| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic infection with HCV - genotype 1 |
| Infección cróngica con VHC genotipo 1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic infection with Hepatitis C virus |
| Infección crónica por el virus de la hepatitis C |
|
| 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 | 15.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic 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 |
Aim of the trial is to confirm efficacy and safety of treatment with 600 mg of BID BI 207127 in combination with 120 mg QD Faldaprevir (previously called BI 201335) and RBV for 16 and 24 weeks in target chronically infected HCV GT1 treatment naïve patients, including patients with compensated cirrhosis. This ?target? population excludes GT1a infected patients with the host IL28B rs12979860 CT or TT (non-CC) genotypes.
Primary objective of the trial is to determine if there is a clinically meaningful difference between 16- and 24-week treatment durations. |
El objetivo del estudio es confirmar la eficacia y seguridad del tratamiento con 600 mg BID de BI 207127 en combinación con 120 mg QD de Faldaprevir (nombre anterior BI 201335) y RBV durante 16 y 24 semanas en pacientes diana con infección crónica por HCV genotipo 1 (GT1) sin tratamiento previo, incluidos pacientes con cirrosis compensada. Quedan excluidos de esta población ?diana? los pacientes GT1a infectados con los genotipos IL28B rs12979860 CT o TT (no CC) del huésped.
El objetivo principal es determinar si existe alguna diferencia clínicamente significativa entre el tratamiento mantenido durante 16 y 24 semanas. |
|
| E.2.2 | Secondary objectives of the trial |
| To determine if a minimum historical target SVR12 rate of 71% can be achieved by the combination treatments of BI 207127, Faldaprevir and RBV, including patients with compensated cirrhosis. |
| El objetivo secundario es determinar si los tratamientos combinados de BI 207127, Faldaprevir y RBV pueden obtener una tasa mínima histórica de SVR12 del 71%, incluidos pacientes con cirrosis compensada |
|
| 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 (PK) substudy, 45 patients, 3 PK days with 5 blood draws per days |
| Subestudio de farmacocinética (PD), 45 pacientes, 3 días PK con 5 extracciones de sangre por día. |
|
| E.3 | Principal inclusion criteria |
1. Chronic hepatitis C infection diagnosed by by positive anti-HCV antibodies and detected HCV RNA at screening in addition to at least one of the following:
a. positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening, OR
b. liver biopsy indicating chronic HCV infection, OR
c. history of elevated alanine aminotransferase (ALT) levels at least 6 months prior to screening.
2. HCV infection of sub-GT1b confirmed by genotypic testing at screening, or HCV infection of sub-GT1a, GT1 with undefined subtype or 1a/1b subtype confirmed by genotypic testing at screening in patients with IL-28b CC genotype.
3. Treatment naïve defined as:
a. no prior treatment with any interferon, pegylated interferon, and /or ribavirin
AND
b. no prior treatment with at least one dose of any other licensed or investigational antiviral agent of for acute or chronic hepatitis C infection
4. Plasma HCV RNA >= 1,000 IU/mL at screening
5. Liver biopsy within three years or fibroscan within 6 months prior to randomisation. Note: patients with a liver biopsy performed 3 or more years or fibroscan performed 6 months or more prior to randomisation demonstrating cirrhosis do not need to repeat a liver biopsy or fibroscan. Patients with a liver biopsy performed 3 or more years (or fibroscan performed 6 months or more) prior to randomisation, negative for the presence of cirrhosis need to repeat the liver biopsy or fibroscan, with the result available before randomisation visit.
6. Age 18 - 75 years (inclusive)
7. Female patients
a. with documented hysterectomy, OR
b. who have had both ovaries removed, OR
c. with documented tubal ligation, OR
d. who are post-menopausal with last menstrual period at least 12 months prior to screening, OR
e. of childbearing potential with a negative pregnancy test at screening and on Day 1 (Visit 2), that agree to use two non-hormonal methods of birth control from the date of screening until 7 months after the last dose of ribavirin. They must not breast-feed at any time from the date of screening until 7 months after the last dose of ribavirin. Accepted methods of contraception for females in this trial are diaphragm with spermicide substances, intrauterine devices, cervical caps and condoms. Note: Systemic hormonal contraceptives may not be as effective in women taking BI 207127/FDV combination therapy and are not accepted methods of contraception in the study.
OR
Male patients
a.who are documented to be sterile, OR
b. who consistently and correctly use a condom while their female partners (if of child-bearing potential) agree to use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin, AND
c. without pregnant female partners. It is in the responsibility of the male patient to ensure that his partner (or partners) is not pregnant prior to enrolment into the study or becomes pregnant during the treatment and follow-up phase. Female partners of childbearing potential must perform monthly pregnancy tests from the date of screening until 7 months after the last dose of ribavirin (tests will be provided by the sponsor).
8. Signed informed consent form prior to trial participation |
1. Infección crónica por hepatitis C, diagnosticada por la presencia de anticuerpos anti-HCV positivos y RNA del HCV detectado en la selección, adicionalmente a como mínimo uno de los siguientes criterios:
a. anticuerpos anti-HCV positivos o RNA del HCV detectado como mínimo 6 meses antes del periodo de selección, O
b. biopsia hepática característica de hepatitis C crónica, O
c. antecedentes de niveles elevados de alanina aminotransferasa (ALT) al menos 6 meses antes del periodo de selección.
2. Infección por HCV sub-GT1b confirmada mediante pruebas de genotipado durante la selección o infección por HCV sub-GT1a, GT1 con subtipo indefinido o subtipo 1a/1b confirmada mediante pruebas de genotipado durante la selección en pacientes con el genotipo IL-28b CC.
3. Pacientes sin tratamiento previo, definido como:
a. ningún tratamiento previo con ningún interferón, interferón pegilado ni ribavirina
y
b. ningún tratamiento previo con al menos una dosis de cualquier antiviral aprobado o en fase de investigación para la infección aguda o crónica por el virus de la hepatitisC
4. RNA del HCV plasmático ? 1.000 UI/ml en la selección
5. Biopsia hepática no anterior a tres años o fibroscan en los seis meses previos a la aleatorización.
Nota: aquellos pacientes con una biopsia hepática realizada 3 o más años antes de la selección o con un fibroscan hecho 6 o más meses antes de la selección que demostrase una cirrosis no tendrán que repetir una biopsia hepática o un fibroscan. Los pacientes con una biopsia hepática realizada más de 3 años antes del periodo de aleatorización (o con un fibroscan hecho más de 6 meses antes) y que no mostrase una cirrosis tendrán que repetir la biopsia hepática o el fibroscan y el resultado deberá estar disponible antes de la visita de aleatorización.
6. Edad comprendida entre los 18 ? 75 años (inclusive)
7. Mujeres
a. con histerectomía comprobada, o
b. con extirpación de ambos ovarios, o
c. con ligadura de trompas comprobada, o
d. posmenopáusicas, con el último periodo menstrual al menos 12 meses antes de la selección, o
e. con posibilidad de quedar embarazadas, con prueba de embarazo en suero negativa en la selección y el día 1 (visita 2), que acepten usar dos métodos anticonceptivos no hormonales desde la fecha de selección hasta 7 meses después de la última dosis de ribavirina. Las mujeres deben aceptar no amamantar a su hijo en ningún momento desde la selección y hasta 7 meses después de la última dosis de ribavirina. Los métodos de anticoncepción aceptados para mujeres en este estudio son el diafragma con sustancia espermicida, capuchón cervical, dispositivos intrauterinos y preservativos.
Nota: Es posible que los anticonceptivos hormonales no sean tan eficaces en las mujeres mientras toman la combinación BI 207127/FDV y no se aceptan como métodos anticonceptivos en este estudio.
O:
Hombres
a. que se haya comprobado que son estériles, o
b. que usen de forman constante y correcta un preservativo mientras que sus parejas femeninas (con posibilidad de quedar embarazadas) acepten usar uno de los métodos anticonceptivos médicamente aceptados desde la fecha de selección hasta 7 meses después de la última dosis de ribavirina, y
c. sin parejas embarazadas. Es responsabilidad del paciente varón asegurarse de que su pareja (o parejas) no está embarazada antes de la inclusión en el estudio o de que no se quede embarazada durante la fase de tratamiento y de seguimiento. Las parejas femeninas con posibilidad de quedar embarazadas deben realizarse mensualmente pruebas de embarazo desde la fecha de selección hasta 7 meses después de la última dosis de ribavirina (el promotor proporcionará las pruebas).
8. Formulario de consentimiento firmado antes de participar en el estudio. |
|
| E.4 | Principal exclusion criteria |
1. HCV infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing
at screening
2. HCV subtype 1a, GT1 undefined or 1a/1b in patients with IL28b non-CC
polymorphism
3. Evidence of liver disease mainly due to causes other than chronic HCV infection
such as autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis or
Wilson?s disease.
Note: patients with steatosis as part of the histologic findings on liver biopsy are not
excluded.
4. HIV-1 or HIV-2 infection
5. Hepatitis B virus (HBV) infection based on presence of HBs-Ag
6. Evidence of decompensated liver disease, or history of decompensated liver disease,
defined as history of ascites, hepatic encephalopathy, bleeding esophageal varices or
any other evidence of previous decompensation
7. International Normalized Ratio (INR) of ?1.7
8. Serum albumin ?3.5 g/dL
9. Serum total bilirubin >2.0 times the upper limit of normal (ULN), unless history of
Gilbert?s disease
10. Active or suspected malignancy or history of malignancy within the last 5 years
(with the exception of appropriately treated basal cell carcinoma of the skin or in situ
carcinoma of the uterine cervix)
11. Patients with ongoing or historical photosensitivity or recurrent rash
12. Alcohol or drug abuse (except cannabis) within the past 12 months
13. Body mass index <18 or > 35 kg/m2
14. Usage of any investigational drugs within 28 days prior to randomisation, or the
planned usage of an investigational drug during the course of the current study
15. Known hypersensitivity to any ingredient of the study drugs
16. A condition that is insufficiently diagnosed, treated or clinically unstable 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
17. Alpha fetoprotein value >100ng/mL at screening; if > 20ng/mL and ? 100ng/mL,
patients can be included if there is no evidence of liver cancer in an appropriate
imaging study within 6 months prior to randomisation
18. A history of severe pre-existing cardiac disease, including unstable or uncontrolled
cardiac disease (e.g. congestive heart failure, myocardial infarction, unstable angina
and arrhythmic disorders) current or within the previous 12 months before
randomisation
19. Received concomitant hematopoietic growth factor, or immunomodulatory treatment
within 28 days prior to randomisation
20. Received silymarin (milk thistle), glycyrrhizin, Sho-saiko-to (SST) or any
medication listed in a restricted medication list provided in ISF within 28 days prior
to randomisation, with the exception of parenteral analgesics used during liver biopsy
procedure.
The following exclusion criteria are potential contraindications for the use of PegIFN
+/- RBV (for rationale please cf. Section 3.2)
21. Pre-existing psychiatric conditions including but not limited to severe depression or
hospitalization for depression, suicidal ideation and attempted suicide, schizophrenia,
bipolar illness, severe anxiety or personality disorder, a period of disability or
impairment due to a psychiatric disease current or within the previous 3 years before
randomisation
22. Abnormal thyroid function that cannot be controlled effectively by medication
23. Active autoimmune-mediated disease known to be exacerbated by peginterferon
therapy (e.g., Crohn?s disease, ulcerative colitis, idiopathic thrombocytopenic
purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma,
severe psoriasis)
24. Requirement for chronic systemic corticosteroids (nasal or pulmonary steroids will
be allowed)
25. History or other evidence of severe retinopathy or clinically significant
ophthalmological disorder due to diabetes mellitus or hypertension (but not limited to
these conditions). For subjects with a history of hypertension or diabetes, written
clearance from an ophthalmologist has to be obtained before the start of treatment
26. Hemoglobin <11.0g/dL for women and <12.0g/dL for men
27. Absolute neutrophil count < 1,500 cells/mm3
28. Platelet count < 90,000 /mm3
29. Creatinine clearance ?50 ml/min
30. Diabetes mellitus with HbA1c > 8.5%
31. Clinically evident red blood cell disorders which include but are not limited to
thalassemia major, sickle cell anemia or glucose-6-phosphate dehydrogenase
deficiency or glucose-6-phosphate dehydrogenase deficiency |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Sustained Virologic Response at Week 12 after end of active* treatment (SVR12): Plasma HCV RNA level <25 IU/mL at 12 weeks after end of active* treatment.
*As patients included in Group 1 and respectively Groups 2 and 3 have different durations of
active treatment, SVR 4, 12 and 24 will be assessed at different timepoints, taken into
consideration the time after end of active treatment |
Respuesta virológica mantenida en la semana 12 (SVR12): Nivel de RNA del HCV en plasma <25 UI/ml a las 12 semanas de finalizar el tratamiento.
* Dado que la duración del tratamiento activo de los pacientes incluidos en el grupo 1, grupo 2 y grupo 3, respectivamente, es diferente, SVR 4, 12 y 24 se evaluará en distintos puntos temporales, teniendo en cuenta el tiempo después del final del tratamiento activo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after end of active treatment, meaning Week 28 for Group 1 (16 weeks of active therapy), and Week 36 for Groups 2 and 3 (24 weeks of active therapy), respectively |
| 12 semanas tras la finalización del tratamiento activo, es decir en la semana 28 para el grupo 1 (16 semas de tratamiento activo), y semana 36 para los grupos 2 y 3 (24 semanas de tratamiento activo), respectivamente |
|
| E.5.2 | Secondary end point(s) |
- SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after end of active* treatment.
- SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after end of active*
treatment.
*As patients included in Group 1 and respectively Groups 2 and 3 have different durations of
active treatment, SVR 4, 12 and 24 will be assessed at different timepoints, taken into
consideration the time after end of active treatment |
??SVR4: Nivel plasmático de RNA del HCV <25 UI/ml 4 semanas después del final del tratamiento activo*.
- SVR24: Nivel plasmático de RNA del HCV <25 UI/ml 24 semanas después del final del tratamiento activo*.
* Dado que la duración del tratamiento activo de los pacientes incluidos en el grupo 1, grupo 2 y grupo 3, respectivamente, es diferente, SVR 4, 12 y 24 se evaluará en distintos puntos temporales, teniendo en cuenta el tiempo después del final del tratamiento activo |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SVR 4: 4 weeks after end of active treatment, meaning Week 20 for Group 1 (16 weeks of active therapy), and Week 28 for Groups 2 and 3 (24 weeks of active therapy),respectively.
SVR 24: 24 weeks after end of active treatment, meaning Week 40 for Group 1 (16 weeks of active therapy), and Week 48 for Groups 2 and 3 (24 weeks of active therapy), respectively |
- SVR 4 : 4 semanas tras la finalización del tratamiento activo, es decir, en la semana 20 para el grupo 1 (16 semanas de tratamiento activo), y en la semana 28 para los gurpos 2 y 3 (24 semanas de tratamiento activo), respectivamente.
- SVR 24: 24 semanas tras la finalización del tratamiento activo, es decir, en la semana 40 para el grupo 1 (16 semanas de tratamiento activo) y en la semana 48 para los grupos 2 y 3 (24 semanas de tratamiento activo), respectivamente. |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| groups 1 and 2: double blind, placebo-controlled, group 3: open |
|
| 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 | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Argentina |
| Austria |
| Brazil |
| Canada |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Portugal |
| Romania |
| Russian Federation |
| 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
|
| LVLS: 25 August 2015 |
| LVLS: 25 de agosto de 2015 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 17 |
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