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    Summary
    EudraCT Number:2011-002193-23
    Sponsor's Protocol Code Number:HLS04/2011
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-01-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2011-002193-23
    A.3Full title of the trial
    Long term Immunogenicity of Quadrivalent Human Papillomavirus vaccine (Gardasil) in HIV-infected adolescents and young adults vs. healthy adolescents and young adults: non-randomized controlled clinical study.
    Valutazione a lungo termine dell'immunogenicita' del vaccino quadrivalente anti-HPV (Gardasil) in adolescenti e giovani adulti con infezione da HIV vs. adolescenti e giovani adulti sani: studio clinico controllato non randomizzato.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of Gardasil immunogenicity in HIV+ vs HIV- teenagers.
    Valutazione della immunogenicita' di Gardasil in adolescenti HIV+ vs HIV-
    A.4.1Sponsor's protocol code numberHLS04/2011
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAZIENDA OSPEDALIERA L. SACCO (A.O. DI RILIEVO NAZIONALE)
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRegione Lombardia
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOspedale Luigi Sacco
    B.5.2Functional name of contact pointDivisione Clinicizzata di Pediatria
    B.5.3 Address:
    B.5.3.1Street Addressvia GB Grassi, 74
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code230157
    B.5.3.4CountryItaly
    B.5.4Telephone number02-39042253
    B.5.5Fax number02-39042254
    B.5.6E-mailgianvincenzo.zuccotti@unimi.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GARDASIL*SIR IM 0,5ML C/DISP+
    D.2.1.1.2Name of the Marketing Authorisation holderSANOFI PASTEUR MSD SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHPV 6 TYPE L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHPV TYPE 16 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHPV TYPE 18 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHPV TYPE 11 L1 PROTEIN ADS. ON AMORPHOUS ALUMINIUM HYDROXYPHOSPHATE SULPHATE [PROD. IN S. CEREVISIAE CANADE3C-5 (STRAIN 1895) BY RECOM. DNA TECHNOL.]
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    HIV+ teenagers and young adults versus HIV-negative subjects: high-risk population for HPV-related disease.
    Adolescenti e giovani adulti HIV infetti versus HIV-negativi: popolazione ad elevato rischio di patologie HPV correlate.
    E.1.1.1Medical condition in easily understood language
    HIV+ teenagers and young adults versus HIV-negative subjects
    Adolescenti e giovani adulti HIV infetti versus HIV-negativi
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10063001
    E.1.2Term Human papilloma virus infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To assess the immunogenicity of quadrivalent human papillomavirus vaccine (Gardasil) in male and female HIV-infected adolescents and young adults, by evaluation of type-specific antibody development for HPV types 6, 11, 16 and 18 from seronegative status at baseline (T0) to seropositive status at a month after the completion of HPV vaccine series (T3), compared with the same immunogenicity testings performed in healthy subjects of the same age.
    Valutare l’immunogenicità di un vaccino quadrivalente anti-HPV (Gardasil) in adolescenti e giovani adulti HIV-infetti di entrambi i sessi mediante il dosaggio di anticorpi specifici anti-HPV 6, 11, 16, 18 al baseline (T0) e ad un mese dopo la fine del ciclo vaccinale (T3) a confronto con i risultati ottenuti in una popolazione sana valutata ai medesimi tempi
    E.2.2Secondary objectives of the trial
    Evaluate HPV antibody titers to types 6, 11, 16, 18, one month after each vaccination dose (T1, T2, T3) in HIV-infected adolescents and young adults compared with the same immunological testings in healthy adolscents and young adults.
    To assess long-term immunogenicity of quadrivalent human papillomavirus vaccine (Gardasil) in HIV-infected and healthy subjects by evaluation of persistence of HPV antibody titers to types 6, 11, 16 and 18 at month 12 (T4) and 18 (T5) from baseline (T0).
    To assess the safety and tolerability of three doses of quadrivalent human papillomavirus vaccine (Gardasil) in HIV-infected and healthy subjects by evaluating the occurrence and severity of local and systemic adverse events during the 7 days after each vaccination dose.
    Longitudinal monitoring of HIV-viral load and CD4 count in HIV-infected subjects from baseline (T0), throughout the study.
    Ottenere dati di cinetica anticorpale mediante il dosaggio degli anticorpi specifici anti HPV 6, 11, 16, 18 un mese dopo ciascuna dose di vaccino (T1, T2, T3) nei soggetti HIV-infetti e sani.
    Valutare la persistenza anticorpale nei soggetti HIV- infetti e sani dopo 12 (T4) e 18 mesi (T5) dall’inizio del ciclo vaccinale (T0).
    Valutare il profilo di sicurezza del vaccino quadrivalente anti-HPV (Gardasil) in adolescenti e giovani adulti HIV- infetti e sani di entrambi i sessi.
    Monitorare il profilo viro-immunologico dei soggetti HIV-infetti di entrambi i sessi durante lo studio mediante dosaggio dei linfociti T CD4+ e dell’HIV-RNA al baseline, un mese dopo ciascuna dose di vaccino (T1, T2, T3), a 12 e 18 mesi dal baseline (T4, T5).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For both HIV-infected and healthy subjects:
    • Subjects aged 13-27 years
    • Females or males
    • Written informed consent from parent or guardian if applicable (age <18 years)

    For HIV-infected subjects:
    • HIV-positive
    • Asymptomatic subjects (possible with only generalized lymphadenopathy).
    • Lymphocyte CD4+ count > 350 cell/mm3
    • For subjects receiving HAART:
    - Goog compliance to therapy
    - At least two suppressed viral loads HIV-RNA (<37cp/ml) during 6 months prior to enrollment in study.
    Per entrambe le popolazioni in studio (HIV- infetti e soggetti sani):
    • Soggetti di età compresa tra 13 e 27 anni.
    • Sesso femminile o maschile.
    • Consenso informato firmato dal soggetto maggiorenne o dal genitore o legale rappresentante per i soggetti minorenni.

    Per i soggetti HIV- infetti:
    • Diagnosi certa di infezione da HIV.
    • Soggetti asintomatici al momento dell’arruolamento (o anche solo con linfadenopatia persistente generalizzata).
    • Conta dei linfociti T CD4+ &gt; 350 cell/mm3.
    • Per i soggetti che assumono terapia antiretrovirale:
    - buona compliance alla terapia.
    - almeno due cariche virali negative (&lt;37cp/ml) in due determinazioni distinte nei 6 mesi. antecedenti all’arruolamento nello studio.
    -
    Per i soggetti di sesso femminile sessualmente attive sia HIV- infette che sane:
    • Anamnesi negativa per esame CIN 2/3 con genotipo HPV positivo per 16, 18.
    • Anamnesi negativa per malformazioni e/o interventi chirurgici alla cervice uterina.
    • In soggetti fertili:
    - Test di gravidanza negativo al momento dell’arruolamento.
    E.4Principal exclusion criteria
    For female subjects (both HIV-infected and healthy) :
    • Current (within 6 months prior to study entry) abnormal Pap test with confirmed biopsy results of cervical intraepithelial neoplasia CIN 2/3 caused by genotype HPV 16, 18 or cervical cancer within 180 days prior to study entry.
    • Pregnancy or breastfeeding
    • Total hysterectomy. Participants who have undergone partial hysterectomy and have a cervix are not excluded

    For both females and males (HIV-infected and healthy):
    • Prior vaccination with quadrivalent HPV vaccine (Gardasil) before study entry.
    • History of severe allergic reaction after previous vaccination or hypersensytivity to any vaccine component
    • Any serious chronic or progressive disease (other than HIV) according to the judgment of the investigator:
    - Acute infection requiring therapy or fever at time of enrollment
    - Chronic autoimmune or oncologic disease receiving chemotherapy
    - Tuberculosis
    - Neurologic disease or history of convulsions
    • Concomitant therapies (other than HAART):
    - Chronic therapy ( for more than 14 days consecutively) with immunosoppressive or immunomodulating agents or chemotherapy during the 6 months prior to study entry.
    - Ongoing anti-tubercular therapy
    - Receipt of blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation prior to study entry
    • Severe anemia: hemoglobin less than 8.0 g/dL.
    • Acute or chronic impairment of pulmonary, cardiac, hepatic o renal function.
    • Use of investigational agents within 4 weeks prior to study enrollment.
    • Current drug or alcohol use or dependence
    • Documented history of non-adherence to antiretroviral treatment regimen within 12 months prior to study entry.
    • Precedente immunizzazione con vaccino anti-HPV o prevista vaccinazione anti- HPV diversa da Gardasil durante lo studio in oggetto.
    • Precedente somministrazione di componenti del vaccino in studio.
    • Altre patologie concomitanti:
    - Malattia acuta e/o iperpiressia al momento dell’arruolamento.
    - Malattie croniche autoimmunitarie o oncologiche in terapia.
    - Tubercolosi in fase attiva.
    - Malattie neurologiche o anamnesi positiva per convulsioni.
    • Altre terapie concomitanti:
    - Terapia cronica (definita come terapia per &gt; 14 giorni consecutivi) con immunosoppressori e/o altri farmaci immunomodulanti nei 6 mesi antecedenti la prima dose del vaccino anti- HPV Gardasil.
    - Terapia antitubercolare in corso.
    - Esecuzione di trasfusioni di sangue e/o derivati del sangue e/o immunoglobuline nei 3 mesi antecedenti la vaccinazione o previsione di eseguirle durante il periodo dello studio.
    - Assunzione di trimethoprim/sulpamethoxazole nei 7 giorni antecedenti la prima dose del vaccino anti-HPV o prevista somministrazione durante il periodo di studio.
    • Scarsa compliance alla terapia antiretrovirale per il paziente HIV- infetti in terapia.
    • Somministrazione di un farmaco o vaccino sperimentale o non-registrato nei 30 giorni antecedenti la prima dose di vaccino anti- HPV (Gardasil) o previsto durante lo studio.
    • Ipersensibilità al lattice.
    • Anamnesi positiva per reazioni allergiche ad una precedente vaccinazione o storia di ipersensibilità ad un componente di un vaccino.
    • Soggetti di sesso femminile che durante il periodo dello studio cercheranno una gravidanza o abbiano intenzione di interrompere le precauzioni contraccettive.
    • Gravidanza e /o allattamento.
    • Abuso di alcolici o droghe.
    E.5 End points
    E.5.1Primary end point(s)
    Type-specific antibody development for HPV types 6, 11, 16 and 18 from seronegative status at baseline to seropositive status at a month after the completion of HPV vaccine series.
    Sieroconversione per i differenti sierotipi di HPV (6, 11, 16 e 18 ) ad un mese dopo la fine del ciclo vaccinale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    One month after the completion of HPV vaccine series.
    Un mese dalla fine del ciclo vaccinale.
    E.5.2Secondary end point(s)
    Antibody kinetics and persistance.
    Cinetica e persistenza anticorpale.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 1 month after each dose and 12 and 18 months from the first dose.
    Ad un mese da ogni dose vaccinale e a 12 e 18 mesi dalla prima dose.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    HIV+ vs HIV-
    HIV+ vs HIV-
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LPLV.
    LPLV.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 50
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 50
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-01-05. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    According to the standard follow-up
    Secondo il normale follow-up clinico.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-09-14
    P. End of Trial
    P.End of Trial StatusOngoing
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