E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Human Immunodeficiency Virus (HIV-1) Infection |
Infezione da Virus dell'Immunodeficienza Umana (HIV-1) |
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E.1.1.1 | Medical condition in easily understood language |
Human Immunodeficiency Virus (HIV-1) Infection |
Infezione da Virus dell'Immunodeficienza Umana (HIV-1) |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068341 |
E.1.2 | Term | HIV-1 infection |
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 of E/C/F/TAF fixed dose combination (FDC) after switching from a stable regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent in maintaining HIV-1 RNA < 50 copies/mL at Week 12 (using pure virologic response) in subjects harboring the archived NRTI resistance mutation M184V and/or M184I in HIV-1 reverse transcriptase |
Valutare l¿efficacia di E/C/F/TAF in FDC (Fixed-Dose Combination) dopo il passaggio da un regime stabile composto da FTC/TDF o ABC/3TC con aggiunta di un terzo agente antiretrovirale nel mantenere l¿RNA di HIV-1 <50 copie/ml alla Settimana 12 (mediante risposta virologica pura) nei soggetti che ospitano la mutazione archiviata M184V e/o M184I di resistenza agli NRTI nella trascrittasi inversa di HIV-1.
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E.2.2 | Secondary objectives of the trial |
- To determine the safety and tolerability of E/C/F/TAF FDC in subjects switching from 2 NRTI plus third antiretroviral agent regimens - To evaluate the development of new resistance mutations in subjects who develop virologic failure after switching to E/C/F/TAF FDC - To determine the durability of efficacy at Weeks 24 and 48 in maintaining HIV-1 RNA < 50 copies/mL using pure virologic response (PVR) |
- Stabilire la sicurezza e la tollerabilit¿ di E/C/F/TAF FDC in soggetti che passano da regimi con 2 NRTI con aggiunta di un terzo agente retrovirale - Valutare lo sviluppo di nuove mutazioni di resistenza in soggetti che manifestano fallimento virologico dopo il passaggio a E/C/F/TAF FDC - Stabilire la durata di efficacia alle Settimane 24 e 48 nel mantenere l¿RNA di HIV-1 < 50 copie/ml mediante PVR (pure virologic response, risposta virologica pura)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures. 2) Age = 18 years 3) Documented historical genotype report showing M184V and/or M184I (mixtures are acceptable) in reverse transcriptase. Subjects must not have any primary INSTI or primary PI resistance mutations present on historical genotype; NNRTI mutations are allowed. Proviral DNA test must not have additional exclusion resistance mutations against PIs, NRTIs and INSTIs. - Part 1 (first 50 subjects): Historical genotype report must show M184V and/or M184I in reverse transcriptase WITHOUT any other NRTI resistance mutation (including thymidine analogue-associated mutations (TAMs) [M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion and Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M]. - Part 2 (after the interim efficacy review – 50 subjects): Historical genotype report must show M184V and/or M184I in reverse transcriptase WITH or WITHOUT one or two thymidine analogue-associated mutations (TAMs) [M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R]. Evidence of K65R, K70E, T69 insertion and/or Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M] will not be eligible. 4) Currently receiving an antiretroviral regimen consisting of FTC/TDF or ABC/3TC in combination with one third antiretroviral agent for = 6 consecutive months preceding the Screening Visit. 5) Documented plasma HIV-1 RNA levels < 50 copies/mL for = 6 months preceding the screening visit (measured at least twice using the same assay). 6) Plasma HIV-1 RNA levels < 50 copies/mL at Screening Visit 7) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant) 8) Estimated GFR = 30 mL/min according to the Cockcroft-Gault formula for creatinine clearance 9) Hepatic transaminases (AST and ALT) = 5 × upper limit of normal (ULN) 10) Total bilirubin = 1.5 mg/dL, and normal direct bilirubin (subjects with documented Gilbert’s syndrome or with atazanavir-associated hyperbilirubinemia may have total bilirubin up to 5 × ULN as long as direct biilubin is normal) 11) Adequate hematologic function (absolute neutrophil count = 1,000/mm3; platelets = 50,000/mm3; hemoglobin = 8.5 g/dL) 12) A female subject is eligible to enter the study if it is confirmed that she is: a) Not pregnant confirmed by a negative serum pregnancy test, which is required for female subjects (unless permanently sterile or greater than two years post-menopausal) b) Of non-childbearing potential (e.g., women who have had a hysterectomy, have had both ovaries removed or medically documented ovarian failure, or are postmenopausal women > 54 years of age with cessation (for =12 months) of previously occurring menses) c) Female subjects who have stopped menstruating for = 12 months but do not have documentation of ovarian hormonal failure must have a serum follicle stimulating hormone (FSH) level at screening within the post-menopausal range based on the Central Laboratory Reference range. d) Of childbearing potential and agrees to utilize the protocol specified method of contraception or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following discontinuation of study drugs e) Female subjects who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing. 13) Male subjects must agree to use the protocol specified method(s) of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from screening throughout the study period and for 30 days following the last study drug dose. a) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days after the last study drug dose. |
Fare riferimento alla sinossi e al protocollo. |
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E.4 | Principal exclusion criteria |
1) Subjects will have no evidence of previous virologic failure on a PI/r or INSTI-based regimen (with or without resistance to either class of ART). Subjects may have evidence of prior virologic failure on only an NNRTI plus 2 NRTI-based regimen. 2) Subjects on a current PI/r-based regimen will have no evidence of previous use of any approved or experimental integrase strand transfer inhibitor (INSTI) (for any length of time). 3) A new AIDS-defining condition diagnosed within the 30 days prior to screening (except CD4 cell count and/or percentage criteria) 4) Hepatitis C infection that would require therapy during the study 5) Hepatitis B surface antigen (HBsAg) positive 6) Subjects with clinical evidence of decompensated cirrhosis (e.g., ascites, encephalopathy, variceal bleeding, etc.) 7) Females who are breastfeeding 8) Positive serum pregnancy test 9) Have an implanted defibrillator or pacemaker 10) Current alcohol or substance use judged by the Investigator to potentially interfere with subject study compliance 11) A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 and must not be anticipated to require systemic therapy during the study 12) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 13) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements 14) Participation in any other clinical trial (including observational trials) without prior approval from the sponsor is prohibited while participating in this trial 15) Subjects receiving ongoing therapy with any of the medications in Table 4-2 and those listed in Section 5.4 of the protocol, including drugs not to be used with EVG, COBI, FTC or TAF; or subjects with any known allergies to the excipients of E/C/F/TAF FDC tablets. |
1) I soggetti non devono aver manifestato in precedenza alcun fallimento virologico con un regime a base di PI/r o INSTI (con o senza resistenza a una delle due classi di ART). I soggetti possono aver manifestato un’fallimento virologico precedente con un regime basato su 2 NRTI con aggiunta di un solo NNRTI. 2) I soggetti attualmente trattati con un regime a base di PI/r, non devono presentere alcuna evidenza di uso precedente di INSTI, approvati o sperimentali (per qualsiasi periodo di tempo). 3) Una nuova condizione definente l’AIDS diagnosticata nei 30 giorni precedenti lo screening (eccetto per i criteri della conta e/o della percentuale delle cellule CD4+) (fare riferimento all’Appendice 6 del protocollo completo) 4) Infezione da epatite C che potrebbe richiedere un trattamento durante lo studio 5) Positività all’antigene di superficie dell’epatite B (HBsAg) 6) Soggetti con evidenza clinica di cirrosi scompensata (ad es., ascite, encefalopatia, emorragia varicosa, ecc.) 7) Soggetti di sesso femminile che allattano al seno 8) Test di gravidanza su siero positivo 9) Portatori di pacemaker o defibrillatore 10) Attuale consumo di alcool o sostanze stupefacenti che a giudizio dello Sperimentatore possa interferire con la conformità del soggetto allo studio 11) Anamnesi di malignità negli ultimi 5 anni (prima dello screening) o malignità in corso diverse dal sarcoma cutaneo di Kaposi (KS), dal carcinoma basocellulare o dal carcinoma cutaneo a cellule squamose non invasivo, resecato. I soggetti con KS cutaneo sono idonei, ma non devono aver ricevuto alcuna terapia sistemica per il KS nei 30 giorni precedenti il Giorno 1 e non deve essere prevista la necessità di ricorrere a terapia sistemica durante lo studio 12) Infezioni gravi attive (diverse dall’HIV-1) che richiedono una terapia antibiotica o antimicotica parenterale nei 30 giorni precedenti al Giorno 1 13) Qualsiasi altra condizione clinica o precedente terapia che, a giudizio dello Sperimentatore, possa rendere il soggetto non idoneo allo studio o non in grado di soddisfare i requisiti di dosaggio 14) È vietata la partecipazione a qualsiasi altra sperimentazione clinica (incluse le sperimentazioni osservazionali) senza la previa approvazione dello sponsor durante la partecipazione alla presente sperimentazione 15) Soggetti che ricevono una terapia in corso con uno qualsiasi dei farmaci in Tabella 4-2 e quelli elencati nella Sezione 5.4 del protocollo completo, compresi i farmaci da non utilizzare con EVG, COBI, FTC o TAF (per EVG, COBI e FTC fare riferimento alle informazioni di prescrizione degli agenti individuali; per TAF consultare E/C/F/TAF FDC nel Dossier per lo sperimentatore); o soggetti con allergie note agli eccipienti delle compresse di E/C/F/TAF FDC.
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E.5 End points |
E.5.1 | Primary end point(s) |
proportion of subjects with HIV-1 RNA <50 copies/mL at Week 12
as defined by pure virologic response. |
Percentuale di soggetti con RNA di HIV-1 <50 copie/ml alla
Settimana 12 mediante risposta virologica pura (PVR) |
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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) |
1.Emergence of new mutations in HIV-1 reverse transcriptase and integrase (attempted on any
post Day 1 sample with HIV-1 RNA = 50 copies/mL)
2. HIV-1 RNA< 50 copies/mL at Weeks 24 and 48 using PVR
3. HIV-1 RNA < 50 copies/mL at Weeks 12, 24 and 48 using the FDA snapshot analysis
(sensitivity analysis)
4. CD4+ cell count change from Day 1 at Weeks 12, 24 and 48 |
1. Insorgenza di nuove mutazioni nella trascrittasi e integrasi inversa di HIV-1 (rilevate in ogni campione successivo al Giorno 1 con RNA di HIV-1 = 50 copie/ml)
2. RNA di HIV-1 <50 copie/ml alle Settimane 24 e 48 mediante PVR
3. RNA di HIV-1 < 50 copie/ml alle Settimane 12, 24 e 48 mediante analisi snapshot della FDA (analisi della sensibilit¿)
4. Variazioni nella conta delle cellule CD4+ dal Giorno 1 alle Settimane 12, 24 e 48
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At any time post day 1.
2. At weeks 24 and 48
3. At weeks 12, 24 and 48
4. At weeks 12, 24 and 48. |
1. Ogni giorno dopo il giorno 1
2. Alle settimane 24 e 48
3. Alle settimane 12, 24 e 48
4. Alle settimane 12, 24 e 48
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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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Spain |
United States |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |