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A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls (DoRIS)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02834637
Recruitment Status : Active, not recruiting
First Posted : July 15, 2016
Last Update Posted : January 22, 2021
Sponsor:
Collaborators:
University of York
Catalan Institute of Oncology
National Cancer Institute (NCI)
Karolinska Institutet
Technische Universität Berlin
Tanzanian National Institute for Medical Research
University of Glasgow
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

Tracking Information
First Submitted Date  ICMJE June 29, 2016
First Posted Date  ICMJE July 15, 2016
Last Update Posted Date January 22, 2021
Actual Study Start Date  ICMJE February 23, 2017
Actual Primary Completion Date January 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 19, 2021)
  • non-inferiority of antibody seropositivity of 1 dose compared with 2 or 3 doses of the same vaccine [ Time Frame: Month 24 ]
    Proportion with HPV 16/18-specific seropositivity
  • non-inferiority of antibody geometric mean titre (GMT) of 1 dose of either vaccine compared with historical cohorts of women who received 1 dose in whom efficacy has been demonstrated [ Time Frame: Month 24 ]
    Geometric mean HPV 16/18 titre
  • non-inferiority of antibody seropositivity of 1 dose compared with 2 doses of the same vaccine [ Time Frame: Month 60 ]
    Proportion with HPV 16/18-specific seropositivity
Original Primary Outcome Measures  ICMJE
 (submitted: July 12, 2016)
  • non-inferiority of antibody seropositivity of 1 dose compared with 3 doses of the same vaccine [ Time Frame: Month 36 ]
    Proportion with HPV 16/18-specific seropositivity
  • non-inferiority of antibody avidity of 1 dose compared with 3 doses of the same vaccine [ Time Frame: Month 36 ]
    Mean HPV 16/18 antibody avidity
  • non-inferiority of memory B cell responses of 1 dose compared with 3 doses of the same vaccine [ Time Frame: Month 36 ]
    Proportion with HPV 16/18 memory B cell responses
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 19, 2021)
  • non-inferiority of HPV 16/18 seropositivity after 1 dose compared with 2 or 3 doses of the same vaccine [ Time Frame: Month 12 and Month 36 ]
    Proportion with HPV 16/18-specific seropositivity
  • non-inferiority of HPV 16/18 antibody GMT after 1 dose compared with with historical cohorts of women who received 1 dose in whom efficacy has been demonstrated [ Time Frame: Month 36 ]
    Geometric mean HPV 16/18 titre
  • evaluate HPV 16/18 seropositivity and antibody GMT at all time points when comparing 2 doses with 3 doses of the same vaccine. [ Time Frame: Month 7, Month 12, Month 24 and Month 36 ]
    HPV 16/18-specific seropositivity and antibody GMT
  • equivalence of HPV 16/18 seropositivity and antibody GMT at all time points when comparing the same dose regimen between the 2 vaccine types [ Time Frame: Month 12, Month 24, Month 36 and Month 60 ]
    HPV 16/18-specific seropositivity and antibody GMT
  • evaluate HPV 16/18 antibody avidity and memory B cell responses at all time points, comparing different dose regimens of the same vaccine and the same dose regimen between the two vaccines [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 16/18-specific antibody avidity and memory B cell responses
  • stability of antibody responses when comparing within the same arm. [ Time Frame: Month 24, Month 36 and Month 60 ]
    HPV 16/18-specific antibody GMT
  • evaluate HPV 16/18 seropositivity when comparing 1 dose of either vaccine with historical cohorts of women who received 1, 2 or 3 doses, in whom efficacy has been demonstrated [ Time Frame: Month 24 and Month 36 ]
    HPV 16/18-specific seropositivity
  • evaluate HPV 16/18 seropositivity when comparing the 2 dose regimen of either vaccine with historical cohorts of women who received 3 doses, in whom efficacy has been demonstrated [ Time Frame: Month 24 and Month 36 ]
    HPV 16/18-specific seropositivity
  • non-inferiority of HPV 16/18 antibody GMT when comparing the 2 dose regimen of either vaccine with historical cohorts of women who received 3 doses, in whom efficacy has been demonstrated [ Time Frame: Month 24 and Month 36 ]
    HPV 16/18-specific antibody GMT
  • evaluate HPV 6/11/31/33/45/52/58 antibody seropositivity with the 1 and 2 dose regimens of the 9-valent vaccine compared with the 3-dose regimen [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 6/11/31/33/45/52/58-specific antibody seropositivity
  • evaluate HPV 6/11/31/33/45/52/58 antibody GMT with the 1 and 2 dose regimens of the 9-valent vaccine compared with the 3-dose regimen [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 6/11/31/33/45/52/58-specific antibody GMT
  • unit cost of 1 dose regimens compared with 2 and 3 dose regimens [ Time Frame: up to Month 6 ]
    incremental financial and economic costs of vaccination, using WHO costing tool
  • cost-effectiveness of 1 dose regimens compared with 2 and 3 dose regimens, and of the 9-valent vaccine compared with the 2-valent vaccine [ Time Frame: up to Month 36 ]
    estimates of costs and effects of vaccination will be integrated into an existing HPV cost-effectiveness model (WHO CHOICE)
  • number of participants with treatment related solicited adverse events [ Time Frame: within 30 days after each dose ]
    solicited adverse events considered to have a reasonable possibility of having been contributed to by the vaccine
  • number of participants with treatment related unsolicited adverse events [ Time Frame: up to Month 36 ]
    unsolicited adverse events considered to have a reasonable possibility of having been contributed to by the vaccine
Original Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2016)
  • non-inferiority of HPV 16/18 seropositivity after 1 dose compared with 3 doses of the same vaccine [ Time Frame: Month 12 and Month 24 ]
    Proportion with HPV 16/18-specific seropositivity
  • non-inferiority of HPV 16/18 seropositivity at all time points when comparing 2 doses with 3 doses of the same vaccine. [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 16/18-specific seropositivity
  • non-inferiority of HPV 16/18 antibody titre at all time points when comparing 2 doses with 3 doses of the same vaccine. [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 16/18-specific antibody geometric mean titre (GMT)
  • equivalence of HPV 16/18 seropositivity when comparing the same dose regimen between the two vaccines [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 16/18-specific seropositivity
  • equivalence of HPV 16/18 antibody GMT when comparing the same dose regimen between the two vaccines [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 16/18-specific geometric mean antibody titre
  • non-inferiority of HPV 16/18 antibody avidity when comparing 2 doses with 3 doses of the same vaccine type [ Time Frame: Month 36 ]
    HPV 16/18-specific antibody avidity
  • non-inferiority of HPV 16/18 memory B cell responses when comparing 2 doses with 3 doses of the same vaccine type [ Time Frame: Month 36 ]
    HPV 16/18-specific memory B cell responses
  • stability of antibody responses when comparing within the same arm. [ Time Frame: Month 24 and Month 36 ]
    HPV 16/18-specific antibody titre
  • non-inferiority of immune responses when comparing the 1 dose regimen of either vaccine in our 9-14 year old population with historical data from women aged 18-25 years who received 3 doses [ Time Frame: M36 ]
    HPV 16/18-specific seropositivity
  • non-inferiority of antibody seropositivity when comparing the 2 dose regimen of either vaccine in our 9-14 year old population with historical data from women aged 18-25 years who received 3 doses [ Time Frame: Month 36 ]
    HPV 16/18-specific seropositivity
  • non-inferiority of antibody GMT when comparing the 2 dose regimen of either vaccine in our 9-14 year old population with historical data from women aged 18-25 years who received 3 doses [ Time Frame: Month 36 ]
    HPV 16/18-specific geometric mean antibody titre
  • evaluate HPV 6/11/31/33/45/52/58 antibody response with the 1 and 2 dose regimens of the 9-valent vaccine compared with the 3-dose regimen [ Time Frame: Month 12, Month 24 and Month 36 ]
    HPV 6/11/31/33/45/52/58-specific antibody seropositivity
  • unit cost of 1 dose regimens compared with 2 and 3 dose regimens [ Time Frame: up to Month 6 ]
    incremental financial and economic costs of vaccination, using WHO costing tool
  • cost-effectiveness of 1 dose regimens compared with 2 and 3 dose regimens, and of the 9-valent vaccine compared with the 2-valent vaccine [ Time Frame: up to Month 36 ]
    estimates of costs and effects of vaccination will be integrated into an existing HPV cost-effectiveness model (WHO CHOICE)
  • number of participants with treatment related solicited adverse events [ Time Frame: within 30 days after each dose ]
    solicited adverse events considered to have a reasonable possibility of having been contributed to by the vaccine
  • number of participants with treatment related unsolicited adverse events [ Time Frame: up to Month 36 ]
    unsolicited adverse events considered to have a reasonable possibility of having been contributed to by the vaccine
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls
Official Title  ICMJE A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls
Brief Summary Cervical cancer is the most common cancer in women aged 15-44 years in East Africa, and mortality rates are very high. HPV vaccines are most effective if given to girls who have not yet acquired HPV infection. In Tanzania, HPV vaccine has been shown to be safe, acceptable and can be delivered with high coverage (around 80%). However, the cost of delivering HPV vaccine is considerably higher than costs for traditional infant/child vaccinations. This is primarily because of costs to establish outreach programmes and associated personnel costs including nurses who must spend significant time away from their posts to deliver vaccine, especially if multiple doses are needed. There is global interest in simplifying HPV vaccine delivery by reducing the number of doses. If a single dose could be given, this could halve the costs of delivery, making it more accessible to the populations that need it most. Recently, the WHO recommended that 2 doses of HPV vaccine could be given to young girls, based on studies in high and upper middle income countries. However in Africa high rates of infections like malaria and worms can affect immune responses to vaccines. It is essential to know that reducing the number of doses does not reduce the protective immune response of these vaccines. The investigators are conducting a trial in Tanzanian girls aged 9-14 years to establish whether a single dose of HPV vaccine produces immune responses that are likely to be effective in preventing cervical cancer. Two different HPV vaccines, the bivalent (2-v) vaccine that protects against HPV 16/18 (the cause of 70% of cancers) and a new 9-valent (9-v) vaccine that protects against 9 HPV types, will be compared. The trial will randomise 900 girls to 6 groups and follow them for 36 months. Girls will receive the 2-v or the 9-v HPV vaccine, as 1, 2 or 3 doses. Girls receiving 1 or 2 doses will be compared with those receiving 3 doses of the same vaccine, to ensure that the reduced dose regimen produces an immune response that is not inferior to the standard 3 doses. The immune responses in this study will also be compared with results from other countries where the vaccine has been shown to be protective. This will provide information about whether a reduced number of doses is likely to be protective in Africa. This work will be extremely important in informing future HPV vaccination strategies and will be one of the first randomised trials of 1 and 2 doses of any HPV vaccine in Africa.
Detailed Description

Human papillomavirus (HPV) infection is the primary cause of cervical cancer, a major public health problem in Africa. Currently there are three vaccines (Cervarix, Gardasil® and Gardasil-9®) that offer excellent protection against HPV infection with vaccine-related HPV genotypes. The objective of this trial is to demonstrate non-inferiority of immune responses with 1 dose of HPV vaccine compared with the recommended 2 or 3 doses of the same vaccine by evaluating HPV 16/18-specific seropositivity, antibody avidity and memory B cell responses at M36. Specifically, the investigators will determine whether a single dose of the 2-valent HPV vaccine (Cervarix, that protects against HPV 16/18 genotypes) or of a new 9-valent HPV vaccine (Gardasil-9,that protects against HPV 6/11/16/18/31/33/45/52/58) produces immune responses that are non-inferior to those observed with 3 doses of vaccine when given to HIV-negative 9-14 years old girls in a malaria-endemic region of Tanzania.

The trial will also determine whether the World Health Organization's (WHO) recently recommended 2 dose strategy for girls aged under 15 years produces similar immune responses in Sub-Saharan Africa (SSA) compared to the previously recommended 3 dose schedule. In addition, the cost-effectiveness of alternative dosing schedules and of the two vaccines will be explored.

The trial will enrol 900 girls who are resident in Mwanza into an un-blinded, individually-randomised trial with 6 arms. Arm A will comprise participants randomised to receive 3 doses of the 2-valent vaccine, Arm B those randomised to receive 2 doses of the 2-valent vaccine and Arm C those randomised to receive 1 dose of the 2-valent vaccine. Arms D, E and F will be those participants randomised to receive 3, 2 or 1 dose of the 9-valent vaccine, respectively.

The effect of different dose schedules and type of HPV vaccine on a range of immune responses will be measured up to 36 months after the first dose. In a trial extension that will extend follow-up, we will also determine whether the one dose schedule of these vaccines produces non-inferior immune responses to the recommended two dose schedule for up to 60 months, and examine the long-term stability of the immune responses to 5 years after the first dose.

The protocol will be harmonised, and laboratory procedures and immunological endpoints will be cross-validated, with those of a large HPV vaccine dose-reduction efficacy trial being planned by the NIH in Costa Rica to examine the protective effect of the same vaccines given as 1 or 2 doses.This trial will allow the examination of quality and durability of antibody responses, and safety and cost-effectiveness of reduced dose schedules compared to the originally recommended 3 dose schedule in a population with high burden of malaria and other infections that may affect vaccine immune responses.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Human Papilloma Virus
Intervention  ICMJE
  • Drug: bivalent HPV vaccine
    head to head comparisons of different dose schedules and HPV vaccine types
    Other Name: Cervarix
  • Drug: nonavalent HPV vaccine
    head to head comparisons of different dose schedules and HPV vaccine types
    Other Name: Gardasil9
Study Arms  ICMJE
  • Active Comparator: 3 doses 2valent
    3 doses of bivalent HPV vaccine (Cervarix) given at M0, M1 and M6
    Intervention: Drug: bivalent HPV vaccine
  • Active Comparator: 2 doses 2valent
    2 doses of bivalent HPV vaccine (Cervarix) given at M0 and M6
    Intervention: Drug: bivalent HPV vaccine
  • Active Comparator: 1 dose 2valent
    1 dose of bivalent HPV vaccine (Cervarix) given at M0
    Intervention: Drug: bivalent HPV vaccine
  • Active Comparator: 3 doses 9valent
    3 doses of nonavalent HPV vaccine (Gardasil9) given at M0, M2 and M6
    Intervention: Drug: nonavalent HPV vaccine
  • Active Comparator: 2 doses 9valent
    2 doses of nonavalent HPV vaccine (Gardasil9) given at M0 and M6
    Intervention: Drug: nonavalent HPV vaccine
  • Active Comparator: 1 dose 9valent
    1 dose of nonavalent HPV vaccine (Gardasil9) given at M0
    Intervention: Drug: nonavalent HPV vaccine
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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 6, 2018)
930
Original Estimated Enrollment  ICMJE
 (submitted: July 12, 2016)
900
Estimated Study Completion Date  ICMJE March 2024
Actual Primary Completion Date January 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Born female;
  • Aged between 9 and 14 years inclusive;
  • Enrolled in a government primary or secondary day school in Mwanza city (or neighbouring district if included);
  • Living in Mwanza city (or neighbouring district if included) without plans to move away in the next 36 months;
  • Willing to participate in the study and sign the informed assent form;
  • Supported in this study participation by at least one of their parents (or LAR), who has signed the informed consent document;
  • In good health as determined by a medical history (a physical examination will be conducted if necessary according to the clinician's judgement); and
  • Able to pass a Test of Understanding (TOU) if aged 12 years or above, or if younger than 12 years old, a parent or LAR is able to pass a TOU

Exclusion Criteria:

  • They are diagnosed with chronic conditions, such as autoimmune conditions, degenerative diseases, neurologic or genetic diseases among others;

    • They are HIV positive, or immunocompromised;
    • They are pregnant, less than three months post-partum or currently breastfeeding;
    • They are allergic to one of the vaccine components or to latex;
    • They are sexually active and are not willing to use an effective birth control method from 28 days before the first dose until 60 days after the last vaccine dose;
    • The nurse or clinician determining the eligibility, in agreement with principal investigator, considers that there is a reason that precludes participation;
    • They have been previously vaccinated against HPV
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 9 Years to 14 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Tanzania
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02834637
Other Study ID Numbers  ICMJE MITU-002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party London School of Hygiene and Tropical Medicine
Study Sponsor  ICMJE London School of Hygiene and Tropical Medicine
Collaborators  ICMJE
  • University of York
  • Catalan Institute of Oncology
  • National Cancer Institute (NCI)
  • Karolinska Institutet
  • Technische Universität Berlin
  • Tanzanian National Institute for Medical Research
  • University of Glasgow
Investigators  ICMJE
Principal Investigator: Deborah Watson-Jones, Dr London School of Hygiene and Tropical Medicine
PRS Account London School of Hygiene and Tropical Medicine
Verification Date September 2020

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