E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis C |
hepatitis C crónica |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Hepatitis C |
hepatitis C crónica |
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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 | 14.1 |
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 |
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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 efficacy of daclatasvir and TMC435 with and without ribavirin, as determined by the proportion of subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12. |
Evaluar la eficacia, determinada por el porcentaje de sujetos con RVM12, definida como ARN del VHC < LDC en la semana postratamiento 12. |
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E.2.2 | Secondary objectives of the trial |
? To assess safety, as measured by the frequency of SAEs and discontinuations due to AEs; ? To assess the relationship between efficacy and the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene; ? To assess the efficacy as determined by: ? HCV RNA < LOQ at each of the following time points: Weeks 1, 2, 4, 6, 8 (and 12), EOT, post-treatment Week 24 (SVR24), and post-treatment Week 36 (genotype 1b for 12 week arms); ? HCV RNA undetectable at each of the following time points: Weeks 1, 2, 4, 6, 8 (and 12), EOT, post-treatment Week 12, post treatment Week 24, and post-treatment Week 36 (genotype 1b for 12 week arms). |
.Evaluar la seguridad, medida por la frecuencia de AAG y retiradas debido a AA; ?Evaluar la relación entre eficacia y los polimorfismos de un único nucleótido (SNP) rs12979860 en el gen IL28B; ?Evaluar la eficacia determinada por: ----ARN del VHC < LDC en cada uno de los siguientes puntos temporales: semanas 1, 2, 4, 6, 8 (y 12), FDT, semana 24 postratamiento (RVM24) y semana 36 postratamiento (genotipo 1b para los grupos de 12 semanas); ----ARN del VHC indetectable en cada uno de los siguientes puntos temporales: semanas 1, 2, 4, 6, 8 (y 12), FDT, semana 12 postratamiento, semana 24 postratamiento y semana 36 postratamiento (genotipo 1 b para los grupos de 12 semanas). |
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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 |
See section 5.5 of the study Protocol (Pharmacokinetic Assessments)
A pharmacokinetics sub-study of approximately 36 subjects at specified sites will be included to evaluate the pharmacokinetics of DCV and TMC435. In addition, an additional HCV RNA level at Day 3 will be collected in a subset of approximately 15 subjects at specified sites. |
ver seccion 5.5 del protocolo subestudio de farmacogenetica de aproximadamente 36 sujetos tratados en centros especificadosse incluiran para evaluar la farmacogenetica de DCV y TMC435S. Además, se recogerán en el día 3 muestras de ARN del VHC en un subgrupo de aproximadamente 15 sujetos de centros concretos. |
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E.3 | Principal inclusion criteria |
? HCV Genotype 1a or 1b; ? Males and females, ? 18 years of age; ? HCV RNA > 10,000 IU/mL; ? Subjects with compensated cirrhosis are permitted. ? Advanced fibrosis (F3/F4) is capped at approximately 35% of the total treated population with a minimum of 20% F4 subjects. ? If no cirrhosis, a liver biopsy within 3 years prior to enrollment is required ? If cirrhosis is present, any prior liver biopsy is sufficient |
?Hombres y mujeres, ? 18 años de edad; ?VHC de genotipo 1a o 1b; ?Si la cirrosis está presente, es necesario biopsia hepática ?ARN del VHC > 104 UI/ml (10.000 UI/ml); ?Se permiten los sujetos con cirrosis compensada. ?El número de sujetos con fibrosis avanzada (F3/F4) se corta a aproximadamente el 35% de la población total tratada con un mínimo de un 20% de sujetos F4. ?Si no hay cirrosis, una biopsia de hígado dentro de los 3 años anteriores a la entrada en el estudio |
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E.4 | Principal exclusion criteria |
Target Disease Exceptions ? Liver or any other transplant (other than cornea and hair): ? Evidence of a medical condition contributing to chronic liver disease other than HCV; ? Current or known history of cancer, (except situ carcinoma or adequately tx basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment ? Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy; ? Subjects infected with HIV or HBV; ? Gastrointestinal disease impacting absorption of study drug; ? Uncontrolled diabetes or hypertension;
Medication related ? Prior treatment of HCV with HCV direct acting agent (DAA); ? Any criteria that would exclude the subject from receiving RBV.
Exclusion Laboratory results:
? Confirmed ANC < 1.5 billion cells/L (<1.2 billion cells/L for Black/African-Americans); ? Confirmed platelets < 90 billion cells/L; ? Confirmed hemoglobin < 12 g/dL for females or < 13 g/dL for males; ? ALT? 5 x ULN ? In subjects without cirrhosis, total bilirubin ? 34 ?mol/L (or ? 2 mg/dL) unless subject has a documented history of Gilbert?s disease; ? In subjects with cirrhosis, total bilirubin ? 26 ?mol/L (or ? 1.5 mg/dL); ? INR? 1.7 ? QTcF or QTcB > 500 mSec ? CrCl? 50 mL/min ? AFP > 100 ng/mL OR ? AFP ? 50 ng/mL and ? 100 ng/mL requires a liver ultrasound (HCC are excluded) ? Albumin < 3.5 g/dL (35 g/L) |
?Tratamiento previo del VHC con antivirales de acción directa (AAD) contra el VHC; ?Evidencia de un trastorno médico que contribuye a la hepatopatía crónica distinto a la infección por el VHC; ?Evidencia de enfermedad hepática descompensada incluidos, entre otros, antecedentes de presencia ó criterios radiológicos de ascitis, varices hemorrágicas o encefalopatía hepática; ?Diagnóstico o sospecha de carcinoma hepatocelular u otros tumores; ?Diabetes o hipertensión no controladas; ?En sujetos sin cirrosis, bilirrubina total ? 34 ?mo/l (o ? 2 mg/dl) salvo que el sujeto tenga antecedentes documentados de enfermedad de Gilbert. En sujetos con cirrosis, bilirrubina total ?26 ?mol/L (o ? 1.5 mg/dL);
?ALT confirmada ? 5x LSN; ?Albúmina confirmada < 3,5 g/dl (35 g/l) ?Se excluyen los sujetos con AFP > 100 ng/ml O ? si 50 y? 100 ng/ml que requiere ecografía hepática (o resultados existentes de una prueba de imagen superior en los 3 meses anteriores a la obtención del valor AFP) y los sujetos con sospecha de CHC; ?Para los criterios hematológicos no se deben usar factores de crecimiento para alcanzar los requisitos de entrada en el estudio; ?RAN confirmado < 1,5 x 109 células/l (< 1,2 x 109 células/l en negros/afroamericanos); ?Plaquetas confirmadas < 90 x 109 células/l; ?Hemoglobina confirmada < 12 g/dl para mujeres o < 13 g/dl para hombres; ?Cualquier criterio que excluiría al sujeto de recibir RBV. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Antiviral activity, as determined by the proportion of subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12, for each cohort defined by the previous response status (Naive, Null), HCV genotype, initial treatment regimen and treatment duration. |
?Actividad antiviral, determinada por el porcentaje de sujetos con RVM12, definida como ARN del VHC < LDC en la semana postratamiento 12, para cada cohorte definida, por el estado previo de respuesta (previamente no tratados, respuesta nula), genotipo del VHC, régimen de tratamiento inicial y duración del tratamiento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks post treatment |
12 semana postratamiento |
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E.5.2 | Secondary end point(s) |
? On-treatment safety, as measured by the frequency of SAEs and discontinuations due to AEs from start (Day 1) to end of treatment (up to 24 weeks) plus 7 days. ? Proportion of subjects with SVR12 (HCV RNA < LOQ at post-treatment Week 12) by the rs12979860 single nucleotide polymorphisms (SNP) in the IL28B gene for each treatment arm. ? Proportion of subjects with HCV RNA < LOQ at each of the following time points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms; ? Proportion of subjects with HCV RNA undetectable at each of the following time points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 12 and post-treatment Week 24 for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms. |
?Seguridad durante el período de tratamiento, medida por la frecuencia de AAG y retiradas debidas a AA hasta el final del tratamiento más 7 días. ?Porcentaje de sujetos con RVM12 (ARN del VHC < LDC en la semana postratamiento 12) por polimorfismos de un único nucleótido (SNP) rs12979860 en el gen IL28B para cada grupo de tratamiento. ?Porcentaje de sujetos con ARN del VHC < LDC en cada uno de los siguientes puntos temporales: Semanas 1, 2, 4, 6 y 8 (y 12); FDT (hasta 24 semanas), semana 24 postratamiento (RVM24) para cada grupo de tratamiento y semana 36 postratamiento (genotipo 1b) para los sujetos en los grupos de tratamiento de 12 semanas. ?Porcentaje de sujetos con ARN del VHC indetectable en cada uno de los siguientes puntos temporales: Semanas 1, 2, 4, 6 y 8 (y 12); FDT (hasta 24 semanas), semana 12 postratamiento y semana 24 postratamiento para cada grupo de tratamiento y semana 36 postratamiento (genotipo 1b) para los sujetos en los grupo de tratamiento de 12 semanas. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
? from start (Day 1) to end of treatment (up to 24 weeks) plus 7 days. ? post treatment week 12 ? at each of the following time points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms; ? at each of the following time points: Weeks 1, 2, 4, 6, and 8 (and 12); EOT (up to 24 weeks), post-treatment Week 12 and post-treatment Week 24 for each treatment arm, and post-treatment Week 36 (genotype 1b) for subjects in the 12 week treatment arms. |
desde el principio (1 día) a fin de tratamiento (hasta 24 semanas) más 7 días. post tratamiento semana 12 ?Evaluar la eficacia determinada por: ----ARN del VHC < LDC en cada uno de los siguientes puntos temporales: semanas 1, 2, 4, 6, 8 (y 12), FDT, semana 24 postratamiento (RVM24) y semana 36 postratamiento (genotipo 1b para los grupos de 12 semanas); ----ARN del VHC indetectable en cada uno de los siguientes puntos temporales: semanas 1, 2, 4, 6, 8 (y 12), FDT, semana 12 postratamiento, semana 24 postratamiento y semana 36 postratamiento (genotipo 1 b para los grupos de 12 semanas). |
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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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker; Resistance testing |
Bioindicadores; Pruebas de Resistencia |
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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 | 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 |
daclatasvir (BMS-790052) y TMC435 en combinación con o sin ribavirina (RBV), |
DCV/TMC435 combination with or without RBV |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Chile |
France |
Germany |
Hungary |
Russian Federation |
Spain |
United States |
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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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The last visit is defined as the date of the last post-treatment follow-up visit. The end of the study is defined as the last subject?s last visit date or when the last data point required for statistical analysis is received from the last subject, whichever is later. |
La última visita se define como la fecha de la última visita de seguimiento de postratamiento. el final del estudio se define como la fecha de la última visita del último paciente o cuando la último fecha es requerida para los datos del análisis estadístico y se recibe del último paciente, de cuaquier modo mas tarde |
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 2 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 2 |