ANZCTR - Registration

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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]

None

Universal Trial Number (UTN)

U1111-1279-1017

Trial acronym

Tuhauora

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Inflammation

Obesity

Condition category

Condition code

Inflammatory and Immune System

Normal development and function of the immune system

Diet and Nutrition

Obesity

Diet and Nutrition

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]

Prevention

Comparator / control treatment

Cellulose (metabolically inert)

Control group

Active

Outcomes

Primary outcome [1]

To examine the effect of different doses of kawakawa ingestion on blood levels of IL-6, a pro-inflammatory cytokine

Timepoint [1]

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]

To examine oral glucose tolerance test (OGTT) after 1 week of consuming different doses of kawakawa-containing capsules compared to placebo

Timepoint [1]

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]

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]

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]

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]

Secondary outcome [4]

To examine the impact of kawakawa ingestion on blood markers of insulin resistance; as assessed by Homeostatic model assessment (HOMA-IR)

Timepoint [4]

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]

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]

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]

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]

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]

To examine changes in the whole-body insulin sensitivity assessed by Matsuda index from a 75-gram oral glucose tolerance test

Timepoint [7]

Secondary outcome [8]

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]

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

High Value Nutrition (HVN)

Address [1]

Liggins Institute, 85 Park road, Grafton, Auckland 1023.

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health Health and Disability Ethics Committees 133 Molesworth Street, Thorndon Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

28/10/2022

Approval date [1]

30/01/2023

Ethics approval number [1]

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

Dr Farha Ramzan

Address

Liggins Institute University of Auckland 85 Park Road Grafton Auckland 1023

Country

New Zealand

Phone

+64224505345

Fax

f.ramzan@auckland.ac.nz

Contact person for public queries

Name

Farha Ramzan

Address

Liggins Institute University of Auckland 85 Park Road Grafton Auckland 1023

Country

New Zealand

Phone

+64224505345

Fax

f.ramzan@auckland.ac.nz

Contact person for scientific queries

Name

Farha Ramzan

Address

Liggins Institute University of Auckland 85 Park Road Grafton Auckland 1023

Country

New Zealand

Phone

+64224505345

Fax

f.ramzan@auckland.ac.nz

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 (f.ramzan@auckland.ac.nz). To gain access, requests will need to sign a data access agreement.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
16392	Study protocol			f.ramzan@auckland.ac.nz		384193-(Uploaded-22-02-2023-15-06-58)-Study-related document.docx
16393	Informed consent form			f.ramzan@auckland.ac.nz		384193-(Uploaded-28-02-2023-14-42-15)-Study-related document.docx

Results publications and other study-related documents

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No additional documents have been identified.

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