E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HIV infection |
Infezione da HIV |
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E.1.1.1 | Medical condition in easily understood language |
HIV Infection |
Infezione da HIV |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020441 |
E.1.2 | Term | Human immunodeficiency virus infection, unspecified |
E.1.2 | System Organ Class | 100000004862 |
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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 |
To evaluate the efficacy and feasibility of a rapid ART starting strategy (within 7 days from HIV diagnosis) based on B/F/TAF as initial regimen in HIV-infected naïve individuals presentating with an advanced HIV disease |
Valutare l’efficacia e la fattibilità di una ART ad inizio rapido (entro 7 giorni dalla diagnosi di infezione da HIV) basata su B/F/TAF come regime iniziale in una popolazione di individui naïve che si presentano alla diagnosi con infezione da HIV in stato avanzato. |
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E.2.2 | Secondary objectives of the trial |
• pure virologic response • virologic response determined by ultrasensitive HIV-1 RNA method • evolution of HIV-DNA in PBMC • emergent drug resistance-associated mutations in participants with protocol-defined virological failure • determination of viral co-recettorial tropism at screening • change in immunological competence from baseline • change in immune activation and inflammation from baseline • change in renal function from baseline • change in neurocognitive performance and neuropsychiatric status from baseline, excluding patients with neurological involvement from HIV infection or CNS opportunistic infections • safety and drug-drug interactions • changes of Self- reported adherence and level of therapy satisfaction • changes in PROs at BL, week 24 and week 48 (quaily of life assessment), Columbia-suicide severity rating scale, Pittsburgh sleep quality index • TDM of Bictegravir |
• risposta virologica • risposta virologica determinata mediante la metodica dell’HIV-RNA ultrasensibile • evoluzione dell’HIV-DNA in PBMC • emergenza di mutazioni nei pazienti che presentano fallimento virologico secondo protocollo • determinazione del tropismo co-recettoriale allo screening • cambiamento della competenza immunologica rispetto al BL • cambiamento nei marcatori di immunoattivazione e infiammazione rispetto al BL • cambiamento della funzione renale rispetto al BL • Cambiamento delle funzioni neurocognitive e delle condizioni neuropsichiatriche rispetto al BL, con l’esclusione dei pazienti con infezioni opportunistiche che coinvolgono il SNC o con CNS • Sicurezza del farmaco ed interazioni farmacologiche • Cambiamento nei parametri di aderenza auto-riportata e di soddisfazione della terapia • Cambiamento nei PROs al BL, settimana 24 e settimana 48: Columbia-suicide severity rating scale , Pittsburgh sleep quality index e qualità della vita • TDM del Bictegravir |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age > 18 years; 2. Newly diagnosed with HIV-1 infection within 7 days before the enrolment with either: a) Confirmed or suspected AIDS defining event at screening (see appendix xx for AIDS defining conditions) or; b) Patients with CD4 cell count < 200 µl at the determination closest to the study entry. 3. Naïve to antiretroviral therapy 4. Women of childbearing age must accept the use of one of the following contraceptive methods, starting from screening to the end of the study: - Combined hormonal contraceptives associated with ovulation inhibitors (oral, intravaginal, transdermal); - Progestin hormonal contraceptives associated with an ovulation inhibitor (oral, injectable, implantable); - Intrauterine devices; - Intrauterine devices with hormonal release system; - Bilateral tubal ligation; - Vasectomy of the partner; - Sexual abstinence (for heterosexual intercourse); • Men must accept a highly effective contraceptive method specified during heterosexual intercourse or practice sexual abstinence from the first dose throughout the study period. 5. Be able to understand and sign a written informed consent; |
1. Età > 18 anni; 2. Soggetti con neo-diagnosi di HIV che presentino una delle due seguenti caratteristiche, entro 7 giorni dal BL dello studio: a) Sospetto o confermato evento AIDS definente alla visita di screening (vedi appendice K per le condizioni AIDS definenti) oppure; b) Soggetti con conta di cellule CD4 < 200 µl alla determinazione più vicina all’arruolamento nello studio. 3. Naïve alla terapia antiretrovirale 4. Donne fertili devono accettare l’uso ai uno dei seguenti metodi anticoncezionali a partire dallo screening per tutta la durata dello studio: - Combinazione di pillola anticoncezionale contenente estrogeni associata ad inibitori dell’ovulazione (via orale, via endovaginale, via transdermica); -Combinazione di pillola anticoncezionale contenente progestinici associata ad un inibitore dell’ovulazione (via orale, via endovaginale, via transdermica) - dispositivo intrauterino con meccanismo di barriera; - dispositivo intrauterino a rilascio ormonale; - legatura bilaterale delle tube; - vasectomia del partner; - astinenza sessuale (for rapporti eterosessuali); • Gli uomini devono accettare un metodo anticoncezionale ad alta efficacia (per I rapporti eterosessuali) o praticare l’astinenza sessuale durante il periodo dello studio 5. Essere in gradi di comprendere e firmare il consenso informato; |
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E.4 | Principal exclusion criteria |
• Pregnant/breastfeeding women, or women who are willing to become pregnant or to breastfeed during study; • Impaired renal function defined as CrCl below 30 mL/min according to the CKD-EPI formula; • Severe hepatic impairment defined as Child-Pugh Class C; • Pulmonary or extrapulmonary active tuberculosis or expected treatment requiring Rifampicin or Rifabutin • Meningeal or disseminated cryptococcosis; • Known hypersensitivity to the study drug, the metabolites or formulation excipients; • Patients not able to subscribe informed consent; • Using any concomitant therapy disallowed as per product labelling for the study drugs. • Systemic cancer chemotherapy within 30 days prior to the study entry with the exclusion of Kaposi’s sarcoma and lymphomas |
• Donne in gravidanza / allattamento, o donne che sono disposte a rimanere incinta o ad allattare durante lo studio; • Funzione renale compromessa definita come CrCl inferiore a 30 ml / min secondo la formula CKD-EPI; • Grave compromissione epatica definita come classe C di Child-Pugh; • Tubercolosi attiva polmonare o extrapolmonare o trattamento atteso che richiede rifampicina o rifabutina • criptococcosi meningea o disseminata; • Ipersensibilità nota al farmaco in studio, ai metaboliti o agli eccipienti di formulazione; • Pazienti non in grado di sottoscrivere il consenso informato; • L'uso di qualsiasi terapia concomitante non è consentito secondo l'etichettatura del prodotto per i farmaci in studio. • Chemioterapia per il cancro sistemico entro 30 giorni prima dell'ingresso nello studio con l'esclusione del sarcoma e dei linfomi di Kaposi. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time-to-clinical or virologic failure, as the first occurrence of any of the following components: Virological reasons A) failure to achieve virologic response defined as either: 1. HIV-1 RNA reduction < 1 log10 copies/ml by W12 (confirmed within 2 weeks) 2. HIV-1 RNA >= 200 copies/mL at or after 24 weeks (confirmed within 2 weeks) 3. HIV-1 RNA >= 50 copies /ml at W48 (confirmed within 2 weeks) B) viral rebound, which is subsequently defined as either: 1. rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 copies/mL (confirmed within 2 weeks) 2. rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose viral load has never been suppressed below 50 copies/mL (confirmed within 2 weeks) Clinical reasons A) Change of any component of the initial randomized regimen before week 48 because of toxicity or unmanageable drug-drug interactions or IRIS B) Death due to any cause C) Any new or recurrent AIDS defining event (CDC definition) D) Any new serious non-AIDS defining event |
Tempo al fallimento clinico o virologico, definito come il primo tra i seguenti eventi: Motivi Virologici A) mancato raggiungimento della risposta virologica definita come segue: 1. riduzione dell’HIV-1 RNA < 1 log10 copie/ml entro la settimana 12 (confermato entro due settimane) 2. HIV-1 RNA >=200 copie/mL alla settimana 24 o successivamente (confermato entro due settimane) 3. HIV-1 RNA >= 50 copie /ml alla settimana 48 (confermato entro due settimane) B) rebound virale, definito come segue: 1. incremento HIV-1 RNA >200 copie/mL dopo aver raggiunto HIV-1 RNA <50 copie/mL (confermato entro due settimane) oppure 2. rebound of HIV RNA di >1 log 10 copies/mL rispetto al nadir di viremia, per un paziente la cui viremia non è mai stata inferiore alle 50 copie/mL (confermato entro due settimane) Motivi Clinici A) Modifica di almeno un componente della terapia somministrata prima della settimana 48 per la comparsa di tossicità o di interazioni farmacologiche di incompatibilità o IRIS B) Morte per qualsiasi motivo C) Nuova comparsa o ricorrenza di un evento AIDS D) Comparsa di un nuovo evento serio non-AIDS definente |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. by W12 (confirmed within 2 weeks) 2. a or after 24 weeks (confirmed within 2 weeks) 3. at W48 (confirmed within 2 weeks) B) 1. at any time (confirmed within 2 weeks) 2. at any time Clinical reasons A) before week 48 B) at any time C) at any time D) at any time |
A) 1. entro W12 (confermata entro 2 settimane) 2. a o dopo 24 settimane (confermato entro 2 settimane) 3. alla W48 (confermato entro 2 settimane) B) 1. in qualsiasi momento (confermato entro 2 settimane) 2. in qualsiasi momento Ragioni cliniche A) prima della settimana 48 B) in qualsiasi momento C) in qualsiasi momento D) in qualsiasi momento |
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E.5.2 | Secondary end point(s) |
• Time-to-pure virologic failure, as the first occurrence of any of the following components: 1. failure to achieve virologic response defined as either: - HIV-1 RNA reduction < 1 log10 copies/ml by W12 (confirmed within 2 weeks) - HIV-1 RNA > =200 copies/mL at or after 24 weeks (confirmed within 2 weeks) - HIV-1 RNA > = 50 copies /ml at any time after W48 (confirmed within 2 weeks) • Percentage of subjects with HIV-1 RNA 5 copies/mL at week 48 by ultrasensitive assay • Change in total viral HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) at baseline and at w48 • Assessment of viral co-receptor tropism at screening. If not performed at screening, will be performed at baseline. • Proportion of participants developing resistance-conferring mutations (integrase and reverse transcriptase) by genotypic resistance test (GRT) by standard SS technique at screening and ai PDVF. • Proportion of viral minority variants (>1% prevalence) harboring resistance associated mutations in reverse transcriptase and integrase by NGS will be at the time of PDVF . • Change from baseline in CD4+ T-cells count (absolute and %) and CD4/CD8 ratio in the peripheral blood at any visit • Percentage of activated T-cell lymphocyte subset (%CD38+DR+) and monocyte subset (%CD14+CD16+ and %CD14(dim)CD16+), at baseline, week 24 and 48 • Absolute and percentage values of inflammation and pro-coagulation markers (soluble CD14, soluble CD163, IL-6, D-Dimer, high-sensitivity C-Reactive Protein) at baseline and at week 24 and 48 • Change in urinary tubular damage markers (alpha-1-microglobulin, beta-2-microglobulin) and albumin-creatinine ratio (ACR), at baseline, 24 and 48 weeks. • Change in neurocognitive performance • Proportion of patients discontinuing • WHO grade 3-4 toxicity at any time • Changes of Self- reported adherence and level of therapy satisfaction (HIVTSQ) at week 12, week 24 and week 48 • Changes in PROs at BL, week 24 and week 48 (quaily of life assessment (SF-12; EQ5D) [Appendix F1, F2], Columbia-suicide severity rating scale (C-SSRS) [Appendix G1-G2], Pittsburgh sleep quality index (PSQI) [Appendix J]. , Self-reported symptoms (MSAS-SF) [Appendix O]. • TDM of Bictegravir at week 4, 24, 48. |
• Insufficienza virologica time-to-pure, come prima occorrenza di uno dei seguenti componenti: 1. mancato raggiungimento della risposta virologica definita come: - Riduzione dell'RNA dell'HIV-1 <1 log10 copie / ml dopo W12 (confermata entro 2 settimane) - HIV-1 RNA > =200 copie / ml a o dopo 24 settimane (confermato entro 2 settimane) - HIV-1 RNA > = 50 copie / ml in qualsiasi momento dopo W48 (confermato entro 2 settimane • Percentuale di soggetti con HIV-1 RNA 5 copie / mL alla settimana 48 mediante saggio ultrasensibile • Variazione del HIV-1 DNA virale totale nelle cellule mononucleate del sangue periferico (PBMC) al basale e al w48 • Valutazione del tropismo virale del co-recettore allo screening. Se non eseguito allo screening, verrà eseguito al basale. • Proporzione di partecipanti che sviluppano mutazioni che conferiscono resistenza (integrasi e trascrittasi inversa) mediante test di resistenza genotipica (GRT) mediante tecnica SS standard al PDVF. • La proporzione di varianti di minoranza virale (> 1% di prevalenza) che ospita mutazioni associate alla resistenza nella trascrittasi inversa e nell'integrasi da parte di NGS sarà al momento della PDVF. • Variazione rispetto al basale della conta delle cellule T CD4 + (assolute e%) e del rapporto CD4 / CD8 nel sangue periferico ad ogni visita • Percentuale di sottoinsieme di linfociti a cellule T attivati ¿¿(% CD38 + DR +) e sottoinsieme di monociti (% CD14 + CD16 + e% CD14 (dim) CD16 +), al basale, settimana 24 e 48 • Valori assoluti e percentuali dei marker di infiammazione e pro-coagulazione (CD14 solubile, CD163 solubile, IL-6, D-Dimer, proteina C reattiva ad alta sensibilità) al basale e alla settimana 24 e 48 • Modifica dei marker di danno tubulare urinario (alfa-1-microglobulina, beta-2-microglobulina) e rapporto albumina-creatinina (ACR), al basale, 24 e 48 settimane. • Variazione delle prestazioni neurocognitive |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• To See E.2. • % of subjects with HIV-1 RNA 5 copies / mL -> at week 48 • HIV-1 total DNA in mononuclear cells -> at baseline and at w48 • viral co-receptor tropism -> screening • develop. mutations etc. -> at any time of the study • viral minority variants etc. -> screening and PDVF • T cells and CD4 / CD8 ratio -> at each visit • activated T-cell and subset of monocytes -> at baseline, weeks 24 and 48 • infiamm. and pro-coagulation -> at baseline and at week 24 and 48 • tubular damage nd rapp. alb-creat -> at baseline, 24 and 48 weeks. • neurocognitive perf. -> from baseline to week 48 • patients discontinuing ->at any time • 3-4 toxicity ->at any time • Self- rep. adherence ecc. ->at week 12, week 24 and week 48 • PROs ecc. -> at BL, week 24 and week 48 • TDM -> week 4, 24, 48.; • V |
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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 | No |
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 | No |
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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Pilota, proof of concept, in aperto , braccio singolo |
Pilot, proof of concept, open-label,single-arm |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | Information not present in EudraCT |
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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The trial will be declared concluded with the closure visit of the clinical center by the CTQT. |
La sperimentazione sarà dichiarata conclusa con la visita di chiusura del centro clinico da parte del CTQT. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 18 |
E.8.9.2 | In all countries concerned by the trial days | 0 |