A Dose-escalation Study to Investigate Safety and Toleration of OZ439

Study Overview
=================
Brief Summary
-----------------
A randomised, placebo-controlled, dose-escalation study to investigate safety and toleration of OZ439 OD for 3 days to healthy male and female volunteers. The study aims: To determine the safety and tolerability of ascending doses of OZ439 OD for three days. To assess pharmacokinetic parameters of ascending doses of OZ439 given OD. To identify the maximum tolerated dose of OZ439 administered.

Detailed Description
-----------------
This study will be conducted in a randomised, placebo-controlled dose-escalation design with OZ439 OD administered with full fat milk for three days to healthy male and female subjects between 18 to 55 years of age, using features of an adaptive study design. The study is expected to have three cohorts with a total of 36 healthy male and female subjects. An additional two cohorts may be used if required. The results of this study will inform the maximum tolerated exposure of OZ439 following OD dosing for three days in subjects who are not fasted.

Official Title
-----------------
A Randomised, Placebo-controlled, Dose-escalation Study to Investigate Safety and Toleration of OZ439 OD for 3 Days to Healthy Male and Female Volunteers

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Drug: OZ439


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusions: healthy males or females of any race aged 18 - 55 years BMI of 18 - 30 kg/m2 inclusive at screening Agree to use acceptable methods of contraception if of childbearing potential Capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form Females are either of child bearing potential or are confirmed as post-menopausal. Post-menopausal is defined as being amenorrheic for 12 months without an alternative medical cause with a screening FSH level ≥ 25.8 IU/L Exclusions: Male subjects with female partner(s) who is (are) pregnant or lactating from the time of the first administration of study medication Clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion History of allergic reactions to artemisinin-based compounds or any other clinically relevant allergy to drugs or food Clinically relevant history of both soya and cow's milk intolerance/allergy Clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations conducted at screening or on admission Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening) and/or 24-hour 5 lead Holter ECG (at screening) Any abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes Prolonged QTcF >450 ms or shortened QTcF <340 ms, or family history of Long QT Syndrome History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrinological, metabolic, neurological, psychiatric, or other disease Positive results in any of the serology tests for Hepatitis B Surface Antigen (HbsAg), anti Hepatitis core antibody (anti HBc Ig G [and anti HBc IgM if IgG is positive], Hepatitis C antibodies (anti HCV), and HIV 1 and 2 antibodies (anti HIV 1/2) Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol breath test at screening and on admission History or clinical evidence of alcohol or drug abuse. Alcohol abuse is defined as regular weekly intake of more than 21 units for males and 14 units for females; drug abuse is defined as compulsive, repetitive and/or chronic use of drugs or other substances with or without problems related to their use and/or where stopping or a reduction in dose will lead to withdrawal symptoms Is pregnant or lactating (female subjects who are of childbearing potential must have negative pregnancy tests at screening and admission) Mentally handicapped Participation in a drug trial within 90 days prior to first drug administration Use of any medication (incl. over-the-counter (OTC) medication) within 2 weeks prior to drug administration (Day 1) or within less than 10 times the elimination half-life of the respective drug, or anticipated concomitant medication during the treatment periods, (whichever is longer), including herbal, traditional and alternative medications. Excluding oral contraceptives (combination oestrogen/progesterone pills), injectable progesterone or subdermal implants. Limited amounts (4g/day for 2 days) of paracetamol will be permitted for the treatment of AEs Treatment with herbal supplements during the 7 days prior to drug administration, or use of vitamins during 48 hours prior to drug administration Is not permitted to use strong inhibitors and/or inducers of CYP450 within 21 days prior to the planned first drug administration Subjects have veins unsuitable for intravenous puncture or cannulation on either arm (e.g. veins that are difficult to locate, access or puncture veins with a tendency to rupture during or after puncture) Blood ALT, AST and bilirubin should be in the normal range at screening and on admission Donation of more than 500 mL of blood within 90 days prior to drug administration Subjects must be non-smokers for at least three months prior to first drug administration Any circumstances or conditions, which, in the opinion of the PI, may affect full participation in the trial or compliance with the protocol Legal incapacity or limited legal capacity at screening Subjects who are vegetarians, vegans or have any dietary restrictions conflicting with the study standardised menus

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OZ439 Dose level 1 (300mg)<br>• Cohort 1 (12 subjects: 8 Active [A] and 4 on Placebo [P]) Active dose will consist of 300mg OZ439 drinking solution administered once daily for 3 days | Drug: OZ439<br>* OZ439 x mg once daily for 3 days with milk<br>|
| Experimental: OZ439 Dose level 2<br>• Cohort 2 (12 subjects: 8 A, 4P). Subjects on active will receive X amount of OZ439 (dose level to be determined based on safety and tolerability of previous dose level) drinking solution once daily for 3 days | Drug: OZ439<br>* OZ439 x mg once daily for 3 days with milk<br>|
| Experimental: OZ439 dose level 3<br>Cohort 3 (12 subjects: 8 A, 4P). Subjects on active will receive X amount of OZ439 (dose level to be determined based on safety and tolerability of previous dose level) drinking solution once daily for 3 days | Drug: OZ439<br>* OZ439 x mg once daily for 3 days with milk<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OZ439 Cmax | OZ439 maximum measured plasma concentration | Blood for analysis of OZ439 will be collected at the following times: pre-dose, 2, 4, 6, 8, 12, and 18 hours post-dose Day 1and Day 3, pre dose Day 2 and 4 hours post dose Day 2, and 24, 48, 72, 96 and 168 hours post 3rd dose and at follow up. | 
| OZ439 AUCτ | OZ439 Area under the plasma concentration vs time curve from time zero to the time of the last quantifiable concentration t calculated using a log-linear trapezoidal method | pre-dose, 2, 4, 6, 8, 12, and 18 hours post-dose Day 1and Day 3, pre dose Day 2 and 4 hours post dose Day 2, and 24, 48, 72, 96 and 168 hours post 3rd dose and at follow up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OZ439 Tmax | Time to reach maximum measured OZ439 plasma concentration | pre-dose, 2, 4, 6, 8, 12, and 18 hours post-dose Day 1and Day 3, pre dose Day 2 and 4 hours post dose Day 2, and 24, 48, 72, 96 and 168 hours post 3rd dose and at follow up. | 
| OZ439 t½ | OZ439 estimated terminal phase half life | pre-dose, 2, 4, 6, 8, 12, and 18 hours post-dose Day 1and Day 3, pre dose Day 2 and 4 hours post dose Day 2, and 24, 48, 72, 96 and 168 hours post 3rd dose and at follow up. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
malaria, dose escalation, safety, tolerability, maximum tolerated dose