Dapagliflozin in Patients With Critical Illness (DEFENDER)

Dapagliflozin in Patients With Critical Illness: A Randomized Controlled Trial

To assess the effects of dapagliflozin on a composite hierarchical endpoint in critically ill patients.

Study Overview

• Status: Completed
• Conditions: Sepsis; Critical Illness
• Intervention / Treatment: Other: Standard of Care; Drug: Dapagliflozin 10mg Tab

Detailed Description

Critically ill patients in the intensive care unit (ICU) experience a high mortality rate. Recent data indicates that the mortality rate for unplanned ICU admissions exceeds 30%, highlighting the urgent need for therapies that can reduce mortality in these critical patients.

DEFENDER is an investigator-initiated, multi-center, randomized, open-label clinical trial, conducted in Brazilian ICUs.

The study population will consist of participants who have been admitted to an ICU with an expected length of stay of more than 48 hours with evidence of at least an acute organ dysfunction, such as hypotension, signs of acute kidney injury, and/or the need for new use of high-flow nasal catheter, noninvasive or invasive ventilation. Eligible patients will be enrolled within 24 hours after the onset of organ dysfunction.

Participants will be randomly assigned in a 1:1 ratio to receive either dapagliflozin 10mg (for 14 days or until ICU discharge, whichever occurs sooner) in addition to standard of care, or standard care alone.

The primary outcome of the study is a hierarchical composite endpoint, including: i) hospital mortality, ii) initiation of kidney-replacement therapy, and iii) ICU length of stay. These outcomes will be assessed up to 28 days after randomization, with censoring at the time of hospital discharge.

To ensure participant safety, an independent Data and Safety Monitoring Board will periodically review the data.

• Study Type: Interventional
• Enrollment (Actual): 507
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Barretos, Brazil
    • Santa Casa de Barretos
  • Curitiba, Brazil
    • Santa Casa de Curitiba
  • Jales, Brazil
    • Hospital de Amor de Jales
  • Joinville, Brazil
    • Unimed Joinville
  • Rio De Janeiro, Brazil
    • Hospital São Lucas de Copacabana
  • São Paulo, Brazil
    • Hospital Santa Paula
  • São Paulo, Brazil
    • Hospital Municipal Vila Santa Catarina
  • São Paulo, Brazil
    • Hospital M´Boi Mirim
  • Alagoas
    • Arapiraca, Alagoas, Brazil
      • Hospital de Emergência Dr. Daniel Houly
  • BA
    • Salvador, BA, Brazil
      • Instituto de Ensino e Pesquisa do Hospital da Bahia
  • DF
    • Brasilia, DF, Brazil
      • Hospital Brasilia
  • ES
    • Colatina, ES, Brazil
      • Hospital e Maternidade São José
  • GO
    • Aparecida De Goiânia, GO, Brazil
      • Hospital Municipal de Aparecida de Goiânia
  • MG
    • Poços De Caldas, MG, Brazil
      • Hospital Santa Lucía
  • Paraná
    • Curitiba, Paraná, Brazil
      • Hospital das Nações
    • Curitiba, Paraná, Brazil
      • Hospital Ecoville - Instituto de Neurologia de Curitiba
  • RS
    • Vacaria, RS, Brazil
      • Hospital Nossa Senhora da Oliveira
  • Rio Grande Do Sul
    • Passo Fundo, Rio Grande Do Sul, Brazil
      • Hospital São Vicente de Paulo
  • SC
    • Florianópolis, SC, Brazil
      • Hospital Baia Sul
  • SP
    • São José Do Rio Preto, SP, Brazil
      • Fundação Faculdade Regional de Medicina de São José do Rio Preto
    • São Paulo, SP, Brazil
      • Hospital Nove de Julho
  • Sergipe
    • Aracaju, Sergipe, Brazil, 49055-530
      • Centro de Pesquisa Clinica do Coracao
  • São Paulo
    • Barretos, São Paulo, Brazil
      • Hospital de Amor de Barretos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients admitted to an intensive care unit with expected duration of admission of at least 48 hours in the opinion of the attending physician AND

2. Patients with at least one new organ dysfunction:

   1. Hypotension (mean arteria pressure below 65 mmHg or systolic blood pressure below 90 mmHg or use of vasopressors - norepinephrine, epinephrine, adrenaline, or vasopressin at any dose);
   2. Signs of acute kidney injury (increase in serum creatinine above 0.3 mg/dL over previous measurement or decrease in urinary output - below 0.5 mL/kg/h - in the past six hours;
   3. Need for new use of high-flow nasal catheter or noninvasive ventilation or invasive ventilation.

Exclusion Criteria:

1. Pregnancy or age below 18 years;
2. Patient or legal representative refusal;
3. Patients with chronic kidney disease on dialysis;
4. Planned intensive care unit admission after elective surgery;
5. Known allergy to dapagliflozin;
6. Previous use of dapagliflozin or other sodium-glucose transport protein 2 inhibitor;
7. Patients that cannot receive medications through oral or enteral route;
8. Patients with inclusion criteria number 2 for more than 24 hours.
9. Patients with type 1 diabetes or previous ketoacidosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care; Current standard of care for critically ill patients.	Other: Standard of Care; Current standard of care for management of critically ill patients
Active Comparator: Standard of care plus dapagliflozin; Current standard of care for critically ill patients plus open-label dapagliflozin 10 mg per day for 14 days or until ICU discharge	Drug: Dapagliflozin 10mg Tab; Dapagliflozin 10 mg once per day for 14 days or until intensive care unit discharge or death; Other Names: Farxiga

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Win Ratio	Hierarchical endpoint of hospital mortality, use of kidney replacement therapy and intensive care unit length-of-stay	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital Mortality	Death within index hospitalization	28 days
Use of kidney replacement therapy	Use of kidney replacement therapy during hospital stay	28 days
Intensive Care Unit Free Days	Number of days patient was alive and not in the intensive care unit within index hospitalization	28 days
Hospital Free Days	Number of days patient was alive and not in the hospital	28 days
Vasopressor Free Days	Number of days patient was alive and not using vasopressors at any dose within index hospitalization	28 days
Mechanical Ventilation Free Days	Number of days patient was alive and not using mechanical ventilation within index hospitalization	28 days
Kidney Replacement Therapy Free Days	Number of days patient was alive and not using kidney replacement therapy within index hospitalization	28 days

Collaborators and Investigators

• Sponsor: Hospital Israelita Albert Einstein
• Investigators: Study Chair: Otavio Berwanger, PhD, Academic Research Organization

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Actual): October 20, 2023
• Study Completion (Actual): October 20, 2023

Study Registration Dates

• First Submitted: September 23, 2022
• First Submitted That Met QC Criteria: September 23, 2022
• First Posted (Actual): September 28, 2022

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: critical illness; dapagliflozin
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: DEFENDER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data will be shared upon reasonable request after approval of the steering committee

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No