Hepatitis C Virus
Conditions
Brief summary
This study will evaluate the safety and efficacy of combination treatment with grazoprevir (MK-5172) + elbasvir (MK-8742) for cirrhotic and non-cirrhotic participants with chronic Genotype 1 (GT1) hepatitis C virus (HCV) infection and chronic kidney disease (CKD). The primary study hypothesis is that the proportion of HCV GT1-infected CKD participants within the Immediate Treatment and Intensive Pharmacokinetics (PK) groups achieving a sustained viral response 12 weeks after the end of all study treatment (SVR12) will be \>45%.
Interventions
DRUGGrazoprevir
Grazoprevir 100 mg tablet
DRUGElbasvir
Elbasvir 50 mg tablet
Placebo tablet matched to grazoprevir
Placebo tablet matched to elbasvir
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented chronic (at least 6 months) HCV GT 1 infection (with no evidence of mixed genotypes or genotype that cannot be assigned a type) * Evidence or no evidence of liver cirrhosis based on one of the following: * Liver biopsy performed within 24 months of Day 1 (if participant is cirrhotic then there is no time restriction on biopsy) * Fibroscan performed within 12 months of Day 1 of this study * Fibrosure™ (Fibrotest™) plus aspartate aminotransferase to platelet Ratio Index \[APRI\] obtained during the screening period) * Has HCV status that is one of the following: * Treatment naïve * Prior interferon or pegylated interferon with or without ribavarin failures (null responder, partial responder, or relapser) * Intolerant to prior interferon or pegylated intereferon with or without ribavarin regimen * Chronic kidney disease (defined as glomerular filtration rate \[eGFR\] \<=29) non-dialysis dependent or on hemodialysis for at least 3 months, including individuals awaiting kidney transplant and those with failed kidney transplants but no longer on immunosuppressant therapy) * Female participant of reproductive potential must agree to remain abstinent or use (or have their partner use) 2 acceptable methods of contraception from at least 2 weeks prior to Day 1 through 14 days after the last dose of study drugs, or longer if dictated by local regulations
Exclusion criteria
* Evidence of decompensated liver disease * On peritoneal dialysis for management of kidney disease * Co-infection with hepatitis B virus or human immunodeficiency virus (HIV) * History of malignancy \<=5 years prior to signing informed consent * Clinical diagnosis of substance abuse * Pregnant, breast-feeding, expecting to conceive or donate eggs, or donate sperm from Day 1 through 14 days after the last study dose, or longer if dictated by local regulations * Organ transplant (including hematopoietic stem cell transplant) other than kidney, cornea, and hair * Conditions requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial * Uncontrolled or poorly controlled hypertension * Significant cardiovascular disorder (e.g. myocardial infarction or unstable angina) or cardiovascular procedure within 3 months prior to signing informed consent * New or worsening signs or symptoms of congestive heart failure within 3 months of signing informed consent * Severe active peripheral vascular disease * Recent (within 3 months prior to signing informed consent) episode or recurrence of stroke, transient ischemic attack (TIA) or neurological disorder, including but not limited to seizures * Evidence or history of chronic hepatitis not caused by HCV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12) | Week 24 (Immediate Treatment + Intensive PK) or Week 40 (Deferred Treatment) | SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) lower than the limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL. |
| Number of Participants Experiencing an Adverse Event (AE) During the Initial Treatment and 14-day Follow-up Periods | Up to Week 14 | 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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group. |
| Number of Participants Discontinuing Study Drug Due to AEs During the Initial Treatment Period | Up to Week 12 | 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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24) | Week 36 (Immediate Treatment + Intensive PK) or Week 52 (Deferred Treatment) | SVR24 was defined as HCV RNA \<LLoQ 24 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL. |
| Percentage of Participants With Sustained Virologic Response 4 Weeks After Completing Study Therapy (SVR4) | Week 16 (Immediate Treatment + Intensive PK) or Week 32 (Deferred Treatment) | SVR4 was defined as HCV RNA \<LLoQ 4 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL. |
Participant flow
Recruitment details
This multi-site study enrolled adult, male and female participants with hepatitis C virus (HCV) genotype (GT) 1 with chronic kidney disease (CKD).
Pre-assignment details
The screening period lasted for up to 60 days.
Participants by arm
| Arm | Count |
|---|---|
| Immediate Treatment + Intensive PK Participants received GZR 100 mg tablet + EBR 50 mg tablet q.d. by mouth for 12 weeks, followed by a 24-week follow-up period. A subset of participants also underwent intensive PK testing. | 123 |
| Deferred Treatment Participants received placebo to GZR and EBR q.d. by mouth for 12 weeks. Then, after a 4-week drug-free period, participants received a FDC tablet containing GZR 100 mg + EBR 50 mg tablet q.d. by mouth for 12 weeks, followed by a 24-week follow-up period. | 114 |
| Total | 237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Death | 2 | 5 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Screen Failure | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Immediate Treatment + Intensive PK | Deferred Treatment | Total |
|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 9 | 55.2 Years STANDARD_DEVIATION 10 | 55.9 Years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 30 Participants | 33 Participants | 63 Participants |
| Sex: Female, Male Male | 93 Participants | 81 Participants | 174 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 67 / 122 | 68 / 113 | 39 / 102 |
| serious Total, serious adverse events | 30 / 122 | 22 / 113 | 25 / 102 |
Outcome results
Primary
Number of Participants Discontinuing Study Drug Due to AEs During the Initial Treatment Period
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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group.
Time frame: Up to Week 12
Population: The APaT population includes all enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment + Intensive PK | Number of Participants Discontinuing Study Drug Due to AEs During the Initial Treatment Period | 0 Participants |
| Deferred Treatment | Number of Participants Discontinuing Study Drug Due to AEs During the Initial Treatment Period | 5 Participants |
Primary
Number of Participants Experiencing an Adverse Event (AE) During the Initial Treatment and 14-day Follow-up Periods
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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group.
Time frame: Up to Week 14
Population: The All Participants as Treated (APaT) population includes all enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment + Intensive PK | Number of Participants Experiencing an Adverse Event (AE) During the Initial Treatment and 14-day Follow-up Periods | 93 Participants |
| Deferred Treatment | Number of Participants Experiencing an Adverse Event (AE) During the Initial Treatment and 14-day Follow-up Periods | 96 Participants |
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12)
SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) lower than the limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
Time frame: Week 24 (Immediate Treatment + Intensive PK) or Week 40 (Deferred Treatment)
Population: The modified Full Analysis set (mFAS) includes all participants receiving ≥1 dose of drug and without missing data due to death or early discontinuation from study therapy for reasons unrelated to response to HCV treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment + Intensive PK | Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12) | 99.1 Percentage of participants |
| Deferred Treatment | Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12) | 98.0 Percentage of participants |
Comparison: The primary hypothesis was that the SVR12 rate in the Immediate Treatment plus Intensive PK arm would be \>45%.p-value: 0.001One-sided exact test
Secondary
Percentage of Participants With Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24)
SVR24 was defined as HCV RNA \<LLoQ 24 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
Time frame: Week 36 (Immediate Treatment + Intensive PK) or Week 52 (Deferred Treatment)
Population: The mFAS includes all participants receiving ≥1 dose of drug and without missing data due to death or early discontinuation from study therapy for reasons unrelated to response to HCV treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment + Intensive PK | Percentage of Participants With Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24) | 97.4 Percentage of participants |
| Deferred Treatment | Percentage of Participants With Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24) | 98.0 Percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 4 Weeks After Completing Study Therapy (SVR4)
SVR4 was defined as HCV RNA \<LLoQ 4 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
Time frame: Week 16 (Immediate Treatment + Intensive PK) or Week 32 (Deferred Treatment)
Population: The mFAS includes all participants receiving ≥1 dose of drug and without missing data due to death or early discontinuation from study therapy for reasons unrelated to response to HCV treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment + Intensive PK | Percentage of Participants With Sustained Virologic Response 4 Weeks After Completing Study Therapy (SVR4) | 100.00 Percentage of participants |
| Deferred Treatment | Percentage of Participants With Sustained Virologic Response 4 Weeks After Completing Study Therapy (SVR4) | 99.0 Percentage of participants |