NCT04280497

Brief Summary

Main objective and primary endpoint: 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 and endpoints:

  • Mortality and health-related quality of life at 6 months;
  • Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, 28, and 90);
  • Daily secondary infections (up to 90 days)
  • Daily blood and urinary levels of glucose, sodium and potassium (up to 28 day)
  • Daily gastroduodenal bleeding (up to 28 day)
  • Daily cognitive function and muscles' strength (days 1 to 28, 90 and 180 days).

Trial Health

57
Monitor

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
1,800

participants targeted

Target at P75+ for not_applicable sepsis

Timeline
Completed

Started Apr 2020

Longer than P75 for not_applicable sepsis

Geographic Reach
1 country

1 active site

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

February 17, 2020

Completed
4 days until next milestone

First Posted

Study publicly available on registry

February 21, 2020

Completed
2 months until next milestone

Study Start

First participant enrolled

April 10, 2020

Completed
5.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2025

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2025

Completed
Last Updated

October 1, 2025

Status Verified

September 1, 2025

Enrollment Period

5.6 years

First QC Date

February 17, 2020

Last Update Submit

September 29, 2025

Conditions

Sepsis

Keywords

SepsisCorticosteroidintensive care unitCS-resistant SepsisCS-sensitive Sepsis

Outcome Measures

Primary Outcomes (2)

  • 3-month mortality

    Patient's vital status.

    Daily up to 3 months

  • Persistent organ dysfunction

    Persistent organ dysfunction (defined as continued dependency on mechanical ventilation, renal replacement therapy, or vasopressors) and with SOFA score ≤6 up to 90 days.

    At baseline, 1 month and 3 months

Secondary Outcomes (18)

  • Mortality at 7, 14, 28 day and 6 months

    at 7, 14, 28 day and 6 months

  • Vasopressor free days

    through study completion, an average of 6 month

  • Mechanical ventilation free days

    through study completion, an average of 6 month

  • Organ dysfunction free days

    through study completion, an average of 6 month

  • HRQoL in 6-month survivors assessed by the EuroQol-5D (EQ-5D)

    at 1, 28, 90 day and 6 months

  • +13 more secondary outcomes

Study Arms (12)

Biomarker CIRCI neg: Corticosteroid arm

EXPERIMENTAL

Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment.

Drug: Administration procedures

Biomarker CIRCI neg: Placebo arm

PLACEBO COMPARATOR

Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment.

Drug: Administration procedures

Biomarker endocan: Corticosteroid arm

EXPERIMENTAL

Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment.

Drug: Administration procedures

Biomarker endocan: Placebo arm

PLACEBO COMPARATOR

Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment.

Drug: Administration procedures

Biomarker GILZ: Corticosteroid arm

EXPERIMENTAL

Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment.

Drug: Administration procedures

Biomarker GILZ: Placebo arm

PLACEBO COMPARATOR

Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment.

Drug: Administration procedures

Biomarker CPD: Corticosteroid arm

EXPERIMENTAL

Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment.

Drug: Administration procedures

Biomarker CPD: Placebo arm

PLACEBO COMPARATOR

Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment.

Drug: Administration procedures

Biomarker Transcriptomic SRS: Corticosteroid arm

EXPERIMENTAL

Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment.

Drug: Administration procedures

Biomarker Transcriptomic SRS: Placebo arm

PLACEBO COMPARATOR

Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment.

Drug: Administration procedures

Biomarker Endotype B: Corticosteroid arm

EXPERIMENTAL

Hydrocortisone plus fludrocortisone as treatment: hydrocortisone hemisuccinate and 9 alpha fludrocortisone as experimental treatment.

Drug: Administration procedures

Biomarker Endotype B: Placebo arm

PLACEBO COMPARATOR

Placebo: hydrocortisone placebo and 9 alpha fludrocortisone placebo as placebo treatment.

Drug: Administration procedures

Interventions

Administration proceduresDRUG

Hydrocortisone hemisuccinate / hydrocortisone placebo will be given as 50 mg intravenous bolus every 6 hours; 9 alpha fludrocortisone / 9 alpha fludrocortisone placebo will be given as a 50 μg tablet via a nasogastric tube once per day in the morning. Study drugs will be started immediately after randomization (day 0 of the study), until discharge from ICU for a maximal duration of 7 days. Study drugs will be stopped without tapering off.

Biomarker CIRCI neg: Corticosteroid armBiomarker CIRCI neg: Placebo armBiomarker CPD: Corticosteroid armBiomarker CPD: Placebo armBiomarker Endotype B: Corticosteroid armBiomarker Endotype B: Placebo armBiomarker GILZ: Corticosteroid armBiomarker GILZ: Placebo armBiomarker Transcriptomic SRS: Corticosteroid armBiomarker Transcriptomic SRS: Placebo armBiomarker endocan: Corticosteroid armBiomarker endocan: Placebo arm

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Patient ≥18 years old;
  • Admitted to ICU with proven or suspected infection as the main diagnosis;
  • Community acquired pneumonia related sepsis or vasopressors dependency (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine) or septic shock (vasopressor to maintain mean blood pressure of at least 65 mmHg and lactate levels above 2 mmol/l) or acute respiratory distress syndrome (ARDS: 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;
  • Patients who have been tested for one or more RECORDS specific biomarkers:
  • CIRCI
  • Endocan
  • GILZ
  • DUSP-1
  • MDW
  • lymphopenia
  • Transcriptomic SRS2
  • Endotype B
  • PCR COVID-19
  • PCR Influenza
  • PCR other respiratory virus
  • +5 more criteria

You may not qualify if:

  • Pregnancy;
  • Expected death or withdrawal of life-sustaining treatments within 48 hours;
  • Previously enrolled in this study
  • Formal indication for corticosteroids according to most recent international guidelines
  • Vaccination with live virus within past 6 months
  • Hypersensitivity to hydrocortisone or fludrocortisone or (microsined betamethasone dipropionate\*) or any of their excipients (spc)
  • Women of childbearing potential not using contraception
  • Nursing women \* For patients included in this stratum, if applicable, do not apply the cream to an infected or ulcerated area

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Department of medical and surgical Intensive Care Unit, Raymond Poincaré Hospital - APHP

Garches, Hauts-de-Seine, 92380, France

RECRUITING

Related Publications (13)

  • Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers S, Russell JA, Van den Berghe G. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2017 Dec;43(12):1751-1763. doi: 10.1007/s00134-017-4919-5. Epub 2017 Sep 21.

    PMID: 28940011BACKGROUND

  • Lamontagne F, Rochwerg B, Lytvyn L, Guyatt GH, Moller MH, Annane D, Kho ME, Adhikari NKJ, Machado F, Vandvik PO, Dodek P, Leboeuf R, Briel M, Hashmi M, Camsooksai J, Shankar-Hari M, Baraki MK, Fugate K, Chua S, Marti C, Cohen D, Botton E, Agoritsas T, Siemieniuk RAC. Corticosteroid therapy for sepsis: a clinical practice guideline. BMJ. 2018 Aug 10;362:k3284. doi: 10.1136/bmj.k3284. No abstract available.

    PMID: 30097460BACKGROUND

  • Rochwerg B, Oczkowski SJ, Siemieniuk RAC, Agoritsas T, Belley-Cote E, D'Aragon F, Duan E, English S, Gossack-Keenan K, Alghuroba M, Szczeklik W, Menon K, Alhazzani W, Sevransky J, Vandvik PO, Annane D, Guyatt G. Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med. 2018 Sep;46(9):1411-1420. doi: 10.1097/CCM.0000000000003262.

    PMID: 29979221BACKGROUND

  • Nishida O, Ogura H, Egi M, Fujishima S, Hayashi Y, Iba T, Imaizumi H, Inoue S, Kakihana Y, Kotani J, Kushimoto S, Masuda Y, Matsuda N, Matsushima A, Nakada TA, Nakagawa S, Nunomiya S, Sadahiro T, Shime N, Yatabe T, Hara Y, Hayashida K, Kondo Y, Sumi Y, Yasuda H, Aoyama K, Azuhata T, Doi K, Doi M, Fujimura N, Fuke R, Fukuda T, Goto K, Hasegawa R, Hashimoto S, Hatakeyama J, Hayakawa M, Hifumi T, Higashibeppu N, Hirai K, Hirose T, Ide K, Kaizuka Y, Kan'o T, Kawasaki T, Kuroda H, Matsuda A, Matsumoto S, Nagae M, Onodera M, Ohnuma T, Oshima K, Saito N, Sakamoto S, Sakuraya M, Sasano M, Sato N, Sawamura A, Shimizu K, Shirai K, Takei T, Takeuchi M, Takimoto K, Taniguchi T, Tatsumi H, Tsuruta R, Yama N, Yamakawa K, Yamashita C, Yamashita K, Yoshida T, Tanaka H, Oda S. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016). Acute Med Surg. 2018 Feb 5;5(1):3-89. doi: 10.1002/ams2.322. eCollection 2018 Jan.

    PMID: 29445505BACKGROUND

  • Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.

    PMID: 28101605BACKGROUND

  • Tavare A, O'Flynn N. Recognition, diagnosis, and early management of sepsis: NICE guideline. Br J Gen Pract. 2017 Apr;67(657):185-186. doi: 10.3399/bjgp17X690401. No abstract available.

    PMID: 28360070BACKGROUND

  • van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017 Jul;17(7):407-420. doi: 10.1038/nri.2017.36. Epub 2017 Apr 24.

    PMID: 28436424BACKGROUND

  • Wong HR, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT, Weiss SL, Fitzgerald J, Checchia PA, Meyer K, Shanley TP, Quasney M, Hall M, Gedeit R, Freishtat RJ, Nowak J, Shekhar RS, Gertz S, Dawson E, Howard K, Harmon K, Beckman E, Frank E, Lindsell CJ. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med. 2015 Feb 1;191(3):309-15. doi: 10.1164/rccm.201410-1864OC.

    PMID: 25489881BACKGROUND

  • Antcliffe DB, Burnham KL, Al-Beidh F, Santhakumaran S, Brett SJ, Hinds CJ, Ashby D, Knight JC, Gordon AC. Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial. Am J Respir Crit Care Med. 2019 Apr 15;199(8):980-986. doi: 10.1164/rccm.201807-1419OC.

    PMID: 30365341BACKGROUND

  • Annane D, Pastores SM, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Meduri GU, Olsen KM, Rochwerg B, Rodgers SC, Russell JA, Van den Berghe G. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med. 2017 Dec;43(12):1781-1792. doi: 10.1007/s00134-017-4914-x. Epub 2017 Sep 21.

    PMID: 28940017BACKGROUND

  • Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.

    PMID: 26903338BACKGROUND

  • ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.

    PMID: 22797452BACKGROUND

  • Fleuriet J, Heming N, Meziani F, Reignier J, Declerq PL, Mercier E, Muller G, Colin G, Monnet X, Robine A, Siami S, Uhel F, Quenot JP, Plantefeve G, Badie J, Schneider F, Cerf C, Troche G, Monchi M, Mira JP, Francois B, Chevret S, Annane D; RECORDS consortium; CRICS TRIGGERSEP network. Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis (RECORDS): study protocol for a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial. BMJ Open. 2023 Mar 10;13(3):e066496. doi: 10.1136/bmjopen-2022-066496.

    PMID: 36898751DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

Therapeutics

Condition Hierarchy (Ancestors)

InfectionsSystemic Inflammatory Response SyndromeInflammationPathologic ProcessesPathological Conditions, Signs and Symptoms

Study Officials

  • Djillali ANNANE, MD, PhD

    Department of medical and surgical Intensive Care Unit, - Raymond Poincaré Hospital - APHP

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Djillali ANNANE, MD, PhD

CONTACT

+33 1 47 10 77 87djillali.annane@aphp.fr

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

February 17, 2020

First Posted

February 21, 2020

Study Start

April 10, 2020

Primary Completion

December 1, 2025

Study Completion

December 1, 2025

Last Updated

October 1, 2025

Record last verified: 2025-09

Data Sharing

IPD Sharing
Will not share

Locations

FR(1)