Safety of and Immune Response to a Novel Human Papillomavirus Vaccine in HIV Infected Children

HIV Infections Clinical Trial

Official title:

Phase II Safety and Immunogenicity Study of Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine in HIV Infected Children 7 to 12 Years of Age

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00339040
• Other study ID #: P1047
• Secondary ID: 10163PACTG P1047
• Status: Completed
• Phase: Phase 2
• Start date: October 2006
• Est. completion date: August 2009

Study information

• Verified date: January 2019
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety of and immune response to a new human papillomavirus (HPV) vaccine in HIV (Human immunodeficiency virus) infected children between the ages of 7 and 12 years.

Description:

Genital HPV infection is the most common sexually transmitted infection in the world and may lead to genital warts, anogenital dysplasias, and invasive cancers. HIV infected people and others with compromised immunity are at greater risk for HPV-related complications. In particular, researchers are concerned about the risk of HPV infection to women, who may be infected by their male partners, especially if these partners engage in anal intercourse. HIV infected women tend to have multiple types of HPV (associated with a greater risk of HPV-related disease), are less likely to clear HPV-related conditions, and are more likely to progress to HPV-related disease. The quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine to be tested in this study was safe and generally well tolerated in previous studies conducted in healthy and HPV-exposed adolescents, young adults, and older women. However, it is still unclear if the vaccine will be safe and will elicit a similar immune response in younger children. The purpose of this study is to evaluate the safety and immunogenicity of the novel quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine in HIV infected children 7 to 12 years of age.

This study had two stages and lasted at least 108 weeks. In Stage I, participants were stratified by CD4 percentage (CD4%) nadir and CD4% at study screening (Stratum A: CD4% Nadir < 15 and CD4% ≥ 15 at screening, Stratum B: CD4% Nadir ≥ 15 and < 25 and CD4% ≥ 15 at screening, Stratum C: CD4% Nadir ≥ 25 and CD4% ≥ 25 at screening). Within each stratification group, they were randomly assigned to one of two arms. During Stage I, Arm A (QHPV:Quadrivalent human papillomavirus vaccine) participants received 3 doses of vaccine, while Arm B (Placebo/QHPV) participants received 3 doses of placebo. Participants did not know whether they were receiving vaccine or placebo. Participants received their assigned intervention at study entry and Weeks 8 and 24. At Week 96, Stage II began, and all study participants were told if they received vaccine or placebo in Stage I. Arm A participants received an additional dose of vaccine at Week 96; Arm B participants received doses of vaccine at Weeks 96, 104, and 120. Over the course of the study, there were at least 12 study visits. A physical exam and blood collection occurred at most visits; medical history occurred at selected visits.

After each vaccination, participants were observed for at least 30 minutes to monitor for any allergic reactions possibly resulting from the vaccination. For 15 days following vaccination, parents or guardians were asked to complete a "report card" with details of each child's signs and symptoms. Three days after each vaccination, parents or guardians of study participants were contacted by telephone and asked about any adverse events that a child may have experienced.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: August 2009
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 12 Years

Eligibility

Inclusion Criteria

Children ages = 7 to < 12 years of age.

A confirmed diagnosis of HIV infection, defined as two positive assays from two different samples. The two results may be in any combination of the following:

• at any age: Deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), Ribonucleic acid (RNA) PCR

• age > 4 weeks: p24 antigen detection

• age >18 months: licensed ELISA (Enzyme-linked immunosorbent assay) with confirmatory Western Blot

CD4% = 15 at the time of screening is required (Note that this is a minimum requirement, and that for Stratum C the CD4% needs to be = 25).

For Strata A and B: Currently stable (= 3 months) on highly active antiretroviral therapy (HAART) regimen, defined as three or more antiretrovirals from at least two different therapeutic classes, or therapy with the combination of azidothymidine, lamivudine, and abacavir.

For stratum C no antiretroviral therapy is required.

Parent or legal guardian able and willing to provide signed informed consent.

Negative urine pregnancy test sensitive to 25 International Unit (IU) beta-human chorionic gonadotropin (HCG) for girls who are menstruating (child bearing potential).

Female study volunteers who are participating in sexual activity that could lead to pregnancy must agree to use two reliable methods of contraception, one of which must be a barrier method. A barrier method of contraception (condoms or cervical cap) together with another reliable form of contraception (condoms a , with a spermicidal agent; a diaphragm or cervical cap with spermicide; an intrauterine device [IUD]; or hormonal-based contraception) must be used while on this study. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV-1 transmission

Males participating in the study must not attempt to impregnate a woman, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom.

Exclusion Criteria

Body temperature = 101 F or = 38.3 C, orally determined, within 72 hours prior to the first and each subsequent injection. Subjects may be vaccinated any time in the next seven days thereafter, provided that the site investigator is satisfied that the febrile illness has ended.

Total bilirubin = 5 x Upper Limit of Normal (ULN) at screening.

Alanine transaminase (ALT) or serum glutamic pyruvic transaminase (SGPT) = 5 x ULN at screening in the absence of other explained causes (as determined by the site investigator) at screening.

Serum creatinine = 1.5 mg/dL at screening.

Absolute neutrophil count = 750 cells/mm3 at screening.

Hemoglobin = 9.9 g/dL at screening.

Platelet count = 75,000 cells/mm³ at screening.

Presence of an acute opportunistic non-bacterial or bacterial infection requiring therapy at the time of enrollment; the subject may be entered once he/she is stable on appropriate anti-infective therapy.

Chemotherapy for active malignancy.

Other known or suspected disease of the immune system, or immunosuppressive therapy.

Prior treatment with immunosuppressive or immunomodulation therapy within 60 days of screening.

Prior treatment with three or more week-long courses of corticosteroids (= 2.0 mg/kg or = 20 mg total of prednisone-equivalent) within one year of screening; or any systemic (oral or parenteral) steroids (= 2.0 mg/kg or = 20 mg total of prednisone-equivalent for = 3 days) within 30 days of study entry.

Prior vaccinations with inactivated vaccines received within two weeks of any dose of study vaccine, and no other vaccinations may be planned for two weeks after each dose of study vaccine.

Prior vaccinations with live vaccines received within three weeks before any dose of study vaccine, and no other vaccinations may be planned for two weeks after each dose of study vaccine.

Prior diagnosis of sexually transmitted infections (STIs), genital warts, or juvenile recurrent papillomatosis.

History of any severe allergic reaction (e.g., swelling of the mouth and throat, difficulty breathing, hypotension, or shock) that required medical intervention.

Known allergies to any vaccine component, including aluminum, yeast, or BENZONASE™ (nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]).

Previous treatment with any immune globulin preparation or blood-derived products within the six months prior to the first injection and none may be planned during the study.

Known coagulation disorder that would contraindicate Intramuscular (IM) injections.

Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study.

Breastfeeding.

Related Conditions & MeSH terms

• HIV Infections
• Sexually Transmitted Diseases

Intervention

Biological:
• Quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle (VLP) or Quadrivalent human papillomavirus vaccine (QHPV)
QHPV at week 0, 8, 24 and 96.

Other:
• Placebo/QHPV
Placebo at week 0, 8, 24 and QHPV at week 96, 104, 120.

Locations

Country	Name	City	State
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
Puerto Rico	Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS	San Juan
United States	Usc La Nichd Crs	Alhambra	California
United States	Univ. of Colorado Denver NICHD CRS	Aurora	Colorado
United States	Boston Medical Center Ped. HIV Program NICHD CRS	Boston	Massachusetts
United States	Children's Hosp. of Boston NICHD CRS	Boston	Massachusetts
United States	Bronx-Lebanon CRS	Bronx	New York
United States	Jacobi Med. Ctr. Bronx NICHD CRS	Bronx	New York
United States	SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS	Brooklyn	New York
United States	Chicago Children's CRS	Chicago	Illinois
United States	Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program	Chicago	Illinois
United States	Rush Univ. Cook County Hosp. Chicago NICHD CRS	Chicago	Illinois
United States	Children's Hospital of Michigan NICHD CRS	Detroit	Michigan
United States	DUMC Ped. CRS	Durham	North Carolina
United States	South Florida CDTC Ft Lauderdale NICHD CRS	Fort Lauderdale	Florida
United States	Connecticut Children's Med. Ctr.	Hartford	Connecticut
United States	Texas Children's Hosp. CRS	Houston	Texas
United States	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida
United States	Miller Children's Hosp. Long Beach CA NICHD CRS	Long Beach	California
United States	UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS	Los Angeles	California
United States	St. Jude/UTHSC CRS	Memphis	Tennessee
United States	Univ. of Miami Ped. Perinatal HIV/AIDS CRS	Miami	Florida
United States	Children's Hosp.	New Orleans	Louisiana
United States	Nyu Ny Nichd Crs	New York	New York
United States	Rutgers - New Jersey Medical School CRS	Newark	New Jersey
United States	Children's Hosp. of Orange County	Orange	California
United States	Strong Memorial Hospital Rochester NY NICHD CRS	Rochester	New York
United States	UCSD Mother-Child-Adolescent Program CRS	San Diego	California
United States	Univ. of California San Francisco NICHD CRS	San Francisco	California
United States	Seattle Children's Hospital CRS	Seattle	Washington
United States	SUNY Stony Brook NICHD CRS	Stony Brook	New York
United States	Children's National Med. Ctr. Washington DC NICHD CRS	Washington	District of Columbia
United States	Howard Univ. Washington DC NICHD CRS	Washington	District of Columbia
United States	WNE Maternal Pediatric Adolescent AIDS CRS	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (6)

Ault KA, Giuliano AR, Edwards RP, Tamms G, Kim LL, Smith JF, Jansen KU, Allende M, Taddeo FJ, Skulsky D, Barr E. A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine. 2004 Aug 13;22(23-24):3004-7. — View Citation

Brown DR, Fife KH, Wheeler CM, Koutsky LA, Lupinacci LM, Railkar R, Suhr G, Barr E, Dicello A, Li W, Smith JF, Tadesse A, Jansen KU. Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine. Vaccine. 2004 Jul 29;22(21-22):2936-42. — View Citation

Levin MJ, Moscicki AB, Song LY, Fenton T, Meyer WA 3rd, Read JS, Handelsman EL, Nowak B, Sattler CA, Saah A, Radley DR, Esser MT, Weinberg A; IMPAACT P1047 Protocol Team. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, a — View Citation

P1047 ORAL PRESENTATION at the 25th International Papillomavirus Conference May 8-14 2009, Malmö, Sweden given by Anna Barbara Moscicki. Safety and immunogenicity of Gardasil® in HIV-infected children. Moscicki AB, Weinberg A, Song LY, Handelsman E, Patte

Poland GA, Jacobson RM, Koutsky LA, Tamms GM, Railkar R, Smith JF, Bryan JT, Cavanaugh PF Jr, Jansen KU, Barr E. Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2-year randomized controlled clinical trial. Mayo Clin Proc. 2005 May;80(5):601-10. — View Citation

Weinberg A, Song LY, Handelsman E, Moscicki AB, Patterson J, Saah A, Radley D, Esser M, Read J, and Levin MJ for IMPAACT P1047 Team. The P1047 data up to week 28 have been analyzed and presented to 15th CROI as abstract and poster #619a: Safety and Immuno

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent of Participants Developing Grade 3 or 4 Adverse Events (AEs)	Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (December 2004). The grades used are: Grade 1="Mild", Grade 2="Moderate", Grade 3="Severe", Grade 4="Potentially Life-Threatening". All grade 3 and higher signs, symptoms, and laboratory toxicities were included.	Within 14 days of first three doses of vaccination
Primary	Percent of Participants Developing Grade 3 or 4 Adverse Events (AEs) Attributed to Study Treatment	Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (December 2004). All grade 3 and higher signs, symptoms, and laboratory toxicities attributed to study treatment were included. The relationship between the Adverse Events and the vaccination were evaluated by study team and assigned to, for example, "Treatment related", "Non-treatment related", "Baseline", "Possibly treatment related".	Within 14 days of first three doses of vaccination
Primary	Percent of Participants With Human Papillomavirus (HPV) Type-Specific Seroconversion	Serum anti-HPV 6, 11, 16, and 18 antibody was measured using a competitive Luminex immunoassay (cLIA; reported in milli-Merck Units [mMU]/mL). Sero-positivity was defined as an anti-HPV titer =20, 16, 20, and 24 mMU/mL, for HPV types 6, 11, 16, and 18, respectively.	At week 28 after beginning the vaccination series
Primary	Serum Anti-HPV Antibody Titers (cLIA)	Geometric means of Type-specific Serum anti-HPV antibody titers (cLIA)	Arm A week 0, 28, 72, 96, 97, 100; Arm B week 0, 28, 72, 96, 97, 100, 124.
Secondary	CD4 Count Over Time		Arm A week 0, 8, 12, 24, 28, 72, 96, 100 and 108; Arm B week 0, 8, 12, 24, 28, 72, 96, 100, 104, 108, 120, and 124.
Secondary	CD4 Percent Over Time		Arm A week 0, 8, 12, 24, 28, 72, 96, 100 and 108; Arm B week 0, 8, 12, 24, 28, 72, 96, 100, 104, 108, 120, and 124.
Secondary	HIV-1 Viral Load (Ribonucleic Acid [RNA] Copies/ml) Over Time		Arm A week 0, 8, 12, 24, 28, 72, 96, 100 and 108; Arm B week 0, 8, 12, 24, 28, 72, 96, 100, 104, 108, 120, and 124.

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