Clinical Trials Register

Summary
EudraCT Number:	2018-004323-37
Sponsor's Protocol Code Number:	PEARL-trial
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-09-10
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2018-004323-37

A.3

Full title of the trial

Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt: a multi-centre randomized, double blind, placebo controlled trial. The PEARL trial

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

The PEARL trial

A.4.1

Sponsor's protocol code number

PEARL-trial

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	Academic Medical Centre
B.1.3.4	Country	Netherlands
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	Academic Medical Centre
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	ZonMw
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Norgine B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Academic Medical Centre
B.5.2	Functional name of contact point	Leverresearch
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031205668468
B.5.6	E-mail	leverresearch@amc.uva.nl

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	Xifaxan
D.2.1.1.2	Name of the Marketing Authorisation holder	Nogine B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Xifaxan
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	Lactulose
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Lactulose
D.3.4	Pharmaceutical form	Syrup
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

post-TIPS Hepatic Encephalopathy (HE)

E.1.1.1

Medical condition in easily understood language

Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt placement

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10019660
E.1.2	Term	Hepatic encephalopathy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	24.0
E.1.2	Level	LLT
E.1.2	Classification code	10076204
E.1.2	Term	Minimal hepatic encephalopathy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066599
E.1.2	Term	Hepatic encephalopathy prophylaxis
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10068826
E.1.2	Term	Transjugular intrahepatic portosystemic shunt
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 prophylactic administration of lactulose and rifaximin in patients who undergo Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement, to lower the incidence of post-TIPS over hepatic encephalopathy (OHE) within the first three months.

E.2.2

Secondary objectives of the trial

1. ninety day mortality;
2. transplant-free survival;
3. the development of a second episode of OHE within the first three months after TIPS placement;
4. the development of OHE between three and twelve months after TIPS placement;
5. the change in PHES and S-ANT1 test during the study: at time-points week 4, week 12 and week 52, compared to baseline;
6. differences in molecular composition of peripheral / portal blood samples at TIPS placement;
7. differences in molecular composition of peripheral blood samples at baseline, compared to day 10 post-TIPS, week 4, week 12, and week 52;
8. quality of life;
9. and cost-effectiveness.

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

Substudy 1, protocol version 1.0, date 13 december 2018:
Title: The evolution of microbiota composition and microbiota-host interaction after TIPS placement in relation to post-TIPS HE and outcome
Primary objective of this ancillary study is to assess the effect of TIPS placement on microbiota-host interaction based on the following assessments at baseline, day 10 post-TIPS, month 3 and month 12:
- 16s rRNA based analysis of microbiota in stool
- 16s rRNA based analysis of microbiota in saliva
- Circulating biomarkers for inflammatory, circulatory and endothelial function.

Secondary objectives are:
- to assess the relationship between post-TIPS hepatic encephalopathy and microbiota composition.
- to assess the relationship between post-TIPS hepatic encephalopathy and inflammatory, circulatory and endothelial function respectively.
- to assess the relationship between post-TIPS acute decompensation/ACLF or mortality at short (3 months) and long term (< 12 months) and microbiota composition.
- to assess the relationship between post-TIPS acute decompensation/ACLF or mortality at short (3 months) and long term (< 12 months) and inflammatory, circulatory and endothelial function respectively.

Substudy 2, protocol version 1.0, date 13 december 2018:
Characterisation of monocyte activation status and cytokine production in decompensated cirrhosis, alcoholic hepatitis and acute on chronic liver failure.
Objectives:
• To compare the activation status, immunological and metabolic function of circulating monocytes/macrophages obtained from patients with alcoholic liver cirrhosis (ALD).
• Identify the levels of bacterial products, in the portal and systemic blood from patients with ALD.
• Identify the nature and levels of inflammatory cytokines reaching the liver from the gut in patients with decompensated liver disease undergoing TIPS for intractable ascites
• To determine the pre and post TIPS immunological factors that may be predictive of encephalopathy following TIPS placement.
• To determine the activation status, cytokines responses, immunological- and metabolic function by circulating monocytes present in the peripheral blood of patients admitted with acute alcoholic hepatitis and acute- on- chronic liver failure and how these individual responses may correlate with survival.
• To follow up patients longitudinally and identify a set of parameters and read-outs that can predict patient outcome.

E.3

Principal inclusion criteria

1. Elective TIPS placement for refractory ascites or recurrent variceal bleeding:
• Recurrent tense ascites and one or more of the following criteria:
i. Not responding to the maximal dose of diuretics (400mg spironolactone and 160mg furosemide).
ii. Kidney insufficiency (Creatinine > 135 umol/L) induced by diuretics.
iii. Electrolyte disturbances (Sodium < 125 mmol/l, Potassium > 5.5 mmol/l) induced by diuretics.
iv. Not tolerating higher dose of diuretics (e.g. because of subjective side effects like muscle cramps).
• Recurrent variceal bleeding, not responsive to treatment with endoscopic band ligation and beta-blockers, with a high risk of failure of endoscopic treatment:
i. Patients with a variceal bleeding and Child-Pugh C (10-13 points) cirrhosis
ii. Patients with a variceal bleeding, Child-Pugh B and an active bleeding during endoscopy
2. Age ≥ 18 years
3. Confirmed liver cirrhosis as documented by liver biopsy, elastography (e.g. Fibroscan) or combination of usual radiological and biochemical criteria.
4. Signed informed consent

1. Electieve TIPS plaatsing voor therapie refractaire ascites of therapie refractaire varicesbloeding:
• Refractaire ascites en een of meer van de volgende criteria:
i. Niet reagerend op de maximale dosering diuretica (400mg spironolacton en 160mg furosemide).
ii. Nierinsufficientie (Kreatinine > 135 umol/L) geinduceerd door diuretica.
iii. Electrolyten verstoren (Natrium < 125 mmol/L, Kalium > 5.5 mmol/L) geinduceerd door diuretica.
iv. Niet tolereren van hoge dosering diuretica (b.v. door subjectieve klachten van spierkrampen).
• Therapie refractaire varices bloedingen, niet reagerend op behandeling met endoscopische band ligatie en beta-blokkers, met een hoog risico op falen van endoscopische behandeling:
i. Patienten met varices bloeding en Child-Pugh C (10-13 punten) cirrose
ii. Patienten met varices bloeding, Child-Pugh B en een actieve bloeding tijdens endoscopie
2. Leeftijd ≥ 18 jaar
3. Bevestigde levercirrose: gedocumenteerd leverbiopt, Fibroscan of een combinatie van de gebruikelijke radiologische en biochemsiche criteria.
4. Getekend informed consent formulier

E.4

Principal exclusion criteria

1. Any absolute contraindications for TIPS placement:
a. History of hepatic encephalopathy grade II-IV without precipitating factor
b. Heart failure NYHA ≥ grade 3
c. Hepatocellular carcinoma (multifocal or large or centrally located)
d. Systemic infection / sepsis
e. Severe pulmonary hypertension
f. Unrelieved bile duct obstruction
g. Technically not feasible
h. Poor liver function (MELD score > 20)
2. Use of ciclosporin
3. Life-threating variceal bleeding with emergency TIPS placement
4. Age > 80 years
5. Non-cirrhotic portal hypertension
6. Portal vein thrombosis
7. History of OHE not induced by SBP or gastrointestinal bleed
8. Current or recent (<3 months) use of rifaximin
9. Overt neurologic diseases such as Alzheimer’s disease, Parkinson’s disease
10. Pregnant or breastfeeding women
11. Patients refusing or unable to sign informed consent

1. Een absolute contraindicatie voor TIPS plaatsing:
a. Medische voorgeschiedenis van HE graad II-IV zonder uitlokkende factor
b. Hartfalen NYHA ≥ graad 3
c. Hepatocellulair carcinoom (multifocaal of groot of centraal gelegen)
d. Systemische infectie / sepsis
e. Ernstige pulmonale hypertensie
f. Onopgeloste galweg obstructie
g. Technische niet haalbaar
h. Slechte leverfunctie (MELD score > 20)
2. Gebruik van cyclosporine
3. Levensbedreigende varicesbloeding waarbij direct TIPS plaatsing nodig is
4. Leeftijd > 80
5. Non-cirrotische portale hypertensie
6. Vena portae trombose
7. Medische voorgeschiedenis van klinisch manifeste HE, niet geinduceerd door SBP of gastrointestinale bloeding
8. Huidig of recent (<3 maanden) gebruik van rifaximine
9. Ernstig neurlogische ziekte zoals Alzheimer of Parkinson
10. Zwanger of borstvoedending gevende vrouw
11. Patienten die weigeren informed consent te tekenen

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is the development of OHE within three months after TIPS placement determined by the West Haven criteria.

E.5.1.1

Timepoint(s) of evaluation of this end point

Three months after TIPS placement.

E.5.2

Secondary end point(s)

Secondary endpoints are 90 day mortality; development of a second episode of OHE within the first three months; development of OHE in the period between three and twelve months after TIPS placement; development of MHE between TIPS placement and twelve months after placement; the increase of the PHES and ANT-1 score compared to baseline. Difference in the composition of portal blood samples, drawn at TIPS placement. Furthermore, quality of life will be assessed by the Liver Disease Symptom Index 2.0 (LSDI 2.0) and EQ-5D-5L questionnaires.

E.5.2.1

Timepoint(s) of evaluation of this end point

Quality of life is measured at baseline, three and twelve months after TIPS placement.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

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

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:

226

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

171

F.4.2

For a multinational trial

F.4.2.1

In the EEA

238

F.4.2.2

In the whole clinical trial

238

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)

Standard of care after end of trial.

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

2019-09-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-03

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

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