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Trial registered on ANZCTR


Registration number
ACTRN12620000755932
Ethics application status
Approved
Date submitted
20/05/2020
Date registered
22/07/2020
Date last updated
22/07/2020
Date data sharing statement initially provided
22/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The impact of assessing and treating bile acid malabsorption on function and quality of life in patients with major Low Anterior Resection Syndrome (LARS).
Scientific title
A prospective randomised controlled study on the impact of assessing and treating bile acid malabsorption with colesevelam therapy on function and quality of life in patients with major Low Anterior Resection Syndrome (LARS)
Secondary ID [1] 301338 0
none
Universal Trial Number (UTN)
U1111-1221-6037
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Low Anterior Resection 317542 0
Bile Salt Malabsorption 317543 0
High anterior resection 317744 0
Ultra-low anterior resection 317745 0
Rectal cancer 317746 0
Colorectal cancer 317747 0
Condition category
Condition code
Cancer 315632 315632 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Surgery 315633 315633 0 0
Other surgery
Oral and Gastrointestinal 315813 315813 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
This is a prospective randomised controlled study comparing colesevelam therapy with placebo in a two-period cross-over design, where patients will act as their own controls. Radiological testing for Bile acid malabsorption (BAM) will be performed in a subset of participants prior to the intervention being administered. We aim to test at least half of the participants, but this will be determined by funding and access to radiology. We anticipate that 3-15 patients will undergo this test. Selection will be based on the test being available when the individual is recruited.
The SeHCAT test involves administering 75Se 23-selena-25-homocholic acid and glycocholic acid as an oral capsule to a fasting patient. The initial count rate of 75Se will be measured three hours after the intake of the isotope. On day 7 following administration, there will be further imaging, and the net count rate of 75Se will be expressed as a percentage of the net count rate at day 0. The % retention of 75Se will be recorded. While a positive test is one that shows a retention <15%, the actual levels of 75Se will also be compared to changes in the LARS score.

A 2-sequence, 2-period design will be used with a six-week washout between interventions to account for first-order carryover effects. Participants will be randomised to one of the following sequences: AB|BA, where A=colesevelam therapy and B=placebo.

The intervention will be presented as 312mg capsules. The participant will start by taking two capsules (approximately 625mg) three times a day for three days, and if there are no side effects will then increase to four capsules (1.25g) three times a day. Side effects will be monitored by use of a daily patient diary and telephone interviews on days one and three. Patients will also be encouraged to contact the researcher if they experience any potential side effects. If after 3 days there are side effects, participants will then be dosed down to two capsules four times a day for 3 days, and then reduce down to two capsules three times a day for the remainder of the 35 days. This will be monitored through the use of the diary and telephone contact (Days 5,7,14, 21, 28, and 35). Participants will be advised to take the capsules with a full cup of water or juice, and to take the capsules at least two hours before or after taking any other medications. The capsules (colesevelam in the intervention arm) will be taken for 35 days, and adherence will be monitored through the use of the diary and drug tablet return if not taken. Following this, there will be a washout period of six weeks, after which the participants will then proceed to another five week period with the alternative treatment.
After the first five-week period, there will be a washout period of six weeks. Patients will then receive alternative treatment for the next five weeks. The LARS score and quality of life measures: the short form 12 Health Survey (SF-12), and faecal incontinence QoL (FiQL) with be assessed prior to and immediately following each treatment period. Participants will keep a stool diary during the treatment and washout periods. Both the participants and assessors will be blinded to treatment with colesevelam or placebo.
Intervention code [1] 317633 0
Treatment: Drugs
Comparator / control treatment
The intervention will be presented as 312mg microcellulose capsules. The participant will start by taking two capsules (approximately 625mg) three times a day for three days, and if there are no side effects will then increase to four capsules (1.25g) three times a day. If they develop side effects on the full therapeutic dose, they will then reduce the dose to two capsules four times a day and then if necessary back to two capsules three times a day. Participants will be advised to take the capsules with a full cup of water or juice, and to take the capsules at least two hours before or after taking any other medications. The capsules (placebo ) will be taken for 35 days. Adherence will be monitored through the use of the diary and drug tablet return if not taken. Following this, there will be a washout period of six weeks, after which the participants will then proceed to another five week period with the alternative treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 323868 0
Low Anterior Resection Syndrome (LARS) Score, from a validated questionnaire. This questionnaire will be administered in Dunedin Hospital by a research assistant before and after each treatment.
Timepoint [1] 323868 0
LARS score will be measured prior to commencement of the first treatment, at the end of the first 5-week treatment phase, prior to commencement of the second treatment (approximately 11 weeks post-enrollment), and at the end of the second 5-week treatment phase.
Primary outcome [2] 323869 0
Short-form 12 Health Survey, a quality of life questionnaire. This questionnaire will be administered in Dunedin Hospital by a research assistant before and after each treatment.
Timepoint [2] 323869 0
Quality of life will be measured prior to commencement of the first treatment, at the end of the first 5-week treatment phase, prior to commencement of the second treatment (approximately 11 weeks post-enrollment), and at the end of the second 5-week treatment phase.
Primary outcome [3] 323870 0
Faecal Incontinence Quality of Life Score. This will be administered at Dunedin Hospital by a research assistant.
Timepoint [3] 323870 0
Quality of life will be measured prior to commencement of the first treatment, at the end of the first 5-week treatment phase, prior to commencement of the second treatment (approximately 11 weeks post-enrollment), and at the end of the second 5-week treatment phase.
Secondary outcome [1] 383091 0
The number of bowel motions per day during treatment: A stool diary will be used by the participant to document the number of episodes of bowel motion experienced by the participants per day. A space for making any other comments about abdominal symptoms and bowel function will be included. The stool diary will be completed by the participant at home.
Timepoint [1] 383091 0
During each week of the study, 16 weeks total
Secondary outcome [2] 383092 0
Adverse events. An adverse event (AE) is any untoward medical event affecting a clinical trial participant including where the occurrence does not necessarily have a causal relationship with the intervention. This may include symptoms associated with the disease or disorder under study, which are more severe than expected. Placebo-controlled clinical studies have shown that the following adverse reactions are more common in patients with following administration of Colesevelam when compared with placebo: Constipation (11% of patients), dyspepsia (8.3% of patients), nausea (4.2% of patients), accidental injury (3.7% of patients), asthenia (3.6 % of patients), pharyngitis (3.2 % of patients), flu syndrome (3.2 % of patients), rhinitis (3.2 % of patients), myalgia (2.1% of patients). Colesevelam is only active in the gut, and the symptoms are primarily functional GI problems that will be self-reported, and captured by diary and telephone calls by a research assistant on days 1,3,5,7,14, 21, 28, and 35 after starting the treatment in each period.
However, Colesevelam can interact with Warfarin, decreased absorption. This will be managed proactively (ie If patients are on warfarin, we will check blood levels of INR at 2 and 4 weeks).
Timepoint [2] 383092 0
Adverse events will be recorded as they occur from the first study visit until the last study visit 16 weeks after enrollment.
Secondary outcome [3] 383093 0
Retention of radioisotope 75 Se after radiological testing, which indicates bile acid malabsorption. The initial count rate of 75Se will be measured three hours after the intake of the isotope. On day 7 following administration, there will be further imaging, and the net count rate of 75Se will be expressed as a percentage of the net count rate at day 0. The % retention of 75Se will be recorded.
Timepoint [3] 383093 0
The SeHCAT test will be performed at baseline and 7 days, and assessed only once, before the commencement of any study medication.

Eligibility
Key inclusion criteria
1) Surgery at Dunedin Hospital for rectal cancer between 1999-2015.
2) Surgery includes an anterior resection (High anterior resection, Low anterior resection or ultralow anterior resection).
3) Bowel continuity has been re-established.
4) Major LARS score as determined by a LARS score of 30-42.
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Age >85 years
2) Participant too unwell to answer questionnaires (for example is known to have dementia).
3) Patients who have a stoma. This includes those who had an abdominoperineal excision or a Hartmann’s procedure and those who have a loop ileostomy which has not been reversed.
4) Identified allergy to colesevelam.

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)
The study drug containers will contain a unique study identification number, which corresponds to the patient’s allocation. Only the pharmacy will hold allocation information and be responsible for providing study medication. In the event of a clinical emergency where allocation must be identified, the information will be obtainable from the external pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Screened patients who consent to be involved in this study will be randomised equally to the 2 sequences of this crossover study. We will use a computer-based random number generator to determine the patient’s study group.
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
This is a two-period crossover study
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Patient demographics will be assessed using descriptive statistics. Continuous variables will be reported as mean with standard deviation or as median with inter-quartile range depending on the distribution of results. Categorical variables will be reported as frequency (%).

FIQL and SF-12 baseline scores will be compared with post-treatment scores using paired t or Wilcoxon tests depending on the distribution of the data.

LARS scores will be analysed using mixed effects linear models to assess the effect of treatment. This will account for the repeated measurements that include sequence and carryover effects, as well as sources of intra-patient and inter-patient variability. Statistical significance will be set at p<0.05.

Recruitment
Recruitment status
Not yet 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 outside Australia
Country [1] 22564 0
New Zealand
State/province [1] 22564 0
Otago

Funding & Sponsors
Funding source category [1] 305771 0
Government body
Name [1] 305771 0
Lottery Health Research Grants Board
Address [1] 305771 0
The Department of Internal Affairs: Community Operations
Level One, Bloomfield House
46-50 Bloomfield Terrace
LOWER HUTT 5042
Country [1] 305771 0
New Zealand
Funding source category [2] 305772 0
Charities/Societies/Foundations
Name [2] 305772 0
Health Care Otago Charitable Trust
Address [2] 305772 0
The Healthcare Otago Charitable Trust, P.O. Box 5848 Dunedin 9016
Country [2] 305772 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
201 Great King Street, Dunedin, New Zealand 9016
Country
New Zealand
Secondary sponsor category [1] 306209 0
Hospital
Name [1] 306209 0
Dunedin Hospital
Address [1] 306209 0
201 Great King Street, Dunedin, New Zealand 9016
Country [1] 306209 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306045 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 306045 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 306045 0
New Zealand
Date submitted for ethics approval [1] 306045 0
02/12/2019
Approval date [1] 306045 0
11/04/2020
Ethics approval number [1] 306045 0
19/CEN/209

Summary
Brief summary
Title: A prospective randomised controlled study on the impact of treating bile acid malabsorption on Function and Quality of Life in patients with major Low Anterior Resection Syndrome (LARS)

Participants: Patients who have had an anterior resection for rectal cancer between 1999 and 2018, have major LARS, live in the Dunedin area, and are aged less than or equal to 85 yrs.

Sample Size: 45 patients

Planned Study Duration: We will conduct the study over a 6-month period.

In this study, our primary objective is to determine the response to treatment for BAM in patients with major LARS. We will do this by performing a double-blinded cross-over study of treatment for BAM with colesevelam while measuring changes to the LARS score and to QoL. Our secondary objective is to assess if testing for BAM in patients with major LARS after rectal cancer surgery is helpful, both in terms of reliably measuring the prevalence of BAM and predicting response to treatment. To do this, we will test for BAM with the SeHCAT test in a subset of patients. At the completion of the study, we will assess if the test results predicted the actual responses to treatment with colesevelam as measured by changes in the LARS score.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102530 0
Dr John Woodfield
Address 102530 0
Dunedin School of Medicine
University of Otago
201 Great King Street
Dunedin 9016
Country 102530 0
New Zealand
Phone 102530 0
+64 34740999
Fax 102530 0
Email 102530 0
john.woodfield@otago.ac.nz
Contact person for public queries
Name 102531 0
Dr John Woodfield
Address 102531 0
Dunedin School of Medicine
University of Otago
201 Great King Street
Dunedin 9016
Country 102531 0
New Zealand
Phone 102531 0
+64 34740999
Fax 102531 0
Email 102531 0
john.woodfield@otago.ac.nz
Contact person for scientific queries
Name 102532 0
Dr John Woodfield
Address 102532 0
Dunedin School of Medicine
University of Otago
201 Great King Street
Dunedin 9016
Country 102532 0
New Zealand
Phone 102532 0
+64 34740999
Fax 102532 0
Email 102532 0
john.woodfield@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The population of patients is small and localised. It may be possible to identify participants based on their demographic and clinical details.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
Analytic code
How or where can supporting documents be obtained?
Type [1] 8016 0
Study protocol
Citation [1] 8016 0
We intend to publish the protocol. Until publication, a copy can be obtained from the corresponding investigator
Link [1] 8016 0
Email [1] 8016 0
john.woodfield@otago.ac.nz
Other [1] 8016 0
Attachment [1] 8016 0
Type [2] 8017 0
Statistical analysis plan
Citation [2] 8017 0
A copy of the statistical analysis plan can be obtained from the corresponding investigator
Link [2] 8017 0
Email [2] 8017 0
john.woodfield@otago.ac.nz
Other [2] 8017 0
Attachment [2] 8017 0
Type [3] 8018 0
Informed consent form
Citation [3] 8018 0
A copy of the informed consent form can be obtained by the corresponding investigator.
Link [3] 8018 0
Email [3] 8018 0
john.woodfield@otago.ac.nz
Other [3] 8018 0
Attachment [3] 8018 0
Type [4] 8019 0
Ethical approval
Citation [4] 8019 0
Ethical approval is attached
Link [4] 8019 0
Email [4] 8019 0
john.woodfield@otago.ac.nz
Other [4] 8019 0
Type [5] 8020 0
Analytic code
Citation [5] 8020 0
A copy of the analytic code can be obtained from the corresponding investigator.
Link [5] 8020 0
Email [5] 8020 0
john.woodfield@otago.ac.nz
Other [5] 8020 0
Attachment [5] 8020 0
Summary results
No Results