Hepatitis C
Conditions
Brief summary
This is a randomized, multi-site, open-label trial of the co-administration of a fixed-dose combination (FDC) of EBR 50 mg + GZR (100 mg) (EBR/GZR) and SOF 400 mg, with and without RBV, in treatment-naïve (TN) and treatment-experienced (TE) participants with chronic HCV GT3 infection with compensated cirrhosis.
Interventions
DRUGGrazoprevir
GZR 100 mg is a component of the MK-5172A FDC tablet (also containing EBR 50 mg) and was taken q.d. by mouth in the morning.
DRUGElbasvir
EBR 50 mg is a component of the MK-5172A FDC tablet (also containing GZR 100 mg) and was taken q.d. by mouth in the morning.
DRUGRibavirin
RBV 200 mg capsules taken b.i.d. (morning and evening) by mouth at a total daily dose ranging from 800 mg to 1400 mg (total daily dose was based on participant body weight).
DRUGSofosbuvir
SOF 400 mg tablet taken q.d. by mouth in the morning with food.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* has HCV RNA (\>= 10,000 IU/mL in peripheral blood) at screening * has documented HCV GT3 (with no evidence of non-typeable or mixed GT infection) * has compensated cirrhosis of the liver * has liver imaging within 6 months of Day 1 with no evidence of hepatocellular carcinoma (HCC) * is either HCV TN or TE (i.e., has documented prior virologic failure or intolerance to peg-interferon/ribavirin) * is otherwise healthy as determined by medical history, physical examination, electrocardiogram (ECG), and clinical laboratory measurements * has compensated cirrhosis of the liver * is TN or TE (i.e., documented prior virologic failure or intolerance to peg-interferon/ribavirin) * is not of reproductive potential, or agrees to not impregnate a partner or become pregnant for at least 2 weeks prior to the first dose of study drug, and for 7 months after the final dose of study drug (or longer if dictated by local regulations)
Exclusion criteria
* has previously received one or more doses of a direct-acting antiviral (DAA) * has evidence of decompensated liver disease * is coinfected with hepatitis B (hepatitis B surface antigen \[HBsAg\] positive) * has a recent (within 5 years) history of malignancy or is under evaluation for HCC or other suspected malignancy * is currently or has participated (within past 30 days) in a study with an investigational compound * has clinically-relevant drug or alcohol abuse within the past 12 months of screening * is a female and is pregnant or breast-feeding * is a male whose female partner is/are pregnant * has any of the following: * organ transplants * poor venous access * history of gastric surgery or malabsorption disorder * current or history of clinically significant cardiac abnormalities or dysfunction * chronic pulmonary disease * hemoglobinopathy * history of hospitalization within 3 months prior to enrollment * medical or surgical condition that may result in need for hospitalization during the course of the study * any condition requiring, or likely to require, chronic systemic administration of corticosteroids, tumor necrosis factor (TNF) antagonists, or other immunosuppresant drugs during the course of the study * any condition, prestudy laboratory or ECG abnormality, or history of any illness, which could confound results of the study or pose additional risks in administering study drugs in the opinion of the investigator * has a life-threatening serious AE (SAE) during the screening period * has evidence of history of chronic hepatitis not caused by HCV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy) | Up to Week 28 | The percentage of participants achieving SVR12 (i.e., HCV ribnonucleic acid \[RNA\] \< Lower Limit of Quantification \[LLOQ\] 12 weeks after completing study treatment) was determined. Plasma HCV RNA levels were determined with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL. |
| Percentage of Participants Experiencing an Adverse Event (AE) | Up to 18 weeks (up to 2 weeks after completion of study treatment) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Percentage of Participants Discontinuing From Study Therapy Due to an AE | Up to 16 weeks | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy) | Up to Week 40 | The percentage of participants achieving SVR24 (i.e., HCV RNA \< LLOQ 24 weeks after completing study treatment) was determined. Plasma HCV RNA levels were determined with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL. |
Participant flow
Recruitment details
Adult participants infected with HCV GT3 were enrolled at 14 study centers in the United Kingdom.
Pre-assignment details
A total of 101 participants were randomized, including 1 participant who did not meet inclusion criteria and who should have been considered a screen failure; this participant was not treated with study drug. A total of 100 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: HCV GT3 TN EBG/GZR+SOF+RBV 8 Weeks TN HCV GT3 participants took 1 FDC tablet containing EBR 50 mg + GZR 100 mg and 1 tablet containing SOF 400 mg q.d. with RBV (200 mg capsules; weight-based dosing) b.i.d. for 8 weeks. | 23 |
| Arm 2: HCV GT3 TN EBG/GZR+SOF 12 Weeks TN HCV GT3 participants took 1 FDC tablet containing EBR 50 mg + GZR 100 mg and 1 tablet containing SOF 400 mg q.d. for 12 weeks. | 24 |
| Arm 3: HCV GT3 TE EBG/GZR+SOF 12 Weeks TE HCV GT3 participants took 1 FDC tablet containing EBR 50 mg + GZR 100 mg and 1 tablet containing SOF 400 mg q.d. for 12 weeks. | 17 |
| Arm 4: HCV GT3 TE EBG/GZR+SOF+RBV 12 Weeks TE HCV GT3 participants took 1 FDC tablet containing EBR 50 mg + GZR 100 mg and 1 tablet containing SOF 400 mg q.d. with RBV (200 mg capsules; weight-based dosing) b.i.d. for 12 weeks. | 18 |
| Arm 5: HCV GT3 TE EBG/GZR+SOF 16 Weeks TE HCV GT3 participants took 1 FDC tablet containing EBR 50 mg+GZR 100 mg and 1 tablet containing SOF 400 mg q.d. for 16 weeks. | 18 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 3 | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 1: HCV GT3 TN EBG/GZR+SOF+RBV 8 Weeks | Arm 2: HCV GT3 TN EBG/GZR+SOF 12 Weeks | Arm 3: HCV GT3 TE EBG/GZR+SOF 12 Weeks | Arm 4: HCV GT3 TE EBG/GZR+SOF+RBV 12 Weeks | Arm 5: HCV GT3 TE EBG/GZR+SOF 16 Weeks | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 52.5 Years STANDARD_DEVIATION 9 | 48.1 Years STANDARD_DEVIATION 9.3 | 58.6 Years STANDARD_DEVIATION 6.1 | 56.1 Years STANDARD_DEVIATION 8.4 | 53.8 Years STANDARD_DEVIATION 6.4 | 53.4 Years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 6 Participants | 6 Participants | 3 Participants | 32 Participants |
| Sex: Female, Male Male | 13 Participants | 17 Participants | 11 Participants | 12 Participants | 15 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 23 | 21 / 24 | 16 / 17 | 17 / 18 | 17 / 18 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 2 / 17 | 3 / 18 | 1 / 18 |
Outcome results
Primary
Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy)
The percentage of participants achieving SVR12 (i.e., HCV ribnonucleic acid \[RNA\] \< Lower Limit of Quantification \[LLOQ\] 12 weeks after completing study treatment) was determined. Plasma HCV RNA levels were determined with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL.
Time frame: Up to Week 28
Population: All randomized participants who received at least 1 dose of study drug, were not lost to follow-up for reasons unrelated to study treatment, and had SVR12 data available are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: HCV GT3 TN EBG/GZR+SOF+RBV 8 Weeks | Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy) | 91.3 Percentage of Participants |
| Arm 2: HCV GT3 TN EBG/GZR+SOF 12 Weeks | Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy) | 100.0 Percentage of Participants |
| Arm 3: HCV GT3 TE EBG/GZR+SOF 12 Weeks | Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy) | 100.0 Percentage of Participants |
| Arm 4: HCV GT3 TE EBG/GZR+SOF+RBV 12 Weeks | Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy) | 100.0 Percentage of Participants |
| Arm 5: HCV GT3 TE EBG/GZR+SOF 16 Weeks | Percentage of Participants Achieving SVR12 (Sustained Virologic Response 12 Weeks After the End of All Study Therapy) | 94.4 Percentage of Participants |
Primary
Percentage of Participants Discontinuing From Study Therapy Due to an AE
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 16 weeks
Population: All participants who received at least 1 dose of study drug are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: HCV GT3 TN EBG/GZR+SOF+RBV 8 Weeks | Percentage of Participants Discontinuing From Study Therapy Due to an AE | 0.0 Percentage of Participants |
| Arm 2: HCV GT3 TN EBG/GZR+SOF 12 Weeks | Percentage of Participants Discontinuing From Study Therapy Due to an AE | 0.0 Percentage of Participants |
| Arm 3: HCV GT3 TE EBG/GZR+SOF 12 Weeks | Percentage of Participants Discontinuing From Study Therapy Due to an AE | 0.0 Percentage of Participants |
| Arm 4: HCV GT3 TE EBG/GZR+SOF+RBV 12 Weeks | Percentage of Participants Discontinuing From Study Therapy Due to an AE | 0.0 Percentage of Participants |
| Arm 5: HCV GT3 TE EBG/GZR+SOF 16 Weeks | Percentage of Participants Discontinuing From Study Therapy Due to an AE | 5.6 Percentage of Participants |
Primary
Percentage of Participants Experiencing an Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 18 weeks (up to 2 weeks after completion of study treatment)
Population: All participants who received at least 1 dose of study drug are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: HCV GT3 TN EBG/GZR+SOF+RBV 8 Weeks | Percentage of Participants Experiencing an Adverse Event (AE) | 87.0 Percentage of Participants |
| Arm 2: HCV GT3 TN EBG/GZR+SOF 12 Weeks | Percentage of Participants Experiencing an Adverse Event (AE) | 87.5 Percentage of Participants |
| Arm 3: HCV GT3 TE EBG/GZR+SOF 12 Weeks | Percentage of Participants Experiencing an Adverse Event (AE) | 82.4 Percentage of Participants |
| Arm 4: HCV GT3 TE EBG/GZR+SOF+RBV 12 Weeks | Percentage of Participants Experiencing an Adverse Event (AE) | 94.4 Percentage of Participants |
| Arm 5: HCV GT3 TE EBG/GZR+SOF 16 Weeks | Percentage of Participants Experiencing an Adverse Event (AE) | 94.4 Percentage of Participants |
Secondary
Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy)
The percentage of participants achieving SVR24 (i.e., HCV RNA \< LLOQ 24 weeks after completing study treatment) was determined. Plasma HCV RNA levels were determined with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL.
Time frame: Up to Week 40
Population: All randomized participants who received at least 1 dose of study drug, were not lost to follow-up for reasons unrelated to study treatment, and had SVR24 data available are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: HCV GT3 TN EBG/GZR+SOF+RBV 8 Weeks | Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy) | 91.3 Percentage of Participants |
| Arm 2: HCV GT3 TN EBG/GZR+SOF 12 Weeks | Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy) | 100.0 Percentage of Participants |
| Arm 3: HCV GT3 TE EBG/GZR+SOF 12 Weeks | Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy) | 100.0 Percentage of Participants |
| Arm 4: HCV GT3 TE EBG/GZR+SOF+RBV 12 Weeks | Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy) | 100.0 Percentage of Participants |
| Arm 5: HCV GT3 TE EBG/GZR+SOF 16 Weeks | Percentage of Participants Achieving SVR24 (Sustained Virologic Response 24 Weeks After the End of All Study Therapy) | 93.8 Percentage of Participants |