Clinical trial NCT01732588: A Comparison of the Bioavailability of OZ439 When Delivered Directly to the Small Intestine, or Via the Oral Route
Official title: Three Way Randomised CrossOver Study in Healthy Subjects to Compare the Relative Bioavailability of Nanoparticulate OZ439 Delivered Via the Enterion™ Capsule to the Proximal Small Bowel With Orally Administered OZ439 as PIB Suspension and Orally Administered Nanoparticulate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Bioavailability
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
First posted: 2012-11-26
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to determine the bioavailability of nanoparticulate OZ439 delivered to the proximal small bowel (PSB) via the Enterion™ capsule relative to oral OZ439 suspension (current "powder in bottle" \[PIB\]) and oral nanoparticulate OZ439.

The study will also characterise the plasma concentration time profile of OZ439 when delivered via Enterion capsule to the PSB in comparison with OZ439 PIB formulation delivered orally and nanoparticulate OZ439 delivered orally Safety and tolerability of OZ439 formulations will be determined following delivery to the PSB and administered orally

Detailed description: Previous clinical studies with OZ439 have shown variable PK and a food effect. One hypothesis is that this may be related to a 'common ion effect' leading to precipitation of the drug as a less soluble hydrochloride salt in the stomach, resulting in variable absorption of the drug. This study is designed to investigate the possibility of improving the PK profile by delivering the drug directly to the PSB, thereby bypassing the stomach. The study will compare a previously dosed PIB formulation with oral delivery of a nanoparticulate as a caplet formulation. The same caplet formulation containing nanoparticulate will be administered to the PSB via the Enterion capsule.

Eligibility criteria: Inclusion Criteria:

1. Healthy males, or females of non-childbearing potential ie surgically sterilised or post-menopausal
2. Age 18 to 55 years
3. Body mass index of 18 to 30 kg/m2 inclusive
4. Total body weight \>50 kg
5. Healthy as determined by pre-study medical history, physical examination (including body temperature) and 12-lead ECG
6. Must have haematology, clinical chemistry and urinalysis results at screening that are within the reference range or ncs
7. Must agree to use an adequate method of contraception
8. Must demonstrate their ability to swallow an empty size 000 capsule
9. Must be willing and able to communicate and participate in the whole study
10. Must provide written informed consent

Exclusion Criteria:

1. Evidence or history of clinically significant oncological, pulmonary, chronic respiratory, hepatic, cardiovascular, haematological, metabolic, neurological, immunological, nephrological, endocrine or psychiatric disease, or current infection
2. Clinically relevant abnormalities in the ECG (12 standard leads) and/or QTcF \>450 ms (males) or \>470 ms (females)
3. Evidence or history of clinically significant GI disease or surgery (excluding appendectomy or cholecystectomy)
4. Any condition that could possibly affect drug absorption, eg gastrectomy or diarrhoea
5. History of post-antibiotic colitis
6. History of any drug or alcohol abuse in the past 2 years prior to screening
7. Subjects who have a breath carbon monoxide reading of greater than 10 ppm at screening. Subjects who are tobacco users (including smokers and users of snuff, chewing tobacco and other nicotine or nicotine-containing products) must have stopped use within 90 days before screening
8. Receipt of an investigational drug or participation in another clinical research study within the previous 3 months
9. Subjects who are study site employees, or immediate family members of a study site or sponsor employee
10. Subjects who have previously been enrolled in this study
11. Use of any prescription or non-prescription medications, vitamins, herbal supplements or dietary supplements within 14 days prior to the first dose
12. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab)or human immunodeficiency virus (HIV-1 or HIV-2 antibody) results
13. Positive urine drug screen result
14. History of intolerance or hypersensitivity to artemisinins
15. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients
16. Presence or history of allergy requiring treatment; hayfever is allowed unless it is active
17. Donation or loss of \>400 mL of blood within the previous 3 months
18. Haemoglobin result below the lower limit of the reference range
19. Regular alcohol consumption in males \>21 units per week and females \>14 units per week
20. Subjects who do not have suitable veins
21. Acute diarrhoea or constipation in the 7 days before the predicted first study day.
22. Presence of non-removable metal objects in the abdomen
23. Radiation exposure exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years
24. Failure to satisfy the investigator of fitness to participate for any other reason

Primary outcomes:
measure: OZ439 AUC0-∞
timeFrame: pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
measure: OZ439 Cmax
timeFrame: pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
Secondary outcomes:
measure: OZ439 Tmax
timeFrame: pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: Quotient Clinical
Study officials:
affiliation: Medicines for Malaria Venture
name: Fiona Macintyre, PhD
role: STUDY_DIRECTOR
References: