Background
Methods
Trial setting
Trial population
Trial design
Efficacy assessment
Safety assessments
Statistical analysis
Results
Clinical characteristics and demographic parameters of enrolled patients
Variables | Placebo (N = 76) | Tolvaptan 7.5 mg (N = 153) | Tolvaptan 15 mg (N = 301) | P value |
---|---|---|---|---|
Age (years, mean ± SD) | 54.4 ± 12.3 | 53.8 ± 10.4 | 54.2 ± 10.9 | 0.847† |
Gender male (N, %) | 54 (71.1) | 109 (71.2) | 215 (71.4) | 1.000‡ |
Body weight kg (mean ± SD) | 63.5 ± 12.8 | 60.6 ± 10.1 | 62.9 ± 12.0 | 0.008† |
Abdominal circumference (cm, mean ± SD) | 87.8 ± 12.0 | 84.7 ± 9.0 | 87.9 ± 11.1 | < 0.001† |
Severity of lower limb edema (N, %) | 0.837§ | |||
Non | 50 (65.8) | 106 (69.3) | 212 (70.4) | |
Mild | 17 (22.4) | 28 (18.3) | 59 (19.6) | |
Moderate | 7 (9.2) | 16 (10.5) | 23 (7.6) | |
Severe | 2 (2.6) | 3 (2.0) | 7 (2.3) | |
Duration of cirrhosis (day, mean ± SD) | 842.8 ± 1137.5 | 916.8 ± 1622.6 | 894.8 ± 1460.9 | 0.925† |
Etiology of liver cirrhosis (N, %) | 0.371§ | |||
Hepatitis B | 49 (64.5) | 101 (66.0) | 200 (66.4) | |
Hepatitis C | 9 (11.8) | 9 (5.9) | 18 (6.0) | |
Alcoholic hepatitis | 12 (15.8) | 31 (20.3) | 57 (18.9) | |
Primary biliary cirrhosis | 3 (3.9) | 3 (2.0) | 7 (2.3) | |
Unknown | 3 (3.9) | 7 (4.6) | 16 (5.3) | |
Others | 5 (6.6) | 13 (8.5) | 25 (8.3) | |
Child–Pugh class (N, %) | 0.702§ | |||
Class A | 1 (1.3) | 2 (1.3) | 7 (2.3) | |
Class B | 48 (63.2) | 96 (62.7) | 190 (63.1) | |
Class C | 27 (35.5) | 55 (35.9) | 104 (34.6) | |
Albumin concentration (g/dL, mean ± SD) | 3.0 ± 0.4 | 3.1 ± 0.5 | 3.0 ± 0.5 | 0.218† |
Albumin level (N, %) | 0.430§ | |||
> 3.5 g/dL | 8 (10.5) | 30 (19.6) | 52 (17.3) | |
2.8–3.5 g/dL | 48 (63.2) | 85 (55.6) | 161 (53.5) | |
< 2.8 g/dL | 20 (26.3) | 38 (24.8) | 88 (29.2) | |
Serum sodium (mmol/L, mean ± SD) | 137.7 ± 4.4 | 136.7 ± 5.1 | 136.9 ± 4.8 | 0.322† |
Serum sodium < 135 mmol/L (N, %) | 17 (22.4) | 41 (26.8) | 85 (28.2) | 0.587§ |
Serum potassium (mmol/L, mean ± SD) | 3.9 ± 0.5 | 4.1 ± 0.6 | 4.0 ± 0.5 | 0.022† |
Scr (mg/dL, mean ± SD) | 0.8 ± 0.2 | 0.8 ± 0.3 | 0.9 ± 0.3 | 0.276† |
BUN (mmol/L, mean ± SD) | 6.2 ± 3.0 | 6.3 ± 3.4 | 6.8 ± 3.6 | 0.264† |
TB (µmol/L, mean ± SD) | 43.8 ± 42.1 | 49.2 ± 57.2 | 43.6 ± 47.7 | 0.509† |
AST (IU/L, mean ± SD) | 67.4 ± 54.9 | 68.8 ± 56.9 | 66.0 ± 54.2 | 0.875† |
ALT/GPT (IU/L, mean ± SD) | 42.2 ± 27.1 | 43.1 ± 37.7 | 44.2 ± 39.3 | 0.899† |
Dose of conventional diuretics | ||||
Loop diuretics, furosemide equivalent (N, %) | 73 (96.1) | 144 (94.1) | 278 (92.4) | 0.583§ |
20–39 mg/day | 22 (30.1) | 44 (30.6) | 78 (28.1) | |
40–59 mg/day | 23 (31.5) | 51 (35.4) | 106 (38.1) | |
60–79 mg/day | 11 (15.1) | 18 (12.5) | 36 (12.9) | |
80–99 mg/day | 8 (11.0) | 17 (11.8) | 37 (13.3) | |
100 mg/day | 9 (12.3) | 14 (9.7) | 21 (7.6) | |
Aldosterone antagonist—spironolactone equivalent (N, %) | 76 (100.0) | 153 (100.0) | 300 (99.7) | 0.127§ |
20–39 mg/day | 2 (2.6) | 2 (1.3) | 0 (0.0) | |
40–59 mg/day | 17 (22.4) | 28 (18.3) | 56 (18.7) | |
60–79 mg/day | 6 (7.9) | 15 (9.8) | 22 (7.3) | |
80–99 mg/day | 11 (14.5) | 28 (18.3) | 54 (18.0) | |
100 mg/day | 40 (52.6) | 80 (52.3) | 168 (56.0) |
Changes in body weight
(N = 76) | Tolvaptan | P value | |||||||
---|---|---|---|---|---|---|---|---|---|
7.5 mg/day (N = 153) | 15 mg/day (N = 301) | Difference between 7.5 mg/day and 15.0 mg/day, 95% CI | |||||||
Mean ± SD | Mean ± SD | Difference from placebo, 95% CI | Mean ± SD | Difference from placebo, 95% CI | 7.5 mg Tolvaptan versus placebo | 15.0 mg Tolvaptan versus placebo | 7.5 mg versus 15.0 mg Tolvaptan | ||
Baseline | 63.5 ± 12.8 | 60.6 ± 10.1 | 62.9 ± 12.0 | ||||||
Day 7 | 62.3 ± 12.4 | 58.6 ± 10.1 | 60.8 ± 12.0 | ||||||
Day 7—baseline | − 1.2 ± 2.2 | − 2.0 ± 2.4 | − 0.8 (− 1.4, − 0.1) | − 2.2 ± 2.5 | − 1.0 (− 1.6, − 0.4) | − 0.2 (− 0.7, 0.3) | 0.026 | 0.001 | 0.339 |
Analysis of factors predicting responsiveness
Variable | OR | 95% CI | P value |
---|---|---|---|
Treatment group | |||
Tolvaptan 7.5 mg/day (vs Placebo) | 2.028 | 1.1–3.6 | 0.017 |
Tolvaptan 15 mg/day (vs placebo) | 2.280 | 1.3–3.9 | 0.003 |
Body weight (baseline, kg) | 1.016 | 1.0–1.0 | 0.047 |
Albumin level (g/dL) | |||
2.8–3.5 (vs > 3.5) | 1.395 | 0.8–2.3 | 0.949 |
< 2.8 (vs > 3.5) | 1.900 | 1.1–3.3 | 0.027 |
BUN (baseline, mmol/L) | 0.945 | 0.9–1.0 | 0.027 |
Improvement of ascites and lower extremity oedema
Placebo (mg) (N = 76) | Tolvaptan | P value | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
7.5 mg/day (N = 153) | 15 mg/day (N = 301) | ||||||||||||
Improvement | No changes | Degradation | Improvement | No changes | Degradation | Improvement | No changes | Degradation | 7.5 mg Tolvaptan versus placebo | 15.0 mg Tolvaptan versus placebo | 7.5 mg versus 15.0 mg Tolvaptan | ||
Improvement rate of ascites (N, %) | |||||||||||||
Day 4 | 28 (36.8) | 38 (50.0) | 10 (13.2) | 70 (45.8) | 71 (46.4) | 12 (7.8) | 152 (50.5) | 125 (41.5) | 24 (8.0) | 0.130 | 0.023 | 0.403 | |
Day 7 | 31 (40.8) | 34 (44.7) | 11 (14.5) | 82 (53.6) | 60 (39.2) | 11 (7.2) | 180 (59.8) | 93 (30.9) | 28 (9.3) | 0.037 | 0.003 | 0.342 | |
Improvement rate of lower extremity edema (N, %) | |||||||||||||
Day 4 | 12 (46.2) | 12 (46.2) | 2 (7.7) | 23 (51.1) | 21 (46.7) | 1 (2.2) | 48 (55.2) | 39 (44.8) | 0 (0.0) | 0.395 | 0.223 | 0.766 | |
Day 7 | 14 (53.8) | 10 (38.5) | 2 (7.7) | 33 (71.7) | 12 (26.1) | 1 (2.2) | 60 (67.4) | 27 (30.3) | 2 (2.2) | 0.077 | 0.088 | 0.773 |
Serum sodium and potassium concentrations
Placebo (mg) | Tolvaptan | P value | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
7.5 mg/day | 15 mg/day | |||||||||
Mean ± SD | Changes from baseline | Mean ± SD | Changes from baseline | Mean ± SD | Changes from baseline | 7.5 mg tolvaptan versus placebo | 15.0 mg tolvaptan versus placebo | 7.5 mg versus 15.0 mg tolvaptan | ||
All patients (N) | 76 | 153 | 301 | |||||||
Serum Na+ concentration (mmol/L) | Baseline | 137.7 ± 4.4 | – | 136.7 ± 5.1 | – | 136.9 ± 4.8 | – | – | – | – |
4–8 h | 136.2 ± 5.2 | − 1.4 ± 3.1 | 137.7 ± 5.9 | 1.0 ± 3.6 | 138.2 ± 5.8 | 1.3 ± 3.8 | < 0.001 | < 0.001 | 0.408 | |
Day 1 | 137.6 ± 4.6 | − 0.1 ± 2.8 | 138.8 ± 5.4 | 2.0 ± 3.4 | 140.3 ± 4.9 | 3.4 ± 3.4 | < 0.001 | < 0.001 | < 0.001 | |
Day 4 | 137.4 ± 5.1 | − 0.3 ± 3.14 | 138.3 ± 5.1 | 1.6 ± 3.0 | 139.6 ± 4.7 | 2.7 ± 3.9 | < 0.001 | < 0.001 | 0.002 | |
Day 7 | 137.0 ± 5.1 | − 0.7 ± 3.4 | 138.2 ± 5.1 | 1.4 ± 3.3 | 139.0 ± 4.6 | 2.1 ± 4.0 | < 0.001 | < 0.001 | 0.075 | |
Serum K+ concentration (mmol/L) | Baseline | 3.9 ± 0.5 | – | 4.1 ± 0.6 | – | 4.0 ± 0.5 | – | – | – | – |
Day 4 | 4.0 ± 0.7 | 0.1 ± 0.5 | 4.2 ± 0.4 | 0.1 ± 0.5 | 4.2 ± 0.7 | 0.1 ± 0.7 | 0.752 | 0.845 | 0.494 | |
Day 7 | 4.0 ± 0.5 | 0.1 ± 0.5 | 4.2 ± 0.5 | 0.1 ± 0.5 | 4.2 ± 0.5 | 0.2 ± 0.6 | 0.885 | 0.390 | 0.199 | |
Hyponatremia patients (Na+ baseline< 135 mmol/L) (N) | 17 | 41 | 85 | |||||||
Serum Na+ concentration (mmol/L) | Baseline | 131.3 ± 3.1 | – | 130.2 ± 4.5 | – | 130.9 ± 3.7 | – | – | – | – |
4–8 h | 129.4 ± 4.6 | − 1.9 ± 3.7 | 131.1 ± 5.7 | 1.0 ± 3.9 | 132.7 ± 6.2 | 1.8 ± 4.3 | 0.019 | < 0.001 | 0.260 | |
Day 1 | 132.6 ± 4.9 | 1.2 ± 3.7 | 133.5 ± 6.0 | 3.3 ± 3.8 | 135.6 ± 5.1 | 4.7 ± 3.7 | 0.061 | < 0.001 | 0.057 | |
Day 4 | 131.2 ± 5.0 | − 0.1 ± 4.6 | 133.2 ± 5.9 | 3.0 ± 3.2 | 135.4 ± 5.1 | 4.5 ± 4.6 | 0.013 | < 0.001 | 0.063 | |
Day 7 | 130.3 ± 4.7 | − 1.0 ± 4.1 | 132.8 ± 5.2 | 2.6 ± 3.2 | 134.9 ± 4.9 | 4.0 ± 5.1 | 0.005 | < 0.001 | 0.144 |
24-h urine volume and water intake
Baseline | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | Day 7 | P value (versus placebo) | ||
---|---|---|---|---|---|---|---|---|---|---|
24-h urine volume (mL) | Placebo | 1666.9 ± 713.5 | 2019.5 ± 921.4 | 1920.9 ± 802.5 | 2099.0 ± 868.2 | 1968.7 ± 796.5 | 2066.0 ± 810.0 | 1993.5 ± 789.3 | 1826.6 ± 720.4 | – |
Tolvaptan 7.5 mg | 1951.8 ± 848.2 | 3232.5 ± 1565.2 | 2999.5 ± 1524.0 | 2890.1 ± 1386.1 | 2785.6 ± 1430.2 | 2841.2 ± 1322.5 | 2748.2 ± 1256.8 | 2606.5 ± 1245.3 | < 0.001 | |
Tolvaptan 15 mg | 1831.4 ± 911.8 | 3661.0 ± 1791.4 | 3399.5 ± 1637.1 | 3139.4 ± 1527.9 | 2981.8 ± 1402.5 | 3000.4 ± 1390.7 | 3019.4 ± 1372.5 | 2834.9 ± 1312.7 | < 0.001 | |
24-h fluid intake (mL) | Placebo | 1854.9 ± 708.7 | 1973.1 ± 782.2 | 1929.6 ± 767.1 | 1995.3 ± 839.5 | 1860.9 ± 806.8 | 1953.7 ± 791.7 | 1874.3 ± 802.2 | 1665.4 ± 727.3 | – |
Tolvaptan 7.5 mg | 2042.0 ± 1059.5 | 2505.3 ± 1152.8 | 2643.7 ± 1255.9 | 2447.3 ± 1167.9 | 2381.9 ± 1128.3 | 2339.4 ± 1087.3 | 2416.5 ± 1337.0 | 2175.3 ± 1111.1 | < 0.001 | |
Tolvaptan 15 mg | 1953.4 ± 964.6 | 2745.9 ± 1318.1 | 2795.4 ± 1369.0 | 2605.1 ± 1291.5 | 2537.6 ± 1306.4 | 2456.6 ± 1237.5 | 2493.4 ± 1320.4 | 2295.2 ± 1141.4 | < 0.001 | |
Water balance | Placebo | 189.8 ± 714.1 | − 47.9 ± 746.7 | 11.9 ± 609.0 | − 105.1 ± 793.7 | − 105.0 ± 756.1 | − 115.0 ± 694.1 | − 116.7 ± 768.9 | − 155.0 ± 665.1 | – |
Tolvaptan 7.5 mg | 83.1 ± 1158.7 | − 727.1 ± 1352.0 | − 364.9 ± 1255.9 | − 451.3 ± 1227.9 | − 409.5 ± 1174.4 | − 498.6 ± 1180.2 | − 334.5 ± 1264.2 | − 428.8 ± 941.1 | < 0.001 | |
Tolvaptan 15 mg | 123.5 ± 873.3 | − 921.3 ± 1352.3 | − 610.8 ± 1137.8 | − 539.0 ± 1069.1 | − 447.0 ± 1046.9 | − 546.7 ± 1036.3 | − 529.7 ± 1039.7 | − 553.1 ± 1007.0 | < 0.001 |
Safety assessments
Renal and liver function
Placebo (mg/day) (N = 76) | Tolvaptan | P value | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
7.5 mg/day (N = 153) | 15 mg/day (N = 304) | |||||||||
Mean ± SD | Changes from baseline | Mean ± SD | Changes from baseline | Mean ± SD | Changes from baseline | 7.5 mg/day tolvaptan versus placebo | 15 mg/day mg tolvaptan versus placebo | 7.5 mg/day versus 15.0 mg/day tolvaptan | ||
Serum creatinine (mg/dL) | Baseline | 0.8 ± 0.2 | – | 0.8 ± 0.3 | – | 0.9 ± 0.3 | – | – | – | – |
Day 4 | 0.8 ± 0.2 | 0.0 ± 0.1 | 0.9 ± 0.3 | 0.1 ± 0.2 | 0.9 ± 0.3 | 0.1 ± 0.2 | 0.030 | 0.001 | 0.173 | |
Day 7 | 0.8 ± 0.2 | 0.0 ± 0.2 | 0.9 ± 0.3 | 0.1 ± 0.2 | 0.9 ± 0.3 | 0.1 ± 0.2 | 0.119 | 0.019 | 0.517 | |
BUN (mmol/L) | Baseline | 6.2 ± 3.0 | – | 6.3 ± 3.4 | – | 6.8 ± 3.6 | – | – | – | – |
Day 4 | 5.8 ± 2.7 | − 0.1 ± 1.0 | 6.2 ± 3.4 | 0.1 ± 1.6 | 6.5 ± 3.6 | − 0.1 ± 1.7 | 0.428 | 0.871 | 0.434 | |
Day 7 | 6.7 ± 3.4 | 0.5 ± 2.5 | 6.8 ± 4.0 | 0.5 ± 2.5 | 6.7 ± 3.9 | 0.0 ± 2.0 | 0.987 | 0.086 | 0.027 | |
TB (µmol/L) | Baseline | 43.8 ± 42.1 | – | 49.2 ± 57.2 | – | 43.6 ± 47.7 | – | – | – | – |
Day 4 | 40.7 ± 37.4 | 0.6 ± 11.1 | 45.6 ± 45.0 | 1.1 ± 13.6 | 46.4 ± 57.5 | 2.8 ± 21.0 | 0.809 | 0.252 | 0.317 | |
Day 7 | 44.8 ± 52.8 | 2.6 ± 21.7 | 48.2 ± 50.4 | 3.4 ± 23.7 | 44.6 ± 58.0 | 0.8 ± 20.2 | 0.822 | 0.526 | 0.260 | |
AST (IU/L) | Baseline | 67.4 ± 54.9 | – | 68.8 ± 56.9 | – | 66.0 ± 54.2 | – | – | – | – |
Day 4 | 68.6 ± 61.0 | 3.0 ± 15.2 | 65.7 ± 55.3 | 0.2 ± 20.8 | 65.0 ± 57.9 | − 0.6 ± 22.7 | 0.280 | 0.133 | 0.741 | |
Day 7 | 68.1 ± 66.2 | 2.0 ± 18.6 | 71.0 ± 64.5 | 4.0 ± 32.7 | 69.5 ± 66.1 | 2.2 ± 36.7 | 0.573 | 0.951 | 0.614 | |
ALT/GPT (IU/L) | Baseline | 42.2 ± 27.1 | – | 43.1 ± 37.7 | – | 44.2 ± 39.3 | – | – | – | – |
Day 4 | 40.5 ± 26.8 | − 1.1 ± 8.8 | 42.0 ± 36.9 | 0.6 ± 12.8 | 44.0 ± 35.0 | − 0.5 ± 18.5 | 0.274 | 0.712 | 0.467 | |
Day 7 | 39.3 ± 26.9 | − 1.8 ± 11.6 | 44.3 ± 40.0 | 1.9 ± 19.8 | 45.5 ± 39.5 | 0.4 ± 30.3 | 0.087 | 0.335 | 0.529 |
Adverse events
Placebo N = 76 (%) | Tolvaptan | P value | ||
---|---|---|---|---|
7.5 mg/day N = 153 (%) | 15 mg/day N = 304 (%) | |||
AEs observed during the trial | 46 (60.5) | 98 (64.1) | 218 (71.7) | 0.084 |
AEs observed during the treatment | 35 (46.1) | 81 (52.9) | 182 (59.9) | 0.065 |
AEs observed at a rate of ≥ 5% of patients in any group | ||||
Dry mouth | 8 (10.5) | 25 (16.3) | 42 (13.8) | 0.483 |
Abdominal bloating | 6 (7.9) | 4 (2.6) | 11 (3.6) | 0.140 |
Thirst | 2 (2.6) | 6 (3.9) | 35 (11.5) | 0.003 |
Hypokalemia | 6 (7.9) | 13 (8.5) | 21 (6.9) | 0.823 |
Hepatic encephalopathy | 0.580 | |||
Baseline | 1 (1.32) | 1 (0.65) | 1 (0.33) | |
Post-treatment | 2 (2.63) | 4 (2.61) | 2 (0.66) | |
Increased number (post-baseline) | 1 (1.32) | 3 (1.96) | 1 (0.33) | |
ADRs observed during the trial | 9 (11.8) | 38 (24.8) | 94 (30.9) | 0.003 |
ADRs observed at a rate of ≥ 5% of patients in any group | ||||
Dry mouth | 6 (7.9) | 25 (16.3) | 38 (12.5) | 0.188 |
Thirst | 2 (2.6) | 6 (3.9) | 34 (11.2) | 0.005 |
SADRs | 1 (1.3) | 1 (0.7) | 6 (2.0) | 0.543 |
SAEs observed during the trial | 9 (11.8) | 10 (6.5) | 20 (6.6) | 0.262 |
Upper gastrointestinal bleeding | 5 (6.6) | 4 (2.6) | 4 (1.3) | 0.029 |
Deaths | 3 (3.9) | 4 (2.6) | 8 (2.6) | 0.812 |