A Study to Investigate the Safety, Tolerability and Pharmacokinetics of OZ439 in Healthy Male and Female Subjects

Healthy Volunteers Clinical Trial

Official title:

A Phase I Study To Investigate The Safety, Tolerability And Pharmacokinetic Profile Of OZ439 In Healthy Male and Female Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00928083
• Other study ID #: MMV_OZ439_09_001
• Status: Completed
• Phase: Phase 1
• First received: June 24, 2009
• Last updated: January 7, 2015
• Start date: April 2009
• Est. completion date: December 2009

Study information

• Verified date: January 2015
• Source: Medicines for Malaria Venture
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: December 2009
• Est. primary completion date: October 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Healthy Volunteers
• Malaria
• Malaria Falciparum
• Malaria Vivax
• Malaria, Falciparum

Intervention

Drug:
• OZ439 50mg API capsules

• OZ439 200mg API capsules

• OZ439 400mg aqueous dispersion

• OZ439 800mg aqueous dispersion

• OZ439 100mg API capsules
OZ439 100mg (2x50mg API capsules)
• OZ439 400mg API capsules
OZ439 400mg (2x200mg API capsules)
• OZ439 1600mg aqueous dispersion

• OZ439 800mg API capsules
OZ439 800mg (4x200 API capsules)
• OZ439 1200mg API capsules
OZ439 1200mg (6x200mg API capsules)
• Placebo

• OZ439 200mg aqueous dispersion

Locations

Country	Name	City	State
United States	Comprehensive Phase One Miramar; 3400 Enterprise Way	Miramar	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Medicines for Malaria Venture

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 ot — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events	Safety/Tolerability evaluation took into account the recorded AE profile, clinical laboratory safety tests, vital signs, 12 lead and continuous (Parts A and C) ECG monitoring, audiometry/Brainstem Auditory Evoked Potentials (BAEP) parameters (Parts A and C) including any additional tests required to evaluate any safety concerns.	From screening and at 10 (+/-2) days after last dose of study medication	Yes
Secondary	OZ439 AUC0-t	Area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification (AUC0-t).	Samples collected from Pre-dose up to 96h post dose	No
Secondary	OZ439 AUC0-?	Area under the plasma concentration-time curve from zero to infinity (AUC0-?).	Samples collected from Pre-dose up to 96h post dose	No
Secondary	OZ439 Cmax	Maximum observed plasma drug concentration (Cmax).	Samples collected from Pre-dose up to 96h post dose	No
Secondary	OZ439 Tmax	Time to maximum observed plasma drug concentration of OZ439	Samples collected from Pre-dose up to 96h post dose	No
Secondary	OZ439 t1/2	Apparent terminal half-life (t1/2)	Samples collected from Pre-dose up to 96h post dose	No
Secondary	OZ439 Rac	Accumulation index is the ratio of drug exposure observed during a dosing interval at steady-state divided by drug exposure after a single first dose, as described by the following equations: Accumulation index (Rac) = AUC0-(Day 3)/ AUC0-(Day 1)	Samples collected from Pre-dose up to 96h post dose	No

External Links

•   Medicines for Malaria Venture