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Trial registered on ANZCTR


Registration number
ACTRN12621000450819
Ethics application status
Approved
Date submitted
30/01/2021
Date registered
19/04/2021
Date last updated
22/04/2024
Date data sharing statement initially provided
19/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
ULTRA Pain Study - Ursodeoxycholic acid in Low Phospholipid Associated Cholelithiasis (LPAC) Treating Recurrent Abdominal Pain Study
Scientific title
ULTRA Pain Study - Investigating the effectiveness of Ursodeoxycholic acid on Recurrent Abdominal Pain in adults with Low Phospholipid Associated Cholelithiasis (LPAC)
Secondary ID [1] 303307 0
Nil Known
Universal Trial Number (UTN)
U1111-1264-4951
Trial acronym
ULTRA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Low Phospholipid Associated Cholelithiasis 320521 0
Post cholecystectomy pain 320522 0
Condition category
Condition code
Oral and Gastrointestinal 318382 318382 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ursodeoxycholic acid capsules orally starting at 10mg/kg daily with the ability to be increased to a maximum of 20mg/kg daily at the treating clinician's discretion if the participant is continuing to experience biliary pain. In the event of diarrhoea, ursodeoxycholic acid can be down titrated to 5mg/kg and slowly increased as tolerated. Cross-over trial design. Duration is for 1 year (52 weeks) each for ursodeoxycholic acid and placebo. The wash out period is 2 weeks. Adherence is monitored by the Clinical Trials Pharmacy Department who will monitor unused capsules.
Intervention code [1] 319607 0
Treatment: Drugs
Comparator / control treatment
Placebo - hard white inert gelatin capsule consisting of Maize Starch and Pregelatinised Maize Starch.
Control group
Placebo

Outcomes
Primary outcome [1] 326359 0
Number of episodes of biliary pain. This will be assessed by study-specific questionnaire.
Timepoint [1] 326359 0
3, 6, 9, 12, 15, 18, 21, 24 months (Primary timepoint) post-commence of intervention

Secondary outcome [1] 391172 0
RAPID (Recurrent Abdominal Pain Intensity and Disability) score
Timepoint [1] 391172 0
3, 6, 9, 12, 15, 18, 21, 24 months post-commence of intervention
Secondary outcome [2] 391173 0
Hospital Anxiety and Depression Scale (HADS)
Timepoint [2] 391173 0
12 and 24 months post-commencement of intervention
Secondary outcome [3] 391174 0
Quality of life: SF-36
Timepoint [3] 391174 0
3, 6, 9, 12, 15, 18, 21, 24 months post-commence of intervention
Secondary outcome [4] 391175 0
Quality of life: EQ-5D-5L
Timepoint [4] 391175 0
3, 6, 9, 12, 15, 18, 21, 24 months post-commence of intervention
Secondary outcome [5] 391176 0
Change in liver ultrasound findings
Timepoint [5] 391176 0
12 and 24 months post-commencement of intervention
Secondary outcome [6] 391177 0
Opioid use via study-specific questionnaire
Timepoint [6] 391177 0
3, 6, 9, 12, 15, 18, 21, 24 months post-commence of intervention
Secondary outcome [7] 391178 0
Number of Hospitalisations via study-specific questionnaire and data-linkage to medical records
Timepoint [7] 391178 0
3, 6, 9, 12, 15, 18, 21, 24 months post-commence of intervention
Secondary outcome [8] 391179 0
Adverse events via study-specific questionnaire and data-linkage to medical records. Events of interest are: diarrhoea, pruritis, urticaria, nausea, vomiting, sleep disturbance, hospitalisations.
Timepoint [8] 391179 0
3, 6, 9, 12, 15, 18, 21, 24 months post-commence of intervention

Eligibility
Key inclusion criteria
1) Patients aged greater than 18 years with a previous cholecystectomy with more than 2 episodes of biliary pain in the last 12 months.
Characteristics of biliary pain as defined by the Rome IV criteria:
• Pain located in the epigastrium and/or right upper quadrant and all of the following:
o 1. Builds up to a steady level and lasting 30 minutes or longer.
o 2. Occurring at different intervals (not daily).
o 3. Severe enough to interrupt daily activities or lead to an emergency department visit.
o 4. Not significantly (<20%) related to bowel movements.
o 5. Not significantly (<20%) relieved by postural change or acid suppression.
Supportive Criteria
The pain may be associated with:
o 1. Nausea and vomiting.
o 2. Radiation to the back and/or right infrasubscapular region.
o 3. Waking from sleep.
2) At least 2 additional features of:
a) Age less than 40 years at onset of biliary symptoms.
b) Imaging features consistent with LPAC:
o Intrahepatic echogenic foci in a position consistent with biliary tree, with either comet tail artefact, acoustic shadowing, or twinkle artefact. Echoes that have an appearance consistent with biliary gas will not qualify under this inclusion definition.
o Intrahepatic gallstones evidenced by US, CT, including CT-intravenous cholangiography, direct cholangiography, or MRCP.
o Intrahepatic strictures and dilatation typical of LPAC
c) Familial history of cholecystectomy in first-degree relatives age <40 years
d) Evidence of transiently abnormal liver function tests corresponding with episodes of biliary pain
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Stone in the common bile duct on imaging.
• Known history of primary sclerosing cholangitis, primary biliary cholangitis, colitis, Crohn’s disease, cystic fibrosis, chronic liver disease.
• Presence of significant psychiatric disorders:
o Lifetime psychotic disorders, bipolar disorder;
o Substance use disorders within 6 months;
o Eating disorders within 2 years;
o Moderate & severe depression defined BDI cutoff scores >22 (unless receiving stable psychiatric therapy for six weeks); and/or,
o Suicidal risk - a score of greater than 0 on question 9 of the BDI.
• Pregnancy: Women who are pregnant or are planning a pregnancy within 2 years at the time of screening will be excluded from the study.
• Upper endoscopy examination with significant findings to explain the pain.
• Any functional bowel disorders.
• Cholecystectomy less than 90 days before enrollment.
• Any use of regular narcotics.
• Inability to comply with study procedures and agents.
• Any significant medical illness that would interfere with study participation.
• Any condition that, in the investigator's opinion, makes the subject unsuitable for study participation.

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)
Allocation concealment via sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment assignment will be determined by a predetermined randomisation schedule (in 4 blocks of 6) created prior to study commencement by the trial statistician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
We powered this study and based our sample size calculation on the number of patients needed to assess our primary outcome: number of episodes of biliary pain per year. In our previous cohort of LPAC patients, it was noted that the mean frequency of biliary pain was 3 episodes per year, with a standard deviation (SD) of 1. Assuming that UDCA will reduce the frequency of biliary pain to a mean (SD) of 2 (1) episodes per year, 18 patients will be required to detect this between-treatment difference, with 80% power and a 2-sided alpha of 0.05. Cross-over studies typically require fewer subjects compared to parallel clinical trials given that inter-group variance is less. However, in the sample size calculation, it was conservatively assumed that inter-group variance was the same as would be observed for a parallel clinical trial. To allow for 30% drop-out in the study, a target of 24 patients will be recruited.
An intention-to-treat analysis will be performed in accordance with CONSORT guidelines to provide an assessment of the impact of the treatment.
The repeated measures Mann-Whitney test will be used for comparative analysis of the primary outcome. Categorical variables will be applied to McNemar’s chi squared test or conditional logistic regression (or McNemar’s Exact tests for small samples) while continuous variables will be applied to (parametric) paired t-tests or repeated-measures ANOVA and (non-parametric) Mann-Whitney tests for symmetrically and asymmetrically distributed data, respectively. All data analyses will be undertaken in a blinded manner by the trial statistician.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/04/2022
Actual
10/05/2022
Date of last participant enrolment
Anticipated
30/04/2025
Actual
Date of last data collection
Anticipated
30/04/2025
Actual
Sample size
Target
24
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 18525 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 32864 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 307721 0
Hospital
Name [1] 307721 0
Department of Gastroenterology Royal Melbourne Hospital
Country [1] 307721 0
Australia
Primary sponsor type
Hospital
Name
Melbourne Health
Address
The Royal Melbourne Hospital
Office for Research
Level 2 South West
Grattan Street, Parkville, VIC, 3050
Country
Australia
Secondary sponsor category [1] 308419 0
None
Name [1] 308419 0
Address [1] 308419 0
Country [1] 308419 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307748 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 307748 0
The Royal Melbourne Hospital
Office for Research
Level 2 South West
Grattan Street, Parkville, VIC, 3050
Ethics committee country [1] 307748 0
Australia
Date submitted for ethics approval [1] 307748 0
Approval date [1] 307748 0
09/01/2020
Ethics approval number [1] 307748 0

Summary
Brief summary
Low Phospholipid Associated Cholelithiasis (LPAC) is a cause of post-operative pain and recurrent gallstones after gallbladder removal (cholecystectomy). This is a randomised control trial of a medication called ursodeoxycholic acid in patients with LPAC to prevent pain post gallbladder surgery, improve quality of life, reduce hospital presentations and patient use of strong narcotic painkillers.
This trial is a crossover trial where participants will be randomised to undergo a 1 year experimental (ursodeoxycholic acid) or control arm (placebo). The experimental or control arm will be prescribed a daily dose of 10mg/kg of ursodeoxycholic acid or placebo. Participants will then undergo a 2 week washout period before crossing over to the opposite arm to complete the study. The dose will be prescribed at 10mg/kg daily and can be titrated to a maximum of 20mg/kg daily at the discretion of the treating clinician.
The primary study outcome is number of episodes of biliary pain. Secondary outcomes include quality of life, hospitalisations, liver ultrasound findings.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108362 0
A/Prof Andrew Metz
Address 108362 0
Department of Gastroenterology
Level 3 Centre
The Royal Melbourne Hospital
300 Grattan Street
Parkville, VIC, 3050
Country 108362 0
Australia
Phone 108362 0
+61 3 9342 7000
Fax 108362 0
Email 108362 0
[email protected]
Contact person for public queries
Name 108363 0
Dr Andrew Trinh
Address 108363 0
Department of Gastroenterology
Level 3 Centre
The Royal Melbourne Hospital
300 Grattan Street,
Parkville, VIC, 3050
Country 108363 0
Australia
Phone 108363 0
+61 3 93427 000
Fax 108363 0
Email 108363 0
[email protected]
Contact person for scientific queries
Name 108364 0
A/Prof Andrew Metz
Address 108364 0
Department of Gastroenterology
Level 3 Centre
The Royal Melbourne Hospital
300 Grattan Street,
Parkville, VIC, 3050
Country 108364 0
Australia
Phone 108364 0
+61 3 9342 7000
Fax 108364 0
Email 108364 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All individual participant data will be confidential


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.