Visual Abstract
Keywords: Imarikiren; diabetes; microalbuminuria; direct renin inhibitor; randomized; placebo-controlled; double-blind; candesartan cilexetil; albuminuria; Diabetic Nephropathies; Renin; creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; glomerular filtration rate; Incidence; blood pressure; candesartan; Tetrazoles; Benzimidazoles; Biphenyl Compounds; Albumins
Abstract
Background and objectives
Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.
Design, setting, participants, & measurements
This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.
Results
Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), −16% (imarikiren 5 mg), −27% (imarikiren 20 mg), −38% (imarikiren 40 mg), −39% (imarikiren 80 mg), and −31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated.
Conclusions
Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.
Introduction
Diabetic nephropathy is caused by metabolic and hemodynamic changes associated with sustained hyperglycemia, and it is characterized by persistent albuminuria (1,2). In Japan, diabetic nephropathy is the most common primary kidney disease requiring dialysis (3). Patients with diabetic nephropathy have a higher risk for cardiovascular disease, which contributes to worse outcomes compared with patients with diabetes who do not have nephropathy (4).
Conventionally, diabetic nephropathy is considered a progressive disease characterized by the presence of albuminuria/proteinuria and declining kidney function culminating in ESKD (5). Recent studies suggest that proactive intervention with strict control of blood glucose and BP levels and administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) can induce remission of moderately increased albuminuria to normal albuminuria and/or prevent progression to overt albuminuria for patients with type 2 diabetes and microalbuminuria (6,7). These studies provide a rationale for early-stage proactive treatment, with albuminuria and proteinuria as clinical indicators, to prevent the progression of diabetic nephropathy. However, treatment with ACE inhibitors and ARBs, which are currently recommended for the treatment of type 2 diabetic nephropathy, may not uniformly reduce urine albumin levels; one study evaluating ARBs found that they failed to reduce albuminuria in 34.5% of patients (8). Thus, there remains an unmet need for effective drugs that can prevent progression of diabetic nephropathy.
Direct renin inhibitors inhibit renin, an enzyme that controls the rate-limiting step of the renin-angiotensin system cascade (9). The renin-angiotensin system is a core mechanism in the regulation of BP and fluid homeostasis, and it is also thought to play an important role in the pathogenesis of glomerulosclerosis by promoting fibrosis (9). Direct renin inhibitors, by inhibiting the whole renin-angiotensin system, are expected to have equivalent or superior effects on BP and fibrosis compared with ACE inhibitors or ARBs, which inhibit the middle and distal portions of the renin-angiotensin system pathway (9). In a clinical trial of patients with type 2 diabetes and microalbuminuria, treatment with the first-in-class direct renin inhibitor, aliskiren, reduced the urine albumin excretion rate to a greater degree than the ACE inhibitor ramipril (−42% versus −15%; P<0.01) (10). However, relatively low bioavailability (approximately 2.5%) is a limitation of this agent (11).
Imarikiren hydrochloride (TAK-272; SCO-272) is a novel orally bioavailable direct renin inhibitor (12). The bioavailability of this agent in humans was calculated to be 77% (13). In animal studies, urinary or biliary excretion of imarikiren as unchanged drug was ≤3% (13). In phase 1 clinical studies, treatment with imarikiren resulted in dose-proportional pharmacokinetics, strong and sustained suppression of plasma renin activity, and a favorable safety and tolerability profile (14,15). Furthermore, the 13%‒17% urine excretion of imarikiren suggests that it may have improved bioavailability compared with aliskiren (14). Given the potential of direct renin inhibitors as therapeutic drugs to slow progression of nephropathy, we conducted a trial to evaluate the efficacy and safety of imarikiren in patients with type 2 diabetes and microalbuminuria. The primary efficacy end point was change in the log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment. Secondary efficacy end points included urine albumin-to-creatinine ratios at each assessment point, remission rate, and progression rate. Additional exploratory efficacy end points included eGFR and sitting systolic and diastolic BP values before dosing.
Materials and Methods
Study Design and Patients
This was a randomized, multicenter, double-blind, placebo-controlled, parallel group, phase 2, dose-finding trial of imarikiren 5, 20, 40, and 80 mg administered orally once daily to patients with type 2 diabetes and microalbuminuria conducted at 87 sites in Japan from October 16, 2014 to August 18, 2016. The study objectives were to evaluate the efficacy and safety of imarikiren to determine the clinical dose of imarikiren and explore the clinical effect of imarikiren compared with candesartan cilexetil 8 mg. Candesartan cilexetil was chosen as the comparator, because clinical studies in Japanese patients have confirmed the kidney-protective effect in patients with CKD (16) and its urine albumin-to-creatinine ratio-lowering effect in patients with type 2 diabetes mellitus and microalbuminuria (17). The study duration consisted of a pretreatment period of 8 weeks, a treatment period of 12 weeks, and a follow-up period of 2 weeks (Supplemental Figure 1).
Patients with type 2 diabetes and microalbuminuria were eligible if they were age 20 to <75 years old; had an urine albumin-to-creatinine ratio of the first morning urine of ≥30 to <300 mg/g creatinine on two or more of three measurements at week −8, −4, or –2; and had an eGFR (calculated using an equation on the basis of serum creatinine for the Japanese population [18]) ≥45 ml/min per 1.73 m2 at week –4. Exclusion criteria included hyperkalemia (serum potassium ≥5.0 mEq/L at weeks –8 and −4 or requiring regular use of potassium adsorbent) or onset of hyperkalemia within the previous 2 years; at least class 2 hypertension in the pretreatment period or malignant hypertension; sitting systolic BP <130 mm Hg at week 0; history of major cardiovascular disease within the previous 2 years; presence of clinically significant hepatic disorder; and treatment with any renin-angiotensin inhibitor (ACE inhibitors, ARBs, or direct renin inhibitor) at the time of informed consent among individuals with urine albumin-to-creatinine ratio <30 mg/g creatinine at week −8.
Individuals taking renin-angiotensin system inhibitors before the study were not excluded provided that they did not have a change in their renin-angiotensin system inhibitor or its dose and regimen within the 12 weeks before starting the pretreatment period (week −8), but renin-angiotensin system inhibitors or other excluded medications were not allowed to be used after week −8.
Excluded medications included renin-angiotensin system inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibitors, potassium-sparing diuretics (including aldosterone antagonists), potassium supplements, amphotericin B, aminoglycoside antibacterial drugs, iodine-containing contrast agents, lithium carbonate products, penicillamione products, and moderate or strong cytochrome P450 3A4 inhibitors or inducers.
The protocol was approved by the appropriate institutional review board at the clinical sites; informed consent was obtained in compliance with the Declaration of Helsinki. The trial is registered with ClinicalTrials.gov (NCT02332824) and JapicCTI (JapicCTI-142658).
Treatment
In the pretreatment period from week −4 to week 0, placebo was administered to all patients (placebo run-in period: single blinded). The patients judged to be eligible as a result of the eligibility assessment in the pretreatment period were randomized to imarikiren 5, 20, 40, and 80 mg; candesartan cilexetil 8 mg; or placebo (1:1:1:1:1:1) using a permuted block schedule, which was electronically generated by an independent randomization officer. A double-dummy approach was used. In addition, placebo was administered to all patients in the post-treatment follow-up period (single blinded).
The study drug was administered orally once daily before or after breakfast. Renin-angiotensin system inhibitors and SGLT2 inhibitors were discontinued at week −8 and switched to other therapeutic drugs for hypertension and diabetes mellitus according to the judgment of the investigator as necessary. Therapeutic drugs for hypertension (except for renin-angiotensin system inhibitors), diabetes mellitus (except for SGLT2 inhibitors), and dyslipidemia or hyperlipidemia that were used at week −8 could be used during the treatment period; however, the drugs and their dose and regimen could not be changed. The investigator and the subinvestigator gave consistent instructions regarding diet and exercise therapies (if any) through the study period.
Assessments
Study visits occurred at weeks −8, −4, −2, 0, 2, 4, 8, 12, and 14 (four visits during the pretreatment period, four visits during the treatment period, and one visit during the follow-up period). Efficacy assessments included urine albumin-to-creatinine ratio, eGFR, and urinary biomarkers (urinary type IV collagen, urinary liver-type fatty acid binding protein [L-FABP], and urinary kidney injury molecule-1 [Kim1]). In the treatment and follow-up periods, urinary albumin and urinary creatinine concentrations were measured at a central laboratory using the first morning void urine samples collected on the day of each visit and 1 and 2 days before each visit (3 consecutive days). Urine albumin-to-creatinine ratio corrected by urinary creatinine concentrations was calculated by the central laboratory, and the geometric mean for 3 consecutive days was calculated. The values for eGFR were calculated by the central laboratory for each visit using the equation on the basis of serum creatinine for the Japanese population: eGFR (milliliters per minute per 1.73 m2) =194× creatinine (milligrams per deciliter)−1.094 × age (years)−0.287; this equation was multiplied by 0.739 for women (18).
Urinary type IV collagen, urinary L-FABP, and urinary Kim1 were measured at weeks 0 and 12 using ELISA. These markers were measured because they have been previously established as biomarkers of CKD progression and associated comorbidities (19).
Blood samples for pharmacokinetics and pharmacodynamics (plasma renin activity, active plasma renin concentration, and plasma aldosterone concentration) assessment were collected at weeks 0 (pharmacodynamics only), 2 (pharmacokinetics only), 4, 12, and 14 (pharmacodynamics only). Plasma drug concentrations were measured using liquid chromatography/tandem mass spectrometry. The most recent date and time of the study drug administration and the date and time of blood collection were recorded on the electric case report form. Blood samples for pharmacodynamic assessment were collected after >30 minutes of supine rest to the extent possible before taking the study drug. All pharmacodynamic parameters were measured and calculated at the central laboratory.
Safety measurements and end points included adverse events (AEs), vital signs (standing BP and sitting pulse rate), and laboratory tests at all visits, and weight and resting 12-lead electrocardiogram at weeks 0, 4, and 12. Treatment-emergent AEs were coded using the Medical Dictionary for Regulatory Activities.
Sitting and standing BP (systolic and diastolic) was measured as an exploratory efficacy assessment in all visits. At week −8, sitting BP was measured once in each arm, and the arm with the higher systolic BP was used for the duration of the study. BP measurement was repeated at least three times at 1- to 2-minute intervals after ≥5-minutes of rest in the sitting position. Measurement was discontinued when two consecutive values were within 5 mm Hg for diastolic BP or 10 mm Hg for systolic BP, and these values were recorded. To assess standing BP, pressure was measured after ≥2-minutes of rest in the sitting position and after 1 minute in the standing position, and the results were recorded.
Statistical Analyses
The primary efficacy end point was the change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment. The planned sample size was 68 per group. This would provide at least 80% power at a two-sided significance level of 0.05 in the comparison of imarikiren 20, 40, and 80 mg each against placebo to detect urine albumin-to-creatinine ratio reductions of 35%, 37.5%, and 40%, respectively, assuming the common SD of the primary end point to be 0.8. This assumption was on the basis of studies of azilsartan in patients with hypertension and CKD and studies of candesartan cilexetil in combination with pioglitazone for patients with hypertension and type 2 diabetes, in which the SD of the change in log-transformed urine albumin-to-creatinine ratio from baseline ranged from 0.69 to 0.77 in patients with baseline urine albumin-to-creatinine ratios of 30–300 mg/g creatinine.
The primary end point was analyzed using an analysis of covariance model, with treatment groups as a fixed effect and baseline log-transformed urine albumin-to-creatinine ratio as a covariate. Antilog-transformed values of the least squares (LS) mean and the two-sided 95% confidence interval (95% CI) for each treatment group as well as the LS mean difference between treatment groups (each imarikiren treatment group − placebo or candesartan cilexetil group) and the two-sided 95% CI were calculated. In addition, each imarikiren group and the placebo group were compared on the basis of a fixed sequence testing procedure. Specifically, imarikiren treatment groups were compared with placebo in descending order, where the one step–lower dose of imarikiren was compared next against placebo if and only if the test result of the current dose level of imarikiren versus placebo is statistically significant at a two-sided significance level of 0.05. Using this procedure, the overall type 1 error of the primary analysis was kept under 5% (two sided). A multiple comparison procedure - modeling (MCP-Mod) approach was applied to explore the dose-response relationship of imarikiren. Linear, beta, Emax, sigmoid Emax, and exponential models were chosen as candidate models.
Secondary efficacy end points were the urine albumin-to-creatinine ratio at each assessment point, the remission rate from early-stage nephropathy to prenephropathy stage (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased by ≥30% from baseline) at the end of treatment, and the progression rate from early-stage nephropathy to overt nephropathy (urine albumin-to-creatinine ratio ≥300 mg/g creatinine and increased by ≥30% from baseline) during the treatment period. Additional exploratory efficacy end points included eGFR, sitting systolic and diastolic BP measurements before dosing, plasma renin activity, active plasma renin concentration, and plasma aldosterone concentration. No multiplicity adjustment was performed for secondary and exploratory analyses.
All statistical analyses were performed using SAS, version 9.2.
Results
Enrollment and Patient Disposition
A total of 1027 patients were screened, and 415 were randomly assigned to one of the six treatment groups (Figure 1). Of these, 399 completed the double-blinded study drug administration, and 16 prematurely discontinued the double-blinded study drug administration. The most common reasons for discontinuation were pretreatment events/AEs. There were no major differences in the number of or reasons for premature discontinuation among the treatment groups.
Figure 1.
Patient disposition. AE, adverse event.
Baseline Patient Characteristics
Demographic and other baseline characteristics are shown in Table 1. No clinically significant differences in demographic or other baseline characteristics were observed between treatment groups.
Table 1.
Baseline characteristics
| Characteristic | Placebo, n=67 | Imarikiren 5 mg, n=67 | Imarikiren 20 mg, n=74 | Imarikiren 40 mg, n=68 | Imarikiren 80 mg, n=69 | Candesartan Cilexetil 8 mg, n=70 | Total, n=415 |
|---|---|---|---|---|---|---|---|
| Age, yr, mean (SD) | 62 (8) | 62 (9) | 61 (10) | 60 (10) | 61 (10) | 62 (9) | 61 (9) |
| Sex, men, n (%) | 51 (76) | 56 (84) | 57 (77) | 55 (81) | 51 (74) | 56 (80) | 326 (79) |
| BMI, kg/m2, mean (SD) | 26 (4) | 26 (4) | 27 (5) | 26 (5) | 26 (4) | 27 (5) | 26 (5) |
| Duration of type 2 diabetes, yr, mean (SD) | 12 (8) | 11 (7) | 11 (8) | 11 (7) | 11 (7) | 10 (7) | 11 (7) |
| Hypertension, n (%) | 50 (75) | 46 (69) | 60 (81) | 48 (71) | 60 (87) | 52 (74) | 316 (76) |
| Antihypertension drug, n (%) | 40 (60) | 34 (51) | 46 (62) | 33 (49) | 44 (64) | 45 (64) | 242 (58) |
| Diuretic drug, n (%) | 4 (6) | 3 (4) | 2 (3) | 4 (6) | 4 (6) | 1 (1) | 18 (4) |
| Urine albumin-to-creatinine ratio, mg/g creatinine, median (IQR) | 120 (66‒215) | 93 (54‒139) | 96 (59‒174) | 116 (50‒201) | 87 (54‒153) | 96 (57‒179) | 100 (56‒179) |
| eGFR, ml/min per 1.73 m2, mean (SD) | 77 (19) | 82 (20) | 79 (19) | 81 (20) | 78 (18) | 83 (23) | 80 (20) |
| Sitting diastolic BP before dosing, mm Hg, mean (SD) | 81 (9) | 81 (9) | 81 (9) | 79 (9) | 82 (9) | 81 (9) | 81 (9) |
| Sitting systolic BP before dosing, mm Hg, mean (SD) | 141 (7) | 139 (8) | 138 (7) | 139 (8) | 140 (8) | 141 (8) | 140 (8) |
BMI, body mass index; IQR, interquartile range.
Efficacy
The urine albumin-to-creatinine ratio decreased from baseline in a dose-dependent manner in the imarikiren groups (Figure 2). The antilog-transformed values for changes in LS means of log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment (change from baseline in the urine albumin-to-creatinine ratio) were 1.16 (16%) in the placebo group, 0.84 (−16%) in the imarikiren 5-mg group, 0.73 (−27%) in the imarikiren 20-mg group, 0.62 (−38%) in the imarikiren 40-mg group, 0.61 (−39%) in the imarikiren 80-mg group, and 0.69 (−31%) in the candesartan cilexetil group. Decreases in urine albumin-to-creatinine ratio from baseline were statistically significant in all imarikiren groups compared with placebo (P<0.001 for all comparisons). The antilog-transformed values for the LS mean differences (two-sided 95% CI) between treatment groups (imarikiren group − placebo group) of the change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment are shown in Supplemental Table 1. A dose-response relationship for imarikiren was detected by multiple contrast tests, with contrast coefficients corresponding to predefined dose-response models in the multiple comparison procedure step of the MCP-Mod approach (P<0.001 for all of the tests), and the Emax model was the best-fit model in terms of the Akaike information criterion value in the modeling step. The estimated maximum effect (Emax) and the dose that gives one half of the maximum effect (ED50) were −0.7 (95% CI, −0.85 to −0.54) and 7.0 mg (95% CI, 0.29 to 13.7), respectively.
Figure 2.
Urine albumin-to-creatinine ratio decreased from baseline in a dose-dependent manner in the imarikiren groups. Antilog-transformed values (milligrams per gram creatinine) of mean (95% confidence interval) change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment.
The secondary end point of urine albumin-to-creatinine ratio at each visit is shown in Supplemental Table 2. The geometric mean urine albumin-to-creatinine ratio decreased from baseline in all imarikiren groups at week 2 and continued to decrease through the end of the treatment period (except in the 5-mg dose group), whereas the urine albumin-to-creatinine ratio for the placebo group increased.
The rates of remission to normal to mildly increased albuminuria (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) at the end of the treatment period (secondary end point) were 9%, 9%, 18%, and 25% for patients treated with imarikiren 5, 20, 40, and 80 mg, respectively, compared with 0% for those treated with placebo and 14% for those treated with candesartan cilexetil 8 mg (Table 2). Imarikiren 40 and 80 mg resulted in numerically greater reductions in urine albumin-to-creatinine ratio and remission than candesartan cilexetil 8 mg.
Table 2.
Rates of remission from microalbuminuria to normal albuminuria to mildly increased albuminuria, heightened response, and progression from microalbuminuria to overt albuminuria
| Treatment | n | Rate at the End of Treatment, n (%) | Percentage Difference in Rate Versus Placebo (95% CI) | Percentage Difference in Rate Versus Candesartan Cilexetil (95% CI) |
|---|---|---|---|---|
| Remission | ||||
| Placebo | 66 | 0 (0) | — | — |
| Imarikiren 5 mg | 67 | 6 (9) | 9 (2 to 16) | ‒5 (‒16 to 5) |
| Imarikiren 20 mg | 74a | 7 (9) | 10 (3 to 16) | ‒5 (‒15 to 6) |
| Imarikiren 40 mg | 67 | 12 (18) | 18 (9 to 27) | 4 (‒9 to 16) |
| Imarikiren 80 mg | 69 | 17 (25) | 25 (14 to 35) | 10 (‒3 to 23) |
| Candesartan cilexetil 8 mg | 70 | 10 (14) | 14 (6 to 22) | — |
| Heightened response | ||||
| Placebo | 66 | 1 (2) | — | — |
| Imarikiren 5 mg | 67 | 7 (10) | 9 (1 to 17) | ‒15 (‒28 to ‒3) |
| Imarikiren 20 mg | 74a | 20 (27) | 26 (15 to 37) | 2 (‒13 to 16) |
| Imarikiren 40 mg | 67 | 18 (27) | 25 (14 to 36) | 1 (‒14 to 16) |
| Imarikiren 80 mg | 69 | 27 (39) | 38 (26 to 50) | 13 (‒2 to 29) |
| Candesartan cilexetil 8 mg | 70 | 18 (26) | 24 (14 to 35) | — |
| Progression | ||||
| Placebo | 66 | 12 (18) | — | — |
| Imarikiren 5 mg | 67 | 2 (3) | ‒15 (‒25 to ‒5) | 2 (‒3 to 6) |
| Imarikiren 20 mg | 74a | 0 (0) | ‒18 (‒27 to ‒9) | ‒1 (‒4 to 1) |
| Imarikiren 40 mg | 67 | 0 (0) | ‒18 (‒27 to ‒9) | ‒1 (‒4 to 1) |
| Imarikiren 80 mg | 69 | 0 (0) | ‒18 (‒27 to ‒9) | ‒1 (‒4 to 1) |
| Candesartan cilexetil 8 mg | 70 | 1 (1) | ‒17 (‒26 to ‒7) | — |
Remission: urine albumin-to-creatinine ratio <30 mg/g creatinine and ≥30% decrease in urine albumin-to-creatinine ratio from baseline. Heightened response: ≥50% reduction in urine albumin-to-creatinine ratio from baseline. Progression: urine albumin-to-creatinine ratio ≥300 mg/g creatinine and ≥30% increase in urine albumin-to-creatinine ratio from baseline. 95% CI, 95% confidence interval; —, not applicable.
n=73 for heightened response analysis.
The rates of progression during the treatment period (secondary end point) were 18% in the placebo group, 3% in the imarikiren 5-mg group, 1% in the candesartan cilexetil group, and 0% in the imarikiren ≥20-mg dose groups (Table 2).
The proportions of patients with a heightened response (≥50% reduction in urine albumin-to-creatinine ratio from baseline to the end of treatment; exploratory end point) were 2% in the placebo group, 10% in the imarikiren 5-mg group, 27% in the imarikiren 20-mg group, 27% in the imarikiren 40-mg group, 39% in the imarikiren 80-mg group, and 26% in the candesartan cilexetil group (Table 2).
Safety
Treatment-emergent AEs were reported in 42% of patients in the placebo group, 33% of patients in the imarikiren 5-mg group, 35% of patients in the imarikiren 20-mg group, 41% of patients in the imarikiren 40-mg group, 52% of patients in the imarikiren 80-mg group, and 43% of patients in the candesartan cilexetil group (Supplemental Table 3). The most common treatment-emergent AEs are also shown in Supplemental Table 3. All treatment-emergent AEs were mild or moderate in intensity.
Treatment-emergent AEs leading to study drug discontinuation were reported in 6% of patients in the placebo group, 1% of patients in the imarikiren 40-mg group, 6% of patients in the imarikiren 80-mg group, and 1% of patients in the candesartan cilexetil group. All events but one were unrelated to the study drug (mild dizziness in the imarikiren 40-mg group, which resolved after study drug discontinuation). Serious treatment-emergent AEs were reported in five patients (five events, none of which were considered related to study drug): two patients in the placebo group, two patients in the imarikiren 80-mg group, and one patient in the candesartan cilexetil group. There were no deaths.
Treatment-emergent AEs, which may have been caused by a decrease in BP, were observed in four patients in the imarikiren 40-mg group and two patients in the candesartan cilexetil group. Except for an event of moderate “vertigo” in the candesartan cilexetil group, these events were mild in intensity. One potassium-related treatment-emergent AE was reported in the imarikiren 40-mg group at week 12 (serum potassium increased to 5.8 mEq/L), and it was considered drug related.
No other clinically significant differences were observed among the treatment groups in the results of laboratory parameters and electrocardiogram parameters.
Other Exploratory End Points
A summary of the changes in eGFR, sitting BP before dosing, and urinary biomarkers from baseline is shown in Figure 3, Tables 3 and 4, and Supplemental Tables 4–6. Mean eGFR, sitting BP before dosing, and serum potassium at each measured time point are shown in Supplemental Figure 2 and Supplemental Table 4. The sitting BP before dosing decreased from baseline to the end of treatment in the imarikiren groups and the candesartan cilexetil 8-mg group (Table 3). The imarikiren 80-mg group had numerically greater reductions in sitting systolic BP before dosing than the candesartan cilexetil 8-mg group (−10.1 versus −8.8 mm Hg).
Figure 3.
Sitting BP before dosing decreased from baseline over time with imarikiren or candesartan cilexetil treatment. (A) Mean change from baseline in diastolic BP. (B) Mean change from baseline in systolic BP. Data are mean + SD.
Table 3.
Change from baseline to end of treatment in eGFR and sitting BP before dosing
| eGFR and Sitting BP | Placebo | Imarikiren | Candesartan Cilexetil 8 mg | |||
|---|---|---|---|---|---|---|
| 5 mg | 20 mg | 40 mg | 80 mg | |||
| eGFR, ml/min per 1.73m2 | ||||||
| Change | ||||||
| n | 66 | 67 | 72 | 67 | 69 | 70 |
| Mean (SD) | 0.7 (9.2) | −0.9 (8.8) | −1.3 (8.0) | −3.1 (8.9) | −2.9 (9.1) | −2.3 (8.1) |
| Sitting systolic BP before dosing, mm Hg | ||||||
| Change | ||||||
| n | 66 | 67 | 73 | 67 | 69 | 70 |
| Mean (SD) | −4.1 (11.2) | −4.8 (12.6) | −5.1 (11. 8) | −7.4 (11.6) | −10.1 (11.7) | −8.8 (12.4) |
| Sitting diastolic BP before dosing, mm Hg | ||||||
| Change | ||||||
| n | 66 | 67 | 73 | 67 | 69 | 70 |
| Mean (SD) | −0.8 (6.6) | −1.9 (7.2) | −1.5 (8.2) | −3.3 (7.1) | −5.3 (6.5) | −5.0 (8.1) |
Table 4.
Change from baseline to end of treatment in urinary biomarker values
| Urinary Biomarker | Placebo | Imarikiren | Candesartan Cilexetil 8 mg | |||
|---|---|---|---|---|---|---|
| 5 mg | 20 mg | 40 mg | 80 mg | |||
| Urinary type IV collagen-to-creatinine ratio, μg/g creatinine | ||||||
| Change | ||||||
| n | 66 | 67 | 73 | 67 | 67 | 70 |
| Mean (SD) | 0.79 (3.63) | 0.04 (6.87) | −0.47 (3.85) | −0.20 (3.35) | −0.80 (3.62) | 0.19 (3.85) |
| Urinary L-FABP–to-creatinine ratio, μg/g creatinine | ||||||
| Change | ||||||
| n | 66 | 67 | 73 | 67 | 67 | 70 |
| Mean (SD) | −1.31 (8.40) | −1.05 (11.36) | −3.30 (24.67) | −2.29 (10.32) | −3.76 (22.79) | 1.10 (19.91) |
| Urinary KIM1-to-creatinine ratio, ng/g creatinine | ||||||
| Change | ||||||
| n | 66 | 67 | 73 | 67 | 67 | 70 |
| Mean (SD) | −5 (805) | 61 (539) | −122 (1415) | −296 (2156) | −432 (1767) | −188 (999) |
L-FABP, liver-type fatty acid binding protein; KIM1, kidney injury molecule-1.
A summary of change in serum potassium from baseline is shown in Supplemental Table 7. Spearman correlation coefficient between sitting BP before dosing and urine albumin-to-creatinine ratio was 0.31 for systolic BP and 0.36 for diastolic BP (Supplemental Figure 3). Pharmacokinetic and pharmacodynamic data are shown in Supplemental Material (Supplemental Figure 4).
Discussion
This is the first phase 2 trial to evaluate the efficacy and safety of imarikiren in patients with type 2 diabetes and microalbuminuria. In this population, urine albumin-to-creatinine ratio reductions from baseline were greater in all of the imarikiren groups compared with those of the placebo group, and all differences were statistically significant. A dose-response relationship was observed with imarikiren, and imarikiren 80 mg showed the greatest urine albumin-to-creatinine ratio reduction compared with the placebo. Remission rates were higher in all imarikiren groups compared with in the placebo group, and imarikiren 40 and 80 mg resulted in numerically higher remission rates than candesartan cilexetil 8 mg. The improvement in remission rates is notable given that normalization of albuminuria has been associated with improved cardiovascular outcomes in patients with type 2 diabetes and microalbuminuria (20). Furthermore, a greater proportion of patients in the imarikiren groups than in the placebo groups experienced ≥50% reduction in urine albumin-to-creatinine ratio, and numerically greater proportions of patients in the imarikiren 20-, 40-, and 80-mg groups compared with in the candesartan cilexetil 8-mg group experienced ≥50% reduction in urine albumin-to-creatinine ratio. A ≥50% reduction in urine albumin-to-creatinine ratio in patients with type 2 diabetes has been reported to be a powerful indicator for cardiovascular and kidney risk reduction (21). In one study, patients who achieved a ≥50% reduction in urine albumin-to-creatinine ratio had an adjusted risk for cardiovascular and kidney events of 0.41 in comparison with those without a 50% reduction; in addition, patients who achieved a ≥50% reduction had a significantly lower annual decline of eGFR (21).
In addition to changes in urine albumin-to-creatinine ratio and remission rates, several other efficacy end points were assessed, including changes in eGFR, sitting BP before dosing, and urinary biomarkers (urinary type IV collagen, urinary L-FABP, and urinary Kim1). Although no clear trends were observed in urinary biomarkers, mean eGFR in the imarikiren groups decreased from baseline, indicating the short-term effect of direct inhibition on efferent arteriolar vasodilation. No differences in change of eGFR were observed between the imarikiren groups and the candesartan cilexetil 8-mg group.
Although the incidence of treatment-emergent AEs was slightly higher in the imarikiren 80-mg group (52%) compared with in the other groups (33%–43%), all treatment-emergent AEs were mild or moderate in severity, and imarikiren was well tolerated in all groups during 12 weeks of treatment. Treatment-emergent AEs, which may be caused by a decrease in BP, were observed in four patients in the imarikiren 40-mg group and two patients in the candesartan cilexetil group. These treatment-emergent AEs resolved and were mild in intensity, except for one case of moderate vertigo reported in one patient in the candesartan cilexetil group. No clinically significant changes were observed in all imarikiren groups in the laboratory parameters, including serum potassium. Changes from baseline in serum potassium level at week 12 are shown in Supplemental Table 7. In the imarikiren 40-mg group, one potassium-related treatment-emergent AE was reported at week 12, and the serum potassium level recovered in 2 weeks (week 14) with no treatment. There was no specific symptom related to this treatment-emergent AE in that subject.
In this trial, patients who were normotensive (including those who were and were not receiving antihypertensive drugs) were enrolled, and the efficacy and safety of imarikiren for these patients were assessed in a subgroup analysis. According to a subgroup analysis by baseline systolic BP (<140 versus ≥140 mm Hg), it does not seem that baseline systolic BP affects the urine albumin-to-creatinine ratio reductions from baseline by imarikiren or candesartan cilexetil (Supplemental Table 8). Therefore, it is expected that imarikiren may also provide efficacy with acceptable tolerability for patients who are normotensive with type 2 diabetes and microalbuminuria.
There are some factors that limit the generalizability of the results of this trial. The main limitation of this trial is that it was conducted only in Japanese patients. In addition, patients age <20 or ≥75 years old and those with evident hyperkalemia (≥5.0 mEq/L), kidney impairment (except for type 2 diabetic nephropathy), or hypertension (class 2 or higher) were excluded, and therefore, the effectiveness of imarikiren was not confirmed in these patients. The treatment duration was relatively short, and additional studies are warranted to assess long-term efficacy and safety. Finally, the trial was primarily designed to compare imarikiren with placebo in a relatively small number of patients in each group, and it was not powered for the comparison of imarikiren with candesartan cilexetil 8 mg. A relatively low dose of candesartan cilexetil was used, because 8 mg is the maximum dosage indicated for patients who are hypertensive with kidney dysfunction in Japan.
The experience of aliskiren emphasizes the need for caution in predicting outcomes using results from earlier studies of surrogate measures and their study designs. In the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints, treatment with aliskiren in combination with an ACE inhibitor or ARB may have actually increased the risk of AEs (22). However, we also note that patients with severe disease in several large trials treated with a combination of two renin-angiotensin system classes had an increased risk of similar AEs (23,24). Although it remains to be determined whether the reductions in urine albumin-to-creatinine ratio observed will translate into a renoprotective effect over a longer period, the results of this study are promising. In addition, the combination of imarikiren with other renin-angiotensin system classes is out of scope of this study. Therefore, the use of direct renin inhibitors in a suitable patient population and as monotherapy may result in a better safety profile.
In conclusion, in patients with type 2 diabetes and microalbuminuria, treatment with imarikiren resulted in statistically significant greater urine albumin-to-creatinine ratio reductions from baseline compared with placebo and showed clinically meaningful reductions in urine albumin-to-creatinine ratio in a dose-dependent manner. In addition, imarikiren was safe and well tolerated in all groups for 12 weeks.
Data Sharing
Will Individual Deidentified Participant Data (Including Data Dictionaries) Be Shared?
Requests for access to deidentified participant data (including data dictionaries) by appropriately qualified external researchers are accepted after criteria have been met (relating to a specific study and the associated research program) as set forth in Takeda Pharmaceutical Company Limited’s Data Sharing Policy (see www.TakedaClinicalTrials.com/approach for details).
What Data in Particular Will Be Shared?
Deidentified patient-level clinical trial data (both raw and analysis-ready data) will be shared with approved researchers.
Will Additional Related Documents Be Available (e.g., Study Protocol, Statistical Analyses Plan, etc.)?
Clinical trial documents (e.g., clinical study reports, protocols, statistical analysis plans, and dataset specifications) will be shared with approved researchers.
When Will the Data Become Available and for How Long?
The main criterion that must be met is that studies will be listed as available for data sharing after the clinical development program which that study supported has received marketing authorization or the product’s clinical development is terminated. After that has occurred (and certain other criteria are met), that study will be listed as available for sharing. There is no defined end date for data availability from a study after the data for that study have become available. After researchers get access to the data, they get the data for 12 months, with a one-time additional 12-month extension if needed.
What Access Criteria Are Needed for Data to Be Shared (Including with Whom, for What Types of Analyses, and by What Mechanism)?
To obtain access, qualified researchers must submit a research proposal for adjudication by an existing independent review panel consisting of a chair and five members with a range of expertise, including statistics, conducting clinical trials, ethics, and a lay perspective (biographies of current panel members are listed at https://clinicalstudydatarequest.com/Help/Help-Independent-Review-Panel.aspx). The panel will review the scientific merit of the research and the requestor’s qualifications and conflict of interest that can result in potential bias. After approved, researchers who sign a data-sharing agreement are provided access to these data in a secure research environment known as the SAS Clinical Trial Data Transparency (CTDT) system (https://clinicalstudydatarequest.com/Help/Help-Access-to-Data.aspx). The CTDT portal is hosted by SAS and can be accessed by researchers at their institution. Researchers can use the following link to make a data access request: https://www.clinicalstudydatarequest.com/Default.aspx.
Disclosures
S.I. reports personal fees from Takeda Pharmaceuticals Limited. T.K., T.S., K.S., S.K., Y.S., and Y.U. report current or past employment with Takeda Pharmaceuticals Limited.
Supplementary Material
Acknowledgments
This study was funded by Takeda Pharmaceutical Company Limited. Medical writing assistance was provided by BlueMomentum, an Ashfield company, and supported by Takeda Pharmaceuticals Limited.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.07720618/-/DCSupplemental.
Supplemental Figure 1. Study design.
Supplemental Figure 2. Sitting BP before dosing. (A) Mean diastolic BP and (B) mean systolic BP.
Supplemental Figure 3. Scatter plot of change in log-transformed urine albumin-to-creatinine ratio from baseline against change in sitting BP before dosing from baseline to the end of treatment for the overall imarikiren treatment group. (A) Diastolic BP and (B) systolic BP.
Supplemental Figure 4. Imarikiren pharmacodynamics. (A) PRA inhibition rate, (B) change in PRC from baseline, and (C) change in plasma aldosterone concentration from baseline before dosing.
Supplemental Material. Results.
Supplemental Table 1. Antilog-transformed values (milligrams per gram creatinine) of mean change and least squares mean difference in change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment (ANCOVA).
Supplemental Table 2. Geometric mean ratio of urine albumin to creatinine at each assessment relative to baseline.
Supplemental Table 3. Overview of TEAEs and TEAEs occurring in ≥2% of patients in any treatment group (safety analysis set).
Supplemental Table 4. eGFR, sitting BP before dosing, and serum potassium.
Supplemental Table 5. Baseline and end of treatment urinary biomarker values.
Supplemental Table 6. Mean change from baseline and mean difference in change in eGFR, sitting BP before dosing, and urinary biomarkers.
Supplemental Table 7. Changes from baseline in serum potassium level.
Supplemental Table 8. Subgroup analysis of baseline systolic BP of change in antilog-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment.
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