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

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ClinicalTrials.gov Identifier: NCT02834637
Recruitment Status : Active, not recruiting
First Posted : July 15, 2016
Last Update Posted : August 28, 2019
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

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.

Condition or disease Intervention/treatment Phase
Human Papilloma Virus Drug: bivalent HPV vaccine Drug: nonavalent HPV vaccine Phase 3

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. 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 930 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls
Actual Study Start Date : February 23, 2017
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : March 2021

Arm Intervention/treatment
Active Comparator: 3 doses 2valent
3 doses of bivalent HPV vaccine (Cervarix) given at M0, M1 and M6
Drug: bivalent HPV vaccine
head to head comparisons of different dose schedules and HPV vaccine types
Other Name: Cervarix

Active Comparator: 2 doses 2valent
2 doses of bivalent HPV vaccine (Cervarix) given at M0 and M6
Drug: bivalent HPV vaccine
head to head comparisons of different dose schedules and HPV vaccine types
Other Name: Cervarix

Active Comparator: 1 dose 2valent
1 dose of bivalent HPV vaccine (Cervarix) given at M0
Drug: bivalent HPV vaccine
head to head comparisons of different dose schedules and HPV vaccine types
Other Name: Cervarix

Active Comparator: 3 doses 9valent
3 doses of nonavalent HPV vaccine (Gardasil9) given at M0, M2 and M6
Drug: nonavalent HPV vaccine
head to head comparisons of different dose schedules and HPV vaccine types
Other Name: Gardasil9

Active Comparator: 2 doses 9valent
2 doses of nonavalent HPV vaccine (Gardasil9) given at M0 and M6
Drug: nonavalent HPV vaccine
head to head comparisons of different dose schedules and HPV vaccine types
Other Name: Gardasil9

Active Comparator: 1 dose 9valent
1 dose of nonavalent HPV vaccine (Gardasil9) given at M0
Drug: nonavalent HPV vaccine
head to head comparisons of different dose schedules and HPV vaccine types
Other Name: Gardasil9




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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 and Month 36 ]
    HPV 16/18-specific seropositivity and antibody GMT

  5. 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

  6. stability of antibody responses when comparing within the same arm. [ Time Frame: Month 24 and Month 36 ]
    HPV 16/18-specific antibody GMT

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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)

  14. 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

  15. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   9 Years to 14 Years   (Child)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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

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): NCT02834637


Locations
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Tanzania
Mwanza Intervention Trials Unit (MITU)
Mwanza, Tanzania
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
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
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Principal Investigator: Deborah Watson-Jones, Dr London School of Hygiene and Tropical Medicine

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Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT02834637     History of Changes
Other Study ID Numbers: MITU-002
First Posted: July 15, 2016    Key Record Dates
Last Update Posted: August 28, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Keywords provided by London School of Hygiene and Tropical Medicine:
HPV
cervical cancer
vaccines
HPV vaccine
dose reduction
Human papilloma virus vaccine schedules
Additional relevant MeSH terms:
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Papilloma
Neoplasms, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Vaccines
Immunologic Factors
Physiological Effects of Drugs