Clinical Trials Register

Summary
EudraCT Number:	2020-003942-35
Sponsor's Protocol Code Number:	APHP200018
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-01-20
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2020-003942-35

A.3

Full title of the trial

HydrOcortisone and fludRocortisoNe for critical ILLness-related corticosteroid insufficiency

Impact de l'association hydrocortisone et fludrocortisone sur le devenir de patients souffrant d’insuffisance corticotrope liée aux états critiques

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

HydrOcortisone and fludRocortisoNe for critical ILLness-related corticosteroid insufficiency

A.3.2

Name or abbreviated title of the trial where available

HORNbILL

A.4.1

Sponsor's protocol code number

APHP200018

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Assistance Publique - Hôpitaux Paris
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	health Ministry
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Assistance Publique - Hôpitaux Paris - Direction de la Recherche Clinique et de l'Innovation
B.5.2	Functional name of contact point	project Manager
B.5.3	Address:
B.5.3.1	Street Address	1 avenue Claude Vellefaux
B.5.3.2	Town/ city	paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	+33144841747
B.5.6	E-mail	candy.estevez@aphp.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	FLUCORTAC® 50 μg
D.2.1.1.2	Name of the Marketing Authorisation holder	H.A.C Pharma
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Fludrocortisone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Enteral use (Noncurrent) Nasogastric use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUDROCORTISONE
D.3.9.1	CAS number	127-31-1
D.3.9.4	EV Substance Code	SUB07684MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	HYDROCORTISONE UPJOHN® 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SERB
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hémisuccinate d'hydrocortisone sous forme de sel de sodium
D.3.9.3	Other descriptive name	HYDROCORTISONE SODIUM SUCCINATE
D.3.9.4	EV Substance Code	SUB02569MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Nasogastric use (Noncurrent)
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Critically ill patients with a SOFA score (SOFA; Sequential Organ Failure Assessment) ≥ 6, for at least 6 consecutive hours, suffering from CIRCI, to the notable exception of patients with septic shock.

E.1.1.1

Medical condition in easily understood language

Critically ill patients suffering from CIRCI

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10077264
E.1.2	Term	Critical illness
E.1.2	System Organ Class	10018065 - General disorders and administration site conditions

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy on ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) post randomization of hydrocortisone combined with fludrocortisone compared to placebo in ICU adults with critical illness related corticosteroid insufficiency.

E.2.2

Secondary objectives of the trial

To assess the efficacy of hydrocortisone combined with fludrocortisone, versus placebo, in the treatment of ICU adults with CIRCI on:
• Mortality at ICU and hospital discharge, and at 30 days, 90 days and 180 days after randomization, • Number of vasopressor-free days, of ventilator-free days 30 days after randomization, •Kidney replacement therapy-free days at 30 days after randomization
• Number of 30-day intensive care unit (ICU)–free days, • Organ dysfunction up to day 30 after randomisation
• Fluid balance (during ICU stay), • ICU and hospital length of stay
•Rate of ICU re-admission during the 30 days after randomization
•Health-related quality of life
To assess serious adverse events associated with corticosteroids at day 30 after randomization. To assess ventilation and vasopressors free days in ICU adults devoid of critical illness related corticosteroid insufficiency, at day 30 post SYNACTHENE® test and all-cause mortality at day 90 post SYNACTHENE® test.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

To assess the cutaneous vasoconstrictor response to glucocorticoids in a subgroup of patients : Subjects randomized in one participating center (Hôpital Raymond Poincaré, Garches) will be tested to access the cutaneous vasoconstrictor response to glucocorticoids.

E.3

Principal inclusion criteria

- Adult (≥18 years)
- Hospitalized in an intensive care unit
- SOFA score (SOFA; Sequential Organ Failure Assessment) ≥ 6,(46) for at least 6 consecutive hours.
- Informed written consent from patient or from legally authorized trusted person or next of kin, if present at time of inclusion. When a patient is unable to be informed, and no legally authorized trusted person or next of kin is present, the patient may still be included (emergency procedure), and patient’s, or, where appropriate, the legally authorized trusted person or next of kin’s, deferred consent needs to be obtained as soon as possible (Article L1122-1-3; Public Health Code). Patient under guardianship or tutorship could be included.
- Affiliation to a social security system or to an universal health coverage (Couverture Maladie Universelle, CMU).

E.4

Principal exclusion criteria

- Septic shock
- Active tuberculosis or fungal infection
- Active viral hepatitis or active infection with herpes viruses
- Hypersensitivity to hydrocortisone or fludrocortisone or any of their excipients (SmPC)
- Patient needing either anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason
- Current treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30days
- Pregnant or breastfeeding woman
- Moribund patient
- Participation to another interventional study that focuses on CIRCI and/or corticoid drugs and/or that adresses a similar primary endpoint as Hornbill (survival or use of vasopressors or of mechanical ventilation)Previously enrolled in this study
- Participation to another interventional study

E.5 End points

E.5.1

Primary end point(s)

The primary end point is the number of ventilator- and vasopressor-free days up to day 30, defined as days from randomisation to 30 days thereafter, during which the patient is alive, free of mechanical ventilation, and free of treatment with intravenous vasopressors. Any patient who dies within 30 days will be assigned zero days. After mechanical ventilation and vasopressors are weaned, if either are restarted before day 30 for more than 60 minutes within a 24-hour period, the intervening days will not count as being free of ventilator or vasopressor support. Use of mechanical ventilation or vasopressors during and up to 3 hours after surgery or bedside procedure (eg, hemodialysis session) will be exempt.(35). Such composite outcomes are increasingly used in ICU trials as strong patient-centred outcomes (36–38).
Vasopressor therapy is defined as any intravenous dose of norepinephrine, phenylephrine, dopamine, epinephrine, vasopressin or terlipressin. Mechanical ventilation is defined as invasive mechanical ventilation via endotracheal tube (including tracheostomy) or non-invasive ventilation with >5 cmH2O continuous positive airway pressure and >5 cmH2O pressure support when deployed to avoid intubation. Other uses of non-invasive ventilation (e.g., chronic night-time use for chronic obstructive pulmonary disease) are not counted.
Data on the vital status at day 30 after randomisation will be collected from the medical files (including electronic medical files for the entire hospital), through phone calls to patients and their designated contact persons.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days

E.5.2

Secondary end point(s)

Secondary endpoints concerning randomised patients:
- Mortality rates at ICU and hospital discharge and at day 30, 90 and 180 after randomization
- Number of days alive without vasopressors on day 30 after randomization. Patients who die before vasopressor weaning will be considered as having 0 vasopressor free days.
- Number of days alive free of mechanical ventilation on day 30 after randomization. Patients who die before mechanical ventilation weaning will be considered as having 0 ventilator free days.
- Number of days alive with SOFA <6 in the 30 days after randomization (patients who die before reaching SOFA<6 will be considered having 0 organ failure free days).
The SOFA score is defined in annex 19.1
- Proportion of patients with a decision to withhold and/or withdraw active treatments
- Renal replacement therapy (RRT)-free days up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation)
- Incidence of RRT up to Day 30 after randomisation (counting patients who die as on RRT and excluding patients on RRT for chronic renal failure at time of randomisation)
- Duration of RRT up to Day 30 after randomisation (excluding patients on RRT for chronic renal failure at time of randomisation)
- Overall and individual organ (cardiovascular, respiratory, renal, hepatic, coagulation) scores using a modified version of the Sequential Organ Failure Assessment (SOFA) until ICU discharge
- Incidence of new organ dysfunction and new organ failure (based on the SOFA score) up to Days 7 and 30 after randomisation
- Daily and cumulative fluid balance until ICU discharge (for a maximum of 7 days)
- Daily and cumulative urine output until ICU discharge (for a maximum of 7 days)
- Number of 30-day intensive care unit (ICU)–free days
- ICU and hospital length of stay
- Rate of re-admission to the ICU during the 30 days after randomization
- Score of cutaneous vasoconstrictor response to glucocorticoids (before administration of the corticoid treatment at study or placebo).
- Change in utility, based on the EuroQol group’s 5-dimension 5-level (EQ-5D-5L) questionnaire, up to Day 30 and 90 after randomisation
- 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 30 days after randomization.
o Coma will be defined as a Glasgow coma scale < 8
o 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 (see annex 19.6).
 Proportion of patients affected by hospital-acquired infections
 Number of episodes of hyperglycemia (blood glucose levels >150mg/dl) during ICU stay (or up to day 30, whichever occurs first)
 Number of episodes of hypernatremia (serum sodium > 145 mmol/L) during ICU stay (or up to day 30, whichever occurs first)
 Glasgow coma scale at ICU and hospital discharge (see annex 19.3).
 MRC (Medical research council) score for muscle strength at ICU and hospital discharge(39) (see annex 19.4).
 Number of patients with an episode of stroke (medical diagnosis as registered in the medical file)during ICU stay (or up to day 30, whichever occurs first)
 Gastroduodenal bleeding requiring transfusion or hemostatic treatment during ICU stay (or up to day 30, whichever occurs first)

Secondary endpoint concerning non-randomised patients:
- Ventilation and vasopressors free days at day 30 post SYNACTHENE® test and all cause 90 day mortality post SYNACTHENE® test (assessed using the same definition as for the primary endpoint: see section 4.1.1) in subjects devoid of CIRCI.

All the data for the assessment of the secondary endpoints will be collected from the medical files (including electronic medical files for the entire hospital) and, after the patient’s discharge from the hospital, through telephone calls to patients or their families, by research clinical technician (TEC) from the patient’s centre.

E.5.2.1

Timepoint(s) of evaluation of this end point

7, 30, 90 and 180 after randomization.
30 and 90 days post SYNACTHENE® test

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS (by call)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1638

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1638

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

patients admitted in ICU

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Serum or urine pregnancy test negative in all women of childbearing age

F.4 Planned number of subjects to be included

F.4.1

In the member state

3276

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-03-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-27

P. End of Trial
P.	End of Trial Status	Ongoing

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