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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01461096
• Other study ID #: A5298
• Secondary ID: 11798
• Status: Completed
• Phase: Phase 3
• Start date: March 2012
• Est. completion date: January 2016

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 575
• Est. completion date: January 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 27 Years and older

Eligibility

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:

1. Absolute neutrophil count (ANC) greater than 750 cells/mm^3

2. Hemoglobin greater than or equal to 9.0 g/dL

3. Platelet count greater than or equal to 75,000/mm^3

4. Serum creatinine less than or equal to three times the upper limit of normal (ULN)

5. 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

6. 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

Related Conditions & MeSH terms

• HIV Infections
• Infections

Intervention

Biological:
• Quadrivalent HPV Vaccine
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.
• Placebo Vaccine for Male Participants Only
Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.
• Placebo Vaccine for Female Participants Only
Participants were prescribed one IM injection of the placebo vaccine in the upper arm or thigh at baseline and Weeks 8 and 24.

Locations

Country	Name	City	State
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio de Janeiro
Puerto Rico	Puerto Rico AIDS Clinical Trials Unit CRS	San Juan
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Boston Medical Center CRS	Boston	Massachusetts
United States	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush University CRS	Chicago	Illinois
United States	Cincinnati Clinical Research Site	Cincinnati	Ohio
United States	Denver Public Health CRS	Denver	Colorado
United States	Houston AIDS Research Team CRS	Houston	Texas
United States	UCLA CARE Center CRS	Los Angeles	California
United States	Columbia P&S CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Weill Cornell Chelsea CRS	New York	New York
United States	New Jersey Medical School Clinical Research Center CRS	Newark	New Jersey
United States	Stanford AIDS Clinical Trials Unit CRS	Palo Alto	California
United States	University of Pittsburgh CRS	Pittsburgh	Pennsylvania
United States	The Miriam Hospital Clinical Research Site (TMH CRS) CRS	Providence	Rhode Island
United States	University of Rochester Adult HIV Therapeutic Strategies Network CRS	Rochester	New York
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	UCSD Antiviral Research Center CRS	San Diego	California
United States	Ucsf Hiv/Aids Crs	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Brazil,  Puerto Rico, 

References & Publications (3)

D'Souza G, Wiley DJ, Li X, Chmiel JS, Margolick JB, Cranston RD, Jacobson LP. Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr. 2008 Aug 1;48(4):491-9. doi: 10.1097/QAI.0b013e31817aebfe. — View Citation

Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Mary-Krause M; FHDH-ANRS CO 4. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS. 2008 Jun 19;22(10):1203-11. doi: 10.1097/QAD.0b013e3283023f78. — View Citation

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).

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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