Clinical Trials Register

Summary
EudraCT Number:	2010-024273-38
Sponsor's Protocol Code Number:	UZ1S55168
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-04-11
Trial results	View 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

UK - MHRA

A.2

EudraCT number

2010-024273-38

A.3

Full title of the trial

Supplemental COrTicosteroids in Cirrhotic Hypotensive patients with suspicion of SepsIS. The SCOTCHIS trial

A.3.1

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

Efficacy of treatment with steroids in patients with liver cirrhosis and septic shock

A.3.2

Name or abbreviated title of the trial where available

SCOTCHIS trial

A.4.1

Sponsor's protocol code number

UZ1S55168

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02602210

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	University Hospitals of Leuven
B.1.3.4	Country	Belgium
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	CLIF Consortium
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospitals of Leuven
B.5.2	Functional name of contact point	Alexander Wilmer
B.5.3	Address:
B.5.3.1	Street Address	Herestraat 49
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	3000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3216344275
B.5.6	E-mail	alexander.wilmer@uzleuven.be

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.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Hydrocortisone
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydrocortisone
D.3.9.1	CAS number	50-23-7
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 200
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	Solution for injection/infusion
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

Cirrhotic patients under vasopressors admitted to the Intensive Care Unit (ICU) because of persisting hypotension and with suspected infection.

E.1.1.1

Medical condition in easily understood language

septic shock in patients with liver cirrhosis.

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	10020518
E.1.2	Term	Hydrocortisone
E.1.2	System Organ Class	100000004848

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 determine whether low doses of hydrocortisone improves the 28-day mortality when added to the standard management of cirrhotic patients with vasopressor dependent shock.

E.2.2

Secondary objectives of the trial

•Determine whether therapy with hydrocortisone:
-improve ICU, hospital and 90-day mortality
-shorten time to resolution of shock and reversal of organ failure
-shorten ICU and hospital LOS
-reduce new organ failure
-is associated with shock relapse
-is associated with development of new infection episodes or development of infections
-is associated with development of adverse events related to gastrointestinal bleeding
-is associated with severe hyperglycemia
-is associated with the development of critical illness polyneuropathy
•Estimate the incidence of adrenal failure according to the proposed
definition.
•Identify and characterize those who benefit most from corticosteroid
•Evaluate diagnostic and prognostic value of the Synacthentest in the selection of patients for treatment with steroids.
•Establish diagnostic criteria and propose a definition for cirrhosis related corticosteroid insufficiency
•Elucidate pathophysiology of adrenal insufficiency in cirrhotics

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All patients with known or recently diagnosed cirrhosis who
a) are admitted to the ICU because of persistent hypotension or
b) develop persistent hypotension while admitted to the ICU,
both secondary to proven or suspected infection, in both cases despite adequate fluid resuscitation and with need of norepinephrine (any dose) to maintain a mean arterial blood pressure > 60 mmHg or > 65 mmHg if accompanied with signs of organ hypoperfusion, are eligible for study entry. The diagnosis of cirrhosis is preferably made by histology or based on imaging and laboratory findings.

E.4

Principal exclusion criteria

•Age < 18
•Patients receiving any vasopressor medication, initiated for septic shock, for more than 24 h prior to administration of study drug. Terlipressin initiated for treatment of hepatorenal syndrome or variceal bleeding is allowed.
•Patients with known hypoadrenalism
•Active GI bleeding (unless controlled for > 24 hours) or haemorrhagic shock.
•Cardiogenic shock or severe cardiac dysfunction (CI <2 l/min/ m2)
•Active uncontrolled hepatitis B infection
•HIV infection
•Evidence of advanced malignancy (except hepatocellular carcinoma within transplant criteria or non-melanocytic skin cancer). Malignancies in remission are allowed (for example: small cholangiocarcinomas treated and in theoretical response or breast and prostatic cancers in remission).
•Therapy with any corticosteroid (oral or intravenous) in the last 3 months
•Therapy with any other immunosuppressive drug in the last 3 months
•Patients who received etomidate within the past 3 days
•Severe acute alcoholic hepatitis (biopsy proven), because it compromises the survival
•Chronic haemodialysis
•Severe chronic heart disease (NYHA class III or IV)
•Severe chronic obstructive pulmonary disease (GOLD III or IV)
•Severe psychiatric disorder
•Child-Pugh score C14 -15
•SOFA score > 16 points at inclusion (SOFA is a score of severity of critically ill disease according to number and degree of organ failure)
•Pregnant or breastfeeding women
•Contraindications for systemic steroids
•Refusal to consent
•Patients who cannot provide prior informed consent and when there is documented evidence that the patient has no legal surrogate decision maker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent.

E.5 End points

E.5.1

Primary end point(s)

Patient survival at 28 days analysed from the day of randomisation (28-
day mortality)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. At 28 days, analysed from the day of randomization.

E.5.2

Secondary end point(s)

1. Patient survival at 90 days analyzed from the day of randomization
2. ICU and hospital mortality
3. Reversal of shock: time in days from start of placebo or active medication to resolution of shock as defined as cessation of continuous vasopressor medication (for > 24 hours)
4. Reversal of organ failures: measured with SOFA-score and CLIF-SOFA score
5. Vasopressor doses
6. Vasopressor-free days
7. Mechanical ventilation-free days or duration of mechanical ventilation
8. Number of new organ failures
9. Need for and duration of renal replacement therapy
10. ICU and hospital length-of-stay
11. Acquirement of new infections (bacterial and/or fungal): defined according to CDC criteria (pneumonia, bacteremia, spontaneous bacterial peritonitis, catheter-related bloodstream infections, skin infections and others)
12. Shock relapse defined as hypotension recurrence during the tapering period or within 3 days of total discontinuation of study drug
13. New shock episode: hypotension recurrence with the need for vasopressor therapy after 3 days of total discontinuation of study drug
14. Impact of coagulopathy assessed by DIC-score
15. Clinically important bleeding defined as new melena, new hematemesis or unexplained fall in haemoglobin > 2g/dl (not related to volume expansion). The presence of ‘coffee ground’ aspirate from NG aspirate will not be considered active GI bleeding. Furthermore bleeding assessments will be performed using the WHO bleeding assessment scale (see appendix B). By this ordinal scale, bleeds are graded from 0 to 4, where grade 0 is no bleeding; grade 1 is petechiae; grade 2 is mild blood loss; grade 3 is gross blood loss; and grade 4 is debilitating blood loss. Major bleeding will be classified as WHO grade 3 or higher.
16. Glycemic control: measured as units of insulin required to attain glycemic levels < 140 mg/dl
17. Episode of hyper- (> 180 mg/dl) or hypoglycemia (< 60 mg/dl)
18. Incidence of ICU-acquired weakness

E.5.2.1

Timepoint(s) of evaluation of this end point

at day 90

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

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1