<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03284866</url>
  </required_header>
  <id_info>
    <org_study_id>AMC-099</org_study_id>
    <secondary_id>NCI-2016-00841</secondary_id>
    <secondary_id>AMC-099</secondary_id>
    <secondary_id>AMC-099</secondary_id>
    <secondary_id>UM1CA121947</secondary_id>
    <nct_id>NCT03284866</nct_id>
  </id_info>
  <brief_title>HPV Vaccine Therapy in Reducing High-Grade Cervical Lesions in Patients With HIV and HPV</brief_title>
  <acronym>COVENANT</acronym>
  <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)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AIDS Malignancy Consortium</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Arkansas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>AIDS and Cancer Specimen Resource</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Emmes Company, LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, Los Angeles</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>AIDS Malignancy Consortium</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized phase III trial studies how well human papillomavirus (HPV) vaccine therapy&#xD;
      works in reducing high-grade cervical lesions in patients with human immunodeficiency virus&#xD;
      (HIV) and HPV. Vaccines made from HPV peptides or antigens may help the body build an&#xD;
      effective immune response to kill the HPV virus and prevent cervical lesions from developing&#xD;
      or coming back after being removed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      At screening, potential participants will be tested for cervical human papillomavirus (HPV)&#xD;
      infection (GeneXpert hrHPV assay and HPV DNA PCR) and undergo cervical colposcopy to confirm&#xD;
      the absence of cervical cancer. If eligible, the participant will be randomized to receive&#xD;
      either the 9-valent HPV vaccine or saline placebo.&#xD;
&#xD;
      Participants will return 4 and 26 weeks later for the second dose of vaccine or placebo. At&#xD;
      week 4, participants will have cervical colposcopy and undergo cryotherapy or loop&#xD;
      electrosurgical excisional procedure (LEEP) as appropriate. Participants undergoing cervical&#xD;
      cryotherapy will have cervical biopsies before the treatment. Participants will be followed&#xD;
      with HPV testing (Gene Xpert and HPV DNA PCR) at weeks 26, 52, 78, and 104, and will have&#xD;
      cervical cytology and colposcopy with biopsies at weeks 26, 52, and 104.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 31, 2019</start_date>
  <completion_date type="Anticipated">March 15, 2027</completion_date>
  <primary_completion_date type="Anticipated">March 15, 2025</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of cervical high-grade squamous intraepithelial lesions (HSIL) or cervical cancer</measure>
    <time_frame>After week 4 study visit to week 52 post-randomization</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Occurrence of cervical HSIL from weeks 52-104</measure>
    <time_frame>After week 52 to week 104</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of baseline types and quantity of HPV as predictors of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of presence of HSIL at baseline as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of CD4+ cell count as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of plasma HIV-1 RNA as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of ART use as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of age as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of sexual behavior as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of vaccination use as a predictor of sustained absence</measure>
    <time_frame>At baseline and week 4</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incident cervical vaccine type HPV infections defined as infections at 2 consecutive timepoints and assessed using type specific HPV DNA polymerase chain reaction (PCR)</measure>
    <time_frame>Up to week 104</time_frame>
    <description>Vaccine and placebo participants will be compared with respect to these proportions using the chi-square test corrected for continuity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abnormal cervical cytology</measure>
    <time_frame>Baseline, week 26, 52, and 104</time_frame>
    <description>The proportion of women with abnormal cervical cytology at baseline, week 26, 52, and 104 will be reported and compared between arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalent vulvar HSIL or cancer</measure>
    <time_frame>Up to week 4</time_frame>
    <description>The prevalence of vulvar HSIL or cancer at baseline will be estimated using the binomial proportion and its 95% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incident vulvar HSIL or cancer</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical and demographic factors associated with incident vulvar HSIL or cancer</measure>
    <time_frame>Up to week 104</time_frame>
    <description>Logistic regression analyses will be used to evaluate associations with incident vulvar HSIL or cancer acquisition with clinical and demographic factors and arm.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>HPV type distributions</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>HPV strain variant analysis of cervical and vulvar HSIL specimens</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Tissue microarray library of cervical specimens for biomarker analysis and discovery</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>hrHPV type distribution in the anus</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>hrHPV type prevalence in the anus</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Vaccine-induced antibody titers</measure>
    <time_frame>Up to week 104</time_frame>
    <description>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.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">536</enrollment>
  <condition>AIDS-Related Human Papillomavirus Infection</condition>
  <condition>High Grade Cervical Squamous Intraepithelial Neoplasia</condition>
  <condition>HIV Infection</condition>
  <arm_group>
    <arm_group_label>Arm I, recombinant HPV 9-valent vaccine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II, saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients receive saline placebo vaccine IM at baseline, 4, and 26 weeks, with sample collection for Laboratory Biomarker Analysis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Arm I, recombinant HPV 9-valent vaccine</arm_group_label>
    <arm_group_label>Arm II, saline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Recombinant Human Papillomavirus Nonavalent Vaccine</intervention_name>
    <description>Given IM</description>
    <arm_group_label>Arm I, recombinant HPV 9-valent vaccine</arm_group_label>
    <other_name>Gardasil 9</other_name>
    <other_name>Nonavalent HPV VLP Vaccine</other_name>
    <other_name>Recombinant HPV Nonavalent Vaccine</other_name>
    <other_name>Recombinant Human Papillomavirus 9-valent Vaccine</other_name>
    <other_name>Recombinant HPV 9-valent Vaccine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>Given IM</description>
    <arm_group_label>Arm II, saline</arm_group_label>
    <other_name>Sodium Chloride 0.9%</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or&#xD;
             chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and&#xD;
             confirmed by a licensed western blot or a second antibody test by a method other than&#xD;
             the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load,&#xD;
             or documentation of receipt of antiretroviral therapy; Note: the term &quot;licensed&quot;&#xD;
             refers to a kit that has been certified or licensed by an oversight body within the&#xD;
             participating country and validated internally; WHO (World Health Organization) and&#xD;
             CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation&#xD;
             of the initial test result must use a test that is different from the one used for the&#xD;
             initial assessment; a reactive initial rapid test should be confirmed by either&#xD;
             another type of rapid assay or an E/CIA that is based on a different antigen&#xD;
             preparation and/or different test principle (e.g., indirect versus competitive), or a&#xD;
             western blot or a plasma HIV-1 RNA viral load&#xD;
&#xD;
          -  HPV positive by the GeneXpert hrHPV assay with HPV16, HPV 18/45, or HPV31/33/35/52/58&#xD;
             detected; Note: participants who are hrHPV positive with only HPV51/59 or HPV&#xD;
             39/68/56/66 detected are not eligible&#xD;
&#xD;
          -  Receipt of ART for at least 180 days prior to randomization&#xD;
&#xD;
          -  Participants of childbearing potential, defined as a sexually mature woman who: (1)&#xD;
             has not undergone a hysterectomy or bilateral oophorectomy or (2) has not been&#xD;
             naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at&#xD;
             any time in the preceding 24 consecutive months), must have a negative urine or serum&#xD;
             pregnancy test within 3 weeks prior to enrollment and agree to use an effective form&#xD;
             of contraception (e.g., barrier contraception or hormonal contraception), delaying&#xD;
             pregnancy for at least 12 months and ideally for the duration of the study; Note:&#xD;
             those willing to participate delay pregnancy for at least 6 months, while receiving&#xD;
             the recombinant human papillomavirus nonavalent (9vHPV) vaccine (or placebo)&#xD;
&#xD;
          -  If the participant is of childbearing potential, she should be at least 3 months&#xD;
             postpartum&#xD;
&#xD;
          -  Karnofsky score &gt;= 70%&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current sexually transmitted infection (STI) requiring treatment (women may&#xD;
             participate after adequate treatment, at the discretion of the treating provider)&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to Gardasil or Gardasil 9&#xD;
&#xD;
          -  Uncontrolled intercurrent illness that would limit compliance with study requirements&#xD;
&#xD;
          -  Prior hysterectomy with removal of the cervix&#xD;
&#xD;
          -  Prior treatment for cervical HSIL&#xD;
&#xD;
          -  Prior history of cervical, vulvar, or vaginal cancer&#xD;
&#xD;
          -  Cervical, vulvar, or vaginal lesions suspicious for cancer based on clinical&#xD;
             appearance (e.g. necrotic, ulcerated, and/or fungating masses), unless biopsies show&#xD;
             no invasive cancer&#xD;
&#xD;
          -  Known bleeding diathesis&#xD;
&#xD;
          -  Prior HPV vaccination&#xD;
&#xD;
          -  Current or planned use of anticoagulants other than aspirin or non-steroidal&#xD;
             anti-inflammatory agents&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carla Chibwesha</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Witwatersrand, South Africa</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Carla Chibwesha, MD, MSc</last_name>
    <phone>27-11-276-8850</phone>
    <email>carla_chibwesha@med.unc.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Moi University School of Medicine</name>
      <address>
        <city>Eldoret</city>
        <country>Kenya</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Elkanah Omenge Orang'o</last_name>
      <phone>+254 722 609 132</phone>
      <email>bworango@mu.ac.ke</email>
    </contact>
    <investigator>
      <last_name>Elkanah Omenge Orang'o</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UNC Project Malawi</name>
      <address>
        <city>Lilongwe</city>
        <country>Malawi</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lameck Chinula</last_name>
      <phone>265 88 248 3220</phone>
      <email>lchinula@unclilongwe.org</email>
    </contact>
    <investigator>
      <last_name>Lameck Chinula</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>African Cancer Institute at Stellenbosch</name>
      <address>
        <city>Cape Town</city>
        <country>South Africa</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vikash Sewram</last_name>
      <phone>+27 021 927 7001</phone>
      <email>vsewram@sun.ac.za</email>
    </contact>
    <investigator>
      <last_name>Hennie Botha</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of the Witwatersrand</name>
      <address>
        <city>Johannesburg</city>
        <country>South Africa</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carla J. Chibwesha</last_name>
      <phone>+27-11-276-8800</phone>
      <email>carla_chibwesha@med.unc.edu</email>
    </contact>
    <investigator>
      <last_name>Carla J. Chibwesha</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Uganda Cancer Institute</name>
      <address>
        <city>Kampala</city>
        <country>Uganda</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Carolyn Nakisige</last_name>
      <phone>256-414-540-410</phone>
      <email>carolynnakisige@yahoo.com</email>
    </contact>
    <investigator>
      <last_name>Carolyn Nakisige</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Zimbabwe</name>
      <address>
        <city>Harare</city>
        <country>Zimbabwe</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Felix Muhlanga</last_name>
      <phone>+263 772 335 232</phone>
      <email>fmhlanga@uz-ucsf.co.zw</email>
    </contact>
    <investigator>
      <last_name>Felix Muhlanga</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Kenya</country>
    <country>Malawi</country>
    <country>South Africa</country>
    <country>Uganda</country>
    <country>Zimbabwe</country>
  </location_countries>
  <removed_countries>
    <country>Tanzania</country>
  </removed_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 4, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 15, 2017</study_first_posted>
  <last_update_submitted>May 16, 2023</last_update_submitted>
  <last_update_submitted_qc>May 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Papillomavirus Infections</mesh_term>
    <mesh_term>Squamous Intraepithelial Lesions of the Cervix</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03284866
org study id: AMC-099
secondary id: NCI-2016-00841
secondary id: AMC-099
secondary id: AMC-099
secondary id: UM1CA121947
nct id: NCT03284866
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Occurrence of cervical high-grade squamous intraepithelial lesions (HSIL) or cervical cancer
time frame: After week 4 study visit to week 52 post-randomization
description: 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.
measure: Occurrence of cervical HSIL from weeks 52-104
time frame: After week 52 to week 104
description: 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.
measure: Role of baseline types and quantity of HPV as predictors of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of presence of HSIL at baseline as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of CD4+ cell count as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of plasma HIV-1 RNA as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of ART use as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of age as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of sexual behavior as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: Role of vaccination use as a predictor of sustained absence
time frame: At baseline and week 4
description: 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.
measure: 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
description: Vaccine and placebo participants will be compared with respect to these proportions using the chi-square test corrected for continuity.
measure: Abnormal cervical cytology
time frame: Baseline, week 26, 52, and 104
description: The proportion of women with abnormal cervical cytology at baseline, week 26, 52, and 104 will be reported and compared between arms.
measure: Prevalent vulvar HSIL or cancer
time frame: Up to week 4
description: The prevalence of vulvar HSIL or cancer at baseline will be estimated using the binomial proportion and its 95% confidence interval.
measure: Incident vulvar HSIL or cancer
time frame: Up to week 104
description: 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.
measure: Clinical and demographic factors associated with incident vulvar HSIL or cancer
time frame: Up to week 104
description: Logistic regression analyses will be used to evaluate associations with incident vulvar HSIL or cancer acquisition with clinical and demographic factors and arm.
measure: HPV type distributions
time frame: Up to week 104
description: 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.
measure: HPV strain variant analysis of cervical and vulvar HSIL specimens
time frame: Up to week 104
description: 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.
measure: Tissue microarray library of cervical specimens for biomarker analysis and discovery
time frame: Up to week 104
description: 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.
measure: hrHPV type distribution in the anus
time frame: Up to week 104
description: 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.
measure: hrHPV type prevalence in the anus
time frame: Up to week 104
description: 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.
measure: Vaccine-induced antibody titers
time frame: Up to week 104
description: 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.
arm group label: Arm I, recombinant HPV 9-valent vaccine
arm group type: Experimental
description: 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.
arm group label: Arm II, saline
arm group type: Placebo Comparator
description: Patients receive saline placebo vaccine IM at baseline, 4, and 26 weeks, with sample collection for Laboratory Biomarker Analysis.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Arm I, recombinant HPV 9-valent vaccine
arm group label: Arm II, saline
intervention type: Biological
intervention name: Recombinant Human Papillomavirus Nonavalent Vaccine
description: Given IM
arm group label: Arm I, recombinant HPV 9-valent vaccine
other name: Gardasil 9
other name: Nonavalent HPV VLP Vaccine
other name: Recombinant HPV Nonavalent Vaccine
other name: Recombinant Human Papillomavirus 9-valent Vaccine
other name: Recombinant HPV 9-valent Vaccine
intervention type: Other
intervention name: Saline
description: Given IM
arm group label: Arm II, saline
other name: Sodium Chloride 0.9%
criteria: 
gender: Female
minimum age: 25 Years
maximum age: N/A
healthy volunteers: No
last name: Carla Chibwesha
role: Principal Investigator
affiliation: University of Witwatersrand, South Africa
last name: Carla Chibwesha, MD, MSc
phone: 27-11-276-8850
email: carla_chibwesha@med.unc.edu
facility: 
status: Not yet recruiting
contact: 
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facility: 
status: Recruiting
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facility: 
status: Recruiting
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status: Recruiting
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status: Not yet recruiting
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facility: 
status: Recruiting
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country: Kenya
country: Malawi
country: South Africa
country: Uganda
country: Zimbabwe
country: Tanzania
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Papillomavirus Infections
mesh term: Squamous Intraepithelial Lesions of the Cervix
mesh term: Vaccines
sharing ipd: No