None listed
Conditions
Brief summary
This is a first-in-human (FIH), Phase 1, randomised, double-blind, placebo-controlled study to investigate the safety, tolerability, and PK of single and multiple ascending oral doses of the investigational anti-inflammatory botanical drug Carelwon (zingerone 12.5 mg/mL) in healthy adult participants. The food effect on CarelwonTM PK following ingestion of a high-fat meal will also be evaluated. Evithé Pty Ltd has developed CarelwonTM, an investigational botanical drug processed from the ginger rhizome and administered as a tincture. The main active component of CarelwonTM ginger tincture is zingerone. CarelwonTM offers a novel approach to Rheumatoid Arthritis (RA) management. RA is a chronic, systemic, inflammatory autoimmune disease. It is the most common cause of inflammatory joint pain, swelling and stiffness involving multiple joints, and leading to joint damage and functional disability in adults. Since inflammation is a key factor in the pathophysiology of RA, the major target by the CarelwonTM therapy, is to reduce or reverse inflammation. Zingerone, an anti-inflammatory compound found in ginger, holds promise for reducing synovial inflammation and modulating immune responses. By targeting key inflammatory pathways, the product aims to alleviate joint pain, swelling, and stiffness associated with RA, while potentially slowing disease progression. Its natural origin and anti-inflammatory properties present an exciting avenue to address the unmet needs in RA therapy, offering patients a more holistic and potentially safer option for improving their quality of life. This study is intended to evaluate the safety, tolerability, and pharmacokinetics of CarelwonTM when administered to healthy adult participants. The results of this study will inform the sponsor as well as the clinical investigators about the validity for the continued development of CarelwonTM as a potential safe and effective alternative to current treatments in RA.
Interventions
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
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
Sponsors
Evithé Biotechnology Ltd.
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
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.
Outcome results
None listed