Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03180034
Recruitment Status : Recruiting
First Posted : June 8, 2017
Last Update Posted : April 5, 2019
Sponsor:
Collaborator:
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE June 7, 2017
First Posted Date  ICMJE June 8, 2017
Last Update Posted Date April 5, 2019
Actual Study Start Date  ICMJE November 29, 2017
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
  • 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
  • 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
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: June 7, 2017)
  • 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 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 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 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 ]
Change History Complete list of historical versions of study NCT03180034 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 3, 2019)
  • Compare immunogenicity via measurement of serum antibodies between girls who received one or two doses of Cervarix. [ Time Frame: 48 months ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2017)
  • Compare immunogenicity via measurement of serum antibodies between girls who received one or two doses of Cervarix. [ Time Frame: 48 months ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Conduct a cost and costeffectiveness 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Scientific Evaluation of One or Two Doses of the Bivalent or Nonavalent Prophylactic HPV Vaccines
Official Title  ICMJE A Scientific Evaluation of One or Two Doses of Vaccine Against Human Papillomavirus: the ESCUDDO Study
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....

Detailed Description

Cervical cancer and other HPV-associated cancers comprise an important public health burden worldwide, with over 600,000 HPV-associated cancers diagnosed each year. Prophylactic human papillomavirus (HPV) vaccination with three doses of commercially available vaccines, the regimen currently approved by the FDA, is highly efficacious in preventing targeted carcinogenic HPV infections and related cervical cancer precursors. In some regions of the world, two-dose vaccination schedules for adolescents have started to be recommended, based on immunobridging studies demonstrating immunologic non-inferiority of two doses in that age group, compared with three doses of the vaccine in the adult women in the phase III efficacy trials. Still, the majority of women who are at the greatest lifetime risk for cervical cancer are not being vaccinated because cost and logistical considerations for administering multi-dose vaccine programs continue to impede progress in reducing this preventable cancer.

The NCI-sponsored Costa Rica Vaccine Trial (CVT) and the commercially-sponsored Papilloma TRIal against Cancer In young Adults (PATRICIA Trial), both of which tested the bivalent HPV vaccine, showed similar vaccine efficacy over four years among women who received one, two and three doses of the HPV16/18 vaccine, and stable antibody responses have been observed throughout the seven years of follow-up accrued to date in CVT, suggesting durability of responses. Additionally, 36-month preliminary analysis of a large, post-licensure trial of the quadrivalent vaccine in India showed similar protection against HPV16/18 cervical infection whether the women received one dose, two doses, or three doses. However, vaccine recipients in these trials were not randomized to receive these fewer doses, and immunogenicity among one-dose recipients was lower than that observed following two- or three-doses, leading regulatory bodies to conclude that the level of evidence in support of single-dose HPV vaccination is insufficient to warrant changes in current recommendations for two- or three- dose schedules.

A study of the minimum number of doses needed to confer durable protection could provide seminal evidence to justify changing the current vaccine recommendation from two to one dose for adolescents. Therefore, we are proposing to conduct a trial in Costa Rica to formally evaluate one- and two-dose vaccination, and to estimate the public health benefit of one- and two-dose schedules versus none. More specifically, we will conduct a four-arm trial of 20,000 12-to-16-year-old girls randomized, in two stages, to receive one or two doses of the Merck nonavalent (Gardasil-9) or GlaxoSmithKline Biologicals bivalent (Cervarix) HPV vaccines and to be followed initially for four years, to formally evaluate the non-inferiority of one versus two doses of each of these two vaccines. This trial will be complemented by an epidemiological HPV survey (followed by vaccination) to estimate the public health benefit of reduced-dosage vaccination versus none. As a primary endpoint, we will focus on the prevention of new, persistent infection by HPV types 16 and 18, because they account for the largest public health burden. The trial will also evaluate protection against the other cancer- and genital wart-causing HPV types, while documenting infection by non-vaccine HPV types to verify continued exposure among trial participants.

In addition to the evaluation of efficacy against HPV infection, we propose to monitor participants immunological response to vaccination, to demonstrate robust, stable, and durable antibody responses following one- and two-dose vaccination, and to enable studies to compare immune responses induced by the two vaccines, which contain different adjuvants. This effort will establish the foundation for immunobridging studies that could accelerate future vaccine development. We envision that these immunobridging studies could bridge our study to different populations and age groups and/or to next-generation vaccines that are based on the same virus-like particle technology (i.e., biosimilar vaccines).

We anticipate that results from this proposed effort will provide the evidence required for global policy changes towards single-dose vaccination programs, if non-inferiority of one-dose is demonstrated, and lead to a better understanding of antibody levels required for protection. If one-dose protection is observed in these first four years, follow-up might need to be extended by at least six years to assess durability of the response to vaccination. If one dose of either vaccine is found to be inferior to two doses, our study will also provide estimates of the impact of single dose vaccination versus none, so that policy makers in regions where widespread vaccination programs have yet to be implemented can consider the decrement in efficacy of one versus two dose vaccination in light of the estimated public health impact of a single-dose program. Finally, the proposed work holds the potential to transform current approaches to vaccine development, as it could provide the first example of a single dose (prime only) subunit vaccine that induces durable and protective (sterilizing) immunity.

Randomized trial data on the comparative effectiveness of alternative vaccine and dose regimens is necessary. Public health policy makers also require information on the projected cost and long-term health outcomes associated with each vaccine regimen to make evidence- based decisions regarding the large-scale implementation of sustainable, cost-effective HPV vaccination programs. Mathematical simulation models of cervical carcinogenesis can integrate biologic, epidemiologic, economic, and behavioral data from the 1DT and other studies to project the long-term health and economic impact of different vaccine and dose regimens and evaluate the comparative- and cost-effectiveness of alternative vaccination strategies to inform public health policy. Optimal implementation policies may depend on the level and duration of efficacy for a single dose and achievable completion rates for a two-dose regimen. Even if one- dose protection is found to be lower than protection associated with two or three doses, the relative costs and effects of vaccinating more individuals with one dose might yield a greater reduction in cervical cancer incidence and mortality. We will use mathematical models to quantify the potential tradeoffs between resource utilization, simplicity of implementation and administration, and program effectiveness based on real-world data on intervention costs and effectiveness.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Cervical Cancer
  • Cervical HPV Infection
  • Anti-HPV Antibody Patterns
  • Sexually Transmitted Infections
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • Experimental: Arm 1 (Gardasil 9 1-Dose Group)
    5000 girls ages 12-16 years
    Intervention: Biological: Gardasil 9
  • Experimental: Arm 2 (Cervarix 1-Dose Group)
    5000 girls ages 12-16 years
    Intervention: Biological: Cervarix
  • Active Comparator: Arm 3 (Gardasil 9 2-Dose Group)
    5000 girls ages 12-16 years
    Intervention: Biological: Gardasil 9
  • Active Comparator: Arm 4 (Cervarix 2-Dose Group)
    5000 girls ages 12-16 years
    Intervention: Biological: Cervarix
  • 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 19, 2017)
25000
Original Estimated Enrollment  ICMJE
 (submitted: June 7, 2017)
24000
Estimated Study Completion Date  ICMJE December 31, 2024
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 12 Years to 20 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Aimee R. Kreimer, Ph.D. (240) 276-7102 kreimera@mail.nih.gov
Listed Location Countries  ICMJE Costa Rica
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03180034
Other Study ID Numbers  ICMJE 999917108
17-C-N108
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Bill and Melinda Gates Foundation
Investigators  ICMJE
Principal Investigator: Aimee R. Kreimer, Ph.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date April 2, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP