| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Genotype 1 Hepatitis C Virus Infection |
| Adultes présentant une infection chronique par le virus de l’hépatite C (VHC) de génotype 1 et une cirrhose, et précédemment traités par un inhibiteur de protéase avec PEG+RBV. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis C Virus Infection |
| Infection chronique par le virus de l'hépatite C de génotype 1 (correspondant à une variété du virus) chez des patients ayant déjà reçu un traitement pour cette maladie. |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019751 |
| E.1.2 | Term | Hepatitis C virus |
| E.1.2 | System Organ Class | 100000004848 |
|
| 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 |
The primary objectives of this study are:
• To determine the antiviral efficacy of combination treatment with sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) for 24 weeks + ribavirin (RBV) for 12 weeks as measured by the proportion of subjects with sustained viral response (SVR) 12 weeks after discontinuation
of therapy (SVR12).
• To evaluate the safety and tolerability of each regimen as assessed by review of the accumulated safety data |
L’objectif principal de cette étude est le suivant :
• Déterminer l’efficacité antivirale d’un traitement par l’association à doses fixes (ADF) sofosbuvir (SOF)/ledipasvir (LDV) pendant 24 semaines + ribavirine (RBV) pendant 12 semaines, telle que mesurée par la proportion des sujets présentant une réponse virale persistante (RVS) 12 semaines après l’arrêt du traitement (RVS12).
• Évaluer l’innocuité et la tolérance de chaque protocole de traitement, d’après l’examen des données accumulées sur l’innocuité
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To determine the proportion of subjects who attain SVR at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24)
• To compare the safety profile during the first 12 weeks of treatment of the 24 week SOF/LDV FDC treatment group with the 12-week placebo control treatment period
• To compare, in the deferred start group, the safety profile during the first 12 weeks of the study (placebo period) with the second 12 weeks (SOF/LDV FDC+RBV period) of the study
• To evaluate the kinetics of circulating HCV RNA during treatment and after treatment discontinuation
• To evaluate the emergence of viral resistance to sofosbuvir and ledipasvir during treatment and after treatment discontinuation |
Les objectifs secondaires de cette étude sont les suivants :
• Déterminer la proportion des sujets présentant une RVS 4 et 24 semaines après l’arrêt du traitement (RVS4 et RVS24)
• Comparer le profil d’innocuité durant les 12 premières semaines de traitement du groupe de traitement ADF SOF/LDV sur 24 semaines à la période de traitement témoin de 12 semaines sous placebo.
• Comparer, dans le groupe à début différé, le profil d’innocuité durant les 12 premières semaines de l’étude (période sous placebo) à celui observé durant la seconde période de 12 semaines (période sous ADF SOF/LDV + RBV) de l’étude.
• Évaluer la cinétique de l’ARN circulant du VHC durant le traitement et après son arrêt.
• Évaluer l’émergence d’une résistance virale au sofosbuvir et au ledipasvir durant le traitement et après son arrêt. |
|
| 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 |
- To evaluate the effect of treatment on markers for liver cirrhosis including LOXL-2, Fibrotest®/APRI
- To identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy and/or tolerability of medical therapies through genetic discovery research (eg, pharmacogenomics), in subjects who provide their separate and specific consent
- To assess the effect of treatment on health related quality of life
|
- Évaluer l’effet du traitement sur des marqueurs de cirrhose du foie, dont LOXL-2, Fibrotest®/APRI
- Identifier ou valider des marqueurs génétiques pouvant être prédictifs de l’histoire naturelle de la maladie, de la réponse au traitement et/ou de la tolérance de traitements médicaux par l’intermédiaire de recherches génétiques (par exemple pharmacogénomiques) chez les sujets qui donnent leur consentement distinct et spécifique.
- Évaluer l’effet du traitement sur la qualité de vie liée à la santé
|
|
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent
2. Male or female, age >/= 18 years
3. Body mass index (BMI) >/=18 kg/m2
4. Both HCV Genotype 1 and HCV RNA >/= 104 IU/mL at Screening
5. Prior virologic failure after treatment with a PEG-IFN, RBV, and a protease inhibitor following documented prior virology failure after treatment with a PEG-IFN+RBV regimen. The subject’s medical records must include sufficient detail of prior virologic failure to allow for categorization of prior response during both prior treatment periods (Reference Section 6.4.2), as either:
i. Non-Responder: Subject did not achieve undetectable HCV RNA levels while on treatment, or
ii. Breakthrough: Subject achieved undetectable HCV RNA levels during treatment but subsequently had detectable HCV RNA while continuing treatment
iii. Relapse: Subject achieved undetectable HCV RNA levels during treatment maintained undetectable HCV RNA for the duration of treatment or achieved undetectable HCV RNA within 4 weeks of the
end of treatment but did not achieve a SVR
iv. Stopped due to AE
6. Evidence of cirrhosis defined as any of the following:
-Any biopsy showing cirrhosis
-Transient elastography (where approved) showing cirrhosis results >12.5 kPa
-A FibroTest® score of >0.75 AND an AST:platelet ratio index (APRI) of >2 performed during screening
7. Liver imaging within 3 months of Day 1 excluding HCC
8. Screening ECG without clinically significant abnormalities
9. Subjects must have the following laboratory parameters at screening:
a. ALT </= 10 x the upper limit of normal (ULN)
b. AST </= 10 x ULN
c. Direct bilirubin </= 1.5 x ULN
d. Platelets >/= 50,000
e. HbA1c </= 10%
f. Creatinine clearance (CLcr) >/= 50 mL /min, as calculated by the Cockcroft-Gault equation
g. Hemoglobin >/= 11 g/dL
h. Albumin >/= 3g/dL
i. INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR.
10. Subject has not been treated with any investigational drug or device within 30 days of the Screening visit.
11. A negative serum pregnancy test is required for female subjects (unless surgically sterile or greater than two years post-menopausal; see Appendix 4 for definitions).
12. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 4.
13. Male subjects must agree to refrain from sperm donation from the date of screening until at least 7 months after the last dose of RBV, or 90 days after their last dose of study drug if not taking RBV.
14. Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator.
15. Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments. |
|
| E.4 | Principal exclusion criteria |
1. Current or prior history of any of the following:
a. Clinically-significant illness (other than HCV) or any other major medical disorder that, in the opinion of the investigator, may interfere with subject treatment, assessment or compliance with the protocol; subjects currently under evaluation for a potentially clinically-significant illness (other than
HCV) are also excluded.
b. Gastrointestinal disorder or post operative condition that could interfere with the absorption of the study drug (for example, gastric bypass or severe ulcerative colitis).
c. Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
d. Clinical hepatic decompensation (ie, clinical ascites, encephalopathy or variceal hemorrhage).
e. Solid organ transplantation.
f. Significant pulmonary disease or significant cardiac.
g. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 2 years. Subjects with psychiatric illness that is well-controlled on a stable treatment regimen for at least 12 months prior to randomization or has not required medication in the last 12 months may be included.
h. Malignancy within 5 years prior to screening, with the exception of specific cancers that are entirely cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible.
i. Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2. Prior exposure to approved or experimental HCV-specific DAA(s), other than a NS3/4A protease inhibitor.
3. Pregnant or nursing female, or male with pregnant female partner.
4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency, cholangitis).
5. Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
6. Clinically-relevant drug or alcohol abuse within 12 months of screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator.
7. Contraindications to RBV therapy, including significant history of clinically significant hemoglobinopathy (eg, sickle cell disease, thalassemia).
8. Use of any prohibited concomitant medications as described in the Protocol within 21 days of the Day 1 visit; this washout period does not apply to proton pump inhibitors, which can be taken up to 7 days before Day 1.
9. Chronic use of systemically administered immunosuppressive agents (eg, prednisone equivalent > 10 mg/day).
10. Known hypersensitivity to RBV, LDV, SOF, or formulation excipients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of therapy) in all randomized and treated subjects with chronic genotype 1 HCV infection. In the primary efficacy analysis, the SVR12 rate in each of the 2 treatment groups will be estimated with 2-sided 95% exact CIs using the binomial distribution (Clopper-Pearson method). |
| Le critère principal d’efficacité est la RVS12 chez tous les sujets randomisés et traités présentant une infection chronique par le VHC de génotype 1. Dans l’analyse principale de l’efficacité, le taux de RVS12 dans chacun des deux groupes de traitement sera estimé avec l’intervalle de confiance (IC) bilatéral exact à 95 % en utilisant la distribution binomiale (méthode de Clopper-Pearson). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks post last treatment dose |
| 12 semaines après la dernière prise du traitement |
|
| E.5.2 | Secondary end point(s) |
The proportion of subjects with HCV RNA < LLOQ at 4 weeks and 24 weeks post-treatment;
The proportion of subjects with HCV RNA < LLOQ on treatment;
HCV RNA change from Day 1
The proportion of patients with virologic failure (viral breakthrough and relapse) |
| Les critères secondaires d’efficacité comportent la proportion des sujets présentant un taux d’ARN du VHC inférieur à la limite inférieure de quantification à 4 semaines et à 24 semaines post-traitement ; poussées et rechutes virales. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be assessed at On-Treatment visits at Weeks 1, 2, 4, 8, 12, 13, 14, 16, 20,
and 24 and Post-Treatment Visits at Week 4 and 12. Subjects who achieve SVR12 will also complete a Post-Treatment Week 24. |
| Visites au cours du traitement aux semaines 1, 2, 4, 8, 12, 13, 14, 16, 20 et 24, et visites postérieures au traitement aux semaines 4 et 12. Une visite aura également lieu à la semaine 24 post-traitement chez les sujets ayant présenté une RVS12. |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 20 |
| 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
|
|
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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