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Trial registered on ANZCTR


Registration number
ACTRN12622000890730
Ethics application status
Approved
Date submitted
16/06/2022
Date registered
22/06/2022
Date last updated
1/03/2023
Date data sharing statement initially provided
22/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Kawakawa and its impact on inflammatory markers
Scientific title
Tuhauora: impact of different kawakawa dosing conditions on markers of metabolic health and inflammation in healthy human volunteers
Secondary ID [1] 307358 0
None
Universal Trial Number (UTN)
U1111-1279-1017
Trial acronym
Tuhauora
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammation 326660 0
Obesity 326661 0
Condition category
Condition code
Inflammatory and Immune System 323901 323901 0 0
Normal development and function of the immune system
Diet and Nutrition 323902 323902 0 0
Obesity
Diet and Nutrition 323903 323903 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will involve Three randomised interventions provided as capsules to the participants.
Intervention 1: 4 capsules; each containing 0.25g dry weight of kawakawa to be consumed daily in the morning for one week
Intervention 2: 4 capsules; (2 capsules each containing 0.25g dry weight of kawakawa to be consumed daily for 1 week + 2 capsules each containing 0.25g cellulose (metabolically inert) as a placebo to be consumed daily for 1 week.
Control: 4 capsules, each containing 0.25g cellulose (metabolically inert) as a placebo to be consumed daily for one week

Oral glucose tolerance test will be performed (OGTT) with a 75g glucose load on six different occasions: Intervention Visits 1 &2; (at baseline and after one week of consuming kawakawa capsules); Intervention Visits 3 & 4: (baseline and after one week of consuming placebo capsules) and Intervention Visits 5 & 6: (baseline and after one week of consuming kawakawa+placebo capsules) (randomised cross-over design). Owing to the cross-over design of the study, a 2-week washout period between the three interventions will be observed. Since the postprandial state lasts for approximately 3-5 h post-meal period, the participants must attend the Clinical Research Unit (CRU) of the Liggins Institute on each intervention visit for 3 hours.

Participants will be provided with a simple, standardised meal to eat the evening before each study visit to reduce variability in the fasting substrate oxidation profile. This meal will have identical macronutrient composition and energy content (300gm weight; 526-kilo calories; 50 grams protein; 35 grams fat; 34.3 grams carbohydrates < 1.6 % Sugars) within- and between participants and is to be consumed between 7:30 and 8 pm. Participants will also be advised to abstain from intense exercise and caffeinated and alcoholic drinks in the 24hrs prior to the study visits. Participants are required to come in an overnight (12 h) fasted state.
Upon arrival, the participant’s anthropometric measurements (weight and waist circumference) will be taken, and a spot urine sample will be collected. Participants will then be asked to sit in a comfortable seat in a quiet, temperature-controlled (20-22°C) laboratory. Body temperature will be measured using a tympanic thermometer to exclude the presence of fever. A peripheral venous cannula will be inserted by the Research Nurse for repeated blood sampling. A 16mL fasting baseline blood sample will be collected. Following the fasting sample, a standard oral glucose tolerance test (OGTT) will be performed. Participants will be provided with 75g of glucose drink to be consumed within 10 minutes. Blood samples will be collected at intervals of 30, 60, 90, and 120 mins from an arm vein. A total volume of 70mL will be taken at each study visit. Urine samples will be collected at fasting and then over 3 hours after glucose consumption.

During the one week of each intervention, participants would be asked to maintain a record of their capsule intake by filling out the record form provided to them on visit 1. Also, participants are required to return the capsules at the end of each intervention.
Intervention code [1] 323787 0
Prevention
Comparator / control treatment
Cellulose (metabolically inert)
Control group
Active

Outcomes
Primary outcome [1] 331727 0
To examine the effect of different doses of kawakawa ingestion on blood levels of IL-6, a pro-inflammatory cytokine
Timepoint [1] 331727 0
Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules), and Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules)
Intervention visit 5&6 (baseline and after 1 week of consuming Placebo capsules) (randomized cross-over design)
Secondary outcome [1] 410875 0
To examine oral glucose tolerance test (OGTT) after 1 week of consuming different doses of kawakawa-containing capsules compared to placebo
Timepoint [1] 410875 0
Oral glucose tolerance test will be performed (OGTT) with 75g glucose load on 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules), and Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules)
Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules).
(randomized cross-over design)
Secondary outcome [2] 410876 0
To measure the impact of kawakawa ingestion on plasma lipids. Plasma Lipids will be measured on a Roche Cobas e411 by electro-chemiluminescence immunoassay.
Timepoint [2] 410876 0
Fasting blood samples will be collected. After the OGTT, blood samples will be collected at 15, 30, 60, 90, 120 and 180 mins on 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules) and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules).
(randomized cross-over design)
Secondary outcome [3] 410877 0
To measure the impact of kawakawa ingestion on plasma insulin. Plasma insulin will be measured on a Roche Cobas e411 by electro-chemiluminescence immunoassay.
Timepoint [3] 410877 0
Fasting blood samples will be collected. After the OGTT, blood samples will be collected at 15, 30, 60, 90, 120 and 180 mins on 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules) and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules).(randomized cross-over design).
Secondary outcome [4] 410878 0
To examine the impact of kawakawa ingestion on blood markers of insulin resistance; as assessed by Homeostatic model assessment (HOMA-IR)
Timepoint [4] 410878 0
On 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules), and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules) (randomized cross-over design).
Secondary outcome [5] 410879 0
To examine the change in the plasma metabolic profiles using liquid chromatography with mass spectrometry (LC-MS) techniques. This is an untargeted exploratory analysis.
Timepoint [5] 410879 0
Blood samples will be collected at 0, and 120 min after the OGTT on 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules), and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules) (randomized cross-over design).
Secondary outcome [6] 410880 0
To explore the change in the urine metabolic profiles using liquid chromatography with mass spectrometry (LC-MS) techniques. This is an untargeted exploratory analysis.
Timepoint [6] 410880 0
Urine samples will be collected at 0 and 120 min (3hr) after the OGTTOn 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules), and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules) (randomized cross-over design).
Secondary outcome [7] 410881 0
To examine changes in the whole-body insulin sensitivity assessed by Matsuda index from a 75-gram oral glucose tolerance test
Timepoint [7] 410881 0
On 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules), and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules) (randomized cross-over design).
Secondary outcome [8] 410882 0
To quantify the changes in the combined metabolic and inflammatory-related gene expression. Plasma and peripheral blood mononuclear cell (PBMCs) gene expression will be performed following total RNA extraction for measurement of changes in the expression of genes involved in metabolic homeostasis (such as CPT1A, FAS, UCP) and also in inflammatory gene expression (such as TNF-a, MCP-1, IL-1ß) and microRNAs.
This is a composite outocme and will be assessed by RT-PCR.
Timepoint [8] 410882 0
These will be obtained at fasting (for 12 hours), and at 1 &2 hours after the end of fasting (defined as ingestion of 75g glucose as part of the OGTT) on 6 different occasions: Intervention Visits 1 &2; (at baseline and after 1 week of consuming kawakawa capsules); Intervention Visits 3&4: (baseline and after 1 week of consuming kawakawa + Placebo capsules), and Intervention visits 5&6 (baseline and after 1 week of consuming Placebo capsules) (randomized cross-over design).

Eligibility
Key inclusion criteria
• Gender: both males and females.
• Age: 18-45 yr.
• BMI: 18-25kg/m2
• Non-smokers
• Able to refrain from taking herbal teas
• Self-reported not consuming herbal/botanical supplements or traditional extracts
• Self-reported healthy
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Are taking herbal supplements or herbal remedies which may affect the study outcome
• Are allergic to pepper, nutmeg or similar spices
• Are diagnosed with gastrointestinal disease (i.e. celiac, Crohn’s, colitis, etc.) or pre-existing metabolic disease
• Are currently taking medications expected to interfere with normal digestive or metabolic processes including proton pump inhibitors, laxatives, etc.
• Have used antibiotics within the previous one month or were on long-term antibiotic therapy.
• Have a medical history precluding a healthy state: history of myocardial infarction, angina, stroke, cancer or pre-existing diabetes
• Have recently gained or lost around >5% body weight

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The allocation sequence will be set up through a web-based secure database. Sequences will not be accessible to the research team prior to allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised to receive the interventions or the control as the first in a crossover sequence using computer-generated sequences.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Differences in the primary endpoints will be compared between treatment groups using Repeated measure ANOVA or non-parametric tests where appropriate and followed-up with posthoc tests. The relationship between secondary end-points will be assessed using multiple regression analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/03/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment outside Australia
Country [1] 24840 0
New Zealand
State/province [1] 24840 0
Auckland

Funding & Sponsors
Funding source category [1] 311611 0
Other Collaborative groups
Name [1] 311611 0
High Value Nutrition (HVN)
Country [1] 311611 0
New Zealand
Primary sponsor type
University
Name
Liggins Institute, The University of Auckland
Address
85 Park Road, Grafton, 1023, Auckland
Country
New Zealand
Secondary sponsor category [1] 313044 0
None
Name [1] 313044 0
Address [1] 313044 0
Country [1] 313044 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311053 0
Northern Health and Disability Ethics Committee
Ethics committee address [1] 311053 0
Ministry of Health Health and Disability Ethics Committees 133 Molesworth Street, Thorndon Wellington 6011
Ethics committee country [1] 311053 0
New Zealand
Date submitted for ethics approval [1] 311053 0
28/10/2022
Approval date [1] 311053 0
30/01/2023
Ethics approval number [1] 311053 0
2023 EXP 13822

Summary
Brief summary
Kawakawa (Piper excelsum) is endemic to Aotearoa, New Zealand, and, as a taonga, is of great cultural importance to Maori. Kawakawa is used extensively in rongoa Maori (traditional Maori healing). The pharmacology of kawakawa is complex, with studies reporting kawakawa to contain several biologically active compounds that influence inflammation and related pathways. For example, myristicin inhibits the production of several pro-inflammatory cytokines, such as NO, IL-6 and IL-10, in mouse macrophages and THP-1 monocytes. Elemicin, another aromatic compound in kawakawa, is known to play a role in inhibiting IL-6. We hypothesize that the consumption of kawakawa would impact the inflammatory pathways by enhancing anti-inflammatory effects. However, several confounding variables, such as individualized differences in kawakawa tea preparation and doses and variability in the bioavailability of the active kawakawa constituents, could also alter the anti-inflammatory effects. Therefore, controlled human kawakawa trials are necessary to evaluate the effects of different doses of kawakawa consumption on inflammatory markers. To test our hypothesis, this study aims to quantify the effects of different kawakawa doses on inflammatory markers in healthy human volunteers.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119830 0
Dr Farha Ramzan
Address 119830 0
Liggins Institute University of Auckland 85 Park Road Grafton Auckland 1023
Country 119830 0
New Zealand
Phone 119830 0
+64224505345
Fax 119830 0
Email 119830 0
[email protected]
Contact person for public queries
Name 119831 0
Farha Ramzan
Address 119831 0
Liggins Institute University of Auckland 85 Park Road Grafton Auckland 1023
Country 119831 0
New Zealand
Phone 119831 0
+64224505345
Fax 119831 0
Email 119831 0
[email protected]
Contact person for scientific queries
Name 119832 0
Farha Ramzan
Address 119832 0
Liggins Institute University of Auckland 85 Park Road Grafton Auckland 1023
Country 119832 0
New Zealand
Phone 119832 0
+64224505345
Fax 119832 0
Email 119832 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the Individual participant data (including data dictionaries) collected during the trial will be available after de-identification, along with the study protocol.
When will data be available (start and end dates)?
Data will be available beginning 3 months following the first publication of study results and ending 36 months following publication.
Available to whom?
Data will be available to investigators who provide a methodologically sound proposal approved by the Study Steering Committee, for use to achieve the aims in the approved proposal. Proposals should be directed to the principal investigator. To gain access, requests will need to sign a data access agreement.
Available for what types of analyses?
For use to achieve the aims in an approved proposal.
How or where can data be obtained?
Proposals should be directed to the principal investigator ([email protected]). To gain access, requests will need to sign a data access agreement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16392Study protocol  [email protected] 384193-(Uploaded-22-02-2023-15-06-58)-Study-related document.docx
16393Informed consent form  [email protected] 384193-(Uploaded-28-02-2023-14-42-15)-Study-related document.docx



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.