Quadrivalent HPV Vaccine to Prevent Anal HPV in HIV-infected Men and Women

Study Overview
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Brief Summary
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Men who have sex with men (MSM) have an increased risk of developing anal human papillomavirus (HPV) infections, which can be a risk factor for anal cancer. HIV-infected women are also at risk of anal cancer. This study will evaluate the effectiveness of the Food and Drug Administration (FDA)-approved quadrivalent HPV vaccine, Gardasil, at preventing anal HPV infection in HIV-infected MSM and HIV-infected women.

Detailed Description
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Anal HPV infection can be a risk factor for anal cancer, which is a common non-AIDS-defining cancer among HIV-infected MSM. Screening for anal cancer is not widely available and can be difficult to implement. People who receive the FDA-approved quadrivalent HPV vaccine, Gardasil, may have a reduced risk of developing anal HPV infection, which may in turn reduce the risk of developing anal cancer. The purpose of this study is to evaluate the effectiveness of the quadrivalent HPV vaccine, Gardasil, at reducing the incidence of anal HPV infections in HIV-infected MSM and HIV-infected women. This study enrolled HIV-infected MSM and HIV-infected women. Participants were randomly assigned to receive the HPV vaccine or a placebo vaccine. At the screening study visit, participants underwent a physical examination, blood collection, anal swab procedure, oral examination, questionnaires, a high-resolution anoscopy (HRA), and if female, a pregnancy test, vaginal swab, and gynecologic exam. At the entry study visit, participants underwent most of the procedures performed at screening (with the exception of an HRA and a gynecologic exam if female) plus a saliva test. Participants received the HPV vaccine or placebo as an injection into their upper arm or thigh on Day 0 and Weeks 8 and 24. Study staff called participants 2 to 3 days after each vaccination for follow-up monitoring. Additional study visits and procedures occurred at Week 28, Week 52, and every 26 weeks thereafter for at least 3 years and for a maximum of 4 years after the last participant was enrolled in the study. Female participants also had a gynecologic exam at screening, Week 52, and every 52 weeks thereafter; a pregnancy test at screening, baseline, Week 8, Week 24, and as indicated; and self-collected vaginal swabs at screening, entry, Week 28, Week 52, and every 26 weeks thereafter. Peripheral blood mononuclear cells (PBMCs) were collected from some participants at entry, Week 28, and study exit. The DSMB held a total of four reviews for the study. After careful review of the outcome data in the 4th review held on September 2, 2015, the DSMB commended the study team for a well-run study that provided important results and recommended stopping the study early due to futility. The recommendation was based on meeting the pre-specified criteria for inadequate conditional power to detect a treatment difference at 50% information. The study was prematurely discontinued on December 31, 2015, which was around eight months earlier than originally planned. With approval from SASC, the study team managed to offer high resolution anoscopy (HRA) procedures to participants whose most recent anal Pap tests showed abnormal results, unless the HRA took place on or after 09/01/14.

Official Title
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A Randomized, Double-Blinded, Placebo-Controlled, Phase III Trial of the Quadrivalent HPV Vaccine to Prevent Anal Human Papillomavirus Infection in HIV-Infected Men and Women

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: Quadrivalent HPV Vaccine
* Biological: Placebo Vaccine for Male Participants Only
* Biological: Placebo Vaccine for Female Participants Only


Participation Criteria
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Eligibility Criteria
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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. More information on this criterion can be found in the protocol. Laboratory values obtained within 45 days prior to entry by any U.S. laboratory that has a Clinical Laboratory Improvement Amendment (CLIA) certification or its equivalent, or at any network-approved non-U.S. laboratory that operates in accordance with Good Clinical Practices and participates in appropriate external quality assurance programs: Absolute neutrophil count (ANC) greater than 750 cells/mm^3 Hemoglobin greater than or equal to 9.0 g/dL Platelet count greater than or equal to 75,000/mm^3 Serum creatinine less than or equal to three times the upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) less than or equal to five times the ULN Total or conjugated (direct) bilirubin less than or equal to 2.5 times the ULN For men, receptive anal sex (defined as receptive penile-anal sex or receptive oral-anal sex with another man) within 1 year prior to entry Anal cytology result from specimen obtained within 45 days prior to entry HRA performed within 45 days prior to entry by a certified HRA provider with no evidence of invasive or microinvasive anal cancer by anal biopsy or by visual inspection if no biopsy was obtained. Note: refer to protocol for more information about HRA certification process. For women, gynecologic examination (including screening for cervical disease by exfoliative cytology with or without colposcopy) within 45 days prior to entry. For women of reproductive potential, a negative serum or urine pregnancy test within 45 days prior to study entry by any U.S. laboratory that has a CLIA certification or its equivalent, or at any network-approved non-U.S. laboratory that operates in accordance with Good Clinical Practices and participates in appropriate external quality assurance programs. More information on this criterion can be found in the protocol. Confirmation of the availability of the anal swab, vaginal swab (women only) and Scope oral rinse specimens for HPV DNA PCR obtained at screening. The site must confirm that these samples have been entered into the Laboratory Data Management System (LDMS). Ability and willingness of participant or legal representative to provide informed consent Exclusion Criteria: History or current biopsy diagnosis of invasive or microinvasive cancer, i.e.: For all participants: anal or oropharyngeal cancer For men: penile cancer For women: cervical, vulvar, or vaginal cancer More information on this criterion can be found in the protocol. Anal, cervical, or vaginal cytological results suspicious for invasive carcinoma at any point prior to entry Topical or surgical treatment for intra- or perianal intraepithelial neoplasia or condyloma within 6 months prior to entry. More information on this criterion can be found in the protocol. Prior receipt of one or more doses of an HPV vaccine Receipt of anticoagulants other than aspirin or nonsteroidal anti-inflammatory drugs (NSAIDS) within 14 days prior to entry Known allergy/sensitivity or any hypersensitivity to yeast or any of the components of the study product or its formulation. More information on this criterion can be found in the protocol. Active drug or alcohol use or dependence or other condition that, in the opinion of the site investigator, would interfere with adherence to study requirements Serious illness requiring systemic treatment and/or hospitalization within 21 days prior to entry Hemophilia or other bleeding diatheses Use of any systemic antineoplastic or immunomodulatory treatment, systemic corticosteroids other than inhaled corticosteroids or prednisone less than or equal to 10 mg (or equivalent), investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry. NOTE: Routine standard-of-care vaccines (including hepatitis A, hepatitis B, influenza, pneumococcal, and tetanus vaccines) are not exclusionary. Expected treatment of hepatitis B or hepatitis C virus with immunomodulatory agents in the 7 months after entry Breastfeeding

Ages Eligible for Study
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Minimum Age: 27 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quadrivalent HPV Vaccine<br>Participants were prescribed the quadrivalent HPV vaccine at baseline and Weeks 8 and 24. | Biological: Quadrivalent HPV Vaccine<br>* Participants were prescribed one intramuscular (IM) injection of the quadrivalent HPV vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.<br>|
| Placebo Comparator: Placebo Vaccine<br>Participants were prescribed the placebo vaccine at baseline and Weeks 8 and 24. | Biological: Placebo Vaccine for Male Participants Only<br>* Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.<br>Biological: Placebo Vaccine for Female Participants Only<br>* Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the First New Persistent Infection of HPV 6, 11, 16, or 18 | The outcome for this evaluation was time to the first new persistent infection of any of HPV 6, 11, 16, or 18. Persistent infection was defined as an infection confirmed by positive anal HPV PCR results at 2 consecutive visits at least 16 weeks apart without an intervening negative result. A participant who had a positive measurement on his/her last measurement with no consecutive confirmatory measurement was considered as having a persistent infection. Participants with pre-existing HPV infection at baseline were evaluable for the primary outcome if they were PCR negative for at least one of the four vaccine HPV types at baseline. NOTE: Use 5th and 10th percentiles in years from baseline to the first new persistent infection as the summary measure. | From baseline to participant's last study visit, for up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 or 4 Adverse Events (AEs) That Were Possibly, Probably, or Definitely Related to the Vaccine, as Determined by the Local Investigator | To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, august 2009). | From baseline to participant's last study visit, for up to 4 years | 
| Number of Participants With Biopsy-proven High-grade Anal Intraepithelial Neoplasia (HGAIN) Occurrences and Reoccurrences After Week 52 | HGAIN was defined as AIN2 (moderate dysplasia, with no mention of AIN grade III), AIN3 (severe dysplasia, carcinoma in-situ, or AIN grade II/III), high grade AIN not specified, or adenocarcinoma in situ found in the intra-anal or perianal region. | From Week 52 to participant's last study visit, for up to 4 years | 
| Number of Participants With Anal Cytological Abnormality Occurrences | Anal cytologic abnormalities include: atypical squamous cells undetermined significance (ASCUS), atypical squamous cells favor high-grade SIL/squamous cell carcinoma (ASC-H), low-grade squamous intraepithelial lesion/mild dysplasia/HPV (LSIL), or high-grade SIL/moderate dysplasia to severe dysplasia/carcinoma in situ/features of invasion (HSIL). | At baseline, Week 52, Week 104 and Week 156 | 
| Time to First New Persistent Oral HPV Infection of Vaccine Types Detected From Oral Rinse | The outcome for this evaluation was time to the first new persistent infection of any of oral HPV 6, 11, 16, or 18. Persistent infection was defined as an infection confirmed by positive oral HPV PCR results at 2 consecutive visits at least 16 weeks apart without an intervening negative result. A participant who had a positive measurement on his/her last measurement with no consecutive confirmatory measurement was considered as having a persistent infection. Participants with pre-existing HPV infection at baseline were evaluable for the primary endpoint if they were PCR negative for at least one of the four vaccine HPV types at baseline. NOTE: Use 5th and 10th percentiles in years from baseline to the first new persistent infection as the summary measure. | From baseline to participant's last study visit, for up to 4 years |