection against HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination; protection resultant from two HPV vaccine doses compared to no vaccination will also be investigated. Note that the second epidemiological survey group (the end-of-study survey) will serve as the primary unvaccinated group for these analyses. SECONDARY OBJECTIVES: I. To perform a preliminary evaluation of each vaccine at 4 years. Ia. For each vaccine separately, evaluate non-inferiority of one compared to two vaccination doses in the prevention of new HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination using the first four years of data; Ib. For each vaccine separately, evaluate one dose of HPV vaccination compared to no vaccination in the protection against HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination using data available at four years and the first epidemiologic survey; protection resultant from two doses of the HPV vaccines compared to no vaccination will also be investigated. II. For each vaccine separately, to compare immunogenicity via measurement of serum antibodies between girls who received one and two doses of the HPV vaccines. When looking at these antibodies, the primary focus will be on HPV16/18; antibodies against additional HPV types included in the nonavalent HPV vaccine will also be investigated. III. For the nonavalent vaccine, demonstrate non-inferiority of one versus two doses in the prevention of any new vaccine-type HPV infection (i.e., aggregate HPV 16/18/31/33/45/52/58) that persist 6+ months (note: HPV6/11, the noncarcinogenic HPV types responsible for genital warts, will be investigated as an ancillary objective, per item 1, sub-item iv, below). IV. For each vaccine separately, demonstrate non-inferiority of one versus two doses in the prevention of any new carcinogenic HPV cervical infection (vaccine and/or non-vaccine types) that persists 6+ months. V. Conduct a cost and cost-effectiveness evaluation of HPV vaccination with one versus two doses of the nonavalent and bivalent vaccines in the setting of Costa Rica. ANCILLARY OBJECTIVES: I. For each vaccine separately, demonstrate non-inferiority of one versus two doses in the prevention of study endpoints (including but not limited to those listed below) including a comparison to unvaccinated girls: Ia. Any new HPV16, HPV18, or HPV16/18 infection (i.e., one-time detection); Ib. Any new carcinogenic-type HPV infection (i.e., one-time HPV detection of aggregate HPV vaccine and/or non-vaccine HPV types); Ic. Any new vaccine-type HPV infection (i.e., aggregate HPV 16/18/31/33/45/52/58); Id. Any new HPV6/11 infection (i.e., one-time detection). II. Compare HPV attack rate and immunogenicity of Merck nonavalent versus (vs.) GlaxoSmithKline (GSK) bivalent vaccines with respect to number of vaccine doses received in the prevention of six-month persistent HPV16/18 and any carcinogenic infections, and in the prevention of one-time detection of these types. III. Conditional on demonstrating inferiority of one versus two doses of the vaccine: IIIa. To evaluate inferiority of one versus two doses. IIIb. To evaluate reduction in the HPV attack rate of one and two doses compared to none by time (years 1 through 4). IV. Obtain participants authorization to passively track cervical pre-cancer, carcinoma in situ and cervical cancer outcomes through the national tumor registry, national cytology laboratory, social security registries, national cytology laboratory, and other resources after the trial ends (i.e., to continue indefinitely or until consent is rescinded). V. Establish a biobank including blood components (for example but not limited to serum, red blood cells, plasma, peripheral blood mononuclear cells), urine, oral and cervical swab samples collected from girls in the randomized trial and the epidemiologic HPV survey for futures analysis related to HPV infection, associated diseases, and effects of the vaccine. OUTLINE: There are two components to the study: (1) a controlled, randomized, double-blinded non-inferiority clinical trial to compare one-dose to two-dose vaccination among twenty thousand girls 12 to 16 years old; and (2) a concurrent epidemiologic survey for HPV status among two groups of unvaccinated women 16-21 years old. Trial participants are randomized to 1 of 4 arms. Survey participants are assigned to Arm V. ARM I: Participants receive recombinant human papillomavirus nonavalent vaccine (Gardasil) intramuscularly (IM) at month 0 and diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine adsorbed (DTaP) IM at month 6. ARM II: Participants receive recombinant human papillomavirus bivalent vaccine (Cervarix) IM at month 0 and DTaP IM at month 6. ARM III: Participants receive Gardasil IM at month 0 and 6. ARM IV: Participants receive Cervarix IM at month 0 and 6. After completion of study intervention, trial participants are followed up every 6 months for up to 4 years. ARM V: A concurrent epidemiologic survey for HPV status among two groups of unvaccinated women. Survey participants are followed for two study visits six months apart to determine their HPV deoxyribonucleic acid (DNA) status, with no further follow-up. These women will be offered HPV vaccination (Cervarix) at the two study visits.

Official Title
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A Scientific Evaluation of One or Two Doses of Vaccine Against Human Papillomavirus: the ESCUDDO Study (Estudio de Comparacion de Una y Dos Dosis de Vacunas Contra el Virus de Papiloma Humano (VPH))

Conditions
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Human Papillomavirus Infection, Human Papillomavirus-Related Cervical Carcinoma

Intervention / Treatment
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* Biological: Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed
* Other: Questionnaire Administration
* Biological: Recombinant Human Papillomavirus Bivalent Vaccine
* Biological: Recombinant Human Papillomavirus Nonavalent Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RANDOMIZED TRIAL ELIGIBILITY CRITERIA: Female RANDOMIZED TRIAL ELIGIBILITY CRITERIA: Aged between 12 and 16 years inclusive RANDOMIZED TRIAL ELIGIBILITY CRITERIA: Living in the study area without plans to move outside the country in the next six months RANDOMIZED TRIAL ELIGIBILITY CRITERIA: Able to communicate with study personnel RANDOMIZED TRIAL ELIGIBILITY CRITERIA: Willing to participate in the study and sign the informed assent RANDOMIZED TRIAL ELIGIBILITY CRITERIA: Supported in study participation by at least one of their parents (or guardians), who is willing to sign the informed consent document RANDOMIZED TRIAL ELIGIBILITY CRITERIA: In good health as determined by a medical history (physical exam will be conducted if necessary per the doctor's criterion) INITIAL SURVEY ELIGIBILITY CRITERIA: Same as trial participants except for the age range, which is between 17 and 20 years old inclusive END-OF-STUDY SURVEY ELIGIBILITY CRITERIA: Same as trial and initial survey participants except for the age range, which will be closely matched to the current ages of trial participants when they are attending their E54 visits, and thus is expected to be approximately between 16 and 21 years old inclusive Exclusion Criteria: RANDOMIZED TRIAL ELIGIBILITY CRITERIA: They have a diagnosis of an autoimmune, degenerative, or neurological disease without treatment or adequate control; a progressive or severe neurological disease; a genetic immunodeficiency; or any other serious chronic disease without treatment and / or adequate control that, according to the principal investigator or designee, for which vaccination is contraindicated (NOTE: Potential participants with these conditions can be included after consultation with the external medical advisor of the study or with an appropriate specialist RANDOMIZED TRIAL ELIGIBILITY CRITERIA: They are allergic to one of the vaccine components, yeast, or latex RANDOMIZED TRIAL ELIGIBILITY CRITERIA: The clinician determining the eligibility in agreement with principal investigator considers that there is a reason that precludes participation RANDOMIZED TRIAL ELIGIBILITY CRITERIA: They have been vaccinated against HPV RANDOMIZED TRIAL ELIGIBILITY CRITERIA: The girl or her parent/legal guardian does not have an identification document INITIAL SURVEY ELIGIBILITY CRITERIA: Same as trial participants END-OF-STUDY SURVEY ELIGIBILITY CRITERIA: They have a positive or equivocal urine pregnancy test result END-OF-STUDY SURVEY ELIGIBILITY CRITERIA: They are pregnant END-OF-STUDY SURVEY ELIGIBILITY CRITERIA: investigator considers that there is a reason that precludes participation END-OF-STUDY SURVEY ELIGIBILITY CRITERIA: They have been vaccinated against HPV END-OF-STUDY SURVEY ELIGIBILITY CRITERIA: They or their parent/legal guardian, as applicable, does not have an identification document

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Gardasil, DTaP)<br>Participants receive Gardasil IM at month 0 and DTaP IM at month 6. | Biological: Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed<br>* Given IM<br>* Other names: Tripedia;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Recombinant Human Papillomavirus Nonavalent Vaccine<br>* Given IM<br>* Other names: Recombinant Human Papillomavirus 9-valent Vaccine;|
| Experimental: Arm II (Cervarix, DTaP)<br>Participants receive Cervarix IM at month 0 and DTaP IM at month 6. | Biological: Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed<br>* Given IM<br>* Other names: Tripedia;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Recombinant Human Papillomavirus Bivalent Vaccine<br>* Given IM<br>* Other names: Recombinant HPV Bivalent Vaccine;|
| Active Comparator: Arm III (Gardasil)<br>Participants receive Gardasil IM at month 0 and 6. | Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Recombinant Human Papillomavirus Nonavalent Vaccine<br>* Given IM<br>* Other names: Recombinant Human Papillomavirus 9-valent Vaccine;|
| Active Comparator: Arm IV (Cervarix)<br>Participants receive Cervarix IM at month 0 and 6. | Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Recombinant Human Papillomavirus Bivalent Vaccine<br>* Given IM<br>* Other names: Recombinant HPV Bivalent Vaccine;|
| No Intervention: Arm V (epidemiologic survey)<br>A concurrent epidemiologic survey for HPV status among two groups of unvaccinated women. Survey participants are followed for two study visits six months apart to determine their HPV DNA status, with no further follow-up. These women will be offered HPV vaccination (Cervarix) at the two study visits. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of at least one incident persistent human papillomavirus (HPV)-16 and/or HPV-18 cervical infections | To be considered incident and persistent, an HPV-16 and/or HPV-18 infection must fulfill the following criteria: Two same-type HPV positive (by polymerase chain reaction [PCR]) test results 3+ months apart at consecutive study visits reported after the 6-month visit (i.e. 12-month visit or later); type-specific HPV negative (by urine or, if available, PCR) test results from baseline and 6 month visits. | Months 42 and 48 | 
| Incident persistent HPV-16 and/or HPV-18 cervical infections (According to Protocol [ATP] Cohort) | ATP cohort defined as participants who received both vaccine doses within the protocol-defined schedule and no major protocol deviations. | Baseline, 60 months | 
| Incident persistent HPV-16 and/or HPV-18 cervical infections (End-of-Study Survey Cohort) |  | Baseline, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HPV-16 and HPV-18 specific enzyme-linked immunosorbent assay (ELISA) results | Will be obtained from blood specimens (serum). To confirm that HPV-16 and HPV-18 ELISA results reflect neutralization potential, the HPV-16 and HPV- 18 pseudovirion neutralization (SEAP) assays will also be evaluated on a subset of individuals (30 per arm * 4 arms * 9 visits * 2 assays = 2160 assays) and correlated with the ELISA results. | Up to 36 months |