Clinical Trials Register

Summary
EudraCT Number:	2018-004011-44
Sponsor's Protocol Code Number:	UofATURRIFIC
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:	2020-05-28
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

UK - MHRA

A.2

EudraCT number

2018-004011-44

A.3

Full title of the trial

A randomised trial of URsodeoxycholic acid versus RIFampicin in severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC study, comparing their effectiveness in the reduction of pruritus.

A.3.1

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

Trial of URsodeoxycholic acid versus RIFampicin in severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC study

A.3.2

Name or abbreviated title of the trial where available

TURRIFIC Protocol Version 8

A.4.1

Sponsor's protocol code number

UofATURRIFIC

A.5.4

Other Identifiers

Name:

ANZCTR

Number:

ACTRN12618000332224

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	The University Of Adelaide
B.1.3.4	Country	Australia
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	Department of Health
B.4.2	Country	Australia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The University of Adelaide
B.5.2	Functional name of contact point	Chief Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	72 King William Road
B.5.3.2	Town/ city	NORTH ADELAIDE
B.5.3.3	Post code	5006
B.5.3.4	Country	Australia
B.5.4	Telephone number	61881617000
B.5.5	Fax number	6183131406
B.5.6	E-mail	bill.hague@adelaide.edu.au

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	Information not present in EudraCT
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	Rifampicin
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rifampicin
D.3.9.1	CAS number	13292-46-1
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	equal
D.3.10.3	Concentration number	300
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	Comparator
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	Information not present in EudraCT
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	Ursodeoxycholic acid
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ursodeoxycholic acid
D.3.9.1	CAS number	128-13-2
D.3.9.4	EV Substance Code	AS2
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	500
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Intrahepatic Cholestasis of Pregnancy (ICP) is an serious liver condition in pregnancy. The main symptom of this is itching. Ursodeoxycholic acid is routinely used to treat cholestasis but is not effective in reducing itch in all people who take it. Rifampcin has been used to reduce itch in people with Primary Biliary Cholangitis. This study will randomly allocate women with severe early onset ICP to receive either Ursodeoxycholic Acid, or the "Investigational drug" Rifampicin.

E.1.1.1

Medical condition in easily understood language

ICP is a liver condition in pregnancy where women develop severe itching and high concentration of bile acid in their blood. ICP is associated with increased risk of premature delivery and stillbirth.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

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	10049055
E.1.2	Term	Cholestasis of pregnancy
E.1.2	System Organ Class	10019805 - Hepatobiliary 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	10049055
E.1.2	Term	Cholestasis of pregnancy
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare treatment with Rifampicin (RIF) with the standard treatment, Ursodeoxycholic acid (UDCA) for the reduction of itch, the main symptom of the condition.

E.2.2

Secondary objectives of the trial

1. To compare the effect of RIF treatment with UDCA treatment on short-term outcomes for both mother and baby, including the length of the pregnancy and the rates of caesarean section and preterm birth
2. To compare the effect of RIF treatment with UDCA treatment on serum concentrations of: bile acids, transaminases (liver enzymes), and on metabolites such as serum autotaxin and progesterone sulphated metabolites, and urine glucuronidated 6α-hydroxylated BA.
3. To assess the effect of RIF and UDCA on the metabolome (the results of breakdown of nutrients, hormones and bodily processes) and the microbiome (bacteria in/on the body)
4. To assess the effect of treatment with RIF compared with UDCA on maternal and fetal outcomes analysed by bile acid transporter genotype.

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

The sub-studies are fully described within the Protocol Version 8, 13 May 2020. The sub-studies cover the analysis of the serum, urine, microbiome, metabolome and genetic samples collected. These are:
TURRIFIC tests - Biochemical and microbiological assessments
TURRIFIC genes and viruses - Genetic and virome assessments

Objectives: Currently ICP is diagnosed using the criteria of increased bile acids associated with itch. However, serum bile acid concentration does not always appear to be correlated with itch severity. Thus, serum and urine will be analysed to look at relationship between autotaxin, sulphated progesterone metabolites, total bile acid profile, itch and treatment with Ursodeoxycholic acid/Rifampicin. It is also not known what happens to the gut mircobiome in ICP or in response to medications for ICP. So we plaan to investigate any alterations in gut microflora diversity and abundance. Non-specific viral disease has in some cases been associated with a transient hepatitis, so we plan to investigate whether there is any involvement of viruses in the aetiology of ICP by a study of the virome (viral DNA) in the blood of participants at trial entry. Whole exome analysis of participant DNA will allow study of genes known to be associated with cholestasis, including known mutations of bile acid transporter genes, and their contribution to disease severity.

E.3

Principal inclusion criteria

Women will be considered eligible for inclusion into the trial with the following criteria:
• Severe ICP (defined as pruritus with raised total serum BA ≥40 μmol/L) confirmed
• Viable pregnancy between 14+0 and 33+6 weeks gestation inclusive
• No known lethal fetal anomaly
• Singleton pregnancy
• Obstetric care in a consultant-led unit
• Aged 18 years or over
• Written informed consent has been obtained

E.4

Principal exclusion criteria

A potential participant who meets any of the following criteria will be excluded from participation in this study:
• A decision has already been made for delivery within the next 48 hours
• There is allergy to any component of the UDCA or RIF tablets
• The woman is taking other medication that has a significant interaction with rifampicin treatment
• There is a multi-fetal gestation
• There is laboratory-confirmed active hepatitis A or hepatitis B, or positive serology for hepatitis C
• There is current pre-eclampsia (ISSHP criteria)
• There is a known primary hepatic disorder, including α-1-antitrypsin deficiency and autoimmune hepatitis, including primary biliary cholangitis
• The woman is on current medication causing deranged liver enzymes
• The woman is unwilling for her baby to have standard Vitamin K administration at birth
• The woman has previously participated in TURRIFIC

E.5 End points

E.5.1

Primary end point(s)

Pruritus, defined as worst itch in the previous 24 hours, assessed on a patient-reported visual analogue scale.

E.5.1.1

Timepoint(s) of evaluation of this end point

At study entry, one week post randomisation, then monthly up to delivery, with optional assessments on a weekly basis after 28 weeks gestation.

E.5.2

Secondary end point(s)

1. Outcomes for both mother and infant including the length of gestation and the incidence of caesarean section and preterm birth.
2. Serum concentrations of: bile acids, transaminases, and on metabolites such as serum autotaxin and progesterone sulphated metabolites, and urine glucuronidated 6α-hydroxylated BA.
3. Metabolome and the microbiome.
4. Maternal and fetal outcomes analysed by bile acid transporter genotype.

E.5.2.1

Timepoint(s) of evaluation of this end point

These numbers correspond to the secondary outcomes listed in 23-2 above.
1. assessed at delivery
2. to be assessed at study entry, one week post randomisation, then on a monthly basis up to delivery.
3. to be assessed at study entry, one week post randomisation, then on a monthly basis up to delivery, one and two weeks post delivery
4. to be assessed once for mother using sample collected at study entry, once for baby using sample collected at birth.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

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

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Finland

Netherlands

Sweden

United Kingdom

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

End of trial will be at data base lock. This is so that any "data cleaning" and queries may be completed.

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