Rapid rEcognition of COrticosteroid Resistant or sentive Sepsis - RECORDS

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

10 Apr 2020 → 28 Nov 2025

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS - French Ministry of Health · ANR - French Ministry of Higher Education, Research and Innovation

External identifiers

EU CT number

2024-516407-16-00

EudraCT number

2020-000296-21

ClinicalTrials.gov

NCT04280497

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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

Secondary objectives 9

1. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on 6-month mortality
2. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on 6-month HRQoL
3. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on organ function (days 1, 2, 3, 4, 7, 10, 14, and 28 if in ICU)
4. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on hyperglyceamia as defined by glucose levels of >8.3 mmol/L (150mg/dL) (daily up to day 28)
5. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on hypernatremia as defined by serum sodium levels of >150mmol/L (daily up to day 28)
6. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on secondary infection (daily up to day 90)
7. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on bleeding in the gastrointestinal tract defined by clinical evidence of active bleeding and need for blood transfusion OR hemostatic endoscopic
8. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on neurological cognitive dysfunction defined as by low score on the PROMIS Adult cognitive function score
9. To compare the effect of hydrocortisone plus fludrocortisone vs. Placebo on neuromuscular weakness defined as a grade of 2 or more on Muscular Disability Rating Scale (MDRS)

Conditions and MedDRA coding

Patients admitted to the ICU proven or suspected infection as the main diagnosis.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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 one or more RECORDS specific biomarkers : o CIRCI o Endocan o GILZ o DUSP-1 o MDW o lymphopenia o Transcriptomic SRS2 o Endotype B o PCR COVID19 o PCR Influenza o PCR other respiratory virus o Cutaneous vasoconstrictor response to glucocorticoids o PCR NFKB1-GLCCI1 o Nucleosome
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
9. Patients managed with covid 19 and having biological samples available

Exclusion criteria 8

1. Pregnancy
2. Expected death or withdrawal of life-sustaining treatments within 48 hours
3. Previously enrolled in this study or in an other interventional study
4. Formal indication for corticosteroids according to most recent international guidelines
5. Vaccination with live virus within past 6 months
6. Hypersensitivity to hydrocortisone or fludrocortisone or (microsined betamethasone dipropionate*) or any of their excipients (SPC)
7. Women of childbearing potential not using contraception
8. Nursing women

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 9

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 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).
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: see protocol

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Annane Djillali

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Annane Djillali

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications