A Randomized Study to Evaluate the Safety, Tolerability and Antiviral Activity of ABT-450, ABT-333 and ABT-072

Study Overview
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Brief Summary
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This study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of multiple oral doses of ABT-450/ritonavir (r), ABT-333 (also known as dasabuvir), or ABT-072 in hepatitis C virus (HCV), genotype 1-infected, treatment-naïve adults.

Detailed Description
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This was a Phase 2a, randomized, blinded, placebo-controlled, dose-ranging study in chronically, hepatitis C virus (HCV) genotype 1-infected participants designed to explore the safety, tolerability, pharmacokinetics, antiviral activity, as well as the evolution and persistence to resistance of ABT-450/r, ABT-333, or ABT-072. Participants were treated with ABT-450/r, ABT-333, or ABT-072 monotherapy for 3 days, followed by 81 days (12 weeks minus 3 days of monotherapy) of ABT-450/r, ABT-333, or ABT-072 combined with pegylated interferon/ribavirin (pegIFN/RBV), followed by 36 weeks of pegIFN/RBV alone. Participants randomized to an ABT-450/r treatment group who achieved rapid virologic response (RVR) and had HCV ribonucleic acid (RNA) levels < 25 IU/mL at all subsequent visits were eligible to stop pegIFN/RBV therapy on or after Week 24.

Official Title
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A Blinded, Randomized, Placebo-controlled, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Multiple Doses of ABT-450 With Ritonavir (ABT-450/r), ABT-333 or ABT-072 Each Administered Alone and in Combination With Peginterferon α-2a and Ribavirin (PegIFN/RBV) in Treatment-Naïve Subjects With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection

Conditions
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Hepatitis C, HCV, Chronic Hepatitis C Infection, Hepatitis C Genotype 1

Intervention / Treatment
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* Drug: ABT-450
* Drug: ABT-072
* Drug: ABT-333
* Drug: Ritonavir
* Drug: Peginterferon alpha-2a
* Drug: Ribavirin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis C virus (HCV), genotype 1 infection (HCV ribonucleic acid level greater than or equal to 100,000 IU/mL) at screening Liver biopsy within 3 years with histology consistent with HCV-induced liver damage, with no evidence of cirrhosis or liver pathology due to any cause other than chronic HCV Treatment naïve male or female between the ages of 18 and 65 Females must be post-menopausal for more than 2 years or surgically sterile Negative screen for drugs and alcohol Negative hepatitis B surface antigen (HBsAg) and anti-human immunodeficiency virus antibodies (anti-HIV Ab) No use of cytochrome P450 3A (CYP3A) and cytochrome P450 2C8 (CYP2C8) enzyme inducers or inhibitors within 1 month of dosing Be in a condition of general good health, as perceived by the investigator, other than HCV infection Exclusion Criteria: Significant sensitivity to any drug Use of herbal supplements within 2 weeks prior to study drug dosing History of major depression within 2 years Prior treatment with any investigational or commercially available anti-HCV agents Abnormal laboratory tests

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-450/r (50/100 mg) once daily (QD) + pegIFN/RBV<br>Participants received 50 mg ABT-450 and 100 mg ritonavir (r) monotherapy once daily for 3 days, followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-450<br>* 50 mg capsules co-administered with ritonavir<br>Drug: Ritonavir<br>* 100 mg capsules co-administered with ABT-450<br>* Other names: Norvir;Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-450/r (100/100 mg) once daily (QD) + pegIFN/RBV<br>Participants received 100 mg ABT-450 and 100 mg ritonavir (r) monotherapy once daily for 3 days, followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-450<br>* 50 mg capsules co-administered with ritonavir<br>Drug: Ritonavir<br>* 100 mg capsules co-administered with ABT-450<br>* Other names: Norvir;Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-450/r (200/100 mg) once daily (QD) + pegIFN/RBV<br>Participants received 200 mg ABT-450 and 100 mg ritonavir (r) monotherapy once daily for 3 days, followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-450<br>* 50 mg capsules co-administered with ritonavir<br>Drug: Ritonavir<br>* 100 mg capsules co-administered with ABT-450<br>* Other names: Norvir;Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-072 (100 mg) once daily (QD) + pegIFN/RBV<br>Participants received 100 mg ABT-072 monotherapy once daily for 3 days followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-072<br>* 50 mg tablet<br>Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-072 (300 mg) once daily (QD) + pegIFN/RBV<br>Participants received 300 mg ABT-072 monotherapy once daily for 3 days followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-072<br>* 50 mg tablet<br>Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-072 (600 mg) once daily (QD) + pegIFN/RBV<br>Participants received 600 mg ABT-072 monotherapy once daily for 3 days followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-072<br>* 50 mg tablet<br>Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-333 (400 mg) twice a day (BID) + pegIFN/RBV<br>Participants received 400 mg ABT-333 monotherapy twice a day for 3 days, followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-333<br>* 400 mg tablet<br>* Other names: Dasabuvir;Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Experimental: ABT-333 (800 mg) twice daily (BID) + pegIFN/RBV<br>Participants received 800 mg ABT-333 monotherapy twice a day for 3 days, followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: ABT-333<br>* 400 mg tablet<br>* Other names: Dasabuvir;Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>|
| Placebo Comparator: Placebo + pegIFN/RBV<br>Participants received matching placebo for ABT-450/r, ABT-072, or ABT-333 monotherapy at each dose level for 3 days, followed by the addition of pegylated interferon/ribavirin (pegIFN/RBV) for a total of 12 weeks of combination treatment, followed by 36 weeks of pegIFN/RBV alone. Pegylated interferon was dosed at 180 µg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day. | Drug: Peginterferon alpha-2a<br>* Syringe, 180 µg/0.5 mL for subcutaneous injections<br>Drug: Ribavirin<br>* 200 mg tablet dosed at 1000 or 1200 mg daily divided twice a day<br>Other: Placebo<br>* Matching placebo for ABT-450/r, ABT-072, or ABT-333 monotherapy at each dose level<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-450/r, ABT-333, or ABT-072 Monotherapy Treatment | Plasma HCV RNA levels (reported as log10 IU/mL) were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification of 25 IU/mL. The baseline value was the HCV RNA level before the first dose of study drug on Day 1. The maximal change during monotherapy was the difference from baseline to the lowest log10 HCV RNA level anytime after the first dose of study drug on Day 1 through the last log10 HCV RNA level before the first dose of study drug on Day 4. Data are reported as the mean ± standard deviation. | Prior to dosing on Day 1 to before the morning dose on Day 4 | 
| Maximum Plasma Concentration (Cmax) of ABT-450 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-450 using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ABT-450 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Time to Maximum Plasma Concentration (Tmax) of ABT-450 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-450 using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ABT-450 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of ABT-450 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-450 using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ABT-450 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Maximum Plasma Concentration (Cmax) of Ritonavir | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ritonavir using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ritonavir was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Time to Maximum Plasma Concentration (Tmax) of Ritonavir | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ritonavir using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ritonavir was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of Ritonavir | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ritonavir using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ritonavir was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Maximum Plasma Concentration (Cmax) of ABT-072 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-072 using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ABT-072 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Time to Maximum Plasma Concentration (Tmax) of ABT-072 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-072 using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ABT-072 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC24) Post-dose of ABT-072 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-072 using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ABT-072 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Maximum Plasma Concentration (Cmax) of ABT-333 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-333 using validated analytical methods. The maximum plasma concentration (Cmax; measured in ng/mL) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The Cmax of ABT-333 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Time to Maximum Plasma Concentration (Tmax) of ABT-333 | Blood samples were collected immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose). The samples were analyzed for the concentration of ABT-333 using validated analytical methods. The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax. The Tmax of ABT-333 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and prior to dose on Day 2 (24 hours after Day 1 dose) | 
| Area Under the Plasma Concentration-time Curve From 0 to 12 Hours (AUC12) Post-dose of ABT-333 | Blood samples were collected immediately prior to morning dose (time 0 hours) and at 2, 4, 8, and 12 hours after the morning dose on Day 1. The samples were analyzed for the concentration of ABT-333 using validated analytical methods. The area under the plasma concentration-time curve (AUC; measured in ng*hr/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC12 of ABT-333 was estimated using non-compartmental methods and data are reported as the mean ± standard deviation. | Immediately prior to morning dose (time 0 hours) and at 2, 4, 8, and 12 hours after the morning dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Rapid Virologic Response (RVR) at Week 4 | Plasma hepatitis C virus ribonucleic acid (HCV RNA) levels were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL. Rapid virologic response was defined as HCV RNA level < LLOQ (< 25 IU/mL) at Week 4. Data are reported as the percentage of participants with RVR. | Week 4 | 
| Percentage of Participants With Partial Early Virologic Response (EVR) at Week 12 | Plasma hepatitis C virus ribonucleic acid (HCV RNA) levels were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification of 25 IU/mL. Partial early virologic response (EVR) was defined as HCV RNA levels that decreased > 2 log10 IU/mL at Week 12 as compared to baseline. The baseline value was the last measurement before the first dose on Day 1. Data are reported as the percentage of participants with partial EVR. | Baseline and Week 12 | 
| Percentage of Participants With Complete Early Virologic Response (cEVR) at Week 12 | Plasma hepatitis C virus ribonucleic acid (HCV RNA) levels were determined for each sample using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay that had a lower limit of detection of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL. Complete EVR was defined as HCV RNA levels < LLOQ (< 25 IU/mL) at Week 12. Data are reported as the percentage of participants with cEVR. | Week 12 |