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Trial registered on ANZCTR


Registration number
ACTRN12620001209987p
Ethics application status
Submitted, not yet approved
Date submitted
15/10/2020
Date registered
13/11/2020
Date last updated
13/11/2020
Date data sharing statement initially provided
13/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Dose Determination and Safety Evaluation of the Gastrointestinal ReProgramming (GaRP) Dietary supplement in diarrhoea predominant Irritable Bowel Syndrome patients
Scientific title
Dose Determination and Safety Evaluation of the Gastrointestinal ReProgramming (GaRP) Dietary supplement in IBS-D patients: An adaptive, phase 1/2, Randomized, Double-blind, Placebo-controlled virtual clinical trial
Secondary ID [1] 302540 0
ANR-GARP-001
Universal Trial Number (UTN)
U1111-1259-5826
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Irritable Bowel Syndrome - diarrhoea predominant 319410 0
Condition category
Condition code
Oral and Gastrointestinal 317382 317382 0 0
Inflammatory bowel disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Dosed with oral GaRP equivalent to 240 mg of bromelain twice a day for 8 weeks
Arm 2: Dosed with oral GaRP equivalent to 480 mg of bromelain twice a day for 8 weeks.

Participants will record the time of dosage in their electronic diaries. All unused product will be returned at the completion of the trial for reconciliation.
Intervention code [1] 318826 0
Treatment: Drugs
Comparator / control treatment
Arm 3 : Dosed with oral matching placebo twice a day for 8 weeks
The placebo will be comprised of microcrystalline cellulose coated in the same enteric coating as the treatment
Control group
Placebo

Outcomes
Primary outcome [1] 325418 0
The number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0

The individual components are recognised as generally safe, however it is possible that adverse events could occur from the mixture of the components together. Some side effects of the components of this supplement in the literature include : flatulence, nausea/vomiting, diarrhoea, epigastric pain/heartburn, allergic rash, dizziness, obstipation (severe constipation), meteorism (swollen abdomen), headache, throat irritation/ oro-pharyngeal pain, dyspepsia, dry mouth, loss of appetite, increased thirst and increased urination
Timepoint [1] 325418 0
Baseline to EOT 8 weeks
Primary outcome [2] 325419 0
To review incidence, nature, severity, relatedness, expectedness and outcome of adverse events. Haematology and blood chemistry assessments and vital signs.

composite primary outcome
Timepoint [2] 325419 0
Baseline to EOT 8 weeks

Blood samples and vital signs taken at baseline and , Day 56
Secondary outcome [1] 387886 0
Change in IBS QoL points compared to baseline measured at days 14, 28, 42 and 56 post-baseline. A participant is considered a responder if there is a decrease of greater than 10 points at any measured timepoint.
Timepoint [1] 387886 0
Baseline , 14, 28, 42 and 56 days post-baseline.
Secondary outcome [2] 387887 0
Number of participants who achieve the following IBS-SSS scale scores :
o <75 points on the IBS-SSS scale
o 75-175 points on the IBS-SSS scale
o 175-225 points on the IBS-SSS scale
o 225 -300 points on the IBS-SSS scale
o >300 points on the IBS-SSS scale
Timepoint [2] 387887 0
Days 7, 14, 28, 42 and 56:
Secondary outcome [3] 387888 0
Stool consistency (IBS-D) using the Bristol Stool Form Scale
Timepoint [3] 387888 0
measured at baseline and daily until end of the treatment (day 56)
Secondary outcome [4] 387889 0
IBS Adequate Relief (IBS-AR) asking “In the last 7 days, have you had adequate relief of your IBS symptoms?” compared to baseline. A participant is considered a responder if they answer “yes”. Comparison using the difference between baseline and weekly measurements until Day 56 post commencement of intervention.
.
Timepoint [4] 387889 0
weekly for 8 weeks
Secondary outcome [5] 387890 0
Hospital Anxiety and Depression (HAD) Scale comparing to baseline.
Timepoint [5] 387890 0
Baseline, day 56
Secondary outcome [6] 387891 0
Safety markers - Serum Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline phosphatase (ALP), Gamma-glutamyl transpeptidase (GGT) and full blood count via blood test measured
Timepoint [6] 387891 0
Baseline, day 56,

Eligibility
Key inclusion criteria
Patients who:
• Have irritable bowel syndrome with a moderate IBS-SSS score of 175-300 as assessed by the IBS-SSS questionnaire.
• Have IBS-D as defined by Rome IV including Subtype Classification:
• recurrent abdominal pain on average at least 1 day/week in the last three months associated with two or more of the following:
o Related to defecation
o Associated with a change in frequency of stool
o Associated with a change in form of stool
• During the time when the Rome IV criteria for IBS were met, the patient had at least 25% of bowel movements with Bristol stool types 6 or 7.
• Have abdominal pain intensity where the weekly average of worst daily (in past 24 hours) abdominal pain score is > 30 on a 0 to 100-point scale for each of the two baseline weeks
• Have at least one stool with a consistency of Type 6 or Type 7 Bristol stool score (BSS) on at least 2 days of each of the baseline weeks
• Agree not to make significant changes to their diet or exercise routines during the study.
• If a women of child-bearing potential, agrees to use an acceptable method of birth control (true abstinence, birth control pills, injections or contraceptive implants) while on treatment and following completion of 2 menstrual cycles or 2 months after the last dose of study treatment, and if male a barrier method of birth control from randomisation until the Follow- Up visit.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants who
• Have a body mass index of <18 or >29.9kg/m2.
• Have a significant acute or chronic coexisting illness (psychiatric, gastrointestinal, endocrine, immunological)or any condition which contraindicates, in the investigator’s judgement, entry to the study.
o Participants who have ‘alarm symptoms’ (e.g., unexplained weight loss, family history of colon cancer or inflammatory bowel disease, or rectal bleeding) may be eligible if organic pathology is excluded by a detailed work-up prior to enrolling the participant.
• Have confirmed clinical diagnosis of bile acid diarrhoea and/or are on medication for bile acid diarrhoea.
• Currently have, or have a history of, a diagnosed disease(s) with abdominal symptoms that can resemble IBS
• Currently have, or have a history of, inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease), or have a faecal calprotectin level of >50 ug/g at enrolment or c-reactive protein level of >5.0mg/ml.
• Have diagnosed coeliac disease
• Have had previous abdominal surgery (excluding laparoscopic cholecystectomy, appendectomy, hysterectomy, and hernia repair).
• Have radiation proctitis or other known poorly controlled medical conditions that could interfere with bowel function.
• Have a malignant disease (other than localised skin cancers) or any concomitant end-stage organ failure
• In the opinion of the investigator, are poor attendees or unlikely for any reason to be able to comply with the study requirements.
• Are currently, or in the past 30 days have been, enrolled in another investigational device or drug study(s), or are currently receiving other investigational agent(s)
• Have used systemic steroids or antibiotics within the past month
• Are taking narcotics (eg., tramadol, codeine, morphine,)
• Have changed their diet routine, e.g. FODMAP, gluten-free, within the past month.
• Have started taking probiotics within the past month.
• Have chronic drug therapy that interferes with vitamin D metabolism, such as glucocorticoids, or chronic disease such as renal failure, liver disease, epilepsy or diabetes mellitus.
• Have experienced a cardiovascular event such as a congestive heart failure, heart attack, stroke, or angina (chest pain) in the past 3 months
• Require concomitant treatment during screening/baseline period with any medication that could influence the gastrointestinal tract e.g. Imodium
• Have planned investigational procedures while participating in this study that would interfere with normal food intake or influence abdominal symptoms.
• Have known current infection with HIV, or hepatitis A, B, or C.
• Have abnormal laboratory values at screening deemed by the investigator to be clinically significant.
• Have a known allergy to pineapple.
• Are pregnant or breast feeding.

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
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
For each participant the study will last for 12 weeks; including 8 weeks of treatment, preceded by a 2-week screening/baseline period and followed by a 2-week washout period. Patients will also have the option continue with this washout period for an additional 6 weeks.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The demographic data will be summarised by dose group. The continuous variables will be summarised as sample size, mean, standard deviation, minimum, median, and maximum. The categorical variables will be summarised as frequencies and percentages.

The interim analysis and final analysis comprise a group sequential test for efficacy and non-binding futility. IBS-SSS will be the efficacy variable of interest. At the interim analysis each dose group will be tested against the placebo group. The level of significance was set to 0.025 for the test of each dose group against placebo. Thus the overall level of significance was 0.05. IBS-SSS will be analysed over time with a mixed model for repeated measurements (MMRM) with baseline IBS-SSS as the covariate, and sequential multiple imputation to estimate the missing observations. The fixed effects will include: dose group, time, baseline covariate, and the interaction between dose group and time. The random effects shall be the participant. The variance-covariance structure will be selected based on AIC, and BIC. The assumptions of MMRM such as Normally distributed residuals will be assessed graphically. If necessary rectifying transformations will be applied. For each dose group the t-test for the interim analysis, and the final analysis will be calculated as a one-degree of freedom contrast at Day 56. The IBS-SSS with be displayed graphically over time as mean with 95% CI. The results in each treatment group will be combined to form an ‘all treated’ group which will be assessed in the same manner.

The continuous efficacy variables such as IBS-QoL will be analysed over time with a MMRM as described for IBS-SSS. For all secondary efficacy variables the level of significance will be 0.05 with no adjustment for multiplicity of tests.

The binary and categorical efficacy variables will be analysed respectively with logistic regression, or log-linear models. The log-likelihood ratio statistic, which is chi-square distributed, will be used to test the association between the dose group and the efficacy variable of interest.

Safety analyses will include summaries for adverse events, clinical laboratory tests, vital signs and physical exams. The continuous safety parameters will be summarised by dose group and time as: mean, standard deviation, minimum, median, maximum, and 95% CI; and change from baseline will be summarised similarly. Compliance and concomitant medications will also be summarized

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 in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 306977 0
Commercial sector/Industry
Name [1] 306977 0
Anatara Lifesciences
Address [1] 306977 0
Level 3/62 Lygon St., Carlton, Melbourne VIC 3053 Australia
Country [1] 306977 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Anatara Lifesciences
Address
Level 3/62 Lygon St., Carlton, Melbourne VIC 3053 Australia
Country
Australia
Secondary sponsor category [1] 307539 0
None
Name [1] 307539 0
Address [1] 307539 0
Country [1] 307539 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307108 0
Bellberry
Ethics committee address [1] 307108 0
Bellberry
123 Glen Osmond Road Eastwood Adelaide
South Australia 5063
Ethics committee country [1] 307108 0
Australia
Date submitted for ethics approval [1] 307108 0
13/10/2020
Approval date [1] 307108 0
Ethics approval number [1] 307108 0

Summary
Brief summary
This is a randomised, double-blind, phase 1/2, placebo-controlled, adaptive study to assess the safety and tolerability of a potential new treatment called GaRP in adults with diarrhoea-predominant irritable bowel syndrome. This study will be conducted as a virtual study, with minimal on-site visits and participants completing most assessments via electronic diaries on a smart phone app called ClaimIt. The aim of this study is to determine the safety and tolerability of two different doses of GaRP in IBS-D patients after 8 weeks of intervention.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106062 0
Dr Danielle Meyrick
Address 106062 0
GenesisCare
Building 1, The Mill, 41-43 Bourke Road
Alexandria NSW 2015
Country 106062 0
Australia
Phone 106062 0
+61 2 8005 0920
Fax 106062 0
Email 106062 0
danielle.meyrick@genesiscare.com
Contact person for public queries
Name 106063 0
Ms Kylie Davis
Address 106063 0
Anatara Lifesciences R&D
343 Royal Pde, Parkville, Melbourne VIC 3052
Australia
Country 106063 0
Australia
Phone 106063 0
+61 417310653
Fax 106063 0
Email 106063 0
kdavis@anatara.com
Contact person for scientific queries
Name 106064 0
Ms Kylie Davis
Address 106064 0
Anatara Lifesciences R&D
343 Royal Pde, Parkville, Melbourne VIC 3052
Australia
Country 106064 0
Australia
Phone 106064 0
+61 417310653
Fax 106064 0
Email 106064 0
kdavis@anatara.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results