| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV-1 infected patients |
| pazienti affetti da virus HIV-1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| pazienti affetti da infezione da HIV-1 |
|
| 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 | 10008922 |
| E.1.2 | Term | Chronic infection with HIV |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 explore the 24-week efficacy of a nucleos(t)ide sparing regimen of atazanavir 300 mg QD/ ritonavir 100 mg QD + Dolutegravir 50 mg QD for the management of virologic failure in HIV-1 infected, integrase inhibitor-na¿ve subjects. |
| obiettivo primario dello studio ¿ esplorare in pazienti con infezione da HIV in fallimento virologico l'efficacia a 24 settimane di un regime di combinazione non contenente nucleosidici, con atazanavir 300mg/ritonavir 100 mg (ATV/r) e dolutegravir 50 mg QD |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety profile of DTG + ATV/r combination
2. To evaluate the 4-week efficacy of DTG+ATV/r and the time to achieve undetectability
3. To evaluate the immunological changes from baseline.
4. To evaluate the Cthrough of DTG and ATV at day 8 and at week 4, 8, 12, 16, 24 or at discontinuation
5. To detect potential risk factors related with the virological failure, including adherence and ATV and DTG concentrations
6. To describe genotypic resistance mutations for protease inhibitor and integrase inhibitors in isolates from patients with virological failure |
| Gli obiettivi secondari dello studio saranno: indagare il profilo di sicurezza della combinazione DTG + ATV/r (valutato in base all'incidenza ed alla severit¿ degli eventi avversi e delle alterazioni dei parametri laboratoristici), valutare il recupero immunologico durante il trattamento, descrivere la farmacocinetica di DTG e ATV, identificare i fattori di rischio correlati con l'eventuale fallimento del trattamento in studio e descrivere le mutazioni di farmacoresistenza secondarie al fallimento stesso. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subjects with age >18 years
• Willing and able to provide informed consent
• Failing a stable (at least 3 months) antiretroviral therapy (HIV-RNA > 200 copies/ml)
• Any CD4 cell count
• HBsAg non reactive
• Virus susceptible to atazanavir, defined as a genotypic mutation score < 15 according to the HIV drug resistance database (Stanford University)
• No previous exposure to integrase inhibitors
• Absolute neutrophil count (ANC) ¿500/mm3
• Haemoglobin¿8.0 g/dL
• Platelet count¿60,000/mm3
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ¿ 5 ¿ ULN
• Total bilirubin ¿ 2.5 x ULN
• e-GFR> 60 ml/min using CKD-EPI equation
|
Pazienti adulti, in fallimento virologico con l’attuale terapia antiretrovirale stabile da almeno 3 mesi (carica virale > 200 copie m/L )
Nessuna precedente esposizione agli inibitori dell’integrasi.
Qualsiasi conta dei linfociti CD4
HbsAg negativi
Virus sensibile ad atazanavir secondo il metodo della Stanford University
|
|
| E.4 | Principal exclusion criteria |
• Active AIDS-defining condition at Screening
• Serious illness requiring systemic treatment and/or hospitalization
• Current use of immunomodulant or immunosuppressive drugs
• Requirement for any concomitant medications that are prohibited with any study drugs (see protocol section 3.6)
• History or presence of hypersensitivity to any of the active substances or to the excipients
• Alanine aminotransferase (ALT) more than 5 times the upper limit of normal (ULN), OR ALT more than 3xULN and bilirubin more than 1.5xULN (with >35% direct bilirubin)
• Subjects positive for Hepatitis B at screening (HBsAg+)
• Subjects with anticipated need for Hepatitis C virus (HCV) therapy during the study
• Presence of moderate or severe hepatic impairment (defined as a Class B or C at Child Pugh Classification; appendix 7) or presence of unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice) or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Pregnancy or pregnancy wish; breastfeeding
Moreover, all clinical conditions reported as an absolute contraindication in the summary of product characteristics of the study drugs, will be considered as exclusion criteria.
|
- Donne in gravidanza o allattamento
- AIDS defining events allo screening o SAE in corso di screening
- Insufficienza epatica da moderata a grave (Classe B o C alla classificazione Child Pugh) e scompenso epatico
- Con necessità di trattamento per epatite C
- Uso di farmaci controindicati dallo studio (vedi sez.3.6 del protocollo)
- Ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti per tutti i medicinali in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • The proportion of patients with undetectable HIV RNA viral load ( < 50 copies/ml) at week 24. |
| Proporzione di pazienti con viremia non rilevabile (intesa come carica virale < 50 copie m/L) alla settimana 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
¿ Proportion of patients with undetectable HIV RNA viral load (< 50 copies/ml) at Week 4.
¿ Change from baseline in CD4+ cell count.
¿ Time to achieve undetectability
¿ Occurrence of genotypic resistance mutations for protease inhibitor and integrase inhibitors in isolates from patients with virological failure
¿ Atazanavir and dolutegravir Cthrough
¿ Proportion of patients with adverse events (any grade), proportion of patients with = grade 2 adverse events or abnormal laboratory tests, proportion of patients with side effects leading to discontinuation; reasons for treatment discontinuation (e.g. due to AE/Loss of viral control/Death/Patient decision).
¿ changes in lipid (total TG, total COL, HDL-col, LDL-col, total COL/HDL ratio), clearance creatinine (using CKD-EPI equation) and glycemic profile changes from baseline.
¿ Changes of ECG parameters
¿ Adherence changes since the first evaluation
|
| 1 Efficacia e sicurezza; proporzione di pazienti con viremia non rilevabile alla settimana 4. 2 Variazione del numero di cellule CD4 rispetto al basale. 3 Presenza di mutazioni genotipiche (test genotipico) in campioni di plasma e di resistenza fenotipica (test fenotipici) per inibitori della proteasi e della integrasi nei pazienti in fallimento virologico. Percentuale dei pazienti con grado 2, di eventi avversi o anormalit¿ di laboratorio, proporzione di pazienti con effetti collaterali che hanno portato alla sospensione , cambiamenti dei lipidi rispetto al basale (TG totale, COLt totale, HDL-col, LDL-col, totale COL/HDL). Atazanavir e dolutegravir Ctrought. 8. Modifiche riguardo l¿ aderenza rispetto alla week 4, 12 e 24. 9.Modifiche dell¿ECG rispetto alla baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All the secondary endpoints will be evaluated at each timepoint of the corresponding data collection, unless otherwise specified. |
| tutti gli end points secondari verranno rilevati ad ogni momento previsto per la raccolta del dato |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 a singolo braccio |
| a pilot single arm study |
|
| 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.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 | 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
|
|
| 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 | 13 |
| E.8.9.1 | In the Member State concerned days | 39 |
| 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 | 13 |
| E.8.9.2 | In all countries concerned by the trial days | 39 |
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