Safety, Tolerability, Pharmacokinetics, and Food Effect Study of RV299 in Healthy Adults

A Randomised, Double Blinded, Placebo-controlled Single and Multiple Ascending Dose Study of Orally Administered RV299 to Evaluate Safety, Tolerability, Pharmacokinetics and Food Effect in Healthy Adult Participants

The main aims of the study are to assess the safety, tolerability, pharmacokinetics and food effects of RV299 compared to Placebo in healthy adult participants.

The study consists of three parts: single ascending dose (Part A), multiple ascending doses (Part B) and food effect (Part C) in Caucasian participants.

This is a randomised, double blind, placebo-controlled Phase I study to assess the safety, tolerability, pharmacokinetics and food effect of RV299 in healthy participants aged ≥ 20 to ≤ 40 years.

The clinical study consists of 3 parts (Parts A - C):

Part A: single ascending doses (SAD) of RV299 in healthy adult Caucasian participants (up to 3 dose levels of RV299 in 3 cohorts; 6 participants/cohort)

Part B: multiple ascending doses (MAD) of RV299 in healthy adult Caucasian participants (up to 2 dose levels of RV299 in 2 cohorts of 8 participants dosed for 5 consecutive days). Part B will incorporate a drug-drug interaction (DDI) design to investigate interaction between RV299 and midazolam in one cohort (Cohort 3) of 8 participants.

Part C: food effect (FE) in healthy adult Caucasian participants (one cohort of 8 participants to be randomised to receive either RV299 in the first treatment period fasted and in the second treatment period fed, or vice versa)

The study will be conducted as an adaptive integrated design since various study parts can be triggered at appropriate times during the conduct of other parts of the study. Dose escalation to the following scheduled dose or progression to a consecutive part of the study will only occur after satisfactory review of all safety, tolerability and pharmacokinetic (PK) data.

Inclusion Criteria:

1. Male or Female, Caucasian, aged greater than or equal to 20 to less than or equal to 40 years at the date of signing informed consent.
2. Participants in Caucasian cohorts should be distinguished by very light to brown skin pigmentation and straight to wavy or curly hair, and should be indigenous to Europe, northern Africa, western Asia, India. This includes Caucasian participants from North America, Australia and South Africa.
3. Healthy as defined by: a) the absence of clinically significant illness and surgery within four weeks prior to dosing; b) the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, haematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
4. Participants must agree to use contraceptive requirements as described in the study protocol for the applicable duration.
5. Participants must agree not to donate sperm or ova from the time of the first administration of trial medication until 3 months after three months after the last follow-up visit.
6. Participants must have a body mass index (BMI) between 18.0-25.0 kg/m² inclusive at screening.
7. Satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluation that is reasonably likely to interfere with the participant's participation in or ability to complete the trial as assessed by the Investigator.
8. Ability to provide written, personally signed, and dated informed consent.
9. An understanding, ability, and willingness to fully comply with trial procedures and restrictions.

Exclusion Criteria:

1. Current or recurrent disease (e.g., cardiovascular, haematological, neurological, endocrine, immunological, renal, hepatic or gastrointestinal or other conditions) that could affect the action, absorption, or disposition of RV299, or could affect clinical assessments or clinical laboratory evaluations.
2. Current or relevant history of physical or psychiatric illness that are not stable or may require a change in treatment, use of prohibited therapies during the trial or make the participant unlikely to fully comply with the requirements of the trial or complete the trial, or any condition that presents undue risk from the investigational product or trial procedures.
3. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial may influence the result of the trial, or the participant's ability to participate in the trial.
4. Use or intention to use any medications/products that are known inhibitors of the CYP3A4 enzymes or substrates of Aldehyde oxidase (AO), Pglycoprotein (PgP) or Breast Cancer Resistance Protein (BCRP) for 2 weeks prior to Day 1 of the dosing period up to the follow-up visit. (The Indiana University (2016) "Cytochrome P450 Drug Interaction Table" should be utilized to determine inhibitors of CYP3A) (http://medicine.iupui.edu/clinpharm/ddis/table.aspx).
5. The history or presence of any of the following cardiac conditions known structural cardiac abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; exercise related clinically significant cardiac events.
6. Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or clinically important abnormalities that may interfere with the interpretation of QTc interval changes. (Participants with borderline abnormalities may be included if the deviations do not pose a safety risk, and if agreed between the appointed Cardiologist and the PI.)
7. Has vital signs outside of the following normal range at screening or Day -1/Day-2.
8. Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening;
9. Has a haemoglobin, platelet count, total white blood cell count, lymphocyte or monocyte count less than lower limit of normal (LLN) (up to two repeats may be taken).
10. Has total bilirubin, ALT or AST consistently greater than ULN at Screening (up to two repeats may be taken).
11. Any other abnormal findings on vital signs, ECG, physical examination or laboratory evaluation of blood and urine samples that the Investigator judges as likely to interfere with the trial or pose an additional risk in participating.
12. Positive test results for alcohol or drugs of abuse at screening or Day-1/Day-2.
13. History or clinical evidence of substance and/or alcohol abuse within the 2 years before screening.
14. Treatment with an investigational drug within 90 days or 5 half-lives preceding the first dose of trial medication (or as determined by the local requirement, whichever is longer).
15. Use of tobacco in any form (e.g., smoking or chewing) or other nicotine containing products in any form (e.g., gum, patch, electronic cigarettes) within 3 months prior to the planned first day of dosing.
16. Has used any other prescription medication within 14 days or 10 half-lives (whichever is longer) prior to Day 1 of the dosing period that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating.
17. Has used any over-the-counter medication (including multivitamin, herbal, or homeopathic preparations; excluding paracetamol - up to 2g paracetamol per day permitted) during the 7 days or 10 half-lives of the drug (whichever is longer) prior to Day 1 of the dosing period, that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating.
18. Consumption of herbal remedies or dietary supplements containing St. John's Wort in the three weeks before the planned Day 1 of the dosing period.
19. Known or suspected intolerance or hypersensitivity to the investigational product, any closely related compound, or any of the stated ingredients.
20. History of significant allergic reaction (anaphylaxis, angioedema) to any product (food, pharmaceutical, etc).
21. Donation of blood or blood products (excluding plasma) within 90 days prior to trial medication administration.
22. Has a mental incapacity or language barriers precluding adequate understanding, co-operation, and compliance with the trial requirements.
23. An inability to follow a standardised diet and meal schedule or inability to fast, as required during the trial.
24. Participants with veins on either arm that are unsuitable for intravenous puncture or cannulation.
25. Prior screen failure (where the cause of the screen failure is not deemed to be temporary), randomisation, participation, or enrolment in this trial. Participants who initially failed due to temporary non-medically significant issues are eligible for re-screening once the cause has resolved.
26. Participants who have received or are planning on receiving a COVID-19 vaccination two weeks before first dose administration, or within one week after the final follow-up visit for the study.
27. Known or suspected intolerance or hypersensitivity to the investigational product, the non-investigational product (midazolam), any closely related compound, or any of the stated ingredients.
28. Female participants currently on combined hormonal contraception or hormonal replacement therapy containing oestradiol or ethinyloestradiol.