Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000621819
Ethics application status
Approved
Date submitted
31/03/2021
Date registered
24/05/2021
Date last updated
24/05/2021
Date data sharing statement initially provided
24/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Kiwifruit Ingestion to Normalise Gut Symptoms in the Christchurch IBS cohort
Scientific title
A single blinded, negative controlled, randomised, parallel design study to determine if kiwifruit Ingestion can normalise gastrointestinal symptoms in individuals with Functional Constipation (FC) or Constipation-predominant Irritable Bowel Syndrome (IBS-C).
Secondary ID [1] 303835 0
Nil known
Universal Trial Number (UTN)
Trial acronym
KINGS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Functional Constipation 321362 0
Constipation-predominant Irritable Bowel Syndrome 321363 0
Condition category
Condition code
Oral and Gastrointestinal 319143 319143 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
The main intervention will consist of two Zespri™ green kiwifruit per day, which will be eaten orally without the skin for 4 weeks.
The study duration is a nominal total of 9 weeks; 3-week lead-in phase, 4-week intervention phase, and final 2-week follow-up phase.
The 3-weeks lead-in phase requires participants to record their bowel motion on a developed app every day (until study completion); complete a questionnaire in regards to their socioeconomic status and general wellbeing, complete a non-consecutive 3-day food diary and a fibre-specific food frequency questionnaire (2nd week of lead-in phase). Participants will consume a provided evening standardised meal, provide a faecal sample and fast overnight for 9 hours one day prior to their baseline visit (3rd week of lead-in phase). Participants will provide a blood sample, complete a set of questionnaires in regards to their mental and physical health, general well-being, and clinical variables, undergo Magnetic Resonance Imaging (MRI), ingest diagnostic devices (Atmo and Smart Pill) in capsule form, and blue food dye to measure whole gut transit during their baseline visit (3rd week of lead-in phase).
Participants with FC and IBS-C will be randomised by using randomised permuted blocks, block size 4 to consume either two Zespri® green kiwifruit or 25g of maltodextrin (energy matched) per day throughout the 4 weeks intervention. The fruits will be provided by the research team in bulk. Selected participants will take the interventions home. Leftover fruit will be counted to measure adherence.
Participants will repeat all of the aforementioned baseline visit procedures before and on their post-intervention visit. Prior to the follow up visit, participants will again complete the same set of questionnaires, provide a faecal sample and fast overnight for 9 hours. Participants will provide a blood sample and receive their reimbursement during their follow up visit. Attendance of clinic visits and completion of questionnaire will be assessed to measure the adherence of participants.
The data generated with the questionnaires will be correlated to the data of the biological samples, such as the abundance of metabolites (including neurotransmitters), population and genetic composition of the microbiota as well as physiome data from MRI, blue food dye, Atmo, and Smartpill capsules, to determine the differences between the two groups.
Intervention code [1] 320149 0
Treatment: Other
Comparator / control treatment
The placebo will be commercially sourced maltodextrin, which is a polysaccharide that is used as a food additive, given in one dose per day for 4 weeks. Maltodextrin amount will be energy-matched to two kiwifruits and would be approximately 25g per serve. Oral intake of maltodextrin powder will be mixed into participants’ preferred food or beverage i.e. 25g per serve added to their usual diet by sprinkling on top of cereal, etc.
Maltodextrin will be provided by the research team in bulk and will be brought back home by participants.

Participants will also provide faecal and blood samples, and will complete questionnaires in regards to their mental and physical health, general well-being, clinical and demographic variables, undergo Magnetic Resonance Imaging (MRI), ingest blue food dye to measure whole gut transit before and after the taking Maltodextrin. Attendance of clinic visits and completion of the questionnaires will be assessed to measure the adherence of participants.

The data generated with the questionnaires will be correlated to the data of the biological samples, such as the abundance of metabolites (including neurotransmitters), population and genetic composition of the microbiota as well as physiome data from MRI, blue food dye, Atmo, and SmartPill capsules, to determine the differences between the two groups.
Control group
Placebo

Outcomes
Primary outcome [1] 327035 0
A change in digestive comfort as indicated by a change in abdominal pain relief as measured by the Gastrointestinal Symptom Rating Scale (GSRS).
The GSRS is a validated instrument with a 1-week recall that assesses symptom severity using a 7-grade Likert scale, ranging from 1 (“no discomfort at all”) to 7 (“very severe discomfort”). An abdominal pain responder will be one who reports a reduction in pain of at least 30% from baseline.
Timepoint [1] 327035 0
Participants will fill out GSRS questionnaires at baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [1] 393524 0
A change in complete spontaneous bowel movements using a bowel habit diary app.
Timepoint [1] 393524 0
Daily starting from 3 weeks prior to intervention commencement and finishing at 2 weeks after the intervention has concluded.
Secondary outcome [2] 393560 0
A change in classification during the trial and changes to upper gastrointestinal symptoms assessed as a composite outcome using the validated Rome IV questionnaire for Adult FGIDs (R4DQ)
Timepoint [2] 393560 0
Collected at enrolment, baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [3] 393561 0
To determine habitual food intake before and after the intervention using a three-day food diary
Timepoint [3] 393561 0
One week prior to baseline (2nd week of lead in-phase) and 3rd week of the study intervention.
Secondary outcome [4] 393562 0
A change in habitual fibre intake using validated inulin and oligofructose food frequency questionnaire.
Timepoint [4] 393562 0
One week prior to baseline (2nd week of lead in-phase) and 3rd week of the study intervention.
Secondary outcome [5] 393563 0
A change in gastrointestinal symptoms using a (validated) Structured Assessment of Gastrointestinal Symptoms (SAGIS)
Timepoint [5] 393563 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [6] 393564 0
A change in gastrointestinal symptoms specifically bowel movements, pain, bloating, reflux, assessed as a composite outcome using the Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Gastrointestinal)
Timepoint [6] 393564 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [7] 393565 0
A change in IBS symptoms and its treatment using Irritable Bowel Syndrome- Quality of Life survey (IBS-QOL).
Timepoint [7] 393565 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [8] 393566 0
A change in current wellbeing using World Health Organisation - Five question Well-Being Index (WHO-5).
Timepoint [8] 393566 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [9] 393567 0
A change in mental wellbeing covering feeling and functioning aspects in relation to the past two weeks, adjusted to one week using the Warwick-Edinburgh Mental Wellbeing Scales (WEMWBS).
Timepoint [9] 393567 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [10] 393568 0
A change in fatigue scores using Multidimensional Fatigue Inventory (MFI)
Timepoint [10] 393568 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [11] 394675 0
A change in anxiety scores using Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Anxiety)
Timepoint [11] 394675 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [12] 394676 0
A change in depression scores using Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Depression)
Timepoint [12] 394676 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [13] 394681 0
A change in the faecal metabolome, metagenome (DNAseq), metagenome assemblies, bile and organic acid production assessed as a composite outcome from faecal sample.
Timepoint [13] 394681 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [14] 394682 0
A change in plasma metabolome and neurotransmitters, and immune markers (cytokine, phenotyping) (PBMC) assessed as a composite outcome by collecting blood (PBMC) and plasma samples.
Timepoint [14] 394682 0
At baseline (3rd week of lead-in phase), immediately after the intervention concluded (4th week), and at follow-up (2 weeks after the intervention concluded).
Secondary outcome [15] 394683 0
A change in small and large gastrointestinal transit, gastrointestinal gas content and composition assessed as a composite outcome measured by ingesting blue food dye (Royal Blue Liqua-gel® food colouring (12 drops/1.5g) in water, swallowing of Atmo gas capsule, and SmartPill®.
Timepoint [15] 394683 0
SmartPill®, Atmo gas capsule, and blue food dye will be ingested immediately after MRI scan at baseline (3rd week of lead-in phase), and immediately after the intervention concluded (4th week).
Secondary outcome [16] 394684 0
Changes in small and large gastrointestinal transit time and faecal water content assessed as a composite outcome measured by MRI scan.
Timepoint [16] 394684 0
Fasting MRI scans will be conducted at baseline (3rd week of lead-in phase), and immediately after the intervention concluded (4th week)

Eligibility
Key inclusion criteria
Adult with FC or IBS-C (18-65 years) with a BMI between 18 and 35kg/m2.

A. The FC participants will be selected based on the following criteria:
Presence of FC according to Rome IV Diagnostic Criteria (fulfilled for the last three months with symptom onset at least six months prior to diagnosis):
1. Must include two or more of the following:
- Straining during more than 25% of defecations
- Lumpy or hard stools during more than 25% of defecations
- Sensation of incomplete evacuation for more than 25% of defecations
- Sensation of anorectal obstructions/blockage for more than 25% of defecations
- Manual manoeuvres to facilitate more than 25% of defecations (e.g. digital evacuation, support of the pelvic floor)
- Fewer than three complete spontaneous bowel movements per week

2. Loose stools are rarely present without the use of laxatives
3. Insufficient criteria for irritable bowel syndrome

The participants with mild IBS-C will be selected based on the following Rome IV Diagnostic Criteria (fulfilled for the last three months with symptom onset at least six months prior to diagnosis):
1. Recurrent abdominal pain, on average, at least one day per week in the last three months, associated with two or more of the following:
- Related to defecation
- Associated with a change in frequency of stool
- Associated with a change in form (appearance) of stool

2. More than 25% of bowel movements with Bristol Stool form types 1 or 2 and less than 25% of Bowel movements of types 6 or 7.

Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability to give informed consent
- Pregnancy, breastfeeding or planning a pregnancy in the three months post-selection (study time frame)
- Alarm features associated with bowel habits, such as recent changes in bowel habits (onset less than three months), rectal bleeding, sudden weight loss, occult blood in stool, anaemia, anal fissures, bleeding haemorrhoids, and family history of gastrointestinal cancer at a young age or Irritable Bowel Disease (IBD)
- Known significant gastrointestinal disorder and disease other than IBS-C, diverticulitis, coeliac disease, IBS-D or mixed IBS, or previous bowel resection.
- Known systemic disease that could influence the gut directly or through medication use (e.g. diabetes, opiate or NSAID use)
- Chronic disease such as cardiovascular, cancer, renal failure, previous gastrointestinal surgery other than cholecystectomy or appendectomy, neurological conditions such as multiple sclerosis, spinal cord injury, or stroke
- Fasting blood glucose equals to or more than 6.0 mmol/l
- Known kiwifruit or latex allergy
- Inability to swallow pills
- Inability to access MRI machines such as presence of pacemakers or cochlear implants
- Laxative use and inability or unwillingness to stop laxative use for the seven days before sample collections.
- An IBS Severity Index score of over 300.
- Indication of inability to comply with the study procedures

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)
Only specified members of the research team who are not the investigator or involved in anaysis will be responsible for the randomisation, the blinding of the other members of the team, the handout of the interventions, and the management of the stock.
Allocation of participants will be done by specified unblinded research members picking up either GrKF or Maltodextrin sealed opaque envelopes from a sealed container.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation, block size 4
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The study is powered to detect an effect size of 1 within the abdominal pain domain of the GSRS with 5% significance (a) and 80% power (ß) = 16 participants in regards to a difference between the interventions. This is based on a pooled outcome estimate for the GSRS abdominal pain domain, extracted from published and unpublished reports (pooled difference of -0.845 after KF consumption, pooled SD of 0.85). The pooled estimate was derived from an aggregate summary of the mentioned reports using a random effect model

For MRI outcomes, the study is powered to detect a rise in ascending colon T1 similar to published results using 300g GrKF twice daily and a parallel group design with 5% significance (a) and 90% power (ß) = 22 participants. To account for the lower GrKF intake in the present study (2GrKF, once daily), the total was increased to 30 participants. Therefore, we intentionally powered the study to ensure the detection of differences between the interventions in MRI physiome results.

Evaluation will be composed of analyses of the clinical, demographic, MRI and laboratory variables (see above) with a focus on comparing the results between participants consuming maltodextrin compared to those consuming green kiwifruit.

The methods used for evaluation will depend on the data type, and will contain continuous and categorical data for demographic, clinical, and physical endpoints, metadata for faecal metagenomics, plasma and faecal metabolomics.

Categorical variables: Chi-squared tests (or Fisher’s Exact tests for small samples). Continuous variables will be analysed using (parametric) t-tests and (non-parametric) Mann-Whitney tests for symmetrically and asymmetrically distributed data, respectively.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
24/05/2021
Actual
Date of last participant enrolment
Anticipated
1/11/2021
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment outside Australia
Country [1] 23574 0
New Zealand
State/province [1] 23574 0
Christchurch

Funding & Sponsors
Funding source category [1] 308230 0
Government body
Name [1] 308230 0
Ministry of Business Innovation and Employment
Country [1] 308230 0
New Zealand
Funding source category [2] 308237 0
Commercial sector/Industry
Name [2] 308237 0
Zespri International Limited
Country [2] 308237 0
New Zealand
Primary sponsor type
Individual
Name
Nicole Roy
Address
Department of Human Nutrition, University of Otago
PO Box 56
Dunedin 9054
New Zealand
Country
New Zealand
Secondary sponsor category [1] 309031 0
Individual
Name [1] 309031 0
Richard Gearry
Address [1] 309031 0
Department of Medicine, University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central City
Christchurch
8011
Country [1] 309031 0
New Zealand
Secondary sponsor category [2] 309032 0
Individual
Name [2] 309032 0
Simone Bayer
Address [2] 309032 0
Department of Medicine, University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central City
Christchurch
8011
Country [2] 309032 0
New Zealand
Other collaborator category [1] 281704 0
Individual
Name [1] 281704 0
Karl Fraser
Address [1] 281704 0
AgResearch
Tennent Drive
11 Dairy Farm Road
Fitzherbert
Palmerston North
4442
Country [1] 281704 0
New Zealand
Other collaborator category [2] 281705 0
Individual
Name [2] 281705 0
Wayne Young
Address [2] 281705 0
The Riddet Institute
University Avenue
Fitzherbert
Palmerston North
4474
Country [2] 281705 0
New Zealand
Other collaborator category [3] 281706 0
Individual
Name [3] 281706 0
Jane Mullaney
Address [3] 281706 0
AgResearch
Tennent Drive
11 Dairy Farm Road
Palmerston North
4442

The Riddet Institute
University Avenue
Fitzherbert
Palmerston North
4474
Country [3] 281706 0
New Zealand
Other collaborator category [4] 281707 0
Individual
Name [4] 281707 0
Robin Spiller
Address [4] 281707 0
National Institute of Health Research (NIHR) Nottingham Biomedical Research Centre
C Floor, South Block
Queen's Medical Centre
Derby Road, Nottingham
NG7 2UH
Country [4] 281707 0
United Kingdom
Other collaborator category [5] 281708 0
Individual
Name [5] 281708 0
Janine Cooney
Address [5] 281708 0
Plant and Food Research
120 Mt Albert Road
Sandringham
Auckland 1025
Country [5] 281708 0
New Zealand
Other collaborator category [6] 281709 0
Individual
Name [6] 281709 0
Olivier Gasser
Address [6] 281709 0
Malaghan Institute of Medical Research
Gate 7, Victoria University Central Services Building,
Kelburn,
Wellington
6012
Country [6] 281709 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308212 0
Southern Health and Disability Ethics Commitee (HDEC)
Ethics committee address [1] 308212 0
Ethics committee country [1] 308212 0
New Zealand
Date submitted for ethics approval [1] 308212 0
31/03/2021
Approval date [1] 308212 0
17/05/2021
Ethics approval number [1] 308212 0
21/NTB/96
Ethics committee name [2] 308220 0
University of Otago Christchurch Maori Research Consultation
Ethics committee address [2] 308220 0
Ethics committee country [2] 308220 0
New Zealand
Date submitted for ethics approval [2] 308220 0
12/03/2021
Approval date [2] 308220 0
27/04/2021
Ethics approval number [2] 308220 0
see private notes

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109950 0
Prof Richard Gearry
Address 109950 0
Department of Medicine, University of Otago, Christchurch
2 Riccarton Avenue,
Christchurch Central City,
Christchurch 8011
Country 109950 0
New Zealand
Phone 109950 0
+64 33641790
Fax 109950 0
Email 109950 0
[email protected]
Contact person for public queries
Name 109951 0
Simone Bayer
Address 109951 0
Department of Medicine, University of Otago, Christchurch
2 Riccarton Avenue,
Christchurch Central City,
Christchurch 8011
Country 109951 0
New Zealand
Phone 109951 0
+64 21 279 1519
Fax 109951 0
Email 109951 0
[email protected]
Contact person for scientific queries
Name 109952 0
Simone Bayer
Address 109952 0
Department of Medicine, University of Otago, Christchurch
2 Riccarton Avenue,
Christchurch Central City,
Christchurch 8011
Country 109952 0
New Zealand
Phone 109952 0
+64 21 279 1519
Fax 109952 0
Email 109952 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
Individual data is not available to the public. it would be a breach of data security.


What supporting documents are/will be available?




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.