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

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ClinicalTrials.gov Identifier: NCT03180034

Recruitment Status : Active, not recruiting

First Posted : June 8, 2017

Last Update Posted : December 14, 2020

Sponsor:

Collaborator:

Bill and Melinda Gates Foundation

Information provided by (Responsible Party):

National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Human Papillomavirus Infection Human Papillomavirus-Related Cervical Carcinoma	Biological: Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed Other: Questionnaire Administration Biological: Recombinant Human Papillomavirus Bivalent Vaccine Biological: Recombinant Human Papillomavirus Nonavalent Vaccine	Phase 4

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Detailed Description:

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.

SECONDARY OBJECTIVES:

I. For each vaccine separately, to compare immunogenicity via measurement of serum antibodies between girls who received one and two doses of the HPV vaccines.

II. 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).

III. 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.

IV. 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). IIb. 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 four thousand unvaccinated women 17-20 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 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	25000 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Prevention
Official Title:	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)")
Actual Study Start Date :	November 29, 2017
Estimated Primary Completion Date :	August 1, 2024
Estimated Study Completion Date :	August 1, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Human Papillomaviruses

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (Gardasil, DTaP) Participants receive Gardasil IM at month 0 and DTaP IM at month 6.	Biological: Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed Given IM Other Names: Adacel Daptacel Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Diphtheria Toxoid Tetanus Toxoid Acellular Pertussis Vaccine Adsorbed Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine DTaP Infanrix Tripedia Other: Questionnaire Administration Ancillary studies Biological: Recombinant Human Papillomavirus Nonavalent Vaccine Given IM Other Names: Gardasil 9 Nonavalent HPV VLP Vaccine Recombinant HPV Nonavalent Vaccine Recombinant Human Papillomavirus 9-valent Vaccine
Experimental: Arm II (Cervarix, DTaP) Participants receive Cervarix IM at month 0 and DTaP IM at month 6.	Biological: Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine Adsorbed Given IM Other Names: Adacel Daptacel Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Diphtheria Toxoid Tetanus Toxoid Acellular Pertussis Vaccine Adsorbed Diphtheria Toxoid/Tetanus Toxoid/Acellular Pertussis Vaccine DTaP Infanrix Tripedia Other: Questionnaire Administration Ancillary studies Biological: Recombinant Human Papillomavirus Bivalent Vaccine Given IM Other Names: Cervarix GSK-580299 HPV 16/18 L1 VLP/AS04 VAC HPV-16/18 VLP/AS04 Vaccine Human Papillomavirus 16/18 L1 Virus-Like Particle/AS04 Vaccine Human Papillomavirus Bivalent Types 16 and 18 Vaccine, Recombinant Human Papillomavirus Vaccine L1 16,18 Human Papillomavirus Vaccine, L1 Type 16, 18 Recombinant HPV Bivalent Vaccine
Active Comparator: Arm III (Gardasil) Participants receive Gardasil IM at month 0 and 6.	Other: Questionnaire Administration Ancillary studies Biological: Recombinant Human Papillomavirus Nonavalent Vaccine Given IM Other Names: Gardasil 9 Nonavalent HPV VLP Vaccine Recombinant HPV Nonavalent Vaccine Recombinant Human Papillomavirus 9-valent Vaccine
Active Comparator: Arm IV (Cervarix) Participants receive Cervarix IM at month 0 and 6.	Other: Questionnaire Administration Ancillary studies Biological: Recombinant Human Papillomavirus Bivalent Vaccine Given IM Other Names: Cervarix GSK-580299 HPV 16/18 L1 VLP/AS04 VAC HPV-16/18 VLP/AS04 Vaccine Human Papillomavirus 16/18 L1 Virus-Like Particle/AS04 Vaccine Human Papillomavirus Bivalent Types 16 and 18 Vaccine, Recombinant Human Papillomavirus Vaccine L1 16,18 Human Papillomavirus Vaccine, L1 Type 16, 18 Recombinant HPV Bivalent Vaccine
No Intervention: Arm V (epidemiologic survey) A concurrent epidemiologic survey for HPV status among 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.

Outcome Measures

Primary Outcome Measures :

Incidence of persistent human papillomavirus (HPV)-16 and/or HPV-18 cervical infections [ Time Frame: Months 42 and 48 ]
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.
Incidence of persistent HPV-16 and/or HPV-18 cervical infections [ Time Frame: Baseline, 6 months ]
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 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.

Secondary Outcome Measures :

Immunogenicity of one or two doses of Cervarix [ Time Frame: Up to 4 years ]
Will be compared between girls who received one or two doses of recombinant human papillomavirus bivalent vaccine (Cervarix). Measured via measurement of serum antibodies.
Immunogenicity of one or two doses of Gardasil 9 [ Time Frame: Up to 4 years ]
Will be compared between girls who received one or two doses of recombinant human papillomavirus nonavalent vaccine (Gardasil 9). Measured via measurement of serum antibodies.
Incidence of any new HPV infection (after Gardasil 9) [ Time Frame: Up to 4 years ]
Demonstrate non-inferiority of one versus two doses of Gardasil 9 in the prevention of any new vaccine type HPV infection.
Incidence of any new carcinogenic HPV cervical infection (after Cervarix) [ Time Frame: Up to 4 years ]
Demonstrate non-inferiority of one versus two doses of Cervarix in the prevention of any new carcinogenic HPV cervical infection.
Cost and cost-effectiveness evaluation of HPV vaccination in Costa Rica [ Time Frame: Up to 4 years ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	12 Years to 20 Years (Child, Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Living in the study area without plans to move outside the country in the next six months
Able to communicate with study personnel
Willing to participate in the study and sign the informed assent
Supported in study participation by at least one of their parents (or guardians), who is willing to sign the informed consent document
In good health as determined by a medical history (physical exam will be conducted if necessary per the doctor's criterion)

Exclusion 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
They are allergic to one of the vaccine components, yeast, or latex
The clinician determining the eligibility in agreement with principal investigator considers that there is a reason that precludes participation
They have been vaccinated against HPV
The girl or her parent/legal guardian does not have an identification document

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03180034

Locations

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Costa Rica
Agencia Costarricense de Investigaciones Biomédicas (ACIB)
Liberia, Guanacaste, Costa Rica

Sponsors and Collaborators

National Cancer Institute (NCI)

Bill and Melinda Gates Foundation

Investigators

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Principal Investigator:	Aimee R Kreimer	National Cancer Institute (NCI)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kreimer AR, Cernuschi T, Rees H, Saslow D, Porras C, Schiller J. Prioritisation of the human papillomavirus vaccine in a time of constrained supply. Lancet Child Adolesc Health. 2020 May;4(5):349-351. doi: 10.1016/S2352-4642(20)30038-9. Epub 2020 Feb 17.

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT03180034
Other Study ID Numbers:	NCI-2020-08550 NCI-2020-08550 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 999917108 17-C-N108 ( Other Identifier: National Cancer Institute )
First Posted:	June 8, 2017 Key Record Dates
Last Update Posted:	December 14, 2020
Last Verified:	November 2020

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Additional relevant MeSH terms:

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Infection Papillomavirus Infections DNA Virus Infections Virus Diseases	Tumor Virus Infections Vaccines Immunologic Factors Physiological Effects of Drugs

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