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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] 294051 0
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 306601 0
Condition category
Condition code
Reproductive Health and Childbirth 305695 305695 0 0
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] 300326 0
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] 304785 0
Change in pruritus score, using a 100mm visual analogue scale
Timepoint [1] 304785 0
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] 343169 0
Change in serum autotaxin
Timepoint [1] 343169 0
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] 351315 0
Change in serum progesterone sulphated metabolites
Timepoint [2] 351315 0
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] 351316 0
Changes in urinary glucuronidated 6a-hydroxylated bile acids
Timepoint [3] 351316 0
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] 351317 0
Changes in maternal and neonatal stool microbiome/metabolome
Timepoint [4] 351317 0
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
Gender
Females
Can healthy volunteers participate?
No
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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 10012 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 10013 0
The Canberra Hospital - Garran
Recruitment hospital [3] 10014 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [4] 10015 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 10016 0
Royal Hospital for Women - Randwick
Recruitment hospital [6] 10017 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 10018 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [8] 10019 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 19338 0
5006 - North Adelaide
Recruitment postcode(s) [2] 19339 0
2605 - Garran
Recruitment postcode(s) [3] 19340 0
6008 - Subiaco
Recruitment postcode(s) [4] 19341 0
2065 - St Leonards
Recruitment postcode(s) [5] 19342 0
2031 - Randwick
Recruitment postcode(s) [6] 19343 0
4029 - Herston
Recruitment postcode(s) [7] 19344 0
3084 - Heidelberg
Recruitment postcode(s) [8] 19345 0
3168 - Clayton
Recruitment outside Australia
Country [1] 9584 0
United Kingdom
State/province [1] 9584 0
London, Nottingham
Country [2] 9585 0
Netherlands
State/province [2] 9585 0
Amsterdam
Country [3] 9586 0
Sweden
State/province [3] 9586 0
Gothenburg
Country [4] 20818 0
Finland
State/province [4] 20818 0
Helsinki, Turku

Funding & Sponsors
Funding source category [1] 298676 0
Government body
Name [1] 298676 0
MRFF/NHMRC
Address [1] 298676 0
National Health and Medical Research Council
GPO Box 1421.
Canberra
ACT 2601
Country [1] 298676 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
Adelaide,
SA 5005
Country
Australia
Secondary sponsor category [1] 297847 0
None
Name [1] 297847 0
Address [1] 297847 0
Country [1] 297847 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299630 0
Women's and Children's Hospital Network HREC
Ethics committee address [1] 299630 0
72 King William Road
North Adelaide
SA 5006
Ethics committee country [1] 299630 0
Australia
Date submitted for ethics approval [1] 299630 0
28/03/2018
Approval date [1] 299630 0
29/08/2018
Ethics approval number [1] 299630 0
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 81098 0
Prof William "Bill" Martin Hague
Address 81098 0
Obstetric Medicine
University Department of Obstetrics
Women's and Children's Hospital
72 King William Road
North Adelaide
SA 5006
Country 81098 0
Australia
Phone 81098 0
+61 41 111 4575
Fax 81098 0
+61 8 8161 7652
Email 81098 0
bill.hague@adelaide.edu.au
Contact person for public queries
Name 81099 0
Dr Suzette Coat
Address 81099 0
Robinson Research Institute
University of Adelaide
55 King William Road
North Adelaide
SA 5006
Country 81099 0
Australia
Phone 81099 0
+61 8 8313 1338
Fax 81099 0
+61 8 8161 7652
Email 81099 0
suzette.coat@adelaide.edu.au
Contact person for scientific queries
Name 81100 0
Prof William "Bill" Hague
Address 81100 0
Obstetric Medicine
University Department of Obstetrics
Women's and Children's Hospital
72 King William Road
North Adelaide
SA 5006
Country 81100 0
Australia
Phone 81100 0
+61 41 111 4575
Fax 81100 0
+61 8 8161 7652
Email 81100 0
bill.hague@adelaide.edu.au

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 (bill.hague@adelaide.edu.au).
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
How or where can supporting documents be obtained?
Type [1] 1191 0
Study protocol
Citation [1] 1191 0
Link [1] 1191 0
Email [1] 1191 0
bill.hague@adelaide.edu.au
Other [1] 1191 0
Attachment [1] 1191 0
Type [2] 1192 0
Informed consent form
Citation [2] 1192 0
Link [2] 1192 0
Email [2] 1192 0
bill.hague@adelaide.edu.au
Other [2] 1192 0
Type [3] 1193 0
Ethical approval
Citation [3] 1193 0
Link [3] 1193 0
Email [3] 1193 0
bill.hague@adelaide.edu.au
Other [3] 1193 0
Type [4] 3393 0
Statistical analysis plan
Citation [4] 3393 0
Link [4] 3393 0
Email [4] 3393 0
bill.hague@adelaide.edu.au
Other [4] 3393 0
Attachment [4] 3393 0
Type [5] 3394 0
Clinical study report
Citation [5] 3394 0
Link [5] 3394 0
Email [5] 3394 0
bill.hague@adelaide.edu.au
Other [5] 3394 0
Attachment [5] 3394 0
Summary results
No Results