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Trial registered on ANZCTR

Registration number

ACTRN12618000332224

Ethics application status

Approved

Date submitted

14/02/2018

Date registered

6/03/2018

Date last updated

15/11/2019

Date data sharing statement initially provided

25/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

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

Scientific title

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.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

TURRIFIC

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Severe early-onset intrahepatic cholestasis of pregnancy

Condition category

Condition code

Reproductive Health and Childbirth

Fetal medicine and complications of pregnancy

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

In women with severe (serum Bile Acids >40 umol/L) early-onset (less than 34 weeks gestation), intrahepatic cholestasis of pregnancy, treatment with rifampicin oral tablets 300 mg twice daily up until delivery.
Adherence to treatment will be assessed by the use of a medication dosing card diary, checked at each visit.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Treatment with ursodeoxycholic acid oral tablets, initial dose 450-500 mg (depending on local availability of ursodeoxycholic acid tablets) once or twice daily as per local protocols and increasing up to a maximum of 2000 mg per day, depending on symptoms and serum bile acid concentrations, until delivery.
Adherence to treatment will be assessed by the use of a medication dosing card diary, checked at each visit.

Control group

Active

Outcomes

Primary outcome [1]

Change in pruritus score, using a 100mm visual analogue scale

Timepoint [1]

One week after trial entry, monthly thereafter, if randomised prior to 24 weeks gestation, and then weekly from 24 weeks gestation until delivery (primary timepoint)

Secondary outcome [1]

Change in serum autotaxin

Timepoint [1]

One week after trial entry, monthly thereafter, if randomised prior to 24 weeks gestation, and then weekly from 24 weeks gestation until delivery, and then finally at 6 weeks post partum.

Secondary outcome [2]

Change in serum progesterone sulphated metabolites

Timepoint [2]

One week after trial entry, monthly thereafter, if randomised prior to 24 weeks gestation, and then weekly from 24 weeks gestation until delivery, and then finally at 6 weeks post partum

Secondary outcome [3]

Changes in urinary glucuronidated 6a-hydroxylated bile acids

Timepoint [3]

One week after trial entry, monthly thereafter, if randomised prior to 24 weeks gestation, and then weekly from 24 weeks gestation until delivery, and then finally at 6 weeks post partum

Secondary outcome [4]

Changes in maternal and neonatal stool microbiome/metabolome

Timepoint [4]

One week after trial entry, monthly thereafter, if randomised prior to 24 weeks gestation, and then weekly from 24 weeks gestation until delivery, and then finally at 1 and 6 weeks post partum

Eligibility

Key inclusion criteria

Pregnant women more than 14 weeks and less than 34 weeks gestation with serum bile acids >=40 umol/L
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

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

A decision has already been made for delivery within the next 48 hours
Allergy to any component of the UDCA or Rifampicin tablets
Multi-fetal gestation
Laboratory-confirmed active hepatitis A or hepatitis B or carriage of hepatitis C,
Current pre-eclampsia
A known primary hepatic disorder, including alpha-1-antitrypsin deficiency and autoimmune liver disease, including primary biliary cholangitis, but NOT any of asymptomatic cholelithiasis, a known genetic disorder of bile acid transport, or gestational diabetes
Current medication causing deranged liver enzymes
Previous participation in TURRIFIC

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

central randomisation by computer with telephone back up

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Minimisation algorithms will be used to ensure balance between the groups with respect to the collaborating centre, gestational age at randomisation (less than 30 weeks gestation, 30+0 to 31+6 weeks gestation, 32+0-33+6 weeks gestation), and highest serum BA concentration prior to initial randomisation (less than 100 µmol/L, greater than or equal to 100 µmol/L).

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

All women who develop steatorrhoea will be offered treatment with oral vitamin K tablets (10mg daily).
Women who do not wish their baby to be given parenteral vitamin K at birth will be excluded from the trial.

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

108 women are required to have a 90% chance of detecting, as significant at the 5% level, a decrease in maternal itch score from -16 mm in the UDCA group to -23 mm in the RIF group, (with a standard deviation of 10 mm across both arms and a correlation between baseline and follow-up measurements), allowing for a 5% drop out in each arm.

The results of the trial will be analysed according to the intention to treat principle.

Demographic and clinical data will be summarised with counts and percentages for categorical variables, means (standard deviations) for normally distributed continuous variables and medians (with interquartile or simple ranges) for other continuous variables.

For the primary outcome, the effectiveness of the interventions will be assessed by calculating a risk ratio (RR) with 95% confidence intervals (CI), determined with a log-binomial model.

All comparative analyses will be performed adjusting for stratification variables and baseline measures of the outcome where relevant. Binary outcomes will be analysed using log binomial regression models. Results will be presented as adjusted risk ratios plus 95% CI. If the model is unstable, log Poisson regression models with robust variance estimation will be used. Continuous outcomes will be analysed using linear regression models and results will be presented as adjusted differences in means (with 95% CI). Analysis of outcomes that are measured repeatedly over time (severity of itch and biochemistry measures) will use repeated measures analysis techniques, including generalised estimating equations (GEEs) and/or random effects.Pre-specified subgroup analyses will use the statistical test of interaction and where appropriate, results will be presented as risk ratios with 95% confidence intervals, and the number needed to treat to benefit or harm calculated. Pre- specified subgroups will be based on:
• Serum BA at baseline (<100µmol/L, >=100µmol/L).
• Site

Missing data as a result of women or babies being lost to follow-up are expected to be minimal. A sensitivity analysis will be conducted on the primary outcome and multiple imputation by the fully conditional specification (chained equations) method will be used to impute missing outcome data.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

11/09/2019

Actual

30/10/2019

Date of last participant enrolment

Anticipated

30/08/2022

Actual

Date of last data collection

Anticipated

28/02/2023

Actual

Sample size

Target

108

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

Womens and Childrens Hospital - North Adelaide

Recruitment hospital [2]

The Canberra Hospital - Garran

Recruitment hospital [3]

King Edward Memorial Hospital - Subiaco

Recruitment hospital [4]

Royal North Shore Hospital - St Leonards

Recruitment hospital [5]

Royal Hospital for Women - Randwick

Recruitment hospital [6]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [7]

Mercy Hospital for Women - Heidelberg

Recruitment hospital [8]

Monash Medical Centre - Clayton campus - Clayton

Recruitment postcode(s) [1]

5006 - North Adelaide

Recruitment postcode(s) [2]

2605 - Garran

Recruitment postcode(s) [3]

6008 - Subiaco

Recruitment postcode(s) [4]

2065 - St Leonards

Recruitment postcode(s) [5]

2031 - Randwick

Recruitment postcode(s) [6]

4029 - Herston

Recruitment postcode(s) [7]

3084 - Heidelberg

Recruitment postcode(s) [8]

3168 - Clayton

Recruitment outside Australia

Country [1]

United Kingdom

State/province [1]

London, Nottingham

Country [2]

Netherlands

State/province [2]

Amsterdam

Country [3]

Sweden

State/province [3]

Gothenburg

Country [4]

Finland

State/province [4]

Helsinki, Turku

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

MRFF/NHMRC

Address [1]

National Health and Medical Research Council
GPO Box 1421.
Canberra
ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

University of Adelaide

Address

Adelaide,
SA 5005

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Women's and Children's Hospital Network HREC

Ethics committee address [1]

72 King William Road
North Adelaide
SA 5006

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/03/2018

Approval date [1]

29/08/2018

Ethics approval number [1]

HREC/18/WCHN/36

Summary

Brief summary

Severe early-onset intrahepatic cholestasis of pregnancy (ICP), a recognised rare disease of pregnancy, is associated with increased rates of stillbirth, preterm birth and neonatal morbidity. The optimal treatment and management of women who are diagnosed with this condition are not known. We plan to compare a standard treatment used for cholestatic itch outside pregnancy (rifampicin) with a standard treatment of ICP (ursodeoxycholic acid - UDCA) to determine comparative safety and efficacy.

Trial website

Not current

Trial related presentations / publications

None to date

Public notes

Contacts

Principal investigator

Name

Prof William "Bill" Martin Hague

Address

Obstetric Medicine
University Department of Obstetrics
Women's and Children's Hospital
72 King William Road
North Adelaide
SA 5006

Country

Australia

Phone

+61 41 111 4575

Fax

+61 8 8161 7652

[email protected]

Contact person for public queries

Name

Suzette Coat

Address

Robinson Research Institute
University of Adelaide
55 King William Road
North Adelaide
SA 5006

Country

Australia

Phone

+61 8 8313 1338

Fax

+61 8 8161 7652

[email protected]

Contact person for scientific queries

Name

William "Bill" Hague

Address

Obstetric Medicine
University Department of Obstetrics
Women's and Children's Hospital
72 King William Road
North Adelaide
SA 5006

Country

Australia

Phone

+61 41 111 4575

Fax

+61 8 8161 7652

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Baseline Characteristics: including demographics, including age and study-specific measures for all participants, after de-identification.
Outcome data: all of the individual participant data collected during the trial, after de-identification

When will data be available (start and end dates)?

Beginning 3 months following main results publication; no end date determined

Available to whom?

To researchers who provide a methodologically sound proposal, and on a case-by-case basis at the discretion of Primary Sponsor.

Available for what types of analyses?

For IPD meta-analyses.

How or where can data be obtained?

Access subject to approvals by Principal Investigator ([email protected]).

What supporting documents are/will be available?

Doc. No.	Type	Email	Attachment
1191	Study protocol	[email protected]
1192	Informed consent form	[email protected]	374510-(Uploaded-23-07-2019-18-53-26)-Study-related document.pdf
1193	Ethical approval	[email protected]	374510-(Uploaded-23-07-2019-18-56-32)-Study-related document.pdf
3393	Statistical analysis plan	[email protected]
3394	Clinical study report	[email protected]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.	2021	https://dx.doi.org/10.1186/s12884-020-03481-y

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically