Dapagliflozin for Cardio-renal Protection After ICU Discharge

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.

The phone calls, at 3 and 9 months, will be made by the designated persons and respecting the confidentiality and security of the data collected.

At inclusion (V0) and at 6 months (V1) the treatment will be deliver for the next 6 months. At 6 months (V1), the patient will pick up his treatment at the hospital.

Primary endpoints will be assessed at 6 and 12 months visit and phone calls (3 and 9 months).

Secondary endpoints will be assessed at each visit and phone calls (3, 6, 9, 12 and 12 + 6 weeks).

eGFR (glomerular filtration rate) will be assessed only at 6, 12 months and 12 + 6 weeks. The eGFR (glomerular filtration rate) will not be assessed at phone calls.

At each visit and phone calls, adverse events and severe adverse events will also be assessed.

Inclusion criteria

• 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.

Exclusion criteria

• 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

• oral
• intravaginal
• transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation

• oral
• 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