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Clinical Trials

MainTitle

HPV Vaccine Therapy in Reducing High-Grade Cervical Lesions in Patients With HIV and HPV (COVENANT)

This study is not yet open for participant recruitment. (see Contacts and Locations)

Verified September 2017 by AIDS Malignancy Consortium

Sponsor
AIDS Malignancy Consortium

Collaborator
National Cancer Institute (NCI)
University of Arkansas
AIDS and Cancer Specimen Resource
Merck Sharp & Dohme Corp.
The EMMES Corporation
University of California, Los Angeles

Information provided by (Responsible Party)
AIDS Malignancy Consortium
ClinicalTrials.gov Identifier
NCT03284866

First received: May 4, 2017
Last updated: September 13, 2017
Last Verified: September 2017
History of Changes
Purpose

Purpose

This randomized phase III trial studies how well human papillomavirus (HPV) vaccine therapy works in reducing high-grade cervical lesions in patients with human immunodeficiency virus (HIV) and HPV. Vaccines made from HPV peptides or antigens may help the body build an effective immune response to kill the HPV virus and prevent cervical lesions from developing or coming back after being removed.

Condition Intervention Phase
AIDS-Related Human Papillomavirus Infection
High Grade Cervical Squamous Intraepithelial Neoplasia
HIV Infection

Other : Laboratory Biomarker Analysis
Biological : Recombinant Human Papillomavirus Nonavalent Vaccine
Other : Saline
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Randomized, Placebo-Controlled Trial of HPV Vaccination to Reduce Cervical High-Grade Squamous Intraepithelial Lesions Among HIV-Infected Women Participating in an HPV Test-and-Treat Program (COVENANT)

Further study details as provided by AIDS Malignancy Consortium:

Primary Outcome Measures

  • Occurrence of cervical high-grade squamous intraepithelial lesions (HSIL) or cervical cancer [ Time Frame: After week 4 study visit to week 52 post-randomization ]
    For each arm (vaccine and placebo), the event rate will be estimated using its point estimate and 95% Poisson confidence intervals. Poisson regression analyses will be used to compare the two arms with respect to event rate. In addition, time to event from week 4 to 52 will be described using the Kaplan-Meier method for each arm, and the two arms will be compared with respect to time to event using the log-rank test.
Secondary Outcome Measures:
  • Occurrence of cervical HSIL from weeks 52-104 [ Time Frame: After week 52 to week 104 ]
    The event rate for each arm from week 52 to week 104 for women who are event-free at 52 weeks will be estimated using its point estimate and 95% Poisson confidence interval. Poisson regression will be used to compare the two groups with respect to the event rate from week 52 to 104.
  • Role of baseline types and quantity of HPV as predictors of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if baseline HPV types are associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of presence of HSIL at baseline as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if the presence of HSIL at baseline is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of CD4+ cell count as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if baseline CD4+ cell count is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of plasma HIV-1 RNA as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if baseline plasma HIV-1 RNA count is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of ART use as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if ART use is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of age as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if age is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of sexual behavior as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if sexual behavior is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Role of vaccination use as a predictor of sustained absence [ Time Frame: At baseline and week 4 ]
    Poisson regression analyses will be used to determine if vaccine use is associated with of sustained absence of cervical HSIL and clearance of HPV infections after cryotherapy or LEEP. This analysis will also control for use of LEEP or cryotherapy.
  • Incident cervical vaccine type HPV infections defined as infections at 2 consecutive timepoints and assessed using type specific HPV DNA polymerase chain reaction (PCR) [ Time Frame: Up to week 104 ]
    Vaccine and placebo participants will be compared with respect to these proportions using the chi-square test corrected for continuity.
  • Abnormal cervical cytology [ Time Frame: Baseline, week 26, 52, and 104 ]
    The proportion of women with abnormal cervical cytology at baseline, week 26, 52, and 104 will be reported and compared between arms.
  • Prevalent vulvar HSIL or cancer [ Time Frame: Up to week 4 ]
    The prevalence of vulvar HSIL or cancer at baseline will be estimated using the binomial proportion and its 95% confidence interval.
  • Incident vulvar HSIL or cancer [ Time Frame: Up to week 104 ]
    The proportion of women who acquire vulvar HSIL or cancer among those negative for vulvar HSIL or cancer at baseline for both intervention arms will be estimated as a binomial proportion for both groups. The chi-square test corrected for continuity will be used to compare arms with respect to the proportions who acquire vulvar HSIL during the study.
  • Clinical and demographic factors associated with incident vulvar HSIL or cancer [ Time Frame: Up to week 104 ]
    Logistic regression analyses will be used to evaluate associations with incident vulvar HSIL or cancer acquisition with clinical and demographic factors and arm.
Other Outcome Measures:
  • HPV type distributions [ Time Frame: Up to week 104 ]
    Will characterize the HPV type distribution in baseline histology specimens and compare this to the types observed among incident cervical and vulvar HSIL lesions. Specifically, will compare the number and proportion of vaccine-type and non-vaccine type lesions between arms.
  • HPV strain variant analysis of cervical and vulvar HSIL specimens [ Time Frame: Up to week 104 ]
    For study participants who have the same HPV type in HSIL specimens at baseline and follow-up time points, sequencing will be performed to determine whether or not HSIL is caused by an identical HPV strain. Will use all available pairs of baseline and follow-up HSIL caused by the same HPV type. Will report the proportion of these pairs with the same HPV strain in both treatment arms. Additionally, will report the rates of HSIL caused by new vaccine type infections. We will compare the two study groups using a chi-square test. This will be a descriptive analysis only as no sufficient data on which to power this analysis.
  • Tissue microarray library of cervical specimens for biomarker analysis and discovery [ Time Frame: Up to week 104 ]
    Specimen banking objective. There is no pre-specified statistical analysis plan for this objective. Any future studies using these specimens will need to receive separate approval by NCI and CTEP.
  • hrHPV type distribution in the anus [ Time Frame: Up to week 104 ]
    McNemar's chi-square test to compare the prevalence of that type in the anus and cervix will be used. For each hrHPV type, chi-square analyses will be used to compare the two HPV vaccination groups with respect to the distribution of that type in the (anus, cervix). Will report the proportion of incident cervical infections that were preceded by anal detection of the same type.
  • hrHPV type prevalence in the anus [ Time Frame: Up to week 104 ]
    McNemar's chi-square test to compare the prevalence of that type in the anus and cervix will be used. For each hrHPV type, chi-square analyses will be used to compare the two HPV vaccination groups with respect to the distribution of that type in the (anus, cervix). Will report the proportion of incident cervical infections that were preceded by anal detection of the same type.
  • Vaccine-induced antibody titers [ Time Frame: Up to week 104 ]
    Will explore the antibody titers for the vaccine type found in the HSIL in these women as compared to those without HSIL caused by that type. Analysis of vaccine titers between those with incident vaccine type HPV infections that persist for 2 or more study visits and those that do not will be performed.

Estimated Enrollment: 536
Study Start Date: October 2017
Estimated Study Completion Date: October 2021
Estimated Primary Completion Date: October 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Arm I, recombinant HPV 9-valent vaccine
Patients receive Recombinant Human Papillomavirus Nonavalent Vaccine (Gardasil 9) IM at baseline, 4, and 26 weeks in the absence of disease progression or unacceptable toxicity, with sample collection for Laboratory Biomarker Analysis.
Other: Laboratory Biomarker Analysis

Correlative studies

Biological: Recombinant Human Papillomavirus Nonavalent Vaccine

Given IM

Other Name:
  • Gardasil 9
  • Nonavalent HPV VLP Vaccine
  • Recombinant HPV Nonavalent Vaccine
  • Recombinant Human Papillomavirus 9-valent Vaccine
  • Recombinant HPV 9-valent Vaccine

Placebo Comparator: Arm II, saline
Patients receive saline placebo vaccine IM at baseline, 4, and 26 weeks, with sample collection for Laboratory Biomarker Analysis.
Other: Laboratory Biomarker Analysis

Correlative studies

Other: Saline

Given IM

Other Name: Sodium Chloride 0.9%

Detailed Description:

At screening, potential participants will be tested for cervical human papillomavirus (HPV) infection (GeneXpert hrHPV assay and HPV DNA PCR) and undergo cervical colposcopy to confirm the absence of cervical cancer. If eligible, the participant will be randomized to receive either the 9-valent HPV vaccine or saline placebo.
Participants will return 4 and 26 weeks later for the second dose of vaccine or placebo. At week 4, participants will have cervical colposcopy and undergo cryotherapy or loop electrosurgical excisional procedure (LEEP) as appropriate. Participants undergoing cervical cryotherapy will have cervical biopsies before the treatment. Participants will be followed with HPV testing (Gene Xpert and HPV DNA PCR) at weeks 26, 52, 78, and 104, and will have cervical cytology and colposcopy with biopsies at weeks 26, 52, and 104.

Eligibility

Eligibility

Ages Eligible for Study: 25 Years and older  
Sexes Eligible for Study: Female  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load, or documentation of receipt of antiretroviral therapy; Note: the term "licensed" refers to a kit that has been certified or licensed by an oversight body within the participating country and validated internally; WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment; a reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a western blot or a plasma HIV-1 RNA viral load
  • HPV positive by the GeneXpert hrHPV assay with HPV16, HPV 18/45, or HPV31/33/35/52/58 detected; Note: participants who are hrHPV positive with only HPV51/59 or HPV 39/68/56/66 detected are not eligible
  • Receipt of ART for at least 180 days prior to randomization
  • Participants of childbearing potential, defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy or (2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), must have a negative urine or serum pregnancy test within 3 weeks prior to enrollment and agree to use an effective form of contraception (e.g., barrier contraception or hormonal contraception), delaying pregnancy for at least 12 months and ideally for the duration of the study; Note: those willing to participate delay pregnancy for at least 6 months, while receiving the recombinant human papillomavirus nonavalent (9vHPV) vaccine (or placebo)
  • If the participant is of childbearing potential, she should be at least 3 months postpartum
  • Karnofsky score >= 70%
  • Ability to understand and the willingness to sign a written informed consent document


Exclusion Criteria:
  • Current sexually transmitted infection (STI) requiring treatment (women may participate after adequate treatment, at the discretion of the treating provider)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to Gardasil or Gardasil 9
  • Uncontrolled intercurrent illness that would limit compliance with study requirements
  • Prior hysterectomy with removal of the cervix
  • Prior treatment for cervical HSIL
  • Prior history of cervical, vulvar, or vaginal cancer
  • Cervical, vulvar, or vaginal lesions suspicious for cancer based on clinical appearance (e.g. necrotic, ulcerated, and/or fungating masses), unless biopsies show no invasive cancer
  • Known bleeding diathesis
  • Prior HPV vaccination
  • Current or planned use of anticoagulants other than aspirin or non-steroidal
anti-inflammatory agents

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03284866

Contacts

Contact:   Carla Chibwesha, MD, MSc 27-11-276-8850 carla_chibwesha@med.unc.edu

Locations

Kenya
Moi University School of Medicine Not yet recruiting
Eldoret, Kenya
Contact: Elkanah Omenge Orang'o    +254 722 609 132    bworango@mu.ac.ke
Principal Investigator: Elkanah Omenge Orang'o
Malawi
UNC Project Malawi Not yet recruiting
Lilongwe, Malawi
Contact: Lameck Chinula    265 88 248 3220    lchinula@unclilongwe.org
Principal Investigator: Lameck Chinula
South Africa
African Cancer Institute at Stellenbosch Not yet recruiting
Cape Town, South Africa
Contact: Hennie Botha    +27 21 938 9209    mhbotha@sun.ac.za
Principal Investigator: Hennie Botha
University of the Witwatersrand Not yet recruiting
Johannesburg, South Africa
Contact: Carla J. Chibwesha    +27-11-276-8800    carla_chibwesha@med.unc.edu
Principal Investigator: Carla J. Chibwesha
Tanzania
Bugando Medical Center Not yet recruiting
Mwanza, Tanzania
Contact: Edgard Ndaboine    +255 784 311 825    ndaboine2@yahoo.com
Principal Investigator: Edgard Ndaboine
Uganda
Uganda Cancer Institute Not yet recruiting
Kampala, Uganda
Contact: Carolyn Nakisige    256-414-540-410    carolynnakisige@yahoo.com
Principal Investigator: Carolyn Nakisige
Zimbabwe
University of Zimbabwe Not yet recruiting
Harare, Zimbabwe
Contact: Felix Muhlanga    +263 772 335 232    fmhlanga@uz-ucsf.co.zw
Principal Investigator: Felix Muhlanga

Sponsors and Collaborators

AIDS Malignancy Consortium
National Cancer Institute (NCI)
University of Arkansas
AIDS and Cancer Specimen Resource
Merck Sharp & Dohme Corp.
The EMMES Corporation
University of California, Los Angeles

Investigators

Principal Investigator: Carla Chibwesha University of Witwatersrand, South Africa
More Information

More Information


Responsible Party: AIDS Malignancy Consortium  
ClinicalTrials.gov Identifier: NCT03284866   History of Changes  
Other Study ID Numbers: AMC-099  
  NCI-2016-00841  
  AMC-099  
  AMC-099  
  UM1CA121947  
Study First Received: May 4, 2017  
Last Updated: September 13, 2017  

Studies a U.S. FDA-regulated Drug Product: Yes  
Studies a U.S. FDA-regulated Device Product: No  
Product Manufactured in and Exported from the U.S.: Yes  

Additional relevant MeSH terms:
Infection
Communicable Diseases
HIV Infections
Carcinoma in Situ
Papillomavirus Infections
Squamous Intraepithelial Lesions of the Cervix
Uterine Cervical Dysplasia
Vaccines

ClinicalTrials.gov processed this data on October 17, 2017
This information is provided by ClinicalTrials.gov.