In this double-blind trial, patients with chronic kidney disease and type 2 diabetes were randomly assigned to receive the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone or ...placebo. Treatment with finerenone resulted in lower risks of chronic kidney disease outcomes and cardiovascular outcomes than placebo.
Background: Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a ...novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of finerenone on renal and CV outcomes has not been investigated in long-term trials yet. Methods: The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25–<75 mL/min/1.73 m 2 and albuminuria (urinary albumin-to-creatinine ratio ≥30–≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death. Conclusion: FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.
A randomized, double-blinded, placebo-controlled, parallel trial with 3 arms.
To investigate in acute nonspecific low back pain (LBP) the effectiveness of spinal high-velocity low-amplitude (HVLA) ...manipulation compared with the nonsteroidal anti-inflammatory drug diclofenac and with placebo.
LBP is an important economical factor in all industrialized countries. Few studies have evaluated the effectiveness of spinal manipulation in comparison to nonsteroidal anti-inflammatory drugs or placebo regarding satisfaction and function of the patient, off-work time, and rescue medication.
A total of 101 patients with acute LBP (for <48 hr) were recruited from 5 outpatient practices, exclusion criteria were numerous and strict. The subjects were randomized to 3 groups: (1) spinal manipulation and placebo-diclofenac; (2) sham manipulation and diclofenac; (3) sham manipulation and placebo-diclofenac. Outcomes registered by a second and blinded investigator included self-rated physical disability, function (SF-12), off-work time, and rescue medication between baseline and 12 weeks after randomization.
Thirty-seven subjects received spinal manipulation, 38 diclofenac, and 25 no active treatment. The placebo group with a high number of dropouts for unsustainable pain was closed praecox. Comparing the 2 active arms with the placebo group the intervention groups were significantly superior to the control group. Ninety subjects were analyzed in the collective intention to treat. Comparing the 2 intervention groups, the manipulation group was significantly better than the diclofenac group (Mann-Whitney test: P = 0.0134). No adverse effects or harm was registered.
In a subgroup of patients with acute nonspecific LBP, spinal manipulation was significantly better than nonsteroidal anti-inflammatory drug diclofenac and clinically superior to placebo.
In this double-blind trial, patients with stage 1 to 4 chronic kidney disease and type 2 diabetes were randomly assigned to receive finerenone or placebo. Finerenone treatment was superior with ...regard to the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
The FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor ...antagonist finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. We report the effect of finerenone on individual cardiovascular outcomes and in patients with and without history of atherosclerotic cardiovascular disease (CVD).
This randomized, double-blind, placebo-controlled trial included patients with type 2 diabetes and urine albumin-to-creatinine ratio 30 to 5000 mg/g and an estimated glomerular filtration rate ≥25 to <75 mL per min per 1.73 m
, treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite cardiovascular outcome included time to cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified cardiovascular analyses included analyses of the components of this composite and outcomes according to CVD history at baseline.
Between September 2015 and June 2018, 13 911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite cardiovascular outcome compared with placebo (hazard ratio, 0.86 95% CI, 0.75-0.99;
=0.034), with no significant interaction between patients with and without CVD (hazard ratio, 0.85 95% CI, 0.71-1.01 in patients with a history of CVD; hazard ratio, 0.86 95% CI, 0.68-1.08 in patients without a history of CVD;
value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone versus 0.8% with placebo in patients with CVD and 2.2% with finerenone versus 1.0% with placebo in patients without CVD).
Among patients with chronic kidney disease and type 2 diabetes, finerenone reduced incidence of the composite cardiovascular outcome, with no evidence of differences in treatment effect based on preexisting CVD status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02540993.
In clinical trials investigating treatments for chronic heart failure (CHF), a standard primary endpoint is the time to the first composite of hospitalization for heart failure or cardiovascular ...death (CVD). Since many patients experience several hospitalizations, there is interest in including recurrent hospitalizations into the primary endpoint to better capture disease burden. Several analysis methods have been proposed for recurrent event endpoints, mostly for the situation without a terminal event such as CVD. Only some methods explicitly account for terminal events, for example, the joint frailty model. We compare the power and Type I error rate of recurrent event methods with those of time-to-first event methods in the presence of terminal events. A special focus is the situation where treatment affects the risk of CVD. Our investigations are based on a simulation study, for which the scenarios are motivated by CHF trials, and based on bootstraping data from the Val-HeFT and PARADIGM-HF trials. We find that recurrent event methods can in many situations increase power considerably. But this is not always the case, for example, when there is high probability of treatment discontinuation after the first hospitalization. Also, for both recurrent and time-to-first event methods, the Type I error rate can be inflated in case of a detrimental treatment effect on CVD. Based on the simulation results we give recommendations on the choice of endpoint and analysis method for CHF trials.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Clinical trials in nephrology often use composite end points comprising clinical events, such as onset of ESKD and initiation of kidney function replacement therapy, along with a sustained large ( ...e.g. , ≥50%) decrease in GFR. Such events typically occur late in the disease course, resulting in large trials in which most participants do not contribute clinical events. In addition, components of the end point are considered of equal importance; however, their clinical significance varies. For example, kidney function replacement therapy initiation is likely to be clinically more meaningful than GFR decline of ≥50%. By contrast, hierarchical composite end points (HCEs) combine multiple outcomes and prioritize each patient's most clinically relevant outcome for inclusion in analysis. In this review, we consider the use of HCEs in clinical trials of CKD progression, emphasizing the potential to combine dichotomous clinical events such as those typically used in CKD progression trials, with the continuous variable of GFR over time, while ranking all components according to clinical significance. We consider maraca plots to visualize overall treatment effects and the contributions of individual components, discuss the application of win odds in kidney HCE trials, and review general design considerations for clinical trials for CKD progression with kidney HCE as an efficacy end point.
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