E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of fluid overload in critically ill adult patients in intensive care unit. |
|
E.1.1.1 | Medical condition in easily understood language |
Treatment of excess fluid in the body in critically ill adults admitted to an intensive care unit. |
|
E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015766 |
E.1.2 | Term | Extracellular fluid increased |
E.1.2 | System Organ Class | 100000004861 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016808 |
E.1.2 | Term | Fluid retention in tissues |
E.1.2 | System Organ Class | 100000004861 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022608 |
E.1.2 | Term | Interstitial fluid increased |
E.1.2 | System Organ Class | 100000004861 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033303 |
E.1.2 | Term | Overhydration |
E.1.2 | System Organ Class | 100000004861 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10030102 |
E.1.2 | Term | Oedema generalised |
E.1.2 | System Organ Class | 100000004867 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034611 |
E.1.2 | Term | Peripheral oedema |
E.1.2 | System Organ Class | 100000004867 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess benefits and harms of goal directed fluid removal with furosemide versus placebo on patient-important outcome measures in adult ICU patients with moderate to severe fluid overload. The primary objective is to determine, if forced fluid removal with furosemide compared to placebo (spontaneous fluid excretion) will increase the number of days alive and out of hospital at 90 days. |
|
E.2.2 | Secondary objectives of the trial |
To investigate if goal directed fluid removal compared to placebo in adult ICU patients with fluid overload will change the:
1. All-cause mortality at day 90 after randomization. 2. Days alive at day 90 without life support (vasopressor/inotropic support, invasive mechanical ventilation or renal replacement therapy). 3. All-cause mortality at 1-year after randomization. 4. Number of participants with one or more serious adverse events (SAEs) and serious adverse reactions (SARs) to furosemide.
Explorative outcomes: 1. Health related quality of life 1-year after randomization measured using the EuroQoL (EQ)-5D-5L and EQ-VAS scores. 2. Participants subjective assessment of their quality of life since the treatment in the ICU (unacceptable/neutral/accecptable) comared to (EQ)-5D- 5L and EQ-VAS scores. 3. Cognitive function 1-year after randomization assessed by the Montreal Cognitive Assessment (MoCa) score.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All of the parameters must be met:
• Acute admission to the ICU. • Age ≥ 18 years of age. • Fluid accumulation estimated according to daily fluid charts, the cumulative fluid balance, development in body weight, and clinical examination corresponding ≥ 5% of ideal body weight. • Clinical stable assessed by the clinicians (minimum criteria: MAP > 50 mmHg and maximum infusion of 20 microgram/kg/minute of noradrenaline and lactate < 4,0 mmol/L).
|
|
E.4 | Principal exclusion criteria |
• Known allergy to furosemide or sulphonamides. • Known pre-hospitalization advanced chronic kidney disease (eGFR<30 mL/minute/1.73 m2 or chronic renal replacement therapy). • Ongoing renal replacement therapy • Anuria for ≥ 6 hours • Rhabdomyolysis with indication for forced diuresis • Ongoing life-threatening bleeding. • Acute burn injury of more than 10 % of the body surface area. • Severe dysnatremia (p-Na < 120 mmol/L or >155 mmol/l). • Severe hepatic failure as per the clinical team. • Patients undergoing forced treatment. • Fertile women (women < 50 years) with positive urine human chorionic gonadotropin (hCG) or plasma-hCG. • Consent not obtainable as per the model approved for the specific trial site. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Days alive and out of hospital at day 90 after randomisation. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
90 days post-randomisation. |
|
E.5.2 | Secondary end point(s) |
1. All-cause mortality at day 90 after randomization. 2. Days alive at day 90 without life support (vasopressor/inotropic support, invasive mechanical ventilation or renal replacement therapy). 3. All-cause mortality at 1-year after randomization. 4. Number of participants with one or more serious adverse events (SAEs) and serious adverse reactions (SARs) to furosemide. 5. Health related quality of life 1-year after randomization measured using the EuroQoL (EQ)-5D-5L and EQ-VAS scores. 6. Participants subjective assessment of their quality of life since the treatment in the ICU (unacceptable/neutral/accecptable) comared to (EQ)-5D- 5L and EQ-VAS scores. 7. Cognitive function 1-year after randomization assessed by the Montreal Cognitive Assessment (MoCa) score.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoint number 1,2,4,: 90 days post-randomisation Endpoint number: 3,5,6: 1 year post-randomisation |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
1 year and 3 months post-randomisation of the last included patient in the trial. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 7 |