Re: Crack Trial Age Of Empires 3
Melanie Council
Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown.
The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials.
Within recent years, attention to heart failure (HF) care in patients with type 2 diabetes (T2D) has increased markedly after results from three randomized clinical trials (RCT) evaluating the effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors [1,2,3]. In these safety trials, it was observed that three different SGLT2 inhibitors could prevent development of HF and prolong life in patients with T2D. Recently, the results have been replicated in real life [4, 5]. The mechanism behind these observations are poorly understood and while several hypotheses have been proposed, data are lacking [6,7,8,9].
An exploratory objective of the study is to assess the effect of empagliflozin on daily activity level. Secondary objectives include assessment of the effects on body composition, glucose metabolism, and ketones; GFR, eECV, ePV, urid acid, and urine albumin to creatinine ratio (UACR); cardiac biomarkers including MR-proADM and hs-cTnI; LV diastolic and systolic function at rest and during low-dose dobutamine infusion with echocardiography; central invasive hemodynamics at rest and during exercise; and health-related quality of life.
Stable outpatients with HFrEF on optimal therapy in accordance with most recent European and national guidelines [20]. It is expected that 20% of the patients have known T2D and that an additional 30% of the patients will have a diagnosis of new onset T2D or impaired glucose tolerance based on an oral glucose tolerance test (OGTT) at the randomization visit [21, 22].
Schedule of enrolment, interventions, and assessments in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). #Only performed in the patients enrolled at Herlev-Gentofte Hospital. *Only performed in a sub-group of the patients enrolled at Odense University Hospital. ECG electrocardiogram, OGTT oral glucose tolerance test, DXA dual-energy X-ray absorptiometry, 51Cr-EDTA chromium-51 labeled ethylenediamine tetra-acetic acid. AE adverse event, SAE severe adverse event, IP investigational product
In all the other sub-studies, the sample size is a consequence of the main study on NT-proBNP and confidence intervals will be evaluated critically. Based on previous studies it is expected to observe a possible significant difference with the used sample sizes [24, 39].
The steering committee consists of JJ, MO, CK, MKP, CT, IG, LK (chair), FG, EF, NEB, LV, JEM, and MS. The steering committee is responsible for the design, monitoring, reporting, and publication of the trial. Primary investigators are MS at Herlev-Gentofte Hospital and JEM at Odense University Hospital. The steering committee will have access to the final trial dataset.
Data will be collected and stored using electronic case report forms (eCRFs) constructed in the Research Electronic Data Capture (REDCap) system (Vanderbilt University 2018). Corresponding source documents are stored at the experimental sites in accordance with the rules and regulations of the Danish Data Protection Agency to ensure confidentiality. The study is monitored by the GCP units at the University of Copenhagen and the University of Southern Denmark based on a specific monitoring plan. The GCP units are independent from the steering committee.
The safety of the randomized patients will be monitored continuously based on recording of AEs and severe adverse events (SAEs) from signing the informed consent form through four weeks after the end-of-study visit. The data will be collected and recorded on standardized forms at each contact. After the end-of-study visit, no planned contacts are performed but patients are instructed to contact the investigators if late-occurring AEs are suspected. These data are reported to the relevant authorities in accordance with applicable laws and International Conference of Harmonization Good Clinical Practice (ICH-GCP) guidelines. An independent endocrinologist is the unblinded data monitor and will evaluate the AEs and SAEs when half the patients are enrolled and can make the final decision to terminate the trial based on these safety data. Previously, no hypoglycemic events were observed when HF patients without T2D were included in a trial at Herlev-Gentofte Hospital evaluating the anti-glycemic drug Liraglutide [42]. Empagliflozin is approved for treatment of T2D. As the mechanisms behind the cardioprotective effects of empagliflozin are unknown, the steering committee finds it ethically acceptable to test active medication against placebo, instead of an active comparator. There are ongoing RCTs evaluating SGLT2 inhibitors in HFrEF patients both with and without T2D (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction [EMPEROR-Reduced], ClinicalTrials.gov Identifier NCT03057977; Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure [DAPA HF], ClinicalTrials.gov Identifier NCT03036124). The risk of significant side effects to empagliflozin is estimated to be modest. Compensation to those patients who suffer harm from study participation is set by the public Patient Compensation Association in Denmark.
A research biobank is established in relation to the trial, where blood and urine samples are stored in coded form for later analysis of biomarkers. After the analyses declared in the protocol, the samples will be anonymized and the research biobank will be discontinued in accordance with the rules and regulations of the Danish Data Protection Agency. Patients are informed about the research biobank before signing the informed consent form.
The results of the study will be submitted to international peer-reviewed scientific journals, irrespective of their outcome, and the data will be made available to the public via EudraCT (www.clinicaltrialsregister.eu) and www.clinicaltrials.gov. Positive, inconclusive, and negative results will be presented. Furthermore, the results will be presented at scientific conferences as abstracts, oral presentations, and posters. The steering committee will assess authorship eligibility for the scientific papers related to the study based on the recommendations of the International Committee of Medical Journal Editors (ICMJE).
The anticipated results from ongoing randomized clinical trials will decide whether SGLT2 inhibitors will be a future treatment option in HFrEF patients. The Empire HF trial will complement these event-driven trials with mechanistic insight supporting clinicians and researchers in understanding the underlying mode of action of SGLT2 inhibitors including whether the observed effect on clinical outcomes is cardiac, renal, and/or metabolic, and whether SGLT2 inhibitors have an impact on patient-centered endpoints including physical activity and quality of life.
The study is currently recruiting and enrolling participants. Protocol version 5, 5 October 2018. Start of recruitment: 29 June 2017. Approximate date when recruitment will be completed: 31 October 2019.
JJ, MO, JEM, and MS participate in study concept and design, study operations, and manuscript preparation. CK, MKP, CT, IG, LK, FG, EF, NEB, and LV participated in study concept and design, and in manuscript preparation. PHF participated in study operations. All authors read and approved the final manuscript.
All patients give written informed consent before enrolment. The trial, including the consent form and all other related documentation given to patients, is approved by the Regional Committee on Health Research Ethics, Capital Region of Denmark (reference number H-17010756).
JJ, MO, CK, MKP, CT, IG, LK, EF, NEB, LV, PHF, and JEM declare no conflicts of interest. FG reports lecture fee from Boehringer Ingelheim. MS reports lecture fee from Novo Nordisk and Boehringer Ingelheim.
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Objective: To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels.
Design: A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out.
Interventions: In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features.
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