Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria: A Randomized, Controlled Trial.

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.

Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment.

BACKGROUND AND OBJECTIVE: Imarikiren hydrochloride (TAK-272; SCO-272) is a novel direct renin inhibitor. The objective of this study was to determine the effects of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics and safety of imarikiren. METHODS: This phase I, open-label, parallel-group comparative study evaluated the pharmacokinetics and safety of a single 40 mg oral dose of imarikiren in RI [mild, moderate, severe, or end-stage renal disease (ESRD), and on hemodialysis] or HI (mild or moderate) subjects compared with subjects with normal renal or hepatic function. RESULTS: Following administration of a single 40 mg oral imarikiren dose, the geometric mean imarikiren area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) in subjects with mild, moderate, and severe RI (including non-hemodialysis and ESRD), and hemodialysis subjects compared with normal renal function subjects were approximately 0.5-, 1.2-, 2.7-, and 1.8-fold, respectively, for AUC∞; and approximately 0.6-, 0.8-, 2.1-, and 1.4-fold, respectively, for Cmax. The mean fraction of excretion of imarikiren in dialysate was ~ 3% during the 4 h dialysis period. The geometric mean imarikiren AUC∞ and Cmax in mild and moderate HI subjects compared with normal hepatic function subjects were approximately 1.0- and 1.4-fold, respectively, for AUC∞, and approximately 0.9- and 1.3-fold, respectively, for Cmax. No deaths or serious adverse events were observed; all adverse events were mild or moderate in intensity. CONCLUSIONS: RI and HI are associated with limited changes in imarikiren pharmacokinetics. Imarikiren was safe and well-tolerated, regardless of the severity of RI or HI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02367872.

A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension.

PURPOSE: Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). MATERIALS AND METHODS: The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long-term safety and BP (office and home), respectively. RESULTS: Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. CONCLUSIONS: The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension.

Effects of triple combination therapy with azilsartan/amlodipine/hydrochlorothiazide on office/home blood pressure: a randomized-controlled trial in Japanese essential hypertensive patients.

OBJECTIVE: The efficacy and safety of triple therapy with azilsartan (AZI), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) compared with dual therapy with AZI/AML or HCTZ monotherapy were evaluated in Japanese essential hypertensive patients in a double-blinded manner. PATIENTS AND METHODS: A total of 353 patients with office blood pressure (BP) of at least 150/95 mmHg were randomized to a 10-week treatment with AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, AZI/AML 20/5 mg, HCTZ 12.5 mg, or HCTZ 6.25 mg. RESULTS: The mean change from baseline in office diastolic/systolic BPs at week 10 was -25.9/-41.4, -24.9/-38.6, and -22.4/-34.5 mmHg in the AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, and AZI/AML 20/5 mg groups, respectively. AZI/AML/HCTZ 20/5/12.5 mg led to a significantly greater reduction in diastolic and systolic BP than the dual therapy. In addition, the change in home diastolic BP measured with telemetry devices showed a significant difference between the two triple therapy groups. The incidences of adverse events except dizziness postural were similar among the treatment groups in the triple therapy groups. CONCLUSION: Triple therapy with AZI/AML/HCTZ 20/5/12.5 mg shows a greater antihypertensive effect than the dual therapy and has acceptable safety profiles for Japanese essential hypertensive patients. It was also observed that home BP measurement by automated telemetry could detect changes in BP that were not detected in office BP measurement, although further investigation is needed.