Introduction
Methods
Patients
Study design
Outcomes
Assessments
Statistical analysis
Results
Efficacy
Part 1
Part 1 | Part 2 | ||||
---|---|---|---|---|---|
EBR + 50 mg GZR (n = 31) | EBR + 100 mg GZR (n = 32) | ITG: EBR + GZR (n = 227) | DTG: placebo (n = 74) | Cirrhotic patients (n = 35) | |
Age (years) | |||||
Meana
| 61.1 (9.7) | 58 (12.5) | 61.0 (12.5) | 60.9 (10.8) | 64.8 (9.2) |
Medianb
| 62 (35–78) | 58.5 (30–76) | 63.0 (21–80) | 63.0 (34–80) | 65.0 (43–79) |
Sex | |||||
Male | 12 (38.7%) | 15 (46.9%) | 87 (38.3%) | 21 (28.4%) | 18 (51.4%) |
Female | 19 (61.3%) | 17 (53.1%) | 140 (61.7%) | 53 (71.6%) | 17 (48.6%) |
Japanese patients | 31 (100%) | 32 (100%) | 227 (100%) | 74 (100%) | 35 (100%) |
Body mass index, mean (kg/m2)a
| 22.8 (3.9) | 23 (3.4) | 22.7 (3.0) | 22.3 (3.5) | 23.8 (3.0) |
Baseline HCV RNA, geometric mean (log10 IU/mL)a
| 6.2 (0.5) | 6.2 (0.5) | 6.2 (0.5) | 6.3 (0.5) | 6.2 (0.5) |
HCV genotype | |||||
1a | 0 (0%) | 0 (0%) | 4 (1.8%) | 1 (1.4%) | 1 (2.9%) |
1b | 31 (100%) | 32 (100%) | 223 (98.2%) | 73 (98.6%) | 34 (97.1%) |
IL28B rs12979860 | |||||
Major (CC) | 19 (61.3%) | 20 (62.5%) | 131 (57.7%) | 44 (59.5%) | 22 (62.9%) |
Minor (TC) | 12 (38.7%) | 10 (31.3%) | 86 (37.9%) | 29 (39.2%) | 13 (37.1%) |
Minor (TT) | 0 (0%) | 1 (3.1%) | 10 (4.4%) | 1 (1.4%) | 0 (0%) |
Unknown | 0 (0%) | 1 (3.1%) | 0 (0%) | 0 (0%) | 0 (0%) |
IL28B rs8099917 | |||||
Major (TT) | 19 (61.3%) | 21 (65.6%) | 136 (59.9%) | 46 (62.2%) | 24 (68.6%) |
Minor (TG) | 12 (38.7%) | 10 (31.3%) | 81 (35.7%) | 27 (36.5%) | 11 (31.4%) |
Unknown | 0 (0%) | 1 (3.1%) | 10 (4.4%) | 1 (1.4%) | 0 (0%) |
Cirrhosis | |||||
No | 31 (100%) | 31 (96.9%) | 227 (100%) | 74 (100%) | 0 (0%) |
Yes | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 35 (100%) |
Data missing | 0 (0%) | 1 (3.1%) | 0 (0%) | 0 (0%) | 0 (0%) |
HCV treatment history | |||||
Naïve | 14 (45.2%) | 19 (59.4%) | 149 (65.6%) | 49 (66.2%) | 20 (57.1%) |
Intolerant | 4 (12.9%) | 2 (6.3%) | 11 (4.8%) | 3 (4.1%) | 3 (8.6%) |
Relapse | 7 (22.6%) | 6 (18.8%) | 33 (14.5%) | 12 (16.2%) | 4 (11.4%) |
Breakthrough | 1 (3.2%) | 1 (3.1%) | 7 (3.1%) | 1 (1.4%) | 2 (5.7%) |
Partial responder | 3 (9.7%) | 2 (6.3%) | 10 (4.4%) | 3 (4.1%) | 2 (5.7%) |
Null responder | 2 (6.5%) | 2 (6.3%) | 17 (7.5%) | 6 (8.1%) | 4 (11.4%) |
Laboratory values | |||||
Baseline hemoglobin level, mean (g/dL)a
| 13.6 (1.2) | 13.8 (1.3) | 14.0 (1.5) | 13.7 (1.4) | 13.6 (1.6) |
Baseline platelet count, mean (×104/µL)a
| 19.7 (6.8) | 21.2 (6.5) | 19.2 (5.8) | 19.4 (6.5) | 10.6 (3.9) |
Baseline ALT level, mean (IU/L)a
| 49 (30.5) | 33.8 (12.3) | 45.6 (36.5) | 41.2 (29.4) | 52.6 (24.6) |
Baseline AST level, mean (IU/L)a
| 43.6 (20.9) | 32.7 (12.5) | 43.8 (25.7) | 43.5 (30.7) | 59.2 (21.7) |
Baseline bilirubin level, mean (mg/dL)a
| 0.7 (0.3) | 0.5 (0.2) | 0.7 (0.3) | 0.6 (0.2) | 0.8 (0.3) |
Part 2
Resistance analysis
Pharmacokinetics
Safety
Part 1
AEs | 50 mg EBR + 50 mg GZR (n = 31) | 50 mg EBR + 100 mg GZR (n = 31) |
---|---|---|
≥1 AEa
| 21 (67.7%) | 23 (74.2%) |
Nasopharyngitis | 7 (22.6%) | 10 (32.3%) |
Headache | 4 (12.9%) | 3 (9.7%) |
Pyrexia | 3 (9.7%) | 1 (3.2%) |
Dry eye | 2 (6.5%) | 0 (0%) |
Upper abdominal pain | 2 (6.5%) | 1 (3.2%) |
Diarrhea | 2 (6.5%) | 1 (3.2%) |
Accidental overdose | 1 (3.2%) | 2 (6.5%) |
Drug-related AE | 10 (32.3%) | 9 (29.0%) |
SAEb
| 1 (3.2%) | 1 (3.2%) |
Discontinuation because of AEs | 0 (0%) | 0 (0%) |
Deaths | 0 (0%) | 0 (0%) |
ALT | ||
1.1–2.5 times baseline level | 0 (0%) | 0 (0%) |
>2.5–5.0 times baseline level | 1 (3.2%) | 0 (0%) |
>5.0 times baseline level | 0 (0%) | 0 (0%) |
AST | ||
1.1–2.5 times baseline level | 1 (3.2%) | 1 (3.2%) |
>2.5–5.0 times baseline level | 0 (0%) | 0 (0%) |
>5.0 times baseline level | 0 (0%) | 0 (0%) |
Total bilirubin | ||
>2.5–5.0 times baseline level | 0 (0%) | 0 (0%) |
>5.0–10.0 times baseline level | 0 (0%) | 0 (0%) |
>10.0 times baseline level | 0 (0%) | 0 (0%) |
Alkaline phosphatase | ||
1.1–2.5 times baseline level | 4 (12.9%) | 3 (9.7%) |
>2.5–5.0 times baseline level | 0 (0%) | 0 (0%) |
>5.0 times baseline level | 0 (0%) | 0 (0%) |
Part 2
AEs | ITG: EBR + GZR (n = 227) | DTG: placebo (n = 74) | Percentage point differencef
|
---|---|---|---|
Tier 1 (events of clinical interest) | 8 (3.5%) | 0 (0%) | 3.5 (−1.5 to 6.8); p = 0.102 |
≥1 AEs | 147 (64.8%) | 50 (67.6%) | −2.8 (−14.5 to 10.0) |
Nasopharyngitisa
| 34 (15.0%) | 12 (16.2%) | −1.2 (−12.1 to 7.4) |
ALT level increaseda
| 13 (5.7%) | 1 (1.4%) | 4.4 (−1.8 to 8.5) |
Drug-related AEa
| 58 (25.6%) | 14 (18.9%) | |
ALT level increased | 12 (5.3%) | 1 (1.4%) | |
SAEsb
| 11 (4.8%) | 1 (1.4%) | |
Drug-related SAEsc
| 2 (1%) | 0 (0%) | |
Discontinuation because of AEsd
| 3 (1.3%) | 1 (1.4%) | |
Deathse
| 0 (0.0%) | 0 (0.0%) | |
ALT | |||
1.1–2.5 times baseline level | 6 (2.6%) | 29 (39.2%) | |
>2.5–5.0 times baseline level | 6 (2.6%) | 0 (0%) | |
>5.0 times baseline level | 5 (2.2%) | 1 (1.4%) | |
AST | |||
1.1–2.5 times baseline level | 8 (3.5%) | 26 (35.1%) | |
>2.5–5.0 times baseline level | 6 (2.6%) | 0 (0%) | |
>5.0 times baseline level | 2 (0.9%) | 0 (0%) | |
Total bilirubin | |||
>2.5–5.0 times baseline level | 1 (0.4%) | 0 (0%) | |
>5.0–10.0 times baseline level | 0 (0%) | 0 (0%) | |
>10.0 times baseline level | 0 (0%) | 0 (0%) | |
Alkaline phosphatase | |||
1.1–2.5 times baseline level | 32 (14.1%) | 9 (12.2%) | |
>2.5–5.0times baseline level | 0 (0%) | 0 (0%) | |
>5.0 times baseline level | 0 (0%) | 0 (0%) |
AEs | Cirrhotic patients (n = 35) |
---|---|
Events of clinical interest | 3 (8.6%) |
≥1 AEsa
| 28 (80%) |
Nasopharyngitis | 5 (14.3%) |
Increased ALT level | 5 (14.3%) |
Increased AST level | 5 (14.3%) |
Rash | 3 (8.6%) |
Constipation | 3 (8.6%) |
Diarrhea | 3 (8.6%) |
Malaise | 2 (5.7%) |
Anemia | 2 (5.7%) |
Headache | 2 (5.7%) |
Drug-related AEsb
| 13 (37.1%) |
SAEs | 0 (0%) |
Discontinuation because of AEs | 0 (0%) |
Deaths | 0 (0%) |
ALT | |
1.1–2.5 times baseline level | 2 (5.7%) |
>2.5–5.0 times baseline level | 2 (5.7%) |
>5.0 times baseline level | 1 (2.9%) |
AST | |
1.1–2.5 times baseline level | 3 (8.6%) |
>2.5–5.0 times baseline level | 1 (2.9%) |
>5.0 times baseline level | 1 (2.9%) |
Total bilirubin | |
>2.5–5.0 times baseline level | 0 (0%) |
>5.0–10.0 times baseline level | 0 (0%) |
>10.0× baseline | 0 (0%) |
Alkaline phosphatase | |
1.1–2.5 times baseline level | 7 (20%) |
>2.5–5.0 times baseline level | 0 (0%) |
>5.0 times baseline level | 0 (0%) |