ABT-450 With Ritonavir and ABT-267 and/or ABT-333 With and Without Ribavirin in Genotype 1 Hepatitis C Virus Infected Patients

Study Overview
=================
Brief Summary
-----------------
This is a study of combination direct-acting antiviral agents (DAA) with or without ribavirin (RBV) in patients with chronic Hepatitis C Virus (HCV).

Detailed Description
-----------------
A study to evaluate the safety and effectiveness of experimental drugs ABT-450, ABT-267 (also known as ombitasvir), ABT-333 (also known as dasabuvir), ritonavir, and ribavirin in participants with HCV. The study will test the safety and effects of combinations of these drugs in treatments up to 24 weeks.

Official Title
-----------------
A Randomized, Open-Label, Multicenter Study to Evaluate the Antiviral Activity, Safety, and Pharmacokinetics, of ABT-450 With Ritonavir (ABT-450/r) in Combination With ABT-267 and/or ABT-333 With and Without Ribavirin (RBV) for 8, 12 or 24 Weeks in Treatment-Naïve and Null Responder Subjects With Genotype 1 Chronic Hepatitis C Virus Infection

Conditions
-----------------
Chronic Hepatitis C, Hepatitis C (HCV), Hepatitis C Genotype 1

Intervention / Treatment
-----------------
* Drug: ABT-450
* Drug: ABT-333
* Drug: ABT-267
* Drug: Ribavirin
* Drug: Ritonavir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females 18-70 years old, inclusive Females must be post-menopausal for more than 2 years or surgically sterile or practicing specific forms of birth control Chronic hepatitis C virus (HCV), genotype 1 infection Treatment-naive OR null-responders to previous treatment with pegylated interferon (pegIFN) and ribavirin (at least 12 weeks of treatment and failure to achieve a 2 log10 HCV RNA decrease at Week 12) No evidence of liver cirrhosis Exclusion Criteria: Significant liver disease with any cause other than HCV as the primary cause Positive hepatitis B surface antigen and anti-human immunodeficiency virus antibody Positive screen for drugs and alcohol Significant sensitivity to any drug Use of contraindicated or prohibited medications within 1 month of dosing Abnormal laboratory tests

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 8 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group B<br>Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group C<br>Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group D<br>Treatment-naïve participants received ABT-450 200 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group E<br>Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ABT-333 400 mg twice daily for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group F<br>Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group G<br>Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group H<br>Treatment-naïve participants received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group I<br>Treatment-naïve participants received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group J<br>Participants who were null-responders to previous HCV treatment received ABT-450 200 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, and ribavirin dosed by weight, twice daily, for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group K<br>Participants who were null-responders to previous HCV treatment received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group L<br>Participants who were null-responders to previous HCV treatment received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 12 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group M<br>Participants who were null-responders to previous HCV treatment received ABT-450 100 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|
| Experimental: Group N<br>Participants who were null-responders to previous HCV treatment received ABT-450 150 mg and ritonavir 100 mg once daily, ABT-267 25 mg once daily, ABT-333 400 mg twice daily, and ribavirin dosed by weight, twice daily, for 24 weeks. | Drug: ABT-450<br>* ABT-450 tablets<br>Drug: ABT-333<br>* ABT-333 tablets<br>* Other names: Dasabuvir;Drug: ABT-267<br>* ABT-267 tablets<br>* Other names: Ombitasvir;Drug: Ribavirin<br>* Ribavirin tablets administered at a weight-based dose, between 1,000 to 1,200 mg daily (divided).<br>Drug: Ritonavir<br>* Ritonavir capsules<br>* Other names: Norvir;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each AE to the use of direct-acting antiviral agents (DAAs) and to ribavirin, and rated the severity of each event as either: Mild: The AE was transient and easily tolerated by the participant; Moderate: The AE caused the participant discomfort and interrupted usual activities; Severe: The AE caused considerable interference with the participant's usual activities and could have been incapacitating or life-threatening. A serious adverse event was any event that resulted in death, was life-threatening, resulted in or prolonged hospitalization, resulted in a congenital anomaly or persistent or significant disability or was any other important medical event requiring medical or surgical intervention. | From the time of study drug administration until 30 days following discontinuation of study drug administration (up to 28 weeks). | 
| Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose for 8 Weeks Versus 12 Weeks of Treatment With 3 DAAs and Ribavirin | The percentage of participants achieving sustained virologic response 24 weeks after the last dose of study drug (SVR24), defined as hepatitis C virus (HCV) ribonucleic acid (RNA) less than the lower limit of quantitation (LLOQ), without any confirmed quantifiable (≥ LLOQ) post-treatment value before that time point. HCV RNA levels were measured from plasma by a central laboratory. The LLOQ for the assay was 25 IU/mL. The primary efficacy endpoint was the comparison between treatment-naïve participants following 8 weeks of treatment with 3 DAAs and ribavirin and those with 12 weeks of treatment with 3 DAAs and ribavirin (Group A versus Group G). | Post Treatment Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment of Different Durations With 3 Direct-acting Antiviral Agents (DAAs) and Ribavirin | This outcome measure compares the percentage of participants achieving sustained virologic response 24 weeks after the last dose of study drug (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 3 DAAs (ABT-450/ritonavir, ABT-267, and ABT-333) and ribavirin in both treatment naïve and null-responder participants for 8 weeks (Group A) versus 12 weeks (Groups F + G + K + L) versus 24 weeks (Groups H + I + M + N). | Post-Treatment Week 24 | 
| Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 2 DAAs and Ribavirin Versus 3 DAAs and Ribavirin | This outcome measure compares the percentage of participants achieving sustained virologic response 24 weeks post-dose (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 2 DAAs (ABT-450/ritonavir plus ABT-333 [Group B] or ABT-450/ritonavir plus ABT-267 [Groups C + D + J]) and ribavirin versus 3 DAAs (ABT-450/ritonavir plus ABT-333 and ABT-267) and ribavirin (Groups F + G + K + L). | Post-Treatment Week 24 | 
| Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose Following Treatment for 12 Weeks With 3 DAAs With Versus Without Ribavirin | This outcome measure compares the percentage of participants achieving sustained virologic response 24 weeks post-dose (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 3 DAAs with or without ribavirin (Group E versus Groups F + G + K + L). | Post-Treatment Week 24 | 
| Percentage of Participants With Sustained Virologic Response 24 Weeks Post-dose in Treatment-naïve Versus Null-responders | This outcome measure compares the percentage of participants achieving sustained virologic response 24 weeks post-dose (HCV RNA < LLOQ at post-treatment Week 24) following treatment with 3 DAAs and ribavirin in participants who were treatment-naïve versus those who were null-responders to previous HCV therapy (Groups F + G + H + I versus Groups K + L + M + N). | Post-Treatment Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis C Genotype 1, Hepatitis C, Interferon-Free, HCV, Chronic Hepatitis C