Evaluation of Safety and Immunogenicity of a Human Papillomavirus (HPV) Vaccine in Human Immunodeficiency Virus (HIV) Infected Females

NCT01031069 | Completed Phase 4 Results

• 2 other identifiers: 1098232013-003429-28
• Study Type: interventional
• Target: 873
• Locations: 4 countries
• Sites: 15

Brief Summary

Infection with human papillomavirus (HPV) has been clearly established as the central cause of cervical cancer. This Phase IV, observer-blind study is designed to evaluate the safety and immunogenicity of Cervarix in HIV infected females aged 15 to 25 years as compared to Merck's HPV vaccine (Gardasil). For comparative purposes, a group of HIV negative females will also be evaluated. All subjects will receive the HPV vaccine (either Cervarix or Gardasil) according to a three-dose schedule (Day 0, Week 6, Month 6).

Conditions

Infections, Papillomavirus; Papillomavirus Vaccines

Keywords

Cervarix; Gardasil; Immunogenicity; Cervical cancer; Safety; HPV vaccine

Outcome Measures

Primary Outcomes (13)

• Number of Human Immunodeficiency Virus Positive Subjects (HIV+) With Any and Grade 3 Solicited Local Symptoms

  Assessed solicited local symptoms were pain, redness, swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = significant pain at rest, pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling with a maximum diameter greater than 50 millimeters (mm).

  During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses

• Number of HIV+ Subjects With Any, Grade 3 and Related Solicited General Symptoms

  Assessed solicited general symptoms were arthralgia, fatigue, gastrointestinal \[nausea, vomiting, diarrhoea and/or abdominal pain\], headache, myalgia, rash, temperature \[defined as axillary temperature higher than (\>) 37.5 degrees Celsius (°C)\] and urticaria. Any = occurrence of the symptom regardless of intensity grade and relationship. Grade 3 symptom = symptom that prevented normal activity. Grade 3 temperature = temperature \> 39.0 °C. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Related = symptom assessed by the investigator as related to the vaccination.

  During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses

• Number of HIV+ Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs)

  An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 symptom = symptom that prevented normal activity. Related = symptom assessed by the investigator as related to the vaccination.

  During the 30-day follow-up period (from the day of vaccination up to 29 subsequent days) after any vaccination

• Number of HIV+ Subjects With Serious Adverse Events (SAEs)

  SAEs assessed include any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity or represented a congenital anomaly/birth defect in the offspring of a study subject.

  From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)

• Number of HIV+ Subjects With Medically Significant Conditions (MSCs)

  Medically significant conditions (MSCs) are defined as AEs prompting emergency room or physician visits that were not related to common diseases, or not related to routine visits for physical examination or vaccination, SAEs that were not related to common diseases.

  From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)

• Number of HIV+ Subjects With Potential Immune-mediated Diseases (pIMDs)

  Potential immune-mediated diseases are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.

  From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)

• Number of HIV+ Subjects Reporting Pregnancies and Outcomes of Reported Pregnancies

  Pregnancy related outcomes were: live infant no apparent congenital anomaly, live infant congenital anomaly, elective termination (termin.) no apparent congenital anomaly, elective termination (termin.) congenital anomaly, ectopic pregnancy, spontaneous abortion no apparent congenital (congen.) anomaly, stillbirth no apparent congenital anomaly, stillbirth congenital anomaly, lost to follow-up, pregnancy ongoing, missing.

  From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)

• Number of HIV+ Subjects With Haematological and Biochemical Parameter Abnormalities

  Among assessed haematological and biochemical parameters were: alanine aminotransferase \[ALAT\], basophilis \[BSPH\], creatinine \[CRT\], eosinophils \[ESPH\], haematocrit \[HTCR\], haemoglobin \[HGB\], lymphocytes \[LYMP\], monocytes \[MONO\], neutrophils \[NTPH\], platelets \[PLAT\], red blood cells \[RBC\] and white blood cells \[WBC\]. Unknown = value unknown for the specified visit and laboratory parameter; Below = value below the laboratory reference range defined for the specified visit and laboratory parameter; Within = value within the laboratory reference range defined for the specified visit and laboratory parameter; Above = value above the laboratory reference range defined for the specified visit and laboratory parameter.

  At Month 7 (30 days after the last vaccination dose at Month 6)

• Cluster of Differentiation 4 (CD4+) Cell Count in HIV+ Subjects at Month 7

  CD4+ cell count, expressed in cells/cubic millimeter (mm3), was assessed for HIV+ subjects.

  At Month 7 (30 days after the last vaccination dose at Month 6)

• HIV Viral Load (VL) in HIV+ Subjects at Month 7

  HIV VL, expressed in HIV copies/milliliter (mL), was assessed for HIV+ subjects.

  At Month 7 (30 days after the last vaccination dose at Month 6)

• Number of HIV+ Subjects by World Health Organization (WHO) HIV Clinical Staging

  HIV+ subjects were categorised into clinical stages 1 through 4, as per the WHO classification \[WHO, 2009\].

  At Month 7 (30 days after the last vaccination dose at Month 6)

• Pseudovirion-Based Neutralization Assay (PBNA) Titers of Anti-HPV-16/18 Antibodies in HIV+ Subjects, Based on Adapted According-to-protocol (ATP) Cohort for Immunogenicity

  Titers of anti-HPV-16/18 antibodies, expressed as Geometric Mean Titers (GMTs), with cut-offs greater than or equal to (≥) 40 estimated dose giving 50% signal reduction when compared to a control without serum (ED50), as assessed by the Pseudovirion-Based Neutralization Assay \[PBNA\], in HIV+ subjects. Between-group comparisons to assess non-inferiority were performed on the ATP cohort for immunogenicity (by PBNA, regardless of HPV serostatus at baseline).

  At Month 7 (30 days after the last vaccination dose at Month 6)

• Pseudovirion-Based Neutralization Assay (PBNA) Titers of Anti-HPV-16/18 Antibodies in HIV+ Subjects, Based on Total Vaccinated Cohort (TVC)

  Titers of anti-HPV-16/18 antibodies, expressed as Geometric Mean Titers (GMTs), with cut-offs greater than or equal to (≥) 40 estimated dose giving 50% signal reduction when compared to a control without serum (ED50), as assessed by the Pseudovirion-Based Neutralization Assay \[PBNA\], in HIV+ subjects. Between-group comparisons to assess superiority were performed on the TVC (by PBNA, regardless of HPV serostatus at baseline).

  At Month 7 (30 days after the last vaccination dose at Month 6)

Secondary Outcomes (21)

• Number of HIV- Subjects With Any and Grade 3 Solicited Local Symptoms

  During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses

• Number of HIV- Subjects With Any, Grade 3 and Related Solicited General Symptoms

  During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses

• Number of HIV- Subjects With Unsolicited Adverse Events (AEs)

  During the 30-day follow-up period (from the day of vaccination up to 29 subsequent days) after any vaccination

• Number of HIV- Subjects With Serious Adverse Events (SAEs)

  From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)

• Number of HIV- Subjects With Medically Significant Conditions (MSCs)

  From Day 0 up to Month 7 (from Day 0 up to 30 days after the last vaccination dose at Month 6)

Study Arms (4)

HIV+/Cervarix Group

EXPERIMENTAL

HIV seropositive female subjects, between and including 15 and 25 years of age, who received 3 doses of Cervarix vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6.

Biological: GSK Biologicals' HPV vaccine 580299

HIV+/Gardasil Group

ACTIVE COMPARATOR

HIV seropositive female subjects, between and including 15 and 25 years of age, who received 3 doses of Gardasil vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6.

Biological: Merck's Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine (Gardasil)

HIV-/Cervarix Group

EXPERIMENTAL

HIV seronegative female subjects, between and including 15 and 25 years of age, who received 3 doses of Cervarix vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6.

Biological: GSK Biologicals' HPV vaccine 580299

HIV-/Gardasil Group

ACTIVE COMPARATOR

HIV seronegative female subjects, between and including 15 and 25 years of age, who received 3 doses of Gardasil vaccine, administered intramuscularly in the deltoid muscle of the non-dominant arm, according to a three-dose schedule: at Day 0, Week 6, Month 6.

Biological: Merck's Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine (Gardasil)

Interventions

GSK Biologicals' HPV vaccine 580299 BIOLOGICAL

Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.

Also known as: Cervarix

HIV+/Cervarix Group; HIV-/Cervarix Group

Merck's Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine (Gardasil) BIOLOGICAL

Subjects received three doses of the study vaccine administered intramuscularly according to a Day 0, Week 6, and Month 6 vaccination schedule.

Also known as: Gardasil

HIV+/Gardasil Group; HIV-/Gardasil Group

Eligibility Criteria

• Age: 15 Years - 25 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subjects who the investigator believes that they and/or their parent(s)/legally acceptable representative(s) (LAR) can and will comply with the requirements of the protocol.
• A female between, and including, 15 and 25 years of age at the time of the first vaccination.
• Written informed consent obtained from the subject and/or from the subject's parent or LAR.
• Subjects willing to undergo HIV Voluntary Counseling and Testing (VCT) and willing to be informed of their HIV infection status.
• For HIV seropositive subjects:
• Subjects must be HIV seropositive according to World Health Organization (WHO) case definition.
• Subject must be asymptomatic (or only have persistent generalized lymphadenopathy).
• Subjects should have a CD4 cell count \> 350 cells/mm3.
• If currently taking antiretrovirals (ARVs), subjects must be on compliant to triple therapy (highly active ART) and have undetectable viral load on two previous clinical visits within the six months prior to study entry.
• For HIV seronegative subjects:
• Subjects confirmed as HIV seronegative at the screening visit.
• For non-virgin female subjects:
• Subjects must have no history of abnormal cytology or CIN 1/2/3.
• Subjects must have had no more than six life-time sexual partners prior to enrollment.
• Subjects must have no history of congenital malformations of the uterine cervix, or history of cauterization or surgical procedures involving damage to the transformation zone of the cervix or stenosis.

You may not qualify if:

• Previous vaccination against HPV, or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (Day 0 to Month 24).
• ART not compliant with the National Guidelines.
• Active tuberculosis (TB) visit (criteria mandatory only for HIV+ subjects).
• Current TB therapy.
• Hemoglobin \< 8.0 g/dL at the screening visit.
• Creatinine \> 1.5-fold the upper limit of normal (ULN) at the screening visit.
• Alanine aminotransferase (ALT) \> 2.5-fold ULN at the screening visit.
• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period (Day 0 to Month 24).
• Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or other immune-modifying drugs (with the exception of ART) within six months prior to the first vaccine dose.
• Administration of a vaccine not foreseen by the study protocol within 30 days (Days 0 - 29) before the first dose of study vaccine/control. Enrollment will be postponed until the subject is outside the specified window.
• Planned administration of a vaccine not foreseen by the study protocol within 30 days before or 30 days after (i.e., Days 0 - 29) any dose of study vaccine.
• Previous administration of components of the investigational vaccine.
• Cancer or autoimmune disease under treatment.
• Hypersensitivity to latex.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine/control.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (15)

GSK Investigational Site

Porto Alegre, Rio Grande do Sul, 90035003, Brazil

Location

GSK Investigational Site

Ribeirão Preto, São Paulo, 14049-900, Brazil

Location

GSK Investigational Site

Campinas, 13083-970, Brazil

Location

GSK Investigational Site

Rio de Janeiro, 21040-360, Brazil

Location

GSK Investigational Site

São Paulo, 03015000, Brazil

Location

GSK Investigational Site

Kohtla-Järve, 30322, Estonia

Location

GSK Investigational Site

Tallinn, 10617, Estonia

Location

GSK Investigational Site

Chennai, 600113, India

Location

GSK Investigational Site

Kolkata, 700026, India

Location

GSK Investigational Site

Mumbai, 400014, India

Location

GSK Investigational Site

Pune, 411001, India

Location

GSK Investigational Site

Bangkok, 10330, Thailand

Location

GSK Investigational Site

Bangkok, 10400, Thailand

Location

GSK Investigational Site

Chiang Mai, 50200, Thailand

Location

GSK Investigational Site

Khon Kaen, 40002, Thailand

Location

Related Publications (1)

• Folschweiller N, Teixeira J, Joshi S, Goldani LZ, Supparatpinyo K, Basu P, Chotpitayasunondh T, Chetchotisakd P, Ruxrungtham K, Roteli-Martins C, Grinsztejn B, Quintana SM, Kumarasamy N, Poongulali S, Kulkarni V, Lin L, Datta SK, Descamps D, Dodet M, Dubin G, Friel D, Hezareh M, Karkada N, Meric Camilleri D, Poncelet S, Salaun B, Tavares-da-Silva F, Thomas-Jooris F, Struyf F. Immunogenicity and safety of the AS04-HPV-16/18 and HPV-6/11/16/18 human papillomavirus vaccines in asymptomatic young women living with HIV aged 15-25 years: A phase IV randomized comparative study. EClinicalMedicine. 2020 May 25;23:100353. doi: 10.1016/j.eclinm.2020.100353. eCollection 2020 Jun.

  PMID: 32639485 BACKGROUND

MeSH Terms

Conditions

Papillomavirus Infections; Uterine Cervical Neoplasms

Interventions

human papillomavirus vaccine, L1 type 16, 18; Vaccines; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18

Condition Hierarchy (Ancestors)

Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Communicable Diseases; Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections; Genital Diseases; Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications

Intervention Hierarchy (Ancestors)

Biological Products; Complex Mixtures; Vaccines, Combined; Papillomavirus Vaccines; Viral Vaccines

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2009
• First Posted: December 14, 2009
• Study Start: October 26, 2010
• Primary Completion: January 13, 2016
• Study Completion: April 19, 2017
• Last Updated: July 21, 2020
• Results First Posted: July 24, 2019

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

ES (2); IN (4); TH (4); BR (5)