E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071147 |
E.1.2 | Term | Human papilloma virus immunization |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective is to analyze and compare the immune response to bivalent human papilloma virus (HPV) and quadrivalent HPV vaccine among kidney transplant candidates and recipients.
Specific main objective:
To compare immunogenicity and safety of bivalent and quadrivalent HPV vaccine.
The main hypothesis is that bivalent (AS04 adjuvated) HPV vaccine induces superior immune responses compared with quadrivalent HPV vaccine without affecting graft function in kidney transplant recipients.
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At analysere og sammenligne effekten af de to HPV vacciner Gardasil® og Cervarix® blandt nyretransplanterede og personer med kronisk nedsat nyrefunktion.
Undersøgelsen kan opdeles i 1 hovedstudie og 3 delstudier.
Formål hovedstudie: Analysere og sammenligne immunogenicitet og sikkerhed af bivalent og tetravalent HPV vaccination blandt nyretransplanterede og potentielle transplantationskandidater.
Hovedhypotese:At den ASO4 adjuverede vaccine Cervarix® vil udvise stærkere immunogenicitet i forsøgspopulationen. |
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E.2.2 | Secondary objectives of the trial |
Secundary objectives
1.To compare immunogenicity of HPV vaccination among kidney transplant candidates and recipients.
2.To investigate the impact of in vivo toll-like receptor (TLR) 4 priming (by the AS04 adjuvant in bivalent HPV vaccine) on innate and adaptive immune signaling and activation,and to identify immunological predictors of vaccine response
3.To determine the induction of cellular immunity against HPV16 and 18 L1 antigen following HPV immunization |
Delstudie: 1 At sammenligne immunresponset ved HPV vaccination før og efter nyretransplantation, samt at identificere prædiktorer for vaccineresponset (køn, alder, rygning, D-vitamin status, aktiv HPV infektion etc.).
Delstudie 2: At undersøge betydningen af TLR4 stimulation for innat og adaptiv signalering og aktivering ved vaccination af personer med svær nyresygdom
Delstudie 3: At undersøge effekten af HPV vaccination på cellulær immunitet imod HPV 16 og 18 L1 antigen blandt personer med svær nyresygdom.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria
Transplant candidates:
• Signed Written Informed Consent.
• Men and women aged 18-70 at inclusion
• Chronic renal failure with estimated GRF (e-GFR<30 ml/min)
• No treatment with immunosuppressive agents within 3 months prior to inclusion.
• Assessed as “transplant candidate” by MD specialised in Nephrology.
Renal kidney transplant recipients:
• Signed Written Informed Consent.
• Men and women aged 18-70 at inclusion
• Transplantation minimum 1 year prior to inclusion
• First time of transplantation.
• Kidney function stable and no episodes of rejection 9 months prior to inclusion
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E.4 | Principal exclusion criteria |
• Pregnancy (positive pregnancy test)
• Nursing women
• Women of childbearing potential, unwilling to use effective contraception throughout the study
• History of hypersensitivity to vaccines
• Known allergy to one or more of the vaccine components
• Any medical, psychiatric and/or social reason including alcohol/drug abuse which in the opinion of the investigator, renders the candidate inappropriate for participation in the study
• Previously received a human papilloma virus vaccine.
• Active cancer disease
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E.5 End points |
E.5.1 | Primary end point(s) |
Geometric mean titres (GMT) of neutralizing HPV-16 and -18 serum antibodies measured by pseudovirion based neutralization assay at day 210 after first vaccination with either bivalent HPV vaccine (Cervarix®, GSK) or quadrivalent HPV vaccine (Gardasil®, Merck) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
-Geometric mean titres (GMT) of neutralizing HPV-16 and -18 serum antibodies measured by pseudovirion based neutralization assay
Geometric mean titres (GMT) of neutralizing HPV-31, 45, 52, and 58 serum antibodies measured by pseudovirion based neutralization assay
-Geometric mean titres (GMT) of antibodies against 40 HPV types (Luminex)
-Presence of anal/cervical/penile HPV DNA at inclusion
-Presence of cervical dysplasia at inclusion
-HLA antibodies (transplant recipients)
-Cytokine concentrations related to TH1/TH2/TH17 cellular responses (e.g., IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, IL-17A, IP-10, TNF-α, INF-α, INF- γ) in stimulated PBMCs (stimulated with TLR-4 agonist or bacterial pathogens and by HPV antigen)
B cell profile (CD3, CD19, CD20, CD27, CD38, IgM, IgD), T cell profile (CD3, CD4, CD27, CD38, CD45RA, CCR7), regulatory T cell profile (Live/Dead, CD3, CD4, CD25, CD127, FoxP3), and TH17 cell profile (Live/Dead, CD3, CD4, CD8, IL17A, IL21) by Flow Cytometry (FACSCantoII, BD Biosciences, San Jose, CA, USA).
-Impact of HPV immunization on cellular immunity against HPV:ts: Single, double, and triple cytokine-producing HPV16 and HPV18 L1 antigen-specific CD4 and CD8 T cells determined by intracellular cytokine staining (INF-γ, TNF-α, and IL2) and extracellular staining (CD3, CD4, and CD8) by flow cytometry. Counts and fractions of antigen-specific CD4 and CD8 T cells are compared with and without stratification for vaccine allocation. PBMC supernatant cytokine concentrations (e.g., IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, IP-10, TNF-α, INF-α, INF- γ) measured by as outlined above. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At day 0, 45,180 ,210 and 360 unless otherwise stated below
-Geometric mean titres (GMT) of antibodies against 40 HPV types (Luminex): Day 0,210 and 360
HPV DNA : Day 0
Cervical Dysplasia: Day 0
HLA antibodies: Day 0,210 and 360
B and T cell profiles: Day 0 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |