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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
21/04/2025
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 (67% v/v) 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 Data Safety Monitoring Committee (DSMC) 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. Enrolment of an additional SAD Cohort will be based on the recommendations of the DSMC 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 DSMC review of cumulative safety and available PK data from the preceding SAD fasted Cohorts. The dose selected for investigation in the fed phase of 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 DSMC.

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.

MAD cohort participants will receive either a single QD oral dose of Carelwon™ or placebo for 7 days (Cohort B1) or BID oral doses of Carelwon™ or placebo for 7 days (Cohort B2), per assigned treatment group. For participants in MAD Cohort B2, BID dosing will occur at an interval of approximately 12 hours each day.
The dose of Carelwon tested in the first MAD cohorts (B1) will not be greater than the highest SAD dose that has been declared as safe and well tolerated by the DSMC.
Following DSMC review of safety and tolerability data from at least 7 days post last administered dose (i.e., findings up to and including the Day 14 ± 1 day visit), from all participants in the MAD B1 ongoing cohort, as well as cumulative safety data available from the completed SAD cohorts, initiation of the MAD B2 cohort may proceed based on the recommendations of the DSMC.

All MAD cohort participants will receive their first dose of assigned study treatment on the morning of Day 1 following an overnight fast of at least 10 hours. Study treatment will be administered under fasted conditions with a total of 240 mL of water. Water is permitted except for the period 1 hour before until 1 hour after administration of study treatment. Participants should not consume any food for 4 hours after the first dose of study treatment.
Participants in MAD Cohort B2 will take their evening dose of study drug onsite at the CRU on Day 1. Study treatment for the evening dose on Day 1 will be taken orally with a total of 240 mL of water at least 1 hour before or 2 hours after a meal, with no other fasting requirements. Participants in MAD Cohort B2 will also take both doses of study treatment (morning and evening) onsite at the CRU on Day 7.
Fasting requirements for dosing of MAD Cohort B1 and B2 participants on Day 7 will apply as described for administration of study treatment on Day 1. For MAD Cohort B1, dosing on Day 7 will occur within 1 hour (i.e., ± 1 hour) of the time of administration of the first dose on Day 1. For MAD Cohort B2, the Day 7 morning dose of study treatment should be taken within 1 hour (i.e., ± 1 hour) of the time of administration of the first dose on Day 1. The Day 7 evening dose of study treatment should be taken approximately 12 hours after the Day 7 morning dose.
For MAD Cohort B1, dosing on days 2, 3, 4, 5 and 6 will occur within 1 hour (i.e., ± 1 hour) of the time of administration of the first dose on Day 1, with a total of 240 mL of water and at least 1 hour before or 2 hours after a meal, with no other fasting requirements.
For MAD Cohort B2, dosing on days 2, 3, 4, 5 and 6 will be taken with a total of 240 mL of water and at least 1 hour before or 2 hours after a meal, with no other fasting requirements. The morning dose of study treatment should be taken within 1 hour (i.e., ± 1 hour) of the time of administration of the first dose on Day 1. The evening dose of study treatment should be taken approximately 12 hours after the morning dose.
All MAD cohort participants will take their dose of study treatment (morning dose only for Cohort B2) onsite at the CRU on Day 2 and Day 4.

Participants in the MAD cohorts will be instructed on how to store, and self-administer their daily dose of study treatment on Day 3, Day 5 and Day 6 and will be issued a study diary in which to record the details of each self-administered dosing (dose and time of administration), as well as any Adverse Event (AE) or use of concomitant medications. Diary entries will be reviewed by site staff at each on-site visit during the treatment period.

Note: for participants in the MAD cohorts, the consumption of caffeine-containing products is not permitted from at least 10 hours prior to scheduled onsite visit days until after completion of all specified assessments/sample collections for that visit. For example, consumption of caffeine-containing products is prohibited from at least 10 hours prior to until after the last assessment/sample collection on the following study days:
MAD Cohort B1 and B2: Day 1, Day 2, Day 4, Day 7, Day 8, Day 14
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% v/v); 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 days 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. Note: Owing to ongoing bioanalytical method development, the results of PK analyses may be reported separately in an addendum to the final study report, pending availability of data.
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. 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 (excluding that contained in the IP and placebo) for 48 hours prior to the first administered dose of study treatment on Day 1, and for the duration of dosing during the treatment period. Alcohol consumption is also not permitted for 24 hours prior to all other scheduled onsite 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 drink, coffee, tea, chocolate etc. equivalent to more than 400 mg caffeine per day (equivalent to more than 4 cups per day, or 250g chocolate). Additionally, for participants in the MAD cohorts, the consumption of caffeine-containing products is not permitted from at least 10 hours prior to scheduled onsite visit days until after completion of all specified assessments/sample collections for that visit.
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?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
ANALYSIS
Statistical methods will be outlined in a statistical analysis plan (SAP), which will be finalised before the final database lock.
Results will be presented by study part, treatment group (dose/regimen) and for all participants overall (as appropriate). All placebo data (fasted only) will be pooled.
The baseline result will be the last available non-missing pre-dose assessment collected/assessed prior to the first study treatment administration. Separate baselines will be derived for the fasted and fed periods of SAD Food Effect Cohort A3.
Continuous endpoints will be summarised using descriptive statistics (sample size [n], arithmetic mean, standard deviation [SD], median, minimum, and maximum). Categorical endpoints will be summarised using counts and percentages (%).

POPULATION

SAMPLE SIZE RATIONALE
There are no formal calculations of sample size for this study. The sample size has been chosen based on feasibility, to allow preliminary characterisation of safety and tolerability and PK of single and multiple ascending doses of Carelwon™ administered orally to healthy participants.

ANALYSIS SETS
The following analysis sets are defined for the study:
Intention-to-treat (ITT) set: includes all randomised participants. Participants in the ITT set will be analysed according to their assigned treatment, regardless of which study treatment they received (Carelwon™ or placebo). The ITT set will be used for the summaries of disposition and all baseline and demographic data. In addition, all listings will be produced using the ITT set.

Safety set: includes all randomised participants who receive at least 1 dose of the study treatment. Participants in the Safety set will be analysed by study part, according to the study treatment they received. The Safety set will be used to summarise safety and tolerability data.

PK set: includes all participants in the Safety set who have at least 1 blood and urine sample collected and analysed for plasma and urine drug concentration. The PK set will be used to summarise the plasma and urine concentrations and PK parameters of zingerone and any relevant metabolites.
Participant inclusion into each analysis set will be determined after database lock and prior to unblinding for the final analysis.

STATISTICAL ANALYSIS:

DISPOSITION
A disposition listing will present date of informed consent, date of randomisation, date of the first and last administrations of study treatment, treatment/study completion or study discontinuation, the reason for discontinuation, and whether included in each analysis set, for each participant.
Number of participants that completed and discontinued the study as well as reasons for discontinuation will be summarised by treatment group.
A listing of participants that did not meet all inclusion and/or met exclusion criteria (including a details of the applicable criteria), will also be presented.

DEMOGRAPHICS
All demographic data recorded at screening will be listed and summarised descriptively.

BASELINE CHARACTERISTICS
Medical history will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA®) available at the time of study commencement and will be presented in a by participant data listing.
Prior and concomitant medications will be coded using the latest version of the World Health Organisation Drug Dictionary (WHODrug) available at the time of study commencement. Medications will be mapped to the anatomical therapeutic chemical (ATC) Levels 2, and preferred name (PN), as the primary interest for the analysis.
Prior and concomitant medications are defined as follows:
• Prior medications are defined as any medication taken within 28 days before the first dose of the study treatment where the use was stopped prior to the date of first administration of the study treatment.
• Concomitant medications are defined as any medication (other than the study treatment) that was used at least once on or after the date of first administration of the study treatment through 30 days after the last dose of study treatment.

SAFETY ANALYSIS
Statistical methods for the safety analyses will be primarily descriptive in nature and will be performed for the Safety set.
Adverse event data will be coded using the most current MedDRA® dictionary available at the time of study commencement. All AE data will be listed for each participant including a separate listing of SAEs. All AE summaries will include treatment emergent AEs (TEAEs) only, where TEAEs are defined as AEs that commence on or after the time of first study treatment administration. Treatment emergent AEs will be summarised by MedDRA® system organ class (SOC) and preferred term (PT). Summaries of TEAEs by MedDRA® SOC and PT, maximum severity and strongest relationship to study treatment will also be presented.
All AE data will be summarised by treatment and overall, for each study part.
Vital signs assessments and ECG parameters will be listed for each participant and summarised by treatment and protocol specified collection time point. A summary of change from baseline results at each protocol specified time point will also be presented.
Changes in physical examinations will be listed for each participant and described in the text of the final report.

PHARMACOKINETICS ANALYSIS
All analyses will be based on the PK set.
Owing to ongoing bioanalytical method development, the results of PK analyses may be reported separately in an addendum to the final study report, pending availability of data.

Plasma PK:
Plasma concentrations of zingerone and any relevant metabolites will be listed by individual participant. The plasma concentrations of zingerone and any relevant metabolites after single and multiple oral doses of Carelwon™ will be summarised (n, arithmetic mean, SD, coefficient of variation [%CV], minimum, median, and maximum, geometric mean and geometric %CV) by treatment and nominal sampling time point to assess systemic exposure. Individual and mean PK concentration time profiles will be presented graphically on linear and semi-logarithmic scales.
Where data are sufficient for parameter determination, plasma noncompartmental PK parameters will be estimated for zingerone and any relevant metabolites based on the concentration time profiles.
The methodology for the calculation of PK parameters will be described in detail in the SAP. The actual PK sampling time points will be used for PK analysis.
PK parameters will be listed for each participant and summarised by study part and treatment with descriptive statistics (n, arithmetic mean, SD, %CV, minimum, median, and maximum, geometric mean and geometric %CV).
Appropriate validated PK software will be used for the estimation of all PK parameters.

Dose Proportionality Assessment (SAD and MAD):
Dose proportionality will be assessed based on the Day 1 (SAD and MAD) and Day 7 (MAD) Cmax, AUC0-last and AUC0-inf, using box-and-whiskers plots, and more formally using a power regression model.

Food Effect Assessment (SAD Cohort A3 Only):
The food effect will be determined by comparing plasma PK of Carelwon™ administered without food (reference) with the identical dose of Carelwon™ administered after ingesting a high-fat meal (test). An analysis of variance with treatment as a fixed effect and participant as a random effect will be performed. Cmax, AUC0-last and AUC0-inf will be natural log-transformed prior to analysis. The geometric mean ratios and the corresponding 90% confidence intervals of the test group relative to the reference group will be presented.

Urine PK (SAD and MAD):
Urine PK parameters will be estimated from the urine concentrations of zingerone (and potential metabolites) using noncompartmental methods and appropriate validated PK software, as applicable. Additional parameters may be estimated, as appropriate.
Concentrations will be used for the PK analysis as reported by the bioanalytical laboratory. Urine volumes will be presented and used as supplied from the clinical data base. The handling of values that are below the limit of quantitation will be addressed in the SAP.

PLANNED INTERIM ANALYSIS
No formal interim analysis is planned.
The final analysis will be conducted after the database has been locked, unblinded, and released for statistical analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2024
Actual
10/05/2024
Date of last participant enrolment
Anticipated
24/03/2025
Actual
Date of last data collection
Anticipated
25/04/2025
Actual
Sample size
Target
40
Accrual to date
32
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 the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers who provide a methodologically sound proposal that has been approved by the Sponsor.

Conditions for requesting access:
• -

What individual participant data might be shared?
• Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).

What types of analyses could be done with individual participant data?
• To achieve the aims outlined in the approved proposal

When can requests for individual participant data be made (start and end dates)?
From:
One year after publication until a minimum of 5 years after publication.

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?
• Proposals should be directed to Mrs Michaela Walton via email ([email protected])

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21344Ethical approval    Study-related document.pdf



Results publications and other study-related documents

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