E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Coinfection with HCV genotype 1 and HIV |
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E.1.1.1 | Medical condition in easily understood language |
Coinfection with HCV genotype 1 and HIV |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
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 assess the efficacy and safety of 24 weeks of a triple oral combination with Sofosbuvir/Ledipasvir fixed-dose combination and Ribavirin in subjects with HCV genotype 1 infection and HIV co-infection, who have previously failed a NS3/4A protease inhibitor plus PEG/RBV regimen or stopped prematurely their treatment for intolerance. |
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E.2.2 | Secondary objectives of the trial |
Safety assessment HCV virological assessment Describe HCV virological kinetics and response, globally and according to the subtype (1a or 1b) Study the prognostic factors associated with SVR Assess the emergence of resistance to Sofosbuvir and/or Ledipasvir
HIV virological assessment Hepatic and metabolic evaluation: evaluate the relationship and virological response
Describe Ribavirin residual concentration one month after its introduction and study its relationship with the variation of hemoglobinemia and virological response kinetics
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic substudy version n°1.0. of 18 december 2013 Describe Sofosbuvir and Ledipasvir residual concentrations and study their relationship with the virological response kinetics Describe pharmacokinetic parameters of antiretroviral (Raltegravir and Tenofovir) and anti-HCV (Sofosbuvir and Ledipasvir) drugs (sub-group study) Assess possibles drug-drug interactions between HCV (Sofosbuvir and Ledipasvir) and HIV (Raltegravir and Tenofovir) drugs (sub-group study) |
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E.3 | Principal inclusion criteria |
Adult ≥18 years • Confirmed HIV infection • Infection with HCV genotype 1 only, confirmed at screen visit, with a HCV-RNA ≥ 1000 UI/mL at screen visit • Treatment-experienced subjects with: - previous virological failure to tritherapy with Peginterferon/Ribavirin and protease inhibitor, - or premature discontinuation of previous tritherapy with Peginterferon/Ribavirin and protease inhibitor due to intolerance to Peginterferon or protease inhibitor • Anti-HCV treatment stopped for at least the last 3 months • Patients on a stable (for more than 1 month) antiretroviral treatment consisting of an emtricitabine/tenofovir or lamivudine/tenofovir standard of care backbone plus efavirenz or raltegravir or rilpivirine or enfuvirtide. • CD4 > 100/mm3 and > 15% at screen visit • HIV-RNA < 50cp/ml for more than 3 months at screen visit • Any liver fibrosis grade, with the assessment of the presence or not of cirrhosis at screening, cirrhosis being defined as a METAVIR score of F4 on the liver puncture biopsy and/or with hepatic impulse elastometry ≥ 15 kPa: • Previous liver biopsy exhibiting cirrhosis lesions (METAVIR F4), • and/or significant liver biopsy (cumulative length ≥ 15mm and ≥ 6 portal spaces), within the past 18 months • and/or significant and reliable liver stiffness assessment (Fibroscan®) within the past 6 months (at least 10 measures with IQR less than 25% of the mean value and a success rate of at least 80%). • Male patients, female patients with child-bearing potential, and their heterosexual partners must use adequate contraception from 1 month before initiation of treatment up to 7 months following the end of treatment for men and to 4 months following the end of treatment for women. • Body weight ≥40 kg and ≤125 kg • Informed and signed consent for the main study and the PK sub-study (for the participating patients) • Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle)
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E.4 | Principal exclusion criteria |
Child-Pugh B or C cirrhosis or history of decompensated cirrhosis. Co-infection with Hepatitis B virus (AgHBs +) with HBV DNA > 1000 UI/ml Pregnant or breast-feeding women Transplant recipients Opportunistic infections (stage C), active or occurred within 6 months prior to baseline Evolutive malignancy, including hepatocarcinoma which should be controlled prior to baseline Alcohol or drug consumption which may affect the study participation according to the investigator. Patients included in a programme of substitution with methadone or buprenorphine could be enrolled. The opinion of a consultant in addictology is recommended for patients presenting with current drug use or drug use during the previous year. Patients with a history of non-adherence, who will be at risk of being unable to respect the study follow-up timetable Patients participating in another clinical trial within 30 days prior to inclusion Hb < 10 g/dL (female) or < 11g/dL (male) Platelets < 50 000/mm3 Neutrophil count < 750/mm3 Renal failure defined as creatinine clearance (MDRD) < 60ml/min
Other antiretroviral drugs than those allowed in the study Contra-indications to Sofosbuvir, Ledipasvir, Ribavirin
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E.5 End points |
E.5.1 | Primary end point(s) |
Sustained virological response, defined by an undetectable plasma HCV RNA 12 weeks post-treatment (SVR12) |
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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) |
Safety SVR rate 24 weeks (i.e. W48) after the end of treatment globally and according to the HCV subtype (1a or 1b) Measurements of HCV RNA at D0, W1, W2, W4, W8, W12, W16, W20, W24, and 4, 8, 12, 18 and 24 weeks after the end of the treatment (W28, W32, W36, W42 and W48), globally and according to the HCV subtype (1a or 1b) HCV resistance mutations to Sofosbuvir and/or Ledipasvir (in case of virological failure)
Plasma HIV RNA levels at D0, W4, W8, W12, W16, W20, W24, W36 and W48 CD4 and CD8 cell counts (absolute count, percentage and CD4/CD8 ratio) at D0, W4, W8, W12, W16, W20, W24, W36 and W48
Hepatic and metabolic assessment Biological (Fibrotest®, Fibromètre® or Hepascore ®) and imaging (Fibroscan®) parameters describing the evolution of liver fibrosis between baseline and 24 weeks post-treatment (W48) Insulin resistance measured using the HOMA-IR score (measured at D0 and W36) Parameters that define metabolic syndrome (waist circumference, blood pressure, fasting glucose, triglyceridemia, HDL-cholesterol) measured at D0 and W36
In all patients: Ribavirin residual concentration (Cres) at W4 -In all patients: Sofosbuvir and Ledipasvir residual concentrations at W4, W12 and W24 In a sub-group of 20 voluntary patients (preferred Anti Retroviral Treatment (ART) for these patients will be RAL+ TDF/FTC): PharmacoKinetic (PK) parameters (Cres, Cmax, AUC10, AUC24) of HIV drugs (Raltegravir and Tenofovir) at D0 and W4 PharmacoKinetic (PK) parameters (Cres, Cmax, AUC10, AUC24) of Sofosbuvir and Ledipasvir at W4.
Patients’ reported outcomes (PRO) including perceived symptoms reported by the patients (ANRS AC24 perceived symptoms questionnaire), fatigue intensity and quality of life (MOS-SF12) at follow-up visits D0, W8, W24 and W48. PRO will be available from patients’ answers in the self-administered questionnaires. Patients’ adherence measured using the Inserm-ANRS self–administered questionnaire at follow-up visits D0, W8, W24 and W36.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | No |
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 | 44 |
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 | 6 |
E.8.9.1 | In the Member State concerned days | |