Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000125527
Ethics application status
Approved
Date submitted
9/01/2024
Date registered
12/02/2024
Date last updated
12/06/2024
Date data sharing statement initially provided
12/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of a ginger tincture extract in healthy volunteers.
Scientific title
A First-in-Human, Phase 1, Double-Blind, Randomised, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Ginger Tincture extract (Carelwon®; zingerone 12.5 mg/mL) in Healthy Volunteers.
Secondary ID [1] 311279 0
MRINZ-23-16
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 332842 0
Condition category
Condition code
Inflammatory and Immune System 329202 329202 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Carelwon (zingerone 12.5 mg/ml 4-(4-hydroxy-3-methoxyphenyl)butan-2-one botanical ginger rhizome extract) will be supplied by the Sponsor as an oral tincture solution in ethanol and will be manufactured by Phytex Pty Ltd according to current Good Manufacturing Practice (cGMP). The drug product will be provided to the site dispensing pharmacy in 50 mL amber-coloured bottles containing 25 mL product with child-lock caps.
Carelwon stability studies in the final packaging are ongoing. The drug product should be stored away from light at a stable refrigerated temperature (2-8°C).
A single dose of 4 mL Carelwon contains 50 mg zingerone.

To administer a single dose of Carelwon, a syringe will be used to measure the appropriate volume of the tincture (i.e., 4, 8, or 12 mL).
The Carelwon dose will be diluted into a glass of water (240 mL) and the drink stirred to mix the contents. Participants will be instructed to drink the full volume of water containing the tincture within approximately 5 minutes of preparation.

The study will be conducted in 2 parts, comprised of a single ascending dose (SAD) phase, followed by a multiple ascending dose (MAD) phase. Food effects will be assessed in the SAD phase. The anticipated dose range of Carelwon for investigation in this study is 50, 100 and/or 150 mg. Dose escalation for SAD Cohort A2 (up to a maximum of 150 mg) will be subject to Safety Monitoring Committee (SMC) review of all safety and available PK data from the SAD Cohort A1. An additional SAD Cohort of up to 8 participants (6 active: 2 placebo) may be enrolled to further explore the safety and PK of Carelwon at a lower or intermediate dose. Enrolment of an additional SAD Cohort will be based on the recommendations of the SMC following review of all safety and available PK data from the completed SAD Cohort/s. Dose for the Food Effect Cohort A3 will be determined following SMC review of cumulative safety and PK data from the preceding SAD fasted Cohorts. The dose selected for investigation in the Food Effect Cohort will not exceed the highest dose previously studied in the SAD fasted Cohorts that was determined to be safe and well tolerated by the SMC.

For SAD Cohorts A1, A2 and Food Effect Cohort A3 (Treatment period 1 [fasted]), study treatment will be administered as a single dose on day 1, following an overnight fast of at least 10 hours, with a total of 240 mL of water. Additional water is allowed ad libitum except for the period 1 hour before until 1 hour after drug administration. No additional food will be permitted for at least 4 hours after drug administration.

For the SAD Food Effect Cohort A3 (Treatment period 2 [fed]), participants will have a washout follow-up phase of a minimum of 7 days after dosing on day 1. Following an overnight fast of at least 10 hours, participants will be administered study treatment again as a single dose on day 8 after ingesting a high-fat and high calorie breakfast. The meal should be consumed within a period of 30 minutes. The study treatment will be administered ~30 minutes after the start of meal with a total of 240 mL of water. As described for Treatment period 1, additional water is allowed ad libitum except for the period 1 hour before until 1 hour after drug administration. No additional food will be permitted for at least 4 hours after drug administration.

No strategies will be used to monitor adherence to the intervention in the SAD cohorts, as all study treatments will be administered by trained staff at the clinical site.

Fasting requirements for administration of study treatment in the MAD phase will be confirmed by the Safety Monitoring Committee (SMC) following review of all safety and PK findings from the SAD phase. The dose of Carelwon tested in the MAD phase will not be greater than the highest SAD dose that has been declared as safe and well tolerated by the SMC.

For MAD Cohorts B1 and B2, study treatments will be administered as a single dose by trained staff at the clinical site on Day 1, Day 2, Day 4 and Day 7. Prior to leaving the clinical site on Day 1, MAD cohort participants will be instructed on how to store and self-administer the daily single dose of their assigned dose level of study treatment at home on Day 3, Day 5 and Day 6. Participants will be issued with a study diary to complete at home, where they will record each dose of study treatment as well as any Adverse Events (AEs) and the use of concomitant medications during the treatment period. Diary entries will be reviewed by site staff at each on-site visit during the treatment period.
Intervention code [1] 327731 0
Treatment: Drugs
Comparator / control treatment
Placebo for oral administration will be Herbal Liqueur Flavour Type Italian Bitter flavoured liquid (Berkovitz, 2013) prepared under cGMP conditions and supplied by the Sponsor. The placebo product specification lists the following ingredients: Ethanol (68-72%); flavouring preparations, including extracts from cloves, gentian, cardamon, citrus peel and citrus fruits; and natural flavouring substances. The placebo will be provided in identical packaging to that of the active, and will be administered in a total volume matched to the Carelwon active to ensure no unintentional unblinding occurs. The placebo has been selected to mimic as closely as possible the appearance, smell and taste of the Carelwon active, and dosage specifications, storage conditions and administration instructions are the same for both products.
Control group
Placebo

Outcomes
Primary outcome [1] 337042 0
To evaluate the safety and tolerability as a composite outcome of single and multiple ascending doses of orally administered Carelwon in healthy volunteers.
Timepoint [1] 337042 0
Safety and tolerability will be assessed at screening, prior to dosing on day 1, then post-dose at 15 min, 1 hour, 2 hours, 4 hours, 8 hours and 12 hours; and on day 2 (24hr post-dose) and day 8 (7 dyas post-dose) for Cohorts A1 and A2 (SAD fasted).

Safety and tolerability will be assessed at screening, prior to dosing on day 1, then post-dose at 15 min, 1 hour, 2 hours, 4 hours, 8 hours and 12 hours; on day 2 (24hr post-dose), prior to dosing on day 8, then post-dose at 15 min, 1 hour, 2 hours, 4 hours, 8 hours and 12 hours, on day 9 (24hours) and day 15 (7 days post-dose) for Cohorts A3 (SAD fed).

Safety and tolerability will be assessed at screening, prior to dosing on day 1, then post-dose at 15 min, 1 hour, 2 hours, 4 hours, 8 hours and 12 hours; on day 2 (24hr post-dose), prior to dosing on day 4, then at 15 min and 1 hour post-dose, prior to dosing on day 7, then at 15 min, 1 hour, 2 hours, 4 hours, 8 hours and 12 hours; on day 8 (24 hours post-dose) and on day 14 (7 dyas post-dose) for Cohorts B1 and B2 (MAD).
Secondary outcome [1] 430459 0
To characterise the pharmacokinetics (PK) of single and multiple ascending doses of orally administered Carelwon in healthy volunteers, including the effect of food (high-fat meal)

Blood and urine samples for PK analysis and metabolite profiling will be collected following administration of single and multiple doses of Carelwon in a fasted state.
Blood and urine samples for PK analysis will also be collected following administration of a single dose of Carelwon immediately after ingestion of a high-fat meal.
PK analysis may include but is not limited to plasma and urine concentrations of zingerone and any relevant metabolites. Noncompartmental plasma and urine PK parameters will be determined as data permits.
Timepoint [1] 430459 0
Blood samples for PK analysis and metabolite profiling will be collected on day 1 (within 1 hour prior to dosing and at 10, 20, 30, 45 minutes, 1, 2, 4, 8, and 12 hours post-dose), day 2 (24 hours post-dose), and day 8 for Cohort A1 and A2 (fasted SAD cohorts).

Blood samples for PK analysis and metabolite profiling will be collected on day 1 (within 1 hour prior to dosing and at 10, 20, 30, 45 minutes, 1, 2, 4, 8, and 12 hours post-dose), day 2 (24 hours post-dose), day 8 (within 1 hour prior to dosing and at 10, 20, 30, 45 minutes, 1, 2, 4, 8, and 12 hours post-dose), day 9 (24 hours post-dose) and day 15 for Cohort A3 (fed SAD cohort).

Blood samples for PK analysis and metabolite profiling will be collected on day 1 (within 1 hour prior to dosing and at 10, 20, 30, 45 minutes, 1, 2, 4, 8, and 12 hours post-dose), day 2 (24 hours post-dose), day 4 (within 1 hour prior to dosing), day 7 (within 1 hour prior to dosing and at 10, 20, 30, 45 minutes, 1, 2, 4, 8, and 12 hours post-dose), day 8 (24 hours post-dose) and day 14 for Cohort B1 and B2 (MAD cohorts).

Urine samples for PK analysis and metabolite profiling will be collected on day 1 (within 4 hours prior to dosing, and as pooled samples at 0-4 hours, 4-8 hours and 8-12 hours post-dose) for Cohort A1 and A2 (fasted SAD cohorts).

Urine samples for PK analysis and metabolite profiling will be collected on day 1 (within 4 hours prior to dosing, and as pooled samples at 0-4 hours, 4-8 hours and 8-12 hours post-dose), and day 8 (within 4 hours prior to dosing, and as pooled samples at 0-4 hours, 4-8 hours and 8-12 hours post-dose), for Cohort A3 (fed SAD cohort).

Urine amples for PK analysis and metabolite profiling will be collected on day 1 (within 4 hours prior to dosing, and as pooled samples at 0-4 hours, 4-8 hours and 8-12 hours post-dose), and day 7 (within 4 hours prior to dosing, and as pooled samples at 0-4 hours, 4-8 hours and 8-12 hours post-dose) for Cohort B1 and B2 (MAD cohorts).

Eligibility
Key inclusion criteria
1. Male or female between 18 and 55 years of age, inclusive, at the time of screening.
2. The participant weighs more or equal to 50 kg and has a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive at screening.
3. Participants must be in good physical and mental health as determined by absence of clinically significant (in the opinion of the Investigator) abnormalities based on a medical evaluation including review of medical history, physical examination, safety laboratory tests, vital signs, and 12-lead ECG monitoring at screening and prior to first administration of study treatment on Day 1. Potential participants with a history of childhood asthma (resolved), depression (non-hospitalised, but potentially medicated in the past) and migraine may be considered for study participation. A potential participant with a clinical abnormality or laboratory parameters outside the normal reference range for the population being studied may be re-tested once, at the Investigator’s discretion, and may be included only if the Investigator considers that the finding/s are unlikely to introduce additional risk factors and will not interfere with the study procedures.
Note: The Investigator must first consult the local MM prior to enrolling such a participant, and the local MM will inform the Sponsor as required. All such discussions and the outcomes must be documented.
4. Normal vital signs after more or equal to 5 minutes resting in supine position:
a. Greater than 90 mmHg and less than 160 mmHg systolic blood pressure (SBP)
b. Greater than 40 mmHg and less than 100 mmHg diastolic blood pressure (DBP)
c. Greater than 40 bpm and less than 100 bpm heart rate
d. Body temperature less than or equal to 37.7°C
5. Standard 12-lead ECG parameters after more or equal to 5 minutes resting in supine position with PR greater than 120 msec and less than 220 msec, QRS less than 120 msec, QTcF less than or equal to 450 msec for males and less than or equal to 470 msec for females, and otherwise normal ECG.
6. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or use highly effective contraceptive method (oral contraceptive pills [OCPs], long-acting implantable hormones, injectable hormones, a vaginal ring or an intrauterine device [IUD]) from screening until study completion, including the follow up period for at least 30 days after the last dose of study treatment, or be post-menopausal for greater than or equal to 12 months. Post-menopausal status will be confirmed through testing of follicle-stimulating hormone (FSH) levels (greater than or equal to 25 IU/L) at screening for amenorrheic female participants. Female participants whose only partner has had a vasectomy, and female participants who are abstinent from heterosexual intercourse as part of their usual lifestyle will also be eligible for participation.
7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to administration of the first dose of study treatment on Day 1 and be willing to have additional pregnancy tests as required throughout the study.
8. Males must be surgically sterile (more than 30 days since vasectomy with no viable sperm), abstinent, or if engaged in sexual relations with a WOCBP, the male participant and his partner must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) and/or using an acceptable, highly effective contraceptive method from screening until study completion, including the follow up period, for at least 90 days after the last dose of study treatment. Acceptable methods of contraception include the use of condoms and the use of an effective contraceptive for the female partner (WOCBP) that includes: OCPs, long-acting implantable hormones, injectable hormones, a vaginal ring or an IUD. Male participants whose female partner is post-menopausal, and participants who are abstinent from heterosexual intercourse as part of their usual lifestyle will also be eligible.
9. Male participants must agree to refrain from donating sperm from screening until study completion, including the follow up period, for at least 90 days after the last dose of study treatment.
10. Female participants must refrain from donating oocytes from screening up to at least 90 days after the last dose of study treatment.
11. Participant provides written informed consent and is willing to undergo all study procedures and attend the scheduled follow up visit/s per protocol.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. The participant has uncontrolled, clinically significant neurologic (including seizure disorders), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, or endocrine disease, psychiatric disorder, or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results. It is the responsibility of the Investigator to assess the clinical significance; however, consultation with the MM may be warranted.
2. There is any finding in the participant’s medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking Carelwon, or that might interfere with the conduct of the study.
3. Impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to 2 or total bilirubin greater than or equal to 1.5 x upper limit of normal (ULN), which remains above these limits if re-tested.
4. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of known Gilbert's syndrome or asymptomatic gallstones).
5. Any cardiac/QT risk i.e.
a. Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.
b. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
c. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia, or hypomagnesaemia.
d. ECG abnormalities in the standard 12-lead ECG (at screening) which in the opinion of the Investigator is clinically relevant or will interfere with the ECG analyses on study.
6. The participant has current or recent (within 6 months) gastrointestinal condition that would be expected to influence the absorption of drugs (i.e., a history of malabsorption, oesophageal reflux, peptic ulcer disease, erosive oesophagitis, frequent [more than once per week] occurrence of heartburn, and/or any surgical intervention).
7. The participant has a history of cancer, except basal cell carcinoma or in situ cervical cancer that has been in remission for more than or equal to 5 years prior to first dose of study treatment.
8. Any prior allergies to ginger or ginger-containing products or the participant has a known hypersensitivity to any component of the Carelwon formulation.
9. Consumption of any ginger-containing products within 48 hours or 5 half-lives of those products prior to Day 1 and until completion of the last onsite visit (7 days after last administered dose of study treatment). Participant must abstain from ginger-containing foods which may include: curry dishes with ginger paste, gingerbread, muffins, Chinese stir fry, sushi, soups, apple cake, ginger tea, ginger juice, ginger beer, ginger ale, ginger candy, ginger-containing cocktails, ginger chutney, ginger murabba, ginger cookies, food cooked with ginger seasoning.
10. Participant has a diagnosed bleeding disorder (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with blood draws or is unable to provide a blood sample without undue trauma or distress, or has poor peripheral venous access and is unsuitable for cannulation or repeated venipuncture.
11. The participant has any dietary restrictions or preferences that may interfere with the conduct of the study, including being vegetarian or vegan; being unwilling to abstain from consumption of foods containing poppy seeds (i.e., poppy seed bagels, baked goods with poppy seeds) from 48 hours prior to administration of the study treatment, and from at least 48 hours prior to any scheduled site visits through to the last onsite visit (7 days after the last administered dose); and being unwilling to abstain from consumption of grapefruit, pomelo, or Seville orange whole fruits or juice for 7 days before dosing on Day 1 through to the last onsite visit (7 days after the last administered dose).
12. A history of hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection and/or a positive pre-study HIV, hepatitis B surface antigen or positive hepatitis C antibody result within 3 months of screening.
13. A positive pre-study drug or alcohol screen (see Note). A positive drug or alcohol screen test result may be verified by re-testing (up to 1 false positive result permitted) and may be followed up at the discretion of the Investigator.
Note: Participants may undergo alcohol breath testing at the discretion of the Investigator and per site local practices.
14. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of more than 21 units for males or more than 14 units for females. One unit is equivalent to 10 g of alcohol and the following can be used as a guide: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (30 mL) measure of spirits.
15. The participant is unwilling to abstain from alcohol consumption for 48 hours prior to dosing, and for 24 hours prior to all other outpatient visits to the CRU.
16. The participant is a regular smoker or vaper of more than 5 cigarettes (equivalent to 5 e-cigarettes/1 cigar/1 pipe) a day and is unable to stop smoking or vaping for the duration of the study.
17. Regular excessive consumption of beverages containing xanthine bases, including Red Bull, chocolate, coffee etc. equivalent to more than 400 mg caffeine per day (equivalent to more than 4 cups per day).
18. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of study treatment, unless in the opinion of the Investigator, local MM and Sponsor medical representative the medication will not interfere with the study procedures or compromise participant safety.
19. Participants having received any type of vaccination within 2 weeks of anticipated dosing of study treatment or are expected to be vaccinated within 2 weeks post-dosing.
20. Donation within the last 3 months of whole blood (more than 499 mL) and/or within 2 weeks of plasma donation.
21. Participation in a clinical trial within 30 days before enrolment; use of any experimental therapy within 30 days or 5 half-lives prior to enrolment, whichever is greater; or use of any biologic therapy within 12 weeks or 5 half-lives prior to enrolment, whichever is greater.
22. Participant has a planned elective surgical procedure during the study.
23. Participant who is pregnant, or is planning to become pregnant during the study period or is breastfeeding.
24. Participant unable to provide written informed consent or participant under guardianship.
25. Unwilling or unable to follow protocol requirements, including diary completion (where applicable) and attendance at follow up visit/s, or otherwise unsuitable for study participation in the opinion of the Investigator.

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)
The randomisation schedule will be generated by an independent statistician and provided to the unblinded study pharmacist. Once deemed eligible for study participation, the participant will be enrolled and randomised by being assigned a sequential randomisation number based on a randomisation schedule, prior to the commencement of treatment with the study treatment. This randomisation number together with the participant’s identification number assigned at screening will ensure identification throughout the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
40 evaluable participants will be sequentially enrolled and randomised in a 3:1 ratio (active:placebo)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2024
Actual
10/05/2024
Date of last participant enrolment
Anticipated
2/09/2024
Actual
Date of last data collection
Anticipated
1/10/2024
Actual
Sample size
Target
40
Accrual to date
6
Final
Recruitment outside Australia
Country [1] 26066 0
New Zealand
State/province [1] 26066 0

Funding & Sponsors
Funding source category [1] 315533 0
Commercial sector/Industry
Name [1] 315533 0
Evithé Biotechnology Ltd.
Country [1] 315533 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
Evithé Biotechnology Ltd.
Address
7 Ardal Grove, Lower Hutt 5010, Wellington
Country
New Zealand
Secondary sponsor category [1] 317624 0
None
Name [1] 317624 0
Address [1] 317624 0
Country [1] 317624 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314433 0
Health and Disability Ethics Committee
Ethics committee address [1] 314433 0
Ethics committee country [1] 314433 0
New Zealand
Date submitted for ethics approval [1] 314433 0
09/01/2024
Approval date [1] 314433 0
13/02/2024
Ethics approval number [1] 314433 0
2024 FULL 19276

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

Contacts
Principal investigator
Name 131566 0
Dr Alexander Semprini
Address 131566 0
Medical Research Institute of New Zealand, 7 CSB Wellington Regional Hospital Riddiford Street, Newtown, Wellington 6021
Country 131566 0
New Zealand
Phone 131566 0
+64 21427527
Fax 131566 0
Email 131566 0
[email protected]
Contact person for public queries
Name 131567 0
Michaela Walton
Address 131567 0
Medical Research Institute of New Zealand, 7 CSB Wellington Regional Hospital Riddiford Street, Newtown, Wellington 6021
Country 131567 0
New Zealand
Phone 131567 0
+64 4 805 0244
Fax 131567 0
Email 131567 0
[email protected]
Contact person for scientific queries
Name 131568 0
Alexander Semprini
Address 131568 0
Medical Research Institute of New Zealand, 7 CSB Wellington Regional Hospital Riddiford Street, Newtown, Wellington 6021
Country 131568 0
New Zealand
Phone 131568 0
+64 21427527
Fax 131568 0
Email 131568 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?
Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
When will data be available (start and end dates)?
One year after publication until a minimum of 5 years after publication.
Available to whom?
Researchers who provide a methodologically sound proposal that has been approved by the Sponsor.
Available for what types of analyses?
To achieve the aims outlined in the approved proposal
How or where can data be obtained?
Proposals should be directed to Mrs Michaela Walton via email ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21343Study protocol    This document will be made available during the st... [More Details]
21344Ethical approval    387127-(Uploaded-20-05-2024-07-23-44)-Study-related document.pdf



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