Heart Failure Acute, Heart Failure，Congestive, Heart Failure; With Decompensation
Conditions
Keywords
heart failure, diuretic response, empagliflozin
Brief summary
Acute decompensated heart failure is the fastest growing disease in the world and the leading cause of hospital admissions worldwide. Short term mortality and rehospitalization are extremely high (20-30% within 3-6 months) and there is no therapy available that improves clinical outcome in these patients. Empagliflozin is a selective inhibitor of sodium glucose co-transporter with diuretic and renal- protective properties. In patients with type 2 diabetes at high risk for cardiovascular events, empagliflozin reduced the risk of hospitalization for heart failure by 35%. Based on the promising pharmacological profile of empagliflozin in relation to the needs for treatment of acute decompensated heart failure, we hypothesize that empagliflozin exerts positive effects in acute decompensated heart failure, with or without diabetes, This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo.
Detailed description
This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo. Treatment will be continued until 30 days after index event, and primary efficacy measurements will be carried out during hospitalization and safety events until 60 days after index hospitalisation.
Interventions
DRUGEmpagliflozin 10 MG
10 mg daily, oral, 30 days
DRUGPlacebo Oral Tablet
Matching Placebo, 10 mg daily, oral, 30 days
Sponsors
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double blind, placebo controlled
Intervention model description
randomized, placebo-controlled, double-blind, parallel group, multicenter study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female \>18 years of age; Women of non-child-bearing potential must have a documentation of surgical sterilization (hysterectomy and/or bilateral oophorectomy) OR must have experienced menopause (no menses for \>12 months). Women of child bearing potential must have a negative pregnancy test, AND must use highly effective methods of contraception during treatment with IP plus 5 days after the end of study drug administration. * Hospitalized for AHF; AHF is defined as including all of the followings measured at any time between presentation (including the emergency department) and the end of screening: 1. Dyspnea at rest or with minimal exertion 2. Signs of congestion, such as edema, rales, and/or congestion on chest radiograph 3. BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL (for patients with AF: BNP≥500 pg/mL or NT-proBNP ≥2,000 pg/mL) 4. Treated with loop diuretics at screening * Able to be randomized within 24 hours from presentation to the hospital * Able and willing to provide freely given written informed consent * eGFR (CKD-EPI) ≥30 ml/min/1.73m2 between presentation and randomization
Exclusion criteria
* Diabetes Mellitus Type I * Dyspnea primarily due to non-cardiac causes * Cardiogenic shock * Acute coronary syndrome within 30 days prior to randomization * Planned or recent percutaneous or surgical coronary intervention within 30 days prior to randomization * Signs of keto-acidosis and/or hyperosmolar hyperglaecemic syndrome (pH\>7.30 and glucose \>15 mmol/L and HCO3\>18 mmol/L) * Pregnant or nursing (lactating) women * Current participation in any interventional study * Inability to follow instructions or comply with follow-up procedures * Any other medical conditions that may put the patient at risk or influence study results in the investigator's opinion, or that the investigator deems unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma NTproBNP | From baseline to Day 4 | Change in NTproBNP |
| Dyspnea | From baseline to Day 4 | Change in Dyspnea on VAS analogue scale (AUC) VAS Score is a measure/scale where patients on a scale from 0 to 100 can assign their current dyspnea score. 0 means there can be no worse dyspnea, 100 means it cannot get any better (perfect). The change in Dyspnea VAS means higher score is better outcomes. Individual changes in VAS score are be visualized (virtually) as a curve where the X-axis shows study day baseline to day 4, and y-axis shows VAS score. Using this approach, area under the curves for each study day (trapezoids) can be calculated, and added together, resulting in an overall VAS AUC score (mmxh) and change in VAS can be caculated |
| Diuretic Response | Total weight change from baseline to Day 4 | Weight change from baseline per 40 mg of Furosemide equivalent |
| Length of Stay | within 60 days | Hospital stay of Index admission |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death and/or Heart Failure Re-admission | Day 30 | Death and/or heart failure re-admission at day 30 |
| Inhospital Worsening Heart Failure, All Cause Mortality or Heart Failure Readmission at Day 60 | 60 days | Inhospital Worsening Heart Failure or All Cause mortality or Heart Failure Readmission at day 60 |
| All Cause Mortality | 60 day | All Cause Mortality at 60 days |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | 60 days | SAE including all cause mortality. Per request Clintrials.gov different from Protocol definition |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin Empagliflozin 10 mg daily, oral, 30 days
Empagliflozin 10 MG: 10 mg daily, oral, 30 days | 40 |
| Placebo Matching Placebo 10 mg daily, oral, 30 days
Placebo Oral Tablet: Matching Placebo, 10 mg daily, oral, 30 days | 39 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Empagliflozin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 36 Participants | 27 Participants | 63 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 12 Participants | 16 Participants |
| Age, Continuous | 79 years | 73 years | 76 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 39 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| NTproBNP | 4406 pg/mL | 6168 pg/mL | 4918 pg/mL |
| Region of Enrollment Netherlands | 40 participants | 39 participants | 79 participants |
| Sex: Female, Male Female | 16 Participants | 10 Participants | 26 Participants |
| Sex: Female, Male Male | 24 Participants | 29 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 40 | 3 / 39 |
| other Total, other adverse events | 29 / 40 | 31 / 39 |
| serious Total, serious adverse events | 8 / 40 | 10 / 39 |
Outcome results
Primary
Diuretic Response
Weight change from baseline per 40 mg of Furosemide equivalent
Time frame: Total weight change from baseline to Day 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Diuretic Response | -0.35 kg/40 mg Furosemide equivalent at day 4 | Standard Deviation 0.44 |
| Placebo | Diuretic Response | -0.12 kg/40 mg Furosemide equivalent at day 4 | Standard Deviation 1.52 |
p-value: 0.37t-test, 2 sided
Primary
Dyspnea
Change in Dyspnea on VAS analogue scale (AUC) VAS Score is a measure/scale where patients on a scale from 0 to 100 can assign their current dyspnea score. 0 means there can be no worse dyspnea, 100 means it cannot get any better (perfect). The change in Dyspnea VAS means higher score is better outcomes. Individual changes in VAS score are be visualized (virtually) as a curve where the X-axis shows study day baseline to day 4, and y-axis shows VAS score. Using this approach, area under the curves for each study day (trapezoids) can be calculated, and added together, resulting in an overall VAS AUC score (mmxh) and change in VAS can be caculated
Time frame: From baseline to Day 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Dyspnea | 1264 mmxh | Standard Deviation 1211 |
| Placebo | Dyspnea | 1650 mmxh | Standard Deviation 1240 |
p-value: 0.18t-test, 2 sided
Primary
Length of Stay
Hospital stay of Index admission
Time frame: within 60 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin | Length of Stay | 8 days |
| Placebo | Length of Stay | 8 days |
p-value: 0.58Wilcoxon (Mann-Whitney)
Primary
Plasma NTproBNP
Change in NTproBNP
Time frame: From baseline to Day 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Plasma NTproBNP | -46 % change in NTproBNP at day 4 | Standard Deviation 32 |
| Placebo | Plasma NTproBNP | -42 % change in NTproBNP at day 4 | Standard Deviation 31 |
p-value: 0.63t-test, 2 sided
Secondary
All Cause Mortality
All Cause Mortality at 60 days
Time frame: 60 day
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Empagliflozin | All Cause Mortality | 1 Participants |
| Placebo | All Cause Mortality | 3 Participants |
Secondary
Death and/or Heart Failure Re-admission
Death and/or heart failure re-admission at day 30
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Empagliflozin | Death and/or Heart Failure Re-admission | 3 Participants |
| Placebo | Death and/or Heart Failure Re-admission | 6 Participants |
p-value: 0.31Regression, Logistic
Secondary
Inhospital Worsening Heart Failure, All Cause Mortality or Heart Failure Readmission at Day 60
Inhospital Worsening Heart Failure or All Cause mortality or Heart Failure Readmission at day 60
Time frame: 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Empagliflozin | Inhospital Worsening Heart Failure, All Cause Mortality or Heart Failure Readmission at Day 60 | 4 Participants |
| Placebo | Inhospital Worsening Heart Failure, All Cause Mortality or Heart Failure Readmission at Day 60 | 13 Participants |
p-value: 0.014Regression, Logistic
Other Pre-specified
Serious Adverse Events
SAE including all cause mortality. Per request Clintrials.gov different from Protocol definition
Time frame: 60 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Empagliflozin | Serious Adverse Events | Infectious | 1 Participants |
| Empagliflozin | Serious Adverse Events | All Cause Mortality | 1 Participants |
| Empagliflozin | Serious Adverse Events | Other | 1 Participants |
| Empagliflozin | Serious Adverse Events | Cardiovascular | 4 Participants |
| Empagliflozin | Serious Adverse Events | Respiratory/Pulmonary | 0 Participants |
| Empagliflozin | Serious Adverse Events | Renal/Urinary | 2 Participants |
| Empagliflozin | Serious Adverse Events | Psychiatric | 0 Participants |
| Placebo | Serious Adverse Events | Other | 0 Participants |
| Placebo | Serious Adverse Events | Respiratory/Pulmonary | 1 Participants |
| Placebo | Serious Adverse Events | All Cause Mortality | 3 Participants |
| Placebo | Serious Adverse Events | Infectious | 0 Participants |
| Placebo | Serious Adverse Events | Psychiatric | 1 Participants |
| Placebo | Serious Adverse Events | Renal/Urinary | 0 Participants |
| Placebo | Serious Adverse Events | Cardiovascular | 8 Participants |