A Phase 2 interventional study of ABT-333 and Placebo for ABT-333 in Chronic Hepatitis C Virus Infection, sponsored by AbbVie (prior sponsor, Abbott). Completed at 8 sites in 2 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2018-07-02.
Sponsored by AbbVie (prior sponsor, Abbott) · Phase 2, Interventional, and Treatment
The purpose of this study was to assess the safety, tolerability, pharmacokinetics and antiviral activity of ABT-333 (also known as dasabuvir) in treatment-naïve, hepatitis C virus (HCV)-infected participants.
This was a Phase 2a, blinded, randomized, placebo-controlled clinical trial in hepatitis C virus (HCV)-infected adults with 2 planned sequential evaluations, Part 1 and Part 2. The study evaluated the safety, tolerability, antiviral activity, and pharmacokinetics of ABT-333 or placebo monotherapy, followed by 26 days of ABT-333 or placebo with pegylated interferon a-2a (pegIFN) and ribavirin (RBV) combination therapy. Review of safety and efficacy in Part 1 of the study showed similar response rates across ABT-333 doses so Part 2 of the study was not performed. The study also assessed emergence of resistant HCV in conjunction with kinetics of viral load decay and rebound in treatment-naïve, HCV-infected participants.
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Hepatitis C virus (HCV) positive, treatment-naive participants received 300 mg ABT-333 BID for 2 days followed by 300 mg ABT-333 BID with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.
Drug: ABT-333 · Drug: Pegylated interferon · Drug: Ribavirin
Hepatitis C virus (HCV) positive, treatment-naive participants received 600 mg ABT-333 BID for 2 days followed by 600 mg ABT-333 BID with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.
Drug: ABT-333 · Drug: Pegylated interferon · Drug: Ribavirin
Hepatitis C virus (HCV) positive, treatment-naive participants received 1200 mg ABT-333 QD for 2 days followed by 1200 mg ABT-333 QD with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.
Drug: ABT-333 · Drug: Pegylated interferon · Drug: Ribavirin
Hepatitis C virus (HCV) positive, treatment-naïve participants received matching placebo once daily (QD) or twice daily (BID) for 2 days followed by placebo QD or BID with pegylated interferon/ribavirin (pegIFN/RBV) for 26 days. Pegylated interferon was administered at 180 μg subcutaneously once a week and RBV was dosed 1000 or 1200 mg daily divided twice a day.
Other: Placebo for ABT-333 · Drug: Pegylated interferon · Drug: Ribavirin
Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Monotherapy Treatment
Serum hepatitis C virus ribonucleic acid (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. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. The maximal change during monotherapy was nadir minus the baseline log10 HCV RNA level. Nadir was defined as the lowest log10 HCV RNA level any time 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 3. Data are reported as the least squares mean change from nadir ± standard error.
Time frame: Prior to the first dose on Day 1 to before first dose on Day 3
Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28
Serum hepatitis C virus ribonucleic acid (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. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. The maximal change during treatment was nadir minus the baseline log10 HCV RNA level. Nadir was defined as the lowest log10 HCV RNA level any time after the first dose of study drug on Day 1 through the last log10 HCV RNA level on Day 28. Data are reported as the least squares mean change from nadir ± standard error.
Time frame: Prior to the first dose on Day 1 through Day 28
Maximum Plasma Concentration (Cmax) of ABT-333
Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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.
Time frame: Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2
Time to Maximum Plasma Concentration (Tmax) of ABT-333
Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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.
Time frame: Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2
Area Under the Plasma Concentration-time Curve From 0 to 12 Hours Post-dose (AUC12) of ABT-333
Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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) measures 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.
Time frame: Pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours post-dose on Day 1; and pre-dose on Day 2
Serum Concentrations of Pegylated Interferon (pegIFN)
Blood samples were collected prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28. The samples were analyzed for the concentration of pegIFN (measured in ng/mL) using validated analytical methods and estimated using non-compartmental methods. Data are reported as the mean ± standard deviation.
Time frame: Prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28
Plasma Concentrations of Ribavirin (RBV)
Blood samples were collected prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28. The samples were analyzed for the concentration of RBV (measured in ng/mL) using validated analytical methods and estimated using non-compartmental methods. Data are reported as the mean ± standard deviation.
Time frame: Prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28
Number of Participants Having Treatment-emergent Adverse Events (AEs)
An AE was any untoward medical occurrence that did not have a causal relationship with treatment. An Adverse Drug Reaction (ADR) was any noxious and undesired reaction related to the experimental drug or experiment. A serious adverse event (SAE) was an AE that resulted in death, was life-threatening, resulted in or prolonged hospitalization, resulted in congenital anomaly, was persistent or caused significant disability/incapacity, spontaneous or elective abortion, or required intervention to prevent a serious outcome. AEs were rated for severity as either: 1. Mild - transient and easily tolerated; 2. Moderate - caused discomfort and interrupted usual activities; 3. Severe - caused considerable interference with usual activities, may be incapacitating or life-threatening. AEs related to direct-acting antiviral agents (DAAs) were assessed as being either probably or possibly related by the investigator.
Time frame: AEs were collected from the time of study drug administration to 30 days after last dose of study drug (8 Weeks)
Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28 or Final Visit
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (reported as log10 IU/mL) were determined using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1 and the Day 28 or Final Visit value was the last HCV RNA measurement during the study. Data are reported as the least squares mean change from baseline ± standard error.
Time frame: Day 28 and Final Visit
Percentage of Participants With at Least a 2 log10 Maximal Decrease in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Treatment
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. Data are reported as the percentage of participants.
Time frame: Prior to the first dose on Day 1 and Day 28
Percentage of Participants With Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels ≤ 25 IU/mL (the Lower Limit of Quantitation [LLOQ]) at Day 28 or Final Visit
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined for each sample using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The lower limit of quantification (LLOQ) was defined as HCV RNA levels ≤ 25 IU/mL. Data are reported as the percentage of participants.
Time frame: Day 28 or Final Visit
Percentage of Participants With Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels ≤ 10 IU/mL (Lower Limit of Detection [LLOD]) at Day 28 or Final Visit
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined for each sample using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The lower limit of detection (LLOD) was defined as a HCV RNA level equal to 10 IU/mL. Data are reported as the percentage of participants.
Time frame: Day 28 or Final Visit
Number of Participants With Resistance-Associated Variants in Non-structural Viral Protein 5B (NS5B) Through Day 28
Samples from Days 1, 5, 10, 17, 24 and 28 were analyzed for the presence of resistance-associated amino acids using population sequencing and compared to the baseline non-structural viral protein 5B (NS5B) sequence to assess amino acid changes. The amino acid sequence of NS5B before the first dose of ABT-333 on Day 1 was defined as the baseline sequence. The number of participants with variants at resistance-associated amino acid positions in the post-baseline samples are presented.
Time frame: Days 1, 5, 10, 17, 24 and 28
Number of Participants With Maximal Phenotypic Resistance to ABT-333 >10 Fold Relative to Baseline Through Day 28
Phenotypic resistance to ABT-333 was assessed by calculating the fold difference in the half maximal effective concentration (EC50) compared with the EC50 for the corresponding baseline sample, and the maximal fold change in EC50 from baseline over the Day 5-28 period. The resistance sample drawn before the first dose of ABT-333 on Day 1 was defined as the baseline sample. The number of participants with phenotypic resistance in the post-baseline samples are presented.
Time frame: Days 1 through 28
| Milestone | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Started | 8 | 8 | 8 | 6 |
| Completed | 8 | 7 | 8 | 5 |
| Not completed | 0 | 1 | 0 | 1 |
| Withdrew: Lost to follow-up | 0 | 1 | 0 | 1 |
Serum hepatitis C virus ribonucleic acid (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. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. The maximal change during monotherapy was nadir minus the baseline log10 HCV RNA level. Nadir was defined as the lowest log10 HCV RNA level any time 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 3. Data are reported as the least squares mean change from nadir ± standard error.
| log10 IU/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Monotherapy Treatment | -1.01 ± 0.18 | -0.78 ± 0.18 | -0.68 ± 0.18 | -0.26 ± 0.21 |
Serum hepatitis C virus ribonucleic acid (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. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. The maximal change during treatment was nadir minus the baseline log10 HCV RNA level. Nadir was defined as the lowest log10 HCV RNA level any time after the first dose of study drug on Day 1 through the last log10 HCV RNA level on Day 28. Data are reported as the least squares mean change from nadir ± standard error.
| log10 IU/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Mean Maximal Change From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels Through Day 28 | -3.65 ± 0.51 | -3.96 ± 0.51 | -3.59 ± 0.51 | -1.37 ± 0.59 |
Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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.
| ng/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV |
|---|---|---|---|
| Maximum Plasma Concentration (Cmax) of ABT-333 | 883 ± 575 | 1236 ± 724 | 1975 ± 619 |
Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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.
| Hours | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV |
|---|---|---|---|
| Time to Maximum Plasma Concentration (Tmax) of ABT-333 | 3.80 ± 0.71 | 3.50 ± 0.93 | 3.50 ± 0.93 |
Blood samples were collected pre-dose (time 0 hours); 2, 4, 8, 12, and 16 hours after the morning dose on Day 1; and pre-dose on Day 2. 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) measures 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.
| ng*hr/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV |
|---|---|---|---|
| Area Under the Plasma Concentration-time Curve From 0 to 12 Hours Post-dose (AUC12) of ABT-333 | 5852 ± 4159 | 7548 ± 4016 | 12411 ± 4122 |
Blood samples were collected prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28. The samples were analyzed for the concentration of pegIFN (measured in ng/mL) using validated analytical methods and estimated using non-compartmental methods. Data are reported as the mean ± standard deviation.
| ng/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Prior to morning dose on Day 3 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 |
| 4 hours after morning dose on Day 3 (n=7, 8, 8, 6) | 0.70 ± 0.67 | 1.36 ± 1.51 | 0.09 ± 0.25 | 0.58 ± 0.70 |
| Day 4 (n=8, 8, 7, 6) | 6.96 ± 4.04 | 6.51 ± 5.15 | 4.95 ± 4.50 | 3.42 ± 2.11 |
| Day 5 | 9.06 ± 5.15 | 7.91 ± 4.82 | 5.57 ± 4.29 | 4.85 ± 3.17 |
| Day 10 | 7.91 ± 2.21 | 6.47 ± 3.18 | 4.72 ± 3.28 | 4.48 ± 2.77 |
| Day 17 (n=8, 8, 8, 5) | 12.3 ± 3.99 | 9.26 ± 4.28 | 8.73 ± 5.92 | 7.05 ± 5.06 |
| Day 24 (n=8, 7, 8, 5) | 12.8 ± 3.45 | 12.1 ± 4.78 | 12.1 ± 7.11 | 8.58 ± 6.45 |
| Day 28 (n=8, 7, 8, 5) | 17.4 ± 4.67 | 17.3 ± 3.95 | 17.0 ± 10.1 | 14.3 ± 10.0 |
Blood samples were collected prior to the morning dose on Day 3; 4 hours after the morning dose on Day 3; prior to the morning dose on Days 4 and 5; and single samples were collected on Days 10, 17, 24, and 28. The samples were analyzed for the concentration of RBV (measured in ng/mL) using validated analytical methods and estimated using non-compartmental methods. Data are reported as the mean ± standard deviation.
| ng/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Prior to morning dose on Day 3 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 |
| 4 hours after morning dose on Day 3 | 0.46 ± 0.16 | 0.61 ± 0.40 | 0.51 ± 0.15 | 0.54 ± 0.19 |
| Day 4 (n=5, 7, 5, 5) | 0.33 ± 0.07 | 0.46 ± 0.11 | 0.29 ± 0.17 | 0.36 ± 0.05 |
| Day 5 (n=6, 6, 8, 5) | 0.61 ± 0.10 | 0.69 ± 0.22 | 0.48 ± 0.20 | 0.55 ± 0.14 |
| Day 10 (n=7, 8, 8, 6) | 1.05 ± 0.17 | 1.24 ± 0.29 | 1.02 ± 0.38 | 1.05 ± 0.21 |
| Day 17 (n=8, 8, 8, 5) | 1.47 ± 0.29 | 1.67 ± 0.40 | 1.32 ± 0.36 | 1.34 ± 0.52 |
| Day 24 (n=8, 7, 8, 5) | 1.76 ± 0.31 | 1.91 ± 0.38 | 1.60 ± 0.39 | 1.49 ± 0.19 |
| Day 28 (n=8, 7, 8, 5) | 1.76 ± 0.44 | 2.07 ± 0.53 | 1.56 ± 0.46 | 1.68 ± 0.66 |
An AE was any untoward medical occurrence that did not have a causal relationship with treatment. An Adverse Drug Reaction (ADR) was any noxious and undesired reaction related to the experimental drug or experiment. A serious adverse event (SAE) was an AE that resulted in death, was life-threatening, resulted in or prolonged hospitalization, resulted in congenital anomaly, was persistent or caused significant disability/incapacity, spontaneous or elective abortion, or required intervention to prevent a serious outcome. AEs were rated for severity as either: 1. Mild - transient and easily tolerated; 2. Moderate - caused discomfort and interrupted usual activities; 3. Severe - caused considerable interference with usual activities, may be incapacitating or life-threatening. AEs related to direct-acting antiviral agents (DAAs) were assessed as being either probably or possibly related by the investigator.
| participants | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Any AE | 8 | 8 | 8 | 5 |
| Any AE at least possibly drug related | 4 | 3 | 2 | 1 |
| Any severe AE | 1 | 0 | 0 | 0 |
| Any serious AE | 0 | 0 | 0 | 0 |
| Any AE leading to discontinuation of study drug | 0 | 0 | 0 | 0 |
| Any fatal events | 0 | 0 | 0 | 0 |
| Deaths | 0 | 0 | 0 | 0 |
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (reported as log10 IU/mL) were determined using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1 and the Day 28 or Final Visit value was the last HCV RNA measurement during the study. Data are reported as the least squares mean change from baseline ± standard error.
| log10 IU/mL | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Day 28 (n=8, 7, 7, 5) | -3.65 ± 0.53 | -3.67 ± 0.57 | -3.24 ± 0.57 | -1.45 ± 0.68 |
| Final Visit | -3.65 ± 0.53 | -3.86 ± 0.53 | -3.48 ± 0.53 | -1.35 ± 0.61 |
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The baseline value was the HCV RNA measurement before the first dose of ABT-333 on Day 1. Data are reported as the percentage of participants.
| percentage of participants | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Percentage of Participants With at Least a 2 log10 Maximal Decrease in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels During ABT-333 Treatment | 87.5 | 87.5 | 62.5 | 16.7 |
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined for each sample using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The lower limit of quantification (LLOQ) was defined as HCV RNA levels ≤ 25 IU/mL. Data are reported as the percentage of participants.
| percentage of participants | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Percentage of Participants With Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels ≤ 25 IU/mL (the Lower Limit of Quantitation [LLOQ]) at Day 28 or Final Visit | 37.5 | 25.0 | 62.5 | 0.00 |
Serum hepatitis C virus ribonucleic acid (HCV RNA) levels (measured in IU/mL) were determined for each sample using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. The lower limit of detection (LLOD) was defined as a HCV RNA level equal to 10 IU/mL. Data are reported as the percentage of participants.
| percentage of participants | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV |
|---|---|---|---|---|
| Percentage of Participants With Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels ≤ 10 IU/mL (Lower Limit of Detection [LLOD]) at Day 28 or Final Visit | 37.5 | 0.00 | 12.5 | 0.00 |
Samples from Days 1, 5, 10, 17, 24 and 28 were analyzed for the presence of resistance-associated amino acids using population sequencing and compared to the baseline non-structural viral protein 5B (NS5B) sequence to assess amino acid changes. The amino acid sequence of NS5B before the first dose of ABT-333 on Day 1 was defined as the baseline sequence. The number of participants with variants at resistance-associated amino acid positions in the post-baseline samples are presented.
| participants | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV |
|---|---|---|---|
| Day 1 | 0 | 1 | 0 |
| Day 5 (n=6, 8, 7) | 1 | 1 | 1 |
| Day 10 (n=6, 6, 7) | 1 | 1 | 2 |
| Day 17 (n=5, 5, 6) | 2 | 2 | 2 |
| Day 24 (n=3, 3, 2) | 3 | 3 | 1 |
| Day 28 (n=4, 3, 3) | 2 | 2 | 3 |
Phenotypic resistance to ABT-333 was assessed by calculating the fold difference in the half maximal effective concentration (EC50) compared with the EC50 for the corresponding baseline sample, and the maximal fold change in EC50 from baseline over the Day 5-28 period. The resistance sample drawn before the first dose of ABT-333 on Day 1 was defined as the baseline sample. The number of participants with phenotypic resistance in the post-baseline samples are presented.
| participants | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV |
|---|---|---|---|
| Number of Participants With Maximal Phenotypic Resistance to ABT-333 >10 Fold Relative to Baseline Through Day 28 | 4 | 4 | 5 |
Collected over AEs were collected from the time of study drug administration to 30 days after last dose of study drug ( 8 Weeks); SAEs were also collected from the time that informed consent was obtained to 30 days after last dose of study drug (up to 12 weeks).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| ABT-333 (300 mg) Twice Daily (BID) + (pegIFN/RBV) | — | 0/8 (0%) | 8/8 (100%) |
| ABT-333 (600 mg) Twice Daily (BID) + (pegIFN/RBV) | — | 0/8 (0%) | 8/8 (100%) |
| ABT-333 (1200 mg) Once Daily (QD) + (pegIFN/RBV) | — | 0/8 (0%) | 8/8 (100%) |
| Placebo + (pegIFN/RBV) | — | 0/6 (0%) | 5/6 (83.3%) |
| Event | ABT-333 (300 mg) Twice Daily (BID) + (pegIFN/RBV) | ABT-333 (600 mg) Twice Daily (BID) + (pegIFN/RBV) | ABT-333 (1200 mg) Once Daily (QD) + (pegIFN/RBV) | Placebo + (pegIFN/RBV) |
|---|---|---|---|---|
| FATIGUEGeneral disorders | 5/8 | 1/8 | 1/8 | 1/6 |
| HEADACHENervous system disorders | 5/8 | 5/8 | 4/8 | 2/6 |
| INFLUENZA LIKE ILLNESSGeneral disorders | 1/8 | 2/8 | 3/8 | 3/6 |
| ANAEMIABlood and lymphatic system disorders | 1/8 | 3/8 | 1/8 | 0/6 |
| NAUSEAGastrointestinal disorders | 1/8 | 2/8 | 3/8 | 0/6 |
| ARTHRALGIAMusculoskeletal and connective tissue disorders | 3/8 | 1/8 | 0/8 | 1/6 |
| IRRITABILITYGeneral disorders | 1/8 | 1/8 | 0/8 | 2/6 |
| HYPERURICAEMIAMetabolism and nutrition disorders | 0/8 | 0/8 | 0/8 | 2/6 |
| NEUTROPENIABlood and lymphatic system disorders | 2/8 | 0/8 | 1/8 | 0/6 |
| CHILLSGeneral disorders | 2/8 | 1/8 | 1/8 | 0/6 |
Baseline characteristics were summarized by treatment group for all participants who received at least 1 dose of study drug. The treatment groups were compared with 1-way analysis of variance (ANOVA).
| Age, Continuous(years) | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV | Total |
|---|---|---|---|---|---|
| Mean | 45.8 ± 9.62 | 44.6 ± 12.96 | 47.8 ± 9.50 | 48.2 ± 7.31 | 46.5 ± 9.80 |
| Sex: Female, Male(Participants) | ABT-333 (300 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (600 mg) Twice Daily (BID) + pegIFN/RBV | ABT-333 (1200 mg) Once Daily (QD) + pegIFN/RBV | Placebo + pegIFN/RBV | Total |
|---|---|---|---|---|---|
| Female | 1 | 3 | 4 | 1 | 9 |
| Male | 7 | 5 | 4 | 5 | 21 |
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Studies of the drug tested here: Dasabuvir
AbbVie (prior sponsor, Abbott) →