| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic hepatitis C infection genotype 1 in patients coinfected with HIV-1 |
| Infección crónica por hepatitis C de genotipo 1 en pacientes coinfectados por VIH-1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis C infection in patients with HIV-1 infection |
| Infección por hepatitis C en pacientes infectados por VIH-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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019744 |
| E.1.2 | Term | Hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 |
| Main objective: The objective of this trial is to evaluate the safety and efficacy of an open-label treatment with BI 201335 240 mg once daily given for 12 or 24 weeks in combination with pegylated interferon-α2a and ribavirin given for 24 or 48 weeks in HCV/HIV coinfected patients, who are HCV-treatment naive or HCV-treatment relapsers and HIV treatment-naïve- or, who are being treated with Raltegravir/Truvada® therapy for HIV infection. Results of this trial will be compared with historical efficacy and safety data of randomized trials of 48 weeks of treatment with pegylated interferon-α 2a and ribavirin for HCV GT 1 infection in HIV/HCV co-infected patients. |
| El objetivo de este ensayo es evaluar la seguridad y la eficacia de un tratamiento de diseño abierto con BI 201335 240 mg una vez al día administrado durante 12 ó 24 semanas en combinación con interferón alfa-2a pegilado y ribavirina administrados durante 24 ó 48 semanas en pacientes con coinfección por VHC/VIH sin tratamiento previo para el VHC o con recidiva tras el tratamiento previo para el VHC, y sin tratamiento previo para el VIH o en tratamiento con raltegravir/Truvada® para la infección por VIH. Los resultados de este ensayo se compararán con datos históricos de eficacia y seguridad de ensayos aleatorizados de 48 semanas de tratamiento con interferón alfa-2a y ribavirina para la infección por VHC de GT 1 en pacientes con coinfección por VIH/VHC. |
|
| E.2.2 | Secondary objectives of the trial |
| Evaluate the safety of the BI 201335 240mg once daily in combination with pegylated interferon-alpha 2a and ribavirin in the population of HIV/HCV co-infected patients. |
| Evaluar la seguridad de BI 201335 240 mg una vez al día en combinación con interferón alfa-2a pegilado y ribavirina en pacientes con coinfección por VHC/VIH. |
|
| 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 |
| Trough at steady state for PegIFN and RBV: A plasma sample will be collected for the analysis of RBV concentrations and a serum sample for the analysis of pegIFN α-2a concentrations at Week 12 (Visit 6) and Week 24 (Visit 8). Non-steady state trough for BI 201335, PegIFN and RBV: Trough samples will be collected at Week 0 (Day 2, Visit 2a), Week 1 (Visit 2b). Post-morning dose sample for BI 201335: A plasma sample collected after the morning BI 201335 dose will be collected at 6 hrs, at Week 0 (Visit 2, Day 1) and at varying time at Week 4 (Visit 4) and Week 12 (Visit 6). An HCV RNA viral load sample will also be collected at 6hrs after the morning dose of BI 201335 at Week 0 (Visit 2, Day 1) |
Concentraciones mínimas en estado de equilibrio para PegIFN y RBV: Se obtendrá una muestra de plasma para el análisis de las concentraciones de ribavirina y una muestra de suero para el análisis de las concentraciones de interferón alfa-2a pegilado en las semanas 12 (visita 6) y 24 (visita 8).
Concentraciones mínimas fuera del estado de equilibrio para BI 201335, PegIFN y RBV: Se obtendrán muestras de concentraciones mínimas en la semana 0 (día 2, visita 2a) y la semana 1 (visita 2b).
Muestra posterior a la dosis matutina para BI 201335: Se recogerá una muestra de plasma después de la dosis matutina de BI 201335 a las 6 horas en la semana 0 (visita 2, día 1) y en diferentes momentos en la semana 4 (visita 4) y la semana 12 (visita 6). También se obtendrá una muestra para determinar la carga viral del ARN del VHC a las 2 horas después de la dosis matutina de BI 201335 en la semana 0 (visita 2, día 1). |
|
| E.3 | Principal inclusion criteria |
1. Chronic hepatitis C infection with HCV genotype 1.
2. Chronic HIV -1 infection
3. HCV treatment-Naive or HCV treatment relapser defined as the following:
Treatment-naïve to interferon, pegylated interferon and ribavirin, or
Prior relapser: Undetectable HCV RNA (based on an assay considered sensitive at the time of treatment) at the end of treatment with a pegylated interferon-based regimen, but HCV RNA detectable within 24 weeks of treatment follow up
4. Documentation of liver biopsy within 3 years or fibroscan within 6 months prior to screening visit
5. Age 18 to 70 years.
6. ARV-treatment naïve or patients on stable HAART, defined as the following
ARV-Naive: Never received combination antiretroviral therapy, or never received monotherapy with raltegravir-, or elvitegravir, or an experimental antiretroviral. Must have peripheral CD4 T cell count >=500 cells/mm3 at screening visit, and HIV-1 plasma RNA <100,000 copies/mL.
Patients on stable HAART: Must be on stable Raltegravir/Truvada® therapy for at least 8 weeks prior to initial randomization; Must have peripheral CD4 T cell count >=200 cells/mm3 at screening visit, and HIV-1 plasma RNA <48 copies/mL for at least 6 months prior to initial randomization.
7. Karnofsky score>70
8. No AIDS-defining illness during 6 months prior to screning.
9. Female patients who are infertile or who are of childbearing potential with a negative pregnancy test and agreeing to use one accepted method of birth control in addition to the use of a condom by their male partners, or Male patients who are infertile, who are without pregnant female partners or who consistently and correctly use condoms
10. Signed Informed Consent Form |
1. Infección crónica por hepatitis C con VHC de genotipo 1.
2. Infección crónica por VIH-1.
3. Pacientes sin tratamiento previo para el VHC o pacientes con recidiva tras el tratamiento previo para el VHC, definidos de la siguiente manera:
Sin tratamiento previo con interferón, interferón pegilado y ribavirina, o
Recidiva previa (relapser): ARN del VHC indetectable (basado en una prueba considerada sensible en el momento del tratamiento) al final del tratamiento con interferón pegilado, pero con ARN del VHC a niveles detectables dentro de las 24 semanas de seguimiento del tratamiento.
4. Documentación de una biopsia hepática en los 3 años previos o fibroscan en los 6 meses previos a la visita de selección.
5. Edad entre 18 y 70 años.
6. Pacientes sin tratamiento previo con ARV o pacientes que reciben TARGA estable, definidos de la siguiente manera:
Sin tratamiento previo con ARV: Nunca ha recibido tratamiento antirretroviral combinado o nunca ha recibido raltegravir o elvitegravir en monoterapia o un antirretroviral experimental. Debe presentar un recuento de linfocitos T CD4 periféricos 500 células/mm3 en la visita de selección y ARN del VIH 1 en plasma < 100.000 copias/ml.
Pacientes que reciben TARGA estable: Deben haber recibido un tratamiento estable con raltegravir/Truvada® durante al menos las 8 semanas previas a la aleatorización inicial; deben presentar un recuento de linfocitos T CD4 periféricos 200 células/mm3 en la visita de selección y ARN del VIH 1 en plasma < 48 copias/ml al menos 6 meses antes de la aleatorización inicial.
7. Puntuación de Karnofsky > 70.
8. Ausencia de enfermedad indicativa de sida en los 6 meses previos a la selección.
9. Mujeres infértiles o en edad fértil con una prueba de embarazo negativa que accedan a usar un método anticonceptivo aceptado, además de que sus parejas empleen preservativo.
Pacientes varones infértiles, cuya pareja no esté embarazada o que utilicen preservativos correcta y sistemáticamente.
10. Formulario de consentimiento informado firmado. |
|
| E.4 | Principal exclusion criteria |
| HCV infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening. 2.Evidence of acute or chronic liver disease due to causes other than chronic HCV infection. Incidential steatosis diagnosed by biopsy is not considered evidence of liver disease. 3.Hepatitis B virus (HBV) infection with presence of HBs-Ag. 4.Active malignancy, or history of malignancy within the last 5 years prior to screening 5. Active or history of alcohol or illicit drug abuse other than cannabis within the past 12 months. 6.A condition that is defined as one which in the opinion of investigator may put the patient at risk because of participation in this study, influence the results of this study, or limit the patient’s ability to participate in this study. 7. Usage of any investigational drugs within 28 days prior to screening, or planned usage of an investigational drug during the course of this study. 8 Received concomitant systemic antiviral (other than antiretroviral), hematopoietic growth factor, or immunomodulatory treatment within 28 days prior to enrolment. Patients being treated with oral antivirals such as acyclovir, famcilovir or valacyclovir for recurrent herpes simplex infection; or with oseltamivir or zanamivir for influenza A infection, may be enrolled. 9.Received silymarin (milk thistle), glycyrrhizin, or Sho-saiko-to (SST) within 28 days prior to enrolment. 10.Patients who have been previously treated with at least one dose of any antiviral or inmunomodulatory drug other than interferon alfa or ribavirin for acute or chronic HCV infection including and not restricted to protease or polymerase inhibitors. 11. Known hypersensitivity to any ingredient of the study drugs. 12 Alpha fetoprotein value >100 ng/mL at screening; if > 20 ng/mL and ≤ 100 ng/mL, patients may be included if there is no evidence of liver cancer in an appropriate imaging study (e.g., ultrasound, CT scan, or MRI) within last 6 months prior to randomisation. 13. Decompensated liver disease, or history of decompensated liver disease, as evidenced by ascites, hepatic encephalopathy, esophageal variceal bleeding, and/or laboratory values which add up to > 7 points according to the Child-Turcotte-Pugh (CTP) classification. 14. Patients with stable cardiac disease and Hemoglobin <12 g/dL. 15. Pre-existing psychiatric condition that could interfere with the subject’s participation in and completion of the study including but not limited to prior suicidal attempt, schizophrenia, major depression syndrome, severe anxiety, severe personality disorder, a period of disability or impairment due to a psychiatric disease within the past 5 years. 16. Clinical evidence of significant or unstable cardiovascular disease, including angina, myocardial infarction within 6 months, pulmonary hypertension, cardiomyopathy, congestive heart failure, uncontrolled hypertension, significant arrhythmia or clinically significant abnormalities on ECG at screening. 17. Clinical evidence of chronic pulmonary disease (e.g. chronic obstructive pulmonary disease) associated with functional impairment. 18 Active autoimmune disease, including autoimmune hepatitis. 19. History or evidence of retinopathy or clinically significant ophthalmological disorder including diabetic or hypertensive retinopathy, retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy, or retinal artery/vein obstruction. An eye examination performed within 6 months prior randomisation (visit 2) is required. 20. Organ transplant history other than cornea or hair. 21.A condition that requires chronic systemic corticosteroids (nasal or pulmonary steroids will be allowed). 22. Active seizure disorder within the last 2 years. 23. Red blood cell disorders which include but are not limited to thalassemia major, sickle cell anemia, and G6PD deficiency. Patients with traits or minor diseases (e.g. sickle cell trait or thalassemia minor) may be enrolled if the disease did not result in anemia, according to the investigator’s clinical judgment. 24. Body weight < 40 or > 125 kg. 25. TSH and T4 outside normal limits and inadequately controlled thyroid function; patients with abnormal TSH may be enrolled if free T4 is normal and there is no clinical evidence of hyperthyroidism or hypothyroidism. 26. Hemoglobin £11 g/dL for women and £ 12 g/dL for men. 27. Poorly controlled diabetes mellitus, with HbA1c ³8.5%. 28. White blood cell count < 2,000 cells/mm3 29. Absolute neutrophil count < 1200 cells/mm3 for Blacks/African Americans and <1,500 cells/mm3 for patients of other race/ethnicity. 30.Platelet count < 70,000 cells/mm3. 30. Serum creatinine > 1.5xULN. 31. Antinuclear antibody (ANA) titer ≥ 1:640 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Sustained Virological Response (SVR): Plasma HCV RNA level <25 IU/mL, undetected 24 weeks after the planned treatment duration. |
| Respuesta virológica mantenida (SVR): ARN del VHC en plasma < 25 UI/ml (indetectable) 24 semanas después de la duración del tratamiento prevista. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after the originally planned treatment duration |
| 24 semanas después del final de la duración del tratamiento prevista originariamente |
|
| E.5.2 | Secondary end point(s) |
| • Virological response after 12 weeks of treatment discontinuation (SVR12): Plasma HCV RNA level < 25 IU/mL, (undetected) 12 weeks after the originally planned treatment duration. • ALT normalization: ALT in normal range 24 weeks after the end of the originally planned treatment duration. • Early Treatment Success (ETS): Plasma HCV RNA level<25 IU/mL (detected or undetected) at Week 4 and HCV RNA <25 IU/m (undetected) at Week 8. |
• Respuesta virológica 12 semanas después de suspender el tratamiento (SVR12): ARN del VHC en plasma < 25 UI/ml (indetectable) 12 semanas después del final del tratamiento previsto originariamente.
• Normalización de la ALT: ALT normal 24 semanas después de la duración del tratamiento prevista originariamente.
• Éxito precoz del tratamiento (ETS):
ARN del VHC en plasma < 25 UI/ml (detectable o indetectable) en la semana 4 y ARN del VHC < 25 UI/ml indetectable en la semana 8. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| • 12 weeks of treatment discontinuation • 24 weeks after end of the originally planned treatment duration • At week 4 and week 8 |
| • 12 semanas después del final del tratamiento • 24 semanas después de la duración del tratamiento prevista originariamente • Semana 4 y semana 8 |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| controles históricos |
| historical controls |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 | No |
| 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 |
| Brazil |
| France |
| Germany |
| Italy |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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