Clinical trial NCT00928083: A Study to Investigate the Safety, Tolerability and Pharmacokinetics of OZ439 in Healthy Male and Female Subjects
Official title: A Phase I Study To Investigate The Safety, Tolerability And Pharmacokinetic Profile Of OZ439 In Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malaria Falciparum
Malaria Vivax
Healthy Volunteers
Keywords: Phase I
Safety and tolerability
Pharmacokinetic
synthetic peroxide
trioxolane
treatment of erythrocytic stages of malaria
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
First posted: 2009-06-25
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: OZ439 is a synthetic trioxolane that has potential value as a peroxide antimalarial agent.

This was a Phase I, single-centre, multi-component, double-blind, randomised, placebo-controlled study in healthy male and female subjects. The study was conducted in 3 parts:

* Part A investigated the safety, tolerability and pharmacokinetics (PK) of single oral escalating doses of OZ439. Up to 6 dose levels will be investigated to estimate dose proportionality.
* Part B, the effect of food on a single oral dose of OZ439 was investigated in a 2-way crossover design.
* Part C investigated the safety, tolerability and PK profile of multiple oral doses of OZ439.

The starting oral dose was 50 mg and the maximum single dose to be administered did not exceed 1600 mg per subject. The maximum duration of dosing proposed was 3 days.


Eligibility criteria: Inclusion Criteria:

1. Healthy male//female subjects between 18- 55 years of age (inclusive).
2. Body mass Index (BMI) between 18 - 30 kg/m2, inclusive; and a total body weight \>60 kg (132 lbs).
3. Healthy as determined by pre-study medical history, PE, 12 Lead ECG.
4. Females of childbearing potential must use 1 of birth control methods throughout study and for 30 days after last dose of study drug:

   1. Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) 6 months minimum prior to first dose of study drug.
   2. Intrauterine device (IUD) in place for at least 3 months prior to first dose of study drug.
   3. Barrier methods (condom or diaphragm) with spermicide starting at least 14 days prior to first dose of study drug through 30 days after last dose of study drug.
   4. Surgical sterilization of the partner(s) (vasectomy with zero sperm count for 6 months minimum prior to the first dose of study drug).
   5. Hormonal contraceptives starting at least 3 months prior to first dose of study drug. In addition, subjects must agree to use a barrier method (condom or diaphragm) with spermicide at least 14 days prior to first dose of study drug through 30 days after the last dose of study drug.
5. Post-menopausal women with amenorrhea for at least 1 year will be eligible confirmed by FSH.
6. Male subjects must agree to use double barrier method of contraception, from time of first dose of study drug through 90 days after last dose of study drug and must also agree to not donate sperm for 90 days after last dose of study drug. Clinical laboratory tests within the reference ranges.
7. Able/willing to give written informed consent.
8. Willing/to adhere to lifestyle guideline restrictions outlined in protocol.
9. Willing and able to be confined to Clinical Research Unit as required by the protocol.

Exclusion Criteria:

1. Evidence/history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, current infection.
2. Evidence/history of clinically significant gastrointestinal (some exclusions exist) disease, current infection.
3. Any condition that affecting drug absorption, e.g., gastrectomy.
4. History of post-antibiotic colitis.
5. Breast feeding.
6. QTc greater than 450 msec for males and 470 msec for females as corrected by the Bazett formula.
7. History of drug or alcohol abuse within the past 2 years prior to Screening.
8. Tobacco users
9. Received investigational drug/ participated in another research study within 30 days of first dose of study drug in any part of study.
10. Use of prescription drugs within 14 days prior to the first dose of study drug in Period 1, or need for any antibiotic during study.
11. Received any non prescription meds, vitamins, herbal/dietary supplements within 7 days of administration of first dose of study drug in Period 1 (exceptions exist)
12. Consumed alcohol within 72 hours of Day -1 in any part of study, or have a positive alcohol screen at screening or each admission to Clinical Research Unit (CRU).
13. Consumed grapefruit juice or juices containing grapefruit or ate grapefruit within 7 days prior to first dose of study drug in any part of study.
14. Positive serum pregnancy test at the Screening Visit or on Day -1 prior to inclusion in any part of the study.
15. Positive test for HIV-1, HBsAg,HCV.
16. Positive urine drug screen at Screening or admission to CRU.
17. History of intolerance/ hypersensitivity to artemisinins.
18. Likelihood of requiring treatment during study period with drugs not permitted by protocol.
19. Subjects who have donated blood or experienced significant blood loss within 60 days of screening for study.
20. Subjects whose hemoglobin is \<12.5 g/dL for males/ \<11.5 g/dL for females.
21. Any concern by investigator regarding safe participation of the subject in study or for any other reason investigator considers subject inappropriate for participation in study.

Primary outcomes:
measure: Adverse Events
timeFrame: From screening and at 10 (+/-2) days after last dose of study medication
Secondary outcomes:
measure: OZ439 AUC0-t
timeFrame: Samples collected from Pre-dose up to 96h post dose
measure: OZ439 AUC0-∝
timeFrame: Samples collected from Pre-dose up to 96h post dose
measure: OZ439 Cmax
timeFrame: Samples collected from Pre-dose up to 96h post dose
measure: OZ439 Tmax
timeFrame: Samples collected from Pre-dose up to 96h post dose
measure: OZ439 t1/2
timeFrame: Samples collected from Pre-dose up to 96h post dose
measure: OZ439 Rac
timeFrame: Samples collected from Pre-dose up to 96h post dose
Other outcomes:
Locations:
city: Miramar
country: United States
facility: Comprehensive Phase One Miramar; 3400 Enterprise Way
state: Florida
Study officials:
affiliation: Medicines for Malaria Venture
name: Joerg Moehrle, PhD
role: STUDY_DIRECTOR
affiliation: Comprehensive Phase One Miramar, 3400 Enterprise Way, Miramar, FL 33025
name: Maria Gutierrez, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Moehrle JJ, Duparc S, Siethoff C, van Giersbergen PL, Craft JC, Arbe-Barnes S, Charman SA, Gutierrez M, Wittlin S, Vennerstrom JL. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol. 2013 Feb;75(2):524-37. doi: 10.1111/j.1365-2125.2012.04368.x.