Scientific Evaluation of One or Two Doses of the Bivalent or Nonavalent Prophylactic HPV Vaccines

• Sponsor: National Cancer Institute (NCI)
• Collaborator: Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief Summary:

Background:

Certain types of human papillomavirus (HPV) cause almost all cases of cervical cancer. Vaccines that protect against HPV can substantially reduce the risk of cervical cancer. 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.

Objective:

To find out if giving only one dose of either the Cervarix or Gardasil9 HPV vaccines work the same as giving two doses of these vaccines to young women.

Eligibility:

Females ages 12-20 who live in Costa Rica.

Design:

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; and (2) a concurrent epidemiologic survey for HPV status among unvaccinated women.

The trial will enroll twenty thousand girls 12 to 16 years old residing in Costa Rica. Participants will be randomized in two stages to one of four arms (one dose of the bivalent vaccine, two doses of the bivalent vaccine, one dose of the nonavalent vaccine and two doses of the nonavalent vaccine); the first randomization at enrollment will assign participants to one of the two study vaccines and at the second visit they will be randomized to one or two doses. Girls randomized to the one dose arm will receive an active control (i.e.: Tdap) at the time of the second vaccine dose. After vaccination, girls will be followed every six months for four years.

The epidemiologic HPV survey will enroll a group of unvaccinated girls from the same geographic areas; they will range in age from 17 to 20. These women will attend two study visits six months apart to determine their HPV DNA status, there will be no additional followup. These women will be offered HPV vaccination at the enrollment and six-month study visits.

At each visit, participants will fill out a questionnaire and give a urine sample. They may give blood samples. The older participants will use a swab to collect cervical cells from their vagina....

Condition or disease	Intervention/treatment	Phase
Cervical Cancer; Cervical HPV Infection; Anti-HPV Antibody Patterns; Sexually Transmitted Infections	Biological: Cervarix; Biological: Gardasil 9	Phase 4

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Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 25000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Scientific Evaluation of One or Two Doses of Vaccine Against Human Papillomavirus: the ESCUDDO Study
• Actual Study Start Date: November 29, 2017
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1 (Gardasil 9 1-Dose Group); 5000 girls ages 12-16 years	Biological: Gardasil 9; Vaccine indicated in females 9 through 26 years of age for the prevention of the following diseases: Cervical, vulvar, vaginal, and anal cancer caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58; and Genital warts (condyloma acuminata) caused by HPV types 6 and 11. In Costa Rica, in patients 9-15 years old, this vaccine is approved for two doses (0.5-mL each) intramuscular injection at 0, 6 months (second dose between 5 and 13 months after first dose). In patients 16 years old and older, it is approved for three doses (0.5- mL each) intramuscular injection at 0, 2 months, and 6 months. Intervention will be one dose at 0 months or two doses at 0 and 6 months. One-dose intervention will be in 5000 girls ages 12-16 years, and two-dose intervention will be in 5000 girls ages 12-16 years.
Experimental: Arm 2 (Cervarix 1-Dose Group); 5000 girls ages 12-16 years	Biological: Cervarix; Vaccine indicated in females 9 through 25 years of age for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18: Cervical, vulvar, vaginal, and anal cancer cervical cancer; cervical intraepithelial neoplasia (CIN) Grade2 or worse and adenocarcinoma in situ; and cervical intraepithelial neoplasia (CIN) Grade 1 caused by Human Papillomavirus (HPV) types 16 and 18. In Costa Rica, in patients 9-15 years old, this vaccine is approved for two doses (0.5-mL each) intramuscular injection at 0, 6 (second dose between 5 and 13 months after first dose). In patients 16 years old and older, it is approved for use in females 9 through 25 years of age. Approved for three doses (0.5-mL each) by intramuscular injection at 0, 1, and 6 months. Intervention will be one dose at 0 months or two doses at 0 and 6 months. One-dose intervention will be in 5000 girls ages 12-16 years, and two-dose
Active Comparator: Arm 3 (Gardasil 9 2-Dose Group); 5000 girls ages 12-16 years	Biological: Gardasil 9; Vaccine indicated in females 9 through 26 years of age for the prevention of the following diseases: Cervical, vulvar, vaginal, and anal cancer caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58; and Genital warts (condyloma acuminata) caused by HPV types 6 and 11. In Costa Rica, in patients 9-15 years old, this vaccine is approved for two doses (0.5-mL each) intramuscular injection at 0, 6 months (second dose between 5 and 13 months after first dose). In patients 16 years old and older, it is approved for three doses (0.5- mL each) intramuscular injection at 0, 2 months, and 6 months. Intervention will be one dose at 0 months or two doses at 0 and 6 months. One-dose intervention will be in 5000 girls ages 12-16 years, and two-dose intervention will be in 5000 girls ages 12-16 years.
Active Comparator: Arm 4 (Cervarix 2-Dose Group); 5000 girls ages 12-16 years	Biological: Cervarix; Vaccine indicated in females 9 through 25 years of age for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18: Cervical, vulvar, vaginal, and anal cancer cervical cancer; cervical intraepithelial neoplasia (CIN) Grade2 or worse and adenocarcinoma in situ; and cervical intraepithelial neoplasia (CIN) Grade 1 caused by Human Papillomavirus (HPV) types 16 and 18. In Costa Rica, in patients 9-15 years old, this vaccine is approved for two doses (0.5-mL each) intramuscular injection at 0, 6 (second dose between 5 and 13 months after first dose). In patients 16 years old and older, it is approved for use in females 9 through 25 years of age. Approved for three doses (0.5-mL each) by intramuscular injection at 0, 1, and 6 months. Intervention will be one dose at 0 months or two doses at 0 and 6 months. One-dose intervention will be in 5000 girls ages 12-16 years, and two-dose
No Intervention: Epidemiologic HPV Survey Arm; 4000 Unvaccinated women ages 17 to 20 (1000 women between 17 and 18; 1000 women between 18 and 19; 1000 women between 19 and 20; and 1000 women age 20); Followed for six months

Outcome Measures

Primary Outcome Measures :

1. Evaluate non-inferiority of one compared to two vaccination doses of Cervarix in the prevention of new HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination [ Time Frame: 48 months ]
   Evaluate non-inferiority of one compared to two vaccination doses of Cervarix in the prevention of new HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination
2. Evaluate non-inferiority of one compared to two vaccination doses of Gardasil 9 in the prevention of new HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination. [ Time Frame: 48 months ]
   Evaluate non-inferiority of one compared to two vaccination doses of Gardasil 9 in the prevention of new HPV16/18 cervical HPV infections that persist 6+ months in girls ages 12-16 years at vaccination
3. Evaluate one dose of Cervarix 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. [ Time Frame: 48 months ]
   Evaluate one dose of Cervarix 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
4. Evaluate one dose of Gardasil 9 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. [ Time Frame: 48 months ]
   Evaluate one dose of Gardasil 9 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

Secondary Outcome Measures :

1. Compare immunogenicity via measurement of serum antibodies between girls who received one or two doses of Cervarix. [ Time Frame: 48 months ]
2. Compare immunogenicity via measurement of serum antibodies between girls who received one or two doses of Gardasil 9. The primary focus will be on HPV16/18, but antibodies against additional HPV types included Gardasil 9 will also be investigate... [ Time Frame: 48 months ]
3. Demonstrate non-inferiority of one versus two doses of Gardasil 9 in the prevention of any new vaccinetype HPV infection (i.e., aggregate HPV 16/18/31/33/45/52/58) that persist 6+ months. [ Time Frame: 48 months ]
4. Demonstrate non-inferiority of one versus two doses of Cervarix in the prevention of any new carcinogenic HPV cervical infection (vaccine and/or non-vaccine types) that persists 6+ months. [ Time Frame: 48 months ]
5. Demonstrate non-inferiority of one versus two doses of Gardasil 9 in the prevention of any new carcinogenic HPV cervical infection (vaccine and/or non-vaccine types) that persists 6+ months. [ Time Frame: 48 months ]
6. Conduct a cost and cost-effectiveness evaluation of HPV vaccination with one versus two doses of the Gardasil 9 and Cervarix in the setting of Costa Rica. [ Time Frame: 48 months ]

Eligibility Criteria

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

Criteria

• INCLUSION CRITERIA:

Girls will be deemed eligible if they are:

• Female;
• Aged between 12 and 16 years inclusive
• 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; and,
• In good health as determined by a medical history (physical exam will be conducted if necessary per the doctor s criterion).

EXCLUSION CRITERIA:

Girls will be excluded from enrollment if:

-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

Contacts

Contact: Aimee R. Kreimer, Ph.D.; (240) 276-7102; kreimera@mail.nih.gov

Locations

Costa Rica

Agencia Costarricense de Investigaciones Biomedicas (ACIB); Recruiting

Liberia, Costa Rica

Contact: Paula Gonzalez Not Listed pgonzalez@proyectoguanacaste.org

Sponsors and Collaborators

National Cancer Institute (NCI)

Bill and Melinda Gates Foundation

Investigators

• Principal Investigator: Aimee R. Kreimer, Ph.D.; National Cancer Institute (NCI)

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03180034 History of Changes
• Other Study ID Numbers: 999917108; 17-C-N108
• First Posted: June 8, 2017
• Last Update Posted: April 5, 2019
• Last Verified: April 2, 2019

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Human Papillomavirus; Cervical Cancer; Costa Rica; Fewer Doses; HPV-Associated Cancers

Additional relevant MeSH terms:

Infection; Communicable Diseases; Uterine Cervical Neoplasms; Sexually Transmitted Diseases; Papillomavirus Infections; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Virus Diseases; Genital Diseases, Male; DNA Virus Infections; Tumor Virus Infections; Vaccines; Immunologic Factors; Physiological Effects of Drugs