Background
Methods
Study design
Study endpoints
Prohibited and restricted concomitant medications
Prohibited concomitant medications
Restricted concomitant medications
Sample size estimation
Statistical analysis
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Step 1: Analysis of covariance (ANCOVA) with the slopes calculated from the results obtained during the run-in period as a covariate after assigning contrast coefficients [−1, 0, 1].
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Step 2: ANCOVA with the slopes obtained from the results collected during the run-in period as a covariate after assigning contrast coefficient [−1, 1, 0], only when a statistical significance was detected in Step 1.
Study measurements
Examination by investigator | Objective symptoms (patient interview) |
Physical examination | Body weight, blood pressure, pulse rate, 12-lead ECG |
Hematological examination | WBC, RBC, Hb, Ht, PLT, |
Differential count of leukocytes (basophil, eosinophil, neutrophil, lymphocyte, monocyte) | |
Bleeding and coagulation test | PT, APTT |
Blood biochemistry | TP, Alb, T-BIL, AST(GOT), ALT(GPT), ALP, LDH, γ-GTP, |
TCh, TG, UA, BUN, serum creatinine (SCr), Na, K, Cl, Ca, P, HbA1c, cystatin C, | |
High-sensitive CRP | |
Uremia toxins test in plasma | Guanidino succinate |
Urinalysis (occasional urine) | pH, qualitative protein, glucose, and urobilinogen, occult blood reaction urinary sediment (RBC, WBC, casts), β2 microglobulin (adjusted by creatinine), pregnancy test (hCG) |
Urinalysis (24-hour pooled urine) | Urinary protein excretion, CCr, urea nitrogen, electrolytes (Na, Cl), urine output, creatinine |
Trial registration
Results
Patient disposition
Analysis sets
Parameter | Treatment group | |||
---|---|---|---|---|
Placebo | 120 μg | 240 μg | ||
(n = 34) | (n = 32) | (n = 36) | ||
Sex | Male | 18 (52.9 %) | 17 (53.1 %) | 24 (66.7 %) |
Female | 16 (47.1 %) | 15 (46.9 %) | 12 (33.3 %) | |
Age | Mean ± SD (years) | 59.9 ± 10.0 | 56.5 ± 14.7 | 57.8 ± 13.9 |
Primary disease | Primary glomerular disease | 28 (82.4 %) | 27 (84.4 %) | 25 (69.4 %) |
Nephrosclerosis | 6 (17.6 %) | 5 (15.6 %) | 11 (30.6 %) | |
1/SCr time slope during the run-in period | Mean ± SD (dL/mg over 4 weeks) | −0.01210 ± 0.00497 | −0.01535 ± 0.00808 | −0.01198 ± 0.00788 |
SCra | Mean ± SD (mg/dL) | 2.377 ± 0.665 | 2.251 ± 0.618 | 2.564 ± 0.705 |
Urinary protein excretiona | Mean ± SD (mg/day) | 2103.7 ± 1523.0 | 2037.5 ± 1763.4 | 1753.9 ± 1396.2 |
Systolic blood pressurea | Mean ± SD (mmHg) | 122.7 ± 16.1 | 129.0 ± 13.3 | 129.4 ± 15.6 |
Diastolic blood pressurea | Mean ± SD (mmHg) | 72.5 ± 11.0 | 73.4 ± 10.3 | 75.1 ± 10.6 |
Concomitant medication | ACEI (+) | 13 (38.2 %) | 9 (28.1 %) | 12 (33.3 %) |
ACEI/ARB positive | ARB (+) | 25 (73.5 %) | 26 (81.3 %) | 25 (69.4 %) |
Changes in SCr
Efficacy
Treatment group | No. of patients | 1/SCr versus time slope (dL/mg over 4 weeks) | Difference in the 1/SCr versus time slope (dL/mg over 4 weeks) | ||||
---|---|---|---|---|---|---|---|
Run-in period (R0 ~ R20) | Treatment period (W4 ~ W28) | ||||||
Mean | SD | Mean | SD | Mean | SD | ||
Placebo | 34 | −0.0121 | 0.00497 | −0.0074 | 0.00935 | 0.0047 | 0.01087 |
120 μg | 32 | −0.0154 | 0.00808 | −0.0040 | 0.01345 | 0.0113 | 0.01011 |
240 μg | 36 | −0.0120 | 0.00788 | −0.0045 | 0.00750 | 0.0075 | 0.00953 |
Treatment group | No. of patients | Least square mean of the change in the 1/SCr slope | Difference in the least square mean (versus placebo)a | Contrast test | ||
---|---|---|---|---|---|---|
(P value) | ||||||
Point estimate | 95 % CI | Point estimate | 95 % CI | (−1,0,1) | ||
Placebo | 34 | 0.00516 | [0.00187, 0.00845] | ― | ― | |
120 μg | 32 | 0.01026 | [0.00682, 0.01369] | 0.00510 | [0.00031, 0.00989] | |
240 μg | 36 | 0.00798 | [0.00478, 0.01118] | 0.00282 | [−0.00175, 0.00740] | 0.2234 |
Treatment group | Number of patients | Least square mean of the ratio of SCr | Difference in the least square mean (versus placebo) | P-value* | ||
---|---|---|---|---|---|---|
Point estimate | SE | Point estimate | SE | |||
Placebo | 34 | 1.169 | 0.032 | – | – | – |
120 μg | 32 | 1.069 | 0.033 | 0.100 | 0.045 | 0.0309 |
240 μg | 36 | 1.064 | 0.031 | 0.105 | 0.044 | 0.0204 |
Treatment group | Number of patientsb | Least square mean of the difference in serum cystatin C (mg/L) | Difference in the least square mean (versus placebo) (mg/L) | P-value | ||
---|---|---|---|---|---|---|
Point estimate | SE | Point estimate | SE | |||
Placebo | 32 | 0.253 | 0.065 | ― | ― | ― |
120 μg | 31 | 0.097 | 0.066 | 0.157 | 0.092 | 0.0928 |
240 μg | 35 | 0.052 | 0.063 | 0.201 | 0.090 | 0.0285 |
Ratio of eGFR
Treatment group | Number of patients | Least square mean of the difference in serum cystatin C (mg/L) | Difference in the least square mean (versus placebo) (mg/L) | P-value | ||
---|---|---|---|---|---|---|
Point estimate | SE | Point estimate | SE | |||
Placebo | 34 | 0.877 | 0.025 | ― | ― | ― |
120 μg | 32 | 0.952 | 0.026 | 0.075 | 0.036 | 0.0365 |
240 μg | 36 | 0.942 | 0.024 | 0.065 | 0.035 | 0.0628 |
Safety and tolerability
Parameter | 120 μg | 240 μg | Placebo |
---|---|---|---|
Number of patients evaluated | 36 | 41 | 35 |
Number of patients who experienced adverse events | 27 (75.0 %) | 36 (87.8 %) | 28 (80.0 %) |
Number of patients who experienced serious adverse events | 3 (8.3 %) | 4 (9.8 %) | 1 (2.9 %) |
Number of patients who discontinued the study treatment due to adverse events | 4 (11.1 %) | 7 (17.1 %) | 0 (0.0 %) |
Number of patients who interrupted the study treatment due to adverse events | 0 (0.0 %) | 2 (4.9 %) | 0 (0.0 %) |
Parameter | 120 μg | 240 μg | Placebo |
---|---|---|---|
Number of patients evaluated | 36 | 41 | 35 |
Number of patients who experienced ADR | 7 (19.4 %) | 13 (31.7 %) | 5 (14.3 %) |
Number of patients who experienced serious ADR | 2 (5.6 %) | 0 (0.0 %) | 0 (0.0 %) |
Number of patients who discontinued the study treatment due to ADR | 3 (8.3 %) | 5 (12.2 %) | 0 (0.0 %) |
Number of patients who interrupted the study treatment due to ADR | 0 (0.0 %) | 1 (2.4 %) | 0 (0.0 %) |
Adverse Events | |||||
---|---|---|---|---|---|
120 μg | 240 μg | Placebo | |||
Headache | 5 (13.9 %) | Nasopharyngitis | 11 (26.8 %) | Nasopharyngitis | 8 (22.9 %) |
Nasopharyngitis | 4 (11.1 %) | Headache | 7 (17.1 %) | Pruritus | 3 (8.6 %) |
Back pain | 3 (8.3 %) | Diarrhea | 5 (12.2 %) | Fever | 3 (8.6 %) |
Hyperkalemia | 2 (5.6 %) | Malaise | 3 (7.3 %) | Hyperkalemia | 3 (8.6 %) |
Dizziness | 2 (5.6 %) | Influenza | 2 (5.7 %) | ||
Hypertension | 2 (5.6 %) | Hyperkalemia | 2 (5.7 %) | ||
Upper respiratory tract inflammation | 2 (5.6 %) | Muscle Spasm | 2 (5.7 %) | ||
Diarrhea | 2 (5.6 %) | Genital Bleeding | 2 (5.7 %) | ||
Vomiting | 2 (5.6 %) | ||||
Arthralgia | 2 (5.6 %) | ||||
Adverse drug reactions | |||||
120 μg | 240 μg | Placebo | |||
Hypertension | 2 (5.6 %) | Headache | 6 (14.6 %) | Genital Bleeding | 2 (5.7 %) |
Malaise | 3 (7.3 %) |
Treatment group | Systolic blood pressure | Diastolic blood pressure | |||
---|---|---|---|---|---|
R20 | Final evaluation point | R20 | Final evaluation point | ||
Placebo | No. of patients | 35 | 35 | 35 | 35 |
Mean ± SD | 123.8 ± 17.0 | 127.5 ± 20.3 | 72.7 ± 10.9 | 75.3 ± 9.9 | |
120 μg | No. of patients | 36 | 35 | 36 | 35 |
Mean ± SD | 128.3 ± 13.0 | 127.8 ± 13.5 | 73.6 ± 10.7 | 75.4 ± 10.5 | |
240 μg | No. of patients | 41 | 40 | 41 | 40 |
Mean ± SD | 128.3 ± 16.4 | 129.4 ± 13.7 | 74.4 ± 10.6 | 75.1 ± 8.9 |