Dapagliflozin for Cardio-renal Protection After ICU Discharge: A Prospective, Randomized, Double Blinded, Multicenter Study: "DAPA-ICU Trial"
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 600
- 试验地点
- 2
- 主要终点
- Decrease of eGFR by more than 50% from ICU discharge and/or end stage kidney disease defined as an eGFR<15ml/min/1.73m² and/or initiation of renal replacement therapy and/or kidney transplantation
研究概览
简要总结
Several millions of patients are admitted to ICUs in Europe or USA each year. We and others, have shown that patients discharged from intensive care units (ICU) have a high incidence of cardiovascular and/or renal events and high mortality rate (22%) during the year following ICU discharge. Furthermore, a very recent meta-analysis found an excess hazard of late cardiovascular events which persists for at least 5 years following hospital discharge in sepsis survivors. Hence, many international ICU societies recommended investigating and improving post-ICU outcome with scarce guidance. We demonstrated that the proportion of ICU patients dying or presenting cardiovascular events within the year following ICU discharge is reported ~25% [2], reaching ~40% in some studies when considering patients with acute kidney injury (AKI). Plasma biomarkers at ICU discharge have good predictive value and patients with increased kidney or cardiovascular biomarkers display high risk of such events. In addition, we and others demonstrated that AKI or sub-AKI (patient not meeting the AKI definition but with an increased kidney related biomarker) could induce remote cardio-vascular injury and fibrosis, which may be involved in the poor long-term prognosis of ICU-acquired AKI. We hypothesize that strategy that prevent worsening in cardiovascular and/or renal injuries and/or in cardiovascular consequences of sub-AKI and AKI after ICU discharge improve long-term outcomes in ICU survivors. SGLT2 inhibitors are widely recognized as key drugs to protect the kidney and/or the myocardium in chronic diseases such as diabetes or heart failure. Cardio protective effect of SGLT2 inhibitors is optimal in patients with higher cardiac biomarker.
详细描述
Phase III study Prospective, multicenter, superiority, double-blind, randomized controlled study with two arms (1:1).
Every patient will be screened in the 48h before ICU discharge for trial inclusion and non-inclusion criteria until 72h hours after ICU discharge. After providing written informed consent, patients will be randomly assigned to receive either dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in accordance with the sequestered, fixed-randomization schedule, with the use of balanced blocks to ensure an approximate 1:1 ratio of the two regimens for one year.
Four visits are planned, one at inclusion (V0), one at 6 months (V1), one at the end of the treatment (V2 at one year), one 6 weeks after the end of the treatment (V3, end of the study) and two phone calls at 3 (Phone call 1) and 9 months (phone call 2).
At 6 months (V1) and at 12 months (V2) visits, a clinical exam and biological analysis will be performed at hospital (i.e., HbA1c, glucose level, ionogram, NT-proBNP or BNP, serum creatinine, hematocrit and pregnancy urinary test) by anesthesiologists, cardiologists or nephrologists, to assess primary and secondary endpoints, including eGFR.
At 12 months + 6 weeks (V3) visit, a clinical exam and biological analysis will be performed at hospital (i.e., glucose level, NT-proBNP or BNP, serum creatinine) by anesthesiologists, cardiologists or nephrologists, to assess primary and secondary endpoints, including eGFR.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Treatments will be conditioned and labelled by the Contract manufacturing organization AGEPS according to a list provided by an independent person and assigning a treatment arm to each treatment number.
Randomization and treatment numbers lists are kept strictly confidential until the time of unblinding, and will not be accessible by anyone involved in the study, with the exception of the independent, unblinded statistician approving the randomization scheme; the study will be kept blinded to patients, investigators and study personnel also during the entire study period; The identification of treatment will be concealed by the use of a matching placebo to the study product that will be provided in boxes identical in packaging, labeling and appearance
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >or= 18 years
- •Mechanical ventilation and/or vasopressors/inotropes for more than 24h during ICU stay
- •Patients ready to be discharged from ICU according to physician in charge
- •Inform consent form signed by the patient
- •NT-proBNP greater than 800 ng/L or BNP > 90 ng/L and/or Estimated glomerular filtration rate (eGFR) between 25ml/min/1.73m² and 90ml/min/1.73m² of body-surface area (CKD-EPI formula) at inclusion.
排除标准
- •Pregnancy
- •Ability to become pregnant and refusal to use effective contraception during all study treatment Women of childbearing potential (WOCBP)** must agree to use adequate contraception according to Recommendations related to contraception and pregnancy testing in clinical trials, by Clinical Trial Facilitation Group (CTFG).
- •The inclusion of WOCBP requires use of a highly effective contraceptive measure :
- •combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
- •intravaginal
- •transdermal
- •progestogen-only hormonal contraception associated with inhibition of ovulation
- •injectable
- •implantable
- •intrauterine device (IUD)
- •intrauterine hormone-releasing system ( IUS)
- •bilateral tubal occlusion
- •vasectomised partner
- •sexual abstinence
- •The above mentioned risk mitigation measures (contraception) should be maintained during treatment and until the end of relevant systemic exposure.
- •** a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
- •A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
- •A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
- •Breast feeding
- •Known hypersensitivity to dapagliflozin or any of the excipients
- •Patients treated with dapagliflozin before ICU admission
- •Patients with severe cirrhosis (Child-Pugh C)
- •Patients who admitted or who developed during their ICU stay a urinary tract infection or a perineal infection and patients at risk of skin infection near the perineum (e.g., a sacral pressure ulcer)
- •Estimated glomerular filtration rate (eGFR) below 25 ml per minute per 1.73 m2 of body-surface area (CKD -EPI formula).
- •Patient for whom treatment with Dapagliflozine is strongly recommended according to recent international guidelines:
- •patients with type 2 diabetes mellitus adults for whom the treatment is inadequately controlled as an adjunct to diet and exercise: either as monotherapy when metformin is considered inappropriate due to inadequate tolerance, or in addition to other medications for the treatment of type 2 diabetes,
- •symptomatic chronic heart failure with reduced or preserved left ventricular ejection fraction,
- •chronic kidney disease, in addition to standard therapy with a glomerular filtration rate (GFR) between 25 and 75 mL/min/1.73m² and a urinary albumin-to-creatinine ratio (ACR) between 200 and 5000 mg/g and treated for at least 4 weeks with an ACE inhibitor or angiotensin 2 receptor blocker (ARB II or sartan).
- •Patient without national health insurance, and patient on AME (state medical aid)
- •Persons deprived of liberty by a judicial or administrative decision
- •Participation in other interventional study
研究组 & 干预措施
Dapagliflozin
One tablet of dapagliflozin 10 mg will be administered once daily from randomization and for 12 months period +/- 15 days..
干预措施: Dapagliflozin 10 MG Oral Tablet [Farxiga] (Drug)
Placebo of dapagliflozin
One tablet of placebo of dapagliflozin 10 mg will be administered, per os, once daily from randomization and for 12 months period ± 15 days.
干预措施: One tablet of placebo of dapagliflozin 10 mg (Drug)
结局指标
主要结局
Decrease of eGFR by more than 50% from ICU discharge and/or end stage kidney disease defined as an eGFR<15ml/min/1.73m² and/or initiation of renal replacement therapy and/or kidney transplantation
时间窗: Within the year after randomization
Dialysis, eGFR events (\<15 mL/min/1.73m²; ≥50% decline in eGFR) will be recorded in the eCRF and submitted for adjudication. eGFR baseline is defined as the local laboratory value at inclusion visit. The eGFR will be calculated using CKD-EPI equation without race coefficient \[87, 88\].
All-cause mortality
时间窗: Within the year after randomization
Unscheduled hospital hospitalization for heart failure
时间窗: Within the year after randomization
All potential hospitalizations for heart failure should be recorded in the eCRF and submitted to adjudication. The Clinical Event Adjudication (CEA) committee members will adjudicate the events as specified in the (CEA) Charter.
次要结局
- Unscheduled hospital hospitalization for acute coronary syndrome(Within the year after randomization)
- Unscheduled hospital hospitalization for acute heart failure(Within the year after randomization)
- Unscheduled hospital hospitalization for stroke(Within the year after randomization)
- Occurrence of severe chronic kidney disease(Within the year after randomization)
- • Decrease of estimated glomerular filtration rate of more than 50% from baseline(Within the year after randomization)
- New episode of acute kidney injury (according to the KDIGO criteria) requiring hospitalization(Within the year after randomization)
- Occurrence of end stage kidney disease defined (eGFR<15ml/min/1.73m2) and/or initiation of renal replacement therapy and/or kidney transplantation(Within the year after randomization)
- Change in NT-proBNP (pg/mL) from baseline to end of study(Between 12 months (end of treatment) and 12 months + 6 weeks (end of study))
- Occurrence of cardiovascular events(Within the year after randomization)
- Occurrence of renal events(Within the year of treatment)
- Urinary tract infection(Within the year after randomization)
- Necrotizing fasciitis(Within the year after randomization)
- Symptomatic ketoacidosis(Within the year after randomization)
- Major hypoglycaemia(Within the year after randomization)
- Death of any cause(Within the year after randomization)
- Occurrence of global outcome events(Within the year of treatment)