| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients admitted to the ICU proven or suspected infection as the main diagnosis.
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| 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 | 10040050 |
| E.1.2 | Term | Sepsis NOS |
| E.1.2 | System Organ Class | 100000004862 |
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| 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 compare the effect hydrocortisone plus fludrocortisone vs. placebo on a composite of death or persistent organ dysfunction – defined as continued dependency on mechanical ventilation, new renal replacement therapy, or vasopressors – assessed at 90 days on intensive care unit (ICU) adults and having different biological profiles for immune responses and corticosteroids bioactivity . |
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| E.2.2 | Secondary objectives of the trial |
To compare the effect of hydrocortisone plus fludrocortisone vs. placebo on:
1) 6-month mortality;
2) 6-month HRQoL;
3) organ function (days 1, 2, 3, 4, 7, 10, 14, and 28 if in ICU);
4) hyperglyceamia as defined by glucose levels of >8.3 mmol/L (150mg/dL) (daily up to day 28)
5) hypernatremia as defined by serum sodium levels of >150mmol/L (daily up to day 28)
6) secondary infection (daily up to day 90)
7) beeding in the gastrointestinal tract defined by clinical evidence of active bleeding and need for blood transfusion OR hemostatic endoscopic or surgical procedures
8) neurological cognitive dysfunction defined as by low score on the PROMIS Adult cognitive function score.
9) neuromuscular weakness defined as a grade of 2 or more on Muscular Disability Rating Scale (MDRS).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patients ≥ 18 years old,
2) Admitted to the ICU with proven or suspected infection as the main diagnosis,
3) Community acquired pneumonia related sepsis OR vasopressors dependency (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine) OR septic shock (Singer 2016: vasopressor to maintain mean blood pressure of at least 65 mmHg and lactate levels above 2 mmol/l) OR acute respiratory distress syndrome (ARDS – Ranieri 2012: a- acute onset, i.e. within one week of an apparent clinical insult and with progression of respiratory syndrome, b- bilateral opacities on chest imaging not explained by other pulmonary pathologies, e.g. pleural effusion, atelectasis, nodules etc, c- no evidence for heart failure or volume overload, d- PaO2/FiO2 ≤ 300 mm Hg, - PEEP ≥ 5 cm H2O
4) Patient who has signed an informed and written consent whevener he/she is able of consent, if not ascent from his/her representant whenever he/she is present at time of screening for inclusion
5) Patients who have been tested for RECORDS specific biomarkers
o CIRCI negative
o Endocan < 2 ng/L
o GILZ < x (threshold currently under study)
o CPD positive
o Transcriptomic SRS2
o Endotype B
6) Affiliation to a social security system or to an universal health coverage (Couverture Maladie Universelle, CMU);
7) Patients under guardianship or curatorship will be included;
8) Patients in case of simple emergency (legal definition) will be included. |
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| E.4 | Principal exclusion criteria |
1) Pregnancy
2) Expected death or withdrawal of life-sustaining treatments within 48 hours
3) Previously enrolled in this study or in an other ineterventional study,
4) Hypersensitivity to hydrocortisone or fludrocortisone or any of their excipients ( SPC),
5) Women of childbearing potential not using contraception,
6) Nursing women.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome will be 90-Day organ dysfunction, ventilation and vasopressors free survival after randomization, which is a composite of day 90 mortality and survival free days off vasopressors and mechanical ventilation, and with SOFA score ≤6. Such composite outcomes are increasingly used in ICU trials as reliable patient-centered outcomes .
Data on the vital status at day 90 after randomisation will be collected from the medical files (including electronic medical files for the entire hospital) and phone calls to patients and their designated contact persons. The primary endpoint is a binary variable. Patients will be classed as positive outcome if they are alive at day 90 and free of vasopressor therapy, mechanical ventilation and organ dysfunction. Patients will be classed as negative outcome if they either died in the first 90 days after randomisation or if they remained vasopressor or mechanical ventilation dependent or with a SOFA score >6 beyond 28-days.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary outcomes will include:
1) Mortality at 7, 14, 28 day and 6 months.
2) Vasopressor free days: defined as the number of days with permanent hemodynamic stability in the absence of any vasopressor agent, norepinephrine, phenylephrine, epinephrine, dopamine, vasopressine or its analogs, and soever. When a patient will die on vasopressor therapy, the corresponding vasopressor free day will be 0.
3) Mechanical ventilation free days: defined as the number of days with permanent appropriate oxygenation while the patients is extubated and breathing spontaneously, i.e. no need for non invasive ventilation, high flow oxygen or CPAP. Other uses of non-invasive ventilation (e.g., chronic night-time use for chronic obstructive pulmonary disease) are not counted. When a patient will die on mechanical ventilation or will be discharge home on mechanical ventilation, the corresponding mechanical ventilation free day will be 0.
4) Organ dysfunction free days: Organ function (including renal function) will be assessed by the SOFA score (Vincent 1996). Organ dysfunction will be defined by a SOFA score of > 6 (Annane 2018). Organ dysfunction free days are defined by the number of days with os total SOFA score of 6 or less. When a patient will die on vasopressor therapy, the corresponding vasopressor free day will be 0.
5) HRQoL in 6-month survivors assessed by the EuroQol-5D (EQ-5D). This questionnaire is a standardised measure of health status developed to provide a simple, generic measure of health for clinical and economic appraisal. It is made up for two components; health state description and evaluation. The health status is measured in terms of five dimensions; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In evaluation part, the respondents evaluate their overall health status using the visual analogue scale. See Figure 4.
6) Proportion of patients with a decision to withhold and/or withdraw active treatments
7) ICU and hospital length of stay
8) Rate of re-admission to the ICU during the 180 days after randomization
9) Safety endpoints:
- Proportion of patients affected by any serious adverse events associated with corticosteroids, among the following: hospital-acquired infections, hyperglycemia, hypernatremia, neurological disorders (coma, stroke or muscle weakness, as defined below) during the 90 days after randomization
- Coma will be defined as a Glasgow coma score < 8
- Neurologic sequelae will be assessed according to the score on the Muscular Disability Rating Scale (MDRS), with a score of 1 indicating no deficit, 2 minor deficit with no functional disability, 3 distal motor deficit, 4 mild-to-moderate proximal motor deficit, and 5 severe proximal motor deficit.
- Proportion of patients affected by hospital-acquired infections (CTINILS. Définition des infections associées aux soins. 2007)
- Number of episodes of hyperglycemia (blood glucose levels >150mg/dl) during ICU stay (or up to day 90, whichever occurs first)
- Number of episodes of hypernatremia (serum sodium > 145 mmol/L) during ICU stay (or up to day 90, whichever occurs first)
- Glasgow coma scale at ICU and hospital discharge .
- Number of patients with an episode of stroke (medical diagnosis as registered in the medical file) during ICU stay (or up to day 90, whichever occurs first)
- Gastroduodenal bleeding requiring transfusion or hemostatic treatment during ICU stay (or up to day 90, whichever occurs first).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| The RECORDS Trial is a multicentre concealed-allocation multi-arms, parallel-group, adaptive blinded RCT. Patients will be randomly assigned to hydrocortisone plus fludrcortisone or placebos for 7 days. Our recruitment target is 1800 patients with full follow-up. Since loss to follow up is rare in critical care trials with outcomes measured at day 90, we do not expect missing data for the primary outcome. |
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| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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