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Efficacy and safety of trelagliptin in Japanese patients with type 2 diabetes with severe renal impairment or end-stage renal disease: Results from a randomized, phase 3 study.
Kaku, K, Ishida, K, Shimizu, K, Achira, M, Umeda, Y
Journal of diabetes investigation. 2020;(2):373-381
Abstract
INTRODUCTION To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease. MATERIALS AND METHODS This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug. RESULTS Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively. CONCLUSIONS Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population.
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Serum Uromodulin: A Biomarker of Long-Term Kidney Allograft Failure.
Bostom, A, Steubl, D, Garimella, PS, Franceschini, N, Roberts, MB, Pasch, A, Ix, JH, Tuttle, KR, Ivanova, A, Shireman, T, et al
American journal of nephrology. 2018;(4):275-282
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Abstract
BACKGROUND Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center -European study involving 91 kidney transplant recipients (KTRs). METHODS The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome. RESULTS The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77). CONCLUSIONS Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs.
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Acetylator Status Impacts Amifampridine Phosphate (Firdapse™) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function.
Haroldsen, PE, Sisic, Z, Datt, J, Musson, DG, Ingenito, G
Clinical therapeutics. 2017;(7):1360-1370
Abstract
PURPOSE The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes. METHODS This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations. FINDINGS Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC0-∞ and Cmax were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC0-∞ was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC0-∞, approximately 1.8-fold; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-∞ from normal to severe RI. No new tolerability findings were observed. IMPLICATIONS A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.
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Relationship of renal insufficiency and clinical features or comorbidities with clinical outcome in patients hospitalised for acute heart failure syndromes.
Kajimoto, K, Sato, N, Takano, T, ,
European heart journal. Acute cardiovascular care. 2017;(8):697-708
Abstract
BACKGROUND Renal insufficiency is a well-known predictor of adverse events in patients with acute heart failure syndromes (AHFS). However, it remains unclear whether there are subgroups of AHFS patients in whom renal insufficiency is related to a higher risk of adverse events because of the heterogeneity of this patient population. Therefore, we investigated the relationship between renal insufficiency, clinical features or comorbidities, and the risk of adverse events in patients with AHFS. METHODS AND RESULTS Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4628 patients (95.6%) were evaluated in the present study in order to assess the relationship of renal insufficiency and clinical features or comorbidities with all-cause mortality after admission. Renal insufficiency was defined as an estimated creatinine clearance of ⩽40 mL/min (calculated by the Cockcroft-Gault formula) at admission. The median follow-up period after admission was 524 (391-789) days. The all-cause mortality rate after admission was significantly higher in patients with renal insufficiency (36.7%) than in patients without renal insufficiency (14.4%). Stratified analysis was performed in order to explore the heterogeneity of the influence of renal insufficiency on all-cause mortality. This analysis revealed that an ischaemic aetiology and a history of diabetes, atrial fibrillation, serum sodium, and anaemia at admission had significant influences on the relationship between renal insufficiency and all-cause mortality. CONCLUSIONS The present study demonstrated that the relationship between renal insufficiency and all-cause mortality of AHFS patients varies markedly with clinical features or comorbidities and the mode of presentation due to the heterogeneity of this patient population.
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Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.
Mahindra, A, Hari, P, Fraser, R, Fei, M, Huang, J, Berdeja, J, Callander, N, Costa, L, Diaz, MA, Freytes, C, et al
Bone marrow transplantation. 2017;(12):1616-1622
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Abstract
Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.
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Pharmacokinetics, safety, and efficacy of lenalidomide plus dexamethasone in patients with multiple myeloma and renal impairment.
Bridoux, F, Chen, N, Moreau, S, Arnulf, B, Moumas, E, Abraham, J, Desport, E, Jaccard, A, Fermand, JP
Cancer chemotherapy and pharmacology. 2016;(1):173-82
Abstract
PURPOSE Renal impairment (RI) is a common comorbidity in multiple myeloma (MM). Current dose adjustments recommended for renally excreted lenalidomide are based on data from noncancer patients. This study evaluated the pharmacokinetics, safety, efficacy, and exposure-response for lenalidomide plus dexamethasone in patients with relapsed/refractory MM and stable RI using the recommended dose adjustments. METHODS This phase 2 multicenter, open-label study stratified patients into 5 groups based on creatinine clearance (CrCl) calculated by Cockcroft-Gault equation: normal renal function (CrCl > 80 mL/min), mild RI (50 ≤ CrCl ≤ 80 mL/min), moderate RI (30 ≤ CrCl < 50 mL/min), severe RI (CrCl < 30 mL/min), and end-stage renal disease requiring hemodialysis. Dosing was based on the lenalidomide label. RESULTS Among 38 patients, the median age was 68 (range 62-74) years, and poorer renal function was associated with older age, more advanced disease, and more lines of prior therapy. Lenalidomide clearance declined with decreased CrCl. Mean lenalidomide area under plasma concentration-time curve (AUC) was within ±25 % of the target AUC in each group. Overall response was 76 %, and safety profiles were similar across groups, with no exposure-dependent trend in efficacy or toxicity. Estimated glomerular filtration rates calculated using the simplified Modification of Diet in Renal Disease equation highly correlated with lenalidomide clearance and, in 87 % of patients, would lead to assigning the same starting dose of lenalidomide as CrCl. CONCLUSIONS In patients with stable renal function, the recommended dose adjustments achieved proper plasma exposure and similar safety and efficacy across renal groups.
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Planned randomized conversion from tacrolimus to sirolimus-based immunosuppressive regimen in de novo kidney transplant recipients.
Silva, HT, Felipe, CR, Garcia, VD, Neto, ED, Filho, MA, Contieri, FL, de Carvalho, DD, Pestana, JO
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013;(12):3155-63
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Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention-to-treat population there were no differences in eGFR (66.2 ± 25.3 vs. 70.7 ± 25.1, p = 0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-to-creatinine ratio (0.36 ± 0.69 vs. 0.15 ± 0.53, p = 0.03) and higher incidence of treated acute rejection between months 3-24 (13.4% vs. 4.7%, p = 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months.
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Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment.
Vaduganathan, M, Gheorghiade, M, Pang, PS, Konstam, MA, Zannad, F, Swedberg, K, Grinfeld, L, Burnett, JC, Krasa, HB, Zimmer, C, et al
Journal of cardiovascular medicine (Hagerstown, Md.). 2012;(7):415-22
Abstract
AIMS: Although congestion is the main reason for admission in patients with worsening acute heart failure syndromes, patients presenting with low SBP and renal impairment often do not respond adequately to and may not tolerate traditional diuretic therapy. We sought to determine the short-term hemodynamic effects of tolvaptan in this high-risk population. METHODS In a subset analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, 759 patients (18% of total) had elevated blood urea nitrogen (BUN) (> 20 mg/dl) and low SBP (<105 mmHg) at admission. Of these, 386 were randomized to tolvaptan and 373 to placebo. RESULTS Demographics and baseline characteristics were similar in both groups. Greater reductions from baseline in body weight were observed for tolvaptan (1.63 ± 2.00 vs. 0.76 ± 1.75 kg, P < 0.0001 at day 1 and 3.23 ± 3.36 vs. 2.10 ± 3.47 kg, P < 0.0001 at day 7 or discharge). Greater increases in serum sodium concentration were also observed in the tolvaptan group as early as day 1 (4.41 ± 3.67 vs. 1.32 ± 3.93 mEq/l, P < 0.0001) and persisted through day 7 or discharge (4.79 ± 4.89 vs. 1.25 ± 5.00 mEq/l, P < 0.0001). Similarly, improvements in patient-reported dyspnea and investigator-assessed orthopnea were significantly greater in the tolvaptan group as early as day 1 of treatment. These changes were not associated with significant differences in heart rate, SBP, DBP or serum creatinine between patients in the two treatment groups during hospitalization. In-hospital mortality rates (total and cause-specific) were comparable to patients who had presented with SBP more than 105 mmHg and BUN less than 20 mg/dl. CONCLUSION In this subgroup analysis of patients with hypotension and renal impairment, tolvaptan improved symptoms, reduced body weight and increased serum sodium as early as inpatient day 1 without adversely affecting blood pressure or renal function.
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Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS).
Leizorovicz, A, Siguret, V, Mottier, D, , , Leizorovicz, A, Siguret, V, Mottier, D, Clonier, F, Janas, M, Stinson, J, et al
Thrombosis research. 2011;(1):27-34
Abstract
INTRODUCTION Trials comparing the use of full dose unfractionated heparin (UFH) or low molecular weight heparins (LMWHs) in very elderly patients with impaired renal function are lacking. IRIS aimed to assess whether LMWH is at least as safe as UFH in this population. MATERIALS AND METHODS The study included renally impaired patients ≥70 years with acute symptomatic lower limb deep vein thrombosis (DVT). Patients were randomized to initial treatment with either tinzaparin 175 IU/kg once daily (n=269) or activated partial thromboplastin time-adjusted UFH twice daily (n=270). After acute management both groups received vitamin K antagonist to day 90. RESULTS The trial was stopped prematurely due to a difference in mortality favoring the UFH group (11.5 vs. 6.3%; p=0.035). Rates of clinically relevant bleedings by day 90 were similar in the tinzaparin (11.9%) and UFH (11.9%) groups, as were rates of confirmed recurrent venous thromboembolism (VTE) (2.6 vs. 1.1%; p=0.34). As the mortality difference could not be explained by bleedings or recurrent VTE, a post-hoc analysis was performed. This identified six baseline characteristics significantly correlated with mortality, of which five were over-represented in the tinzaparin group. CONCLUSION The IRIS study was a challenging study involving patients (mean age 83 years) usually excluded from clinical studies, but its early termination has left questions unanswered. The mortality difference observed with tinzaparin vs. UFH in elderly, renally-impaired patients with DVT cannot be explained on the basis of bleedings or recurrent VTE, and may reflect an imbalance of mortality risk factors at baseline.
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The cardioprotective effects of the angiotensin-converting enzyme inhibitor perindopril in patients with stable coronary artery disease are not modified by mild to moderate renal insufficiency: insights from the EUROPA trial.
Brugts, JJ, Boersma, E, Chonchol, M, Deckers, JW, Bertrand, M, Remme, WJ, Ferrari, R, Fox, K, Simoons, ML, ,
Journal of the American College of Cardiology. 2007;(22):2148-55
Abstract
OBJECTIVES This study sought to examine whether the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitor therapy by perindopril are modified by renal function in patients with stable coronary artery disease. BACKGROUND A recent study reported that an impaired renal function identified a subgroup of patients with stable coronary artery disease more likely to benefit from ACE inhibition therapy. In light of the growing interest in tailored therapy for targeting medications to specific subgroups, remarks on the consistency of the treatment effect by ACE inhibitors are highly important. METHODS The present study involved 12,056 patients with stable coronary artery disease without heart failure randomized to perindopril or placebo. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Cox regression analysis was used to estimate multivariable-adjusted hazard ratios. RESULTS The mean eGFR was 76.2 (+/-18.1) ml/min/1.73 m2. During follow-up, the primary end point (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) occurred in 454 of 5,761 patients (7.9%) with eGFR > or =75 and in 631 of 6,295 patients (10.0%) with eGFR <75. Treatment benefits of perindopril were apparent in both patient groups either with eGFR > or =75 (hazard ratio 0.77; 95% confidence interval 0.64 to 0.93) or eGFR <75 (hazard ratio 0.84; 95% confidence interval 0.72 to 0.98). We observed no significant interaction between renal function and treatment benefit (p = 0.47). Using different cutoff points of eGFR at the level of 60 or 90 resulted in similar trends. CONCLUSIONS The treatment benefit of perindopril is consistent and not modified by mild to moderate renal insufficiency.