Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001140741
Ethics application status
Approved
Date submitted
3/08/2022
Date registered
19/08/2022
Date last updated
13/06/2023
Date data sharing statement initially provided
19/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of manuka honey on digestive health in patients with functional dyspepsia
Scientific title
Impact of manuka honey on symptoms and quality of life in patients with functional dyspepsia: a feasibility study
Secondary ID [1] 307493 0
Nil
Universal Trial Number (UTN)
U1111-1277-5072
Trial acronym
SOOTHE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Functional dyspepsia 326899 0
Condition category
Condition code
Oral and Gastrointestinal 324103 324103 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 intervention consists of two manuka honey products containing either A) 0.1 mg or B) 0.4 mg of Lepteridine™ per 10 g of honey. Lepteridine™ is a natural compound unique to manuka honey. The levels of Lepteridine™ in the two honey products are the high and low levels found naturally in manuka honey.
The study duration is a nominal total of ten weeks, with a two-week lead-in phase, six week intervention phase, and follow-up two weeks after the end of the intervention.
The 2-weeks lead-in phase requires participants to record their bowel motion every day on an app designed for this trial, and complete a weekly questionnaire about their digestive health and general wellbeing (to be completed for the full ten weeks); and complete a non-consecutive 3-day food diary on the 2nd week of lead-in phase.
Participants will provide a faecal sample and fast overnight for 9 hours one day prior to their baseline visit (end of 2nd week of lead-in phase). At their baseline visit (beginning of intervention phase) participants will provide a fasted blood sample, have height and weight measured, complete a set of questionnaires in regards to their mental and physical health, general well-being, and clinical variables. A subgroup of participants will provide blood samples before consuming 10 g of their honey product at the clinic, and then provide blood samples 1, 2, 3, and 5 hours after consumption. The first 5 participants in each group who consent to providing these samples will participate in the substudy.
During the six week intervention phase, participants will consume 10 g of their assigned honey product twice per day, before morning and dinner, complete their daily bowel motion app and weekly digestive health questionnaires, for six weeks. The honey will be packaged in sachets containing one serving size. Participants will be given two-weeks supply of honey to take home. Compliance will be monitored by checklist and measuring returned unused sachets.
Participants will attend the study clinic at weeks 2 and 4 to return unused sachets, pick up their next two weeks of honey, and give a fasted blood sample.
At the final clinic visit (end of intervention phase), the aforementioned baseline visit procedures will be repeated, except the sub study blood samples which will not be repeated. Prior to the final visit, participants will again complete the same set of questionnaires and non-consecutive 3-day food diary, provide a faecal sample, and fast overnight for 9 hours. During the clinic visit, they will provide a fasted blood sample and have their weight measured. Participants will receive their reimbursement (grocery vouchers). Attendance of clinic visits and completion of questionnaires will be assessed to measure the adherence of participants.
Two-weeks after the final clinic visit, participants will complete an online survey regarding their mental and physical health, general wellbeing, and gastrointestinal symptoms; the link to this survey will be sent to the participant by email.
Intervention code [1] 324179 0
Treatment: Other
Comparator / control treatment
The control treatment will be a honey flavoured syrup. The syrup will not contain active ingredients found in manuka honey, and will be matched to the energy content of the manuka honey.
Control group
Active

Outcomes
Primary outcome [1] 332199 0
Changes in global Nepean Dyspepsia Index scores in the honey groups compared with the control group.
The Nepean Dyspepsia Index is a validated questionnaire specifically developed to assess symptom severity and quality of life indices specific to functional dyspepsia.
Timepoint [1] 332199 0
Baseline (prior to intervention), 2 weeks, 4 weeks, 6 weeks (primary endpoint) after the commencement of the intervention.
Primary outcome [2] 332200 0
The percent of participants demonstrating 10%, 20%, 30% and 40% change in global Nepean Dyspepsia Index scores, as an exploratory responder analyses.
Timepoint [2] 332200 0
Baseline (prior to intervention), 2 weeks, 4 weeks, 6 weeks (primary endpoint) after the commencement of the intervention.
Primary outcome [3] 332201 0
Feasibility of the intervention determined by a composite of the number of participants recruited and attrition rates, as determined by the number of withdrawals and participants lost to follow up. These data will be sourced from an audit of the study enrollment and withdrawal logs.
Timepoint [3] 332201 0
Data will be collected throughout the duration of the study.
Secondary outcome [1] 413087 0
Changes in gastrointestinal symptoms specifically bowel movements, pain, bloating, reflux, assessed as a composite outcome using the validated Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Gastrointestinal)
Timepoint [1] 413087 0
Measured weekly for the duration of the study (2-week lead-in period, 6-week intervention, and two-week follow-up)
Secondary outcome [2] 413088 0
Changes in anxiety scores using the validated Patient-Reported Outcomes Measurement Information System Questionnaire (PROMIS Anxiety)
Timepoint [2] 413088 0
Measured weekly for the duration of the study (2-week lead-in period, 6-week intervention, and two-week follow-up)
Secondary outcome [3] 413089 0
Changes in dyspepsia-related quality of life scores using the Nepean Dyspepsia Index.
Timepoint [3] 413089 0
Measured at baseline, week 2, week 4 and week 6
Secondary outcome [4] 413090 0
Changes in epigastric pain scores measured by the Nepean Dyspepsia Index, as an exploratory analysis.
Timepoint [4] 413090 0
Measured at baseline, week 2, week 4, week 6, and at the post-intervention follow-up.
Secondary outcome [5] 413091 0
Changes in postprandial discomfort scores measured by the Nepean Dyspepsia Index, as an exploratory analysis.
Timepoint [5] 413091 0
Measured at baseline, week 2, week 4, week 6, and at the post-intervention follow-up.
Secondary outcome [6] 413092 0
Changes in stool form and frequency assessed as a composite outcome, measured through a daily bowel habit diary (mobile phone app).
Timepoint [6] 413092 0
Measured daily for the duration of the study (2-week lead-in period, 6-week intervention, and two-week follow-up)
Secondary outcome [7] 413093 0
Rate of spontaneous symptom resolution during the study determined using the global Nepean Dyspepsia Index score.
Timepoint [7] 413093 0
Measured at baseline, week 2, week 4, week 6, and at the post-intervention follow-up
Secondary outcome [8] 413094 0
Changes in the faecal metabolome, metagenome (DNAseq), metagenome assemblies, bile and organic acid production assessed as an exploratory composite outcome from faecal sample.
Timepoint [8] 413094 0
Measured at baseline and at the end of the intervention (week 6)
Secondary outcome [9] 413095 0
Changes in the composite cardiovascular risk profile measure by lipid profile assessed using a blood sample, height using a stadiometer, weight using weighing scales, and waist circumference using measuring tape.
Timepoint [9] 413095 0
Measured at baseline and at the end of the intervention (week 6)
Secondary outcome [10] 413096 0
Changes in plasma matrix metallopeptidase-9 concentrations.
Timepoint [10] 413096 0
Measured in fasted blood samples collected at baseline, week 2, week 4, and at the end of the intervention (week 6)
Secondary outcome [11] 413097 0
Changes in blood immune markers, as an exploratory outcome.
Timepoint [11] 413097 0
Measured in fasted blood samples collected at baseline, week 2, week 4, and at the end of the intervention (week 6)
Secondary outcome [12] 413098 0
Changes in blood inflammation markers, as an exploratory outcome.
Timepoint [12] 413098 0
Measured in fasted blood samples collected at baseline, week 2, week 4, and at the end of the intervention (week 6).
Secondary outcome [13] 413099 0
Postprandial appearance of manuka honey-derived compounds and their metabolites, as an exploratory composite outcome.
Timepoint [13] 413099 0
Measured at baseline only, in the first five people per group to consent to undertaking the analysis.
Blood samples will be collected prior to consumption of 10 g of manuka honey or control. Postprandial measurements will be taken at 60, 120, 180, and 300 minutes after consumption of the honey or control.

Eligibility
Key inclusion criteria
Adults with mild/moderate functional dyspepsia (FD) and Body Mass Index between 18.5 and 35 kg/m2.
FD participants will be selected based on the ROME IV Diagnostic Criteria (fulfilled for the last three months with symptom onset at least six months prior to diagnosis):
1. Must include one or more of the following:
- Bothersome postprandial fullness
- Bothersome early satiation
- Bothersome epigastric pain severe enough to impact on usual activities
- Bothersome epigastric burning severe sufficient to impact on normal activities
AND
2. No previous diagnosis of structural disease (including at upper endoscopy) that is likely to explain the symptoms
AND
3. Must fulfil criteria for Postprandial Distress Syndrome (PDS) and/or Epigastric Pain Syndrome (EPS) as follows:
a. PDS: must include one or both of the following at least three days a week:
- Bothersome postprandial fullness severe enough to impact on usual activities
- Bothersome early satiation severe enough sufficient to prevent finishing a
regular size meal
b. EPS: must include one or both of the following at least one day a week:
- Bothersome epigastric pain severe enough to impact on usual activities
- Bothersome epigastric burning severe sufficient to impact on usual activities

People with mild to moderate severity of dyspepsia will be identified with the Short Form Leeds Dyspepsia Questionnaire. This consists of eight items that assess the presence and severity of dyspepsia by measuring the frequency and severity of upper abdominal pain/discomfort, heartburn, regurgitation and nausea. Possible scores range from 0 to 32 with higher values corresponding with increasing severity of dyspepsia. A score of 1 to 23 indicates mild to moderate dyspepsia symptoms.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability to give informed consent
- Severe functional dyspepsia, defined by a score of 23 or higher from the Short Form Leeds Dyspepsia Questionnaire
- Taken antibiotics within the month before starting the study
- Use of certain prescribed medication or recreational drugs. People taking Proton Pump Inhibitors, H2-receptor antagonists, antacids, mucosal protectants, prokinetics, antidepressant drugs if they were prescribed solely for controlling dyspepsia symptoms, anticholinergic agents, cholinergic agents, and over-the-counter herbal remedies used to treat dyspepsia symptoms will be required to stop taking four weeks prior to the start of the study
- Helicobacter pylori-positive (physician-diagnosed) or undertaking treatment for H. pylori infection within one month of initiation of study. Potential participants will also be screened for H. pylori infection prior to beginning the lead-in and intervention.
- Alarm features associated with significant GI or other disorders, such as abdominal pain that wakes the patient from sleep; frequent vomiting; family history of gastrointestinal (GI) malignancies suggestive of a significant hereditary cancer syndrome; lower GI bleeding; odynophagia; dysphagia.
- Medical history of upper GI surgery or other significant disorders (inflammatory bowel disease, ulcerative colitis, coeliac disease, Crohn's disease), significant cardiorespiratory disease, diabetes mellitus, significant bleeding disorders, sleep disorders, active psychiatric conditions (major depressive disorder, schizophrenia)
- Significant weight loss (>5% of total body weight) during the six months before starting the study
- Significant dietary changes within the month before starting the study (i.e., being on a controlled diet or dietary weight loss regimen)
- Intolerance or allergy to honey and bee products
- Pregnancy or breastfeeding
- Smokers
- Excessive alcohol intake >20 g of pure alcohol (2 drinks)/d on average (>21 standard drinks a week)

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)
Sealed opaque envelopes, with the manufacturer responsible for labelling the honey and control sachets.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation will be concealed with a pre-specified computer-generated random block randomisation list prepared by the study statistician to ensure blinding. Participants will be randomised (1:1:1) into either one of the honey groups or into the control group.
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
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Since this is a feasibility study, a formal sample size calculation has not been undertaken. The key outcomes for the study include the assessment of recruitment and retention rates and clinical responses to treatments. We will therefore aim to recruit a minimum of 75 participants (25 in each group). While 25 people in each group may not lead to statistically significant outcomes, it will provide mean differences and sufficiently precise 95% CIs for outcomes between the two honey groups, and between the honey groups and control group, for informing the design of a definitive randomised controlled trial.

Presenting features and all outcomes measures with be summarised using standard descriptive statistics including means, medians, standard deviations and ranges and frequencies and percentages depending on the variable types. Outcomes as levels and changes will be compared between groups using general linear models or non-parametric approaches for continuous measures and chi-square tests and logistic regressions for categorical variables. Effect sizes generated from these analyses will inform power calculations for futures studies and assist identifying outcomes and participant groups which are sensitive to the interventions. Analyses will explore dose-response relationships between the three randomised groups and outcomes and also pairwise comparisons amongst the groups. All analyses will be undertaken using SPSS v27 and a two-tailed p-value <0.05 will be taken to indicate statistical significance.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
19/12/2022
Actual
9/01/2023
Date of last participant enrolment
Anticipated
27/10/2023
Actual
Date of last data collection
Anticipated
15/12/2023
Actual
Sample size
Target
75
Accrual to date
18
Final
Recruitment outside Australia
Country [1] 24874 0
New Zealand
State/province [1] 24874 0
Dunedin

Funding & Sponsors
Funding source category [1] 311477 0
Government body
Name [1] 311477 0
Ministry of Business Innovation and Employment
Country [1] 311477 0
New Zealand
Funding source category [2] 311774 0
Commercial sector/Industry
Name [2] 311774 0
Comvita New Zealand Ltd
Country [2] 311774 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 313458 0
None
Name [1] 313458 0
None
Address [1] 313458 0
N/A
Country [1] 313458 0
Other collaborator category [1] 282382 0
University
Name [1] 282382 0
Malaghan Institute of Medical Research
Address [1] 282382 0
Gate 7, Victoria University
Kelburn Parade,
Wellington 6140
New Zealand
Country [1] 282382 0
New Zealand
Other collaborator category [2] 282383 0
University
Name [2] 282383 0
The Riddet Institute
Address [2] 282383 0
Massey University
Private Bag 11 222
Palmerston North 4442
Country [2] 282383 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310941 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 310941 0
Ethics committee country [1] 310941 0
New Zealand
Date submitted for ethics approval [1] 310941 0
23/06/2022
Approval date [1] 310941 0
31/08/2022
Ethics approval number [1] 310941 0
2022 FULL 12734

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

Contacts
Principal investigator
Name 119434 0
Dr Jody Miller
Address 119434 0
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country 119434 0
New Zealand
Phone 119434 0
+64 4 4797559
Fax 119434 0
Email 119434 0
[email protected]
Contact person for public queries
Name 119435 0
Holly Abbotts-Holmes
Address 119435 0
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country 119435 0
New Zealand
Phone 119435 0
+64 021 2790140
Fax 119435 0
Email 119435 0
[email protected]
Contact person for scientific queries
Name 119436 0
Jody Miller
Address 119436 0
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country 119436 0
New Zealand
Phone 119436 0
+64 4 4797559
Fax 119436 0
Email 119436 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16811Informed consent form  [email protected]



Results publications and other study-related documents

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