Two-Stage Single-Arm Trials Are Rarely Analyzed Effectively or Reported Adequately

PURPOSE Two-stage single-arm designs have historically been the most common design used in phase II oncology. They remain a mainstay today, particularly for trials in rare subgroups. Consequently, it is imperative such studies be designed, analyzed, and reported effectively. We comprehensively review such trials to examine whether this is the case. METHODS Oncology trials that used Simon's two-stage design over a 5-year period were identified and reviewed. They were evaluated for whether they reported sufficient design (eg, required sample size) and analysis (eg, CI) details. Articles that did not adjust their inference for the incorporation of an interim analysis were also reanalyzed. RESULTS Four-hundred twenty-five articles were included. Of these, just 47.5% provided the five components that ensure design reproducibility. Only 1.2% and 2.1% reported an adjusted point estimate or CI, respectively. Just 55.3% provided the final stage rejection bound, indicating many trials did not test a hypothesis for their primary outcome. Trial reanalyses suggested reported point estimates underestimated treatment effects and reported CIs were too narrow. CONCLUSION Key design details of two-stage single-arm trials are often unreported. Their inference is rarely performed such as to remove bias introduced by the interim analysis. These findings are particular alarming when considered against the growing trend in which nonrandomized trials make up a large proportion of all evidence on a treatment's effectiveness in a rare biomarker-defined patient subgroup. Future studies must improve the way they are analyzed and reported.

Heart Failure Challenge in T2DM

Introduction Heart failure is a clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.1 There are 463 million patient with diabetes mellitus all over the world .2 People with diabetes have a 2- to 5-fold higher risk of developing HF3, On the other hand more than 30% of patients with heart failure also have diabetes. Patients with heart failure and diabetes have a worse prognosis than those without diabetes4. UKPDs, Accord and advance trials showed that Intensive glycaemic control has not been shown to significantly impact the risk of HF.5,6 SGLT2 inhibitor is a new class of drugs to treat diabetes by inhibiting SGT2 decreases glucose reabsorption and increases urinary glucose excretion, improving glucose control in the diabetic patient.7 At 2015 EMPA-REG OUTCOME trial showed that Empagliflozin in addition to reduction of HBa1c, reduced the 3MAC by 14%, CV death by 38% and HHF by 35%. Is these cardiovascular benefit were a chance? 8 Then DECLARE-TMI58, CNVAS and VIRTIS trials showed that Dapagliflizon, Canagliflozin and ertuglifozin respectively in addition to reduction of HBa1c, reduce HHFso it is a class effect. 9,10,11 Because in these trials starting treatment at the preclinical stage may prevent HF progression and improve outcomes. Objective We have 3 questions to be answered: There are 4 trials to answer these Questions DAPA HF, DELIVER, EMPEROR-Reduced and EMPEROR –Preserved. DAPA-HF and EMPEROR –Reduced include patients with HF with reduced ejection fraction, diabetic and non-diabetic the result of both was reduce the risk of worsening HF or death from cardiovascular causes regardless of the presence or absence of DM. 10,11 Conclusion The results of these trials FDA Approves Dapagliflozin for low EF-Heart Failure in diabetic and Non-diabetic. FDA had granted Fast Track status for empagliflozin. Waiting the result of other trials.12

Glycemic efficacy and safety of the SGLT2 inhibitor ertugliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease: an analysis from the VERTIS CV randomized trial

IntroductionHere we report the glycemic efficacy and safety of ertugliflozin in patients in the VERTIS CV cardiovascular outcome trial with chronic kidney disease (CKD) stage 3.Research design and methodsPrespecified and post-hoc analyses were performed in patients with an estimated glomerular filtration rate (eGFR) 30–<60 mL/min/1.73 m2 at screening. The primary endpoint was glycemic efficacy at week 18. Longer term glycemic efficacy and changes in body weight, systolic blood pressure (SBP), and eGFR were also evaluated.ResultsAmong 8246 patients in VERTIS CV, 1776 patients had CKD stage 3; 1319 patients had CKD stage 3A (eGFR 45–<60 mL/min/1.73 m2); 457 patients had CKD stage 3B (eGFR 30–<45 mL/min/1.73 m2). Week 18 least squares (LS)-mean (95% CI) placebo-adjusted changes from baseline in glycated hemoglobin (HbA1c) for 5 mg and 15 mg ertugliflozin were −0.27% (−0.37% to –0.17%) and −0.28% (−0.38% to –0.17%), respectively, for CKD stage 3 overall and −0.27% (−0.38% to –0.15%) and −0.31% (−0.43% to –0.19%), respectively, for CKD stage 3A (all p<0.001). For CKD stage 3B, the reduction in HbA1c for 5 mg ertugliflozin was −0.28% (−0.47% to –0.08%) (p=0.006) and for 15 mg ertugliflozin was −0.19% (−0.39% to 0.01%) (p=0.064). LS-mean placebo-adjusted reductions in body weight (range: −1.32 to −1.95 kg) and SBP (range: −2.42 to −3.41 mm Hg) were observed across CKD stage 3 categories with ertugliflozin. After an initial dip, eGFR remained above or near baseline with ertugliflozin treatment. The incidence of overall adverse events (AEs), symptomatic hypoglycemia, hypovolemia, and kidney-related AEs did not differ between ertugliflozin and placebo across CKD stage 3 subgroups.ConclusionsIn VERTIS CV patients with CKD stage 3A, ertugliflozin resulted in reductions in HbA1c, body weight and SBP, maintenance of eGFR, and was generally well tolerated. Results in the CKD stage 3B subgroup were generally similar except for an attenuated HbA1c response with the 15 mg dose.Trial registration numberNCT01986881.