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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Medicines for Malaria Venture
ClinicalTrials.gov Identifier:
NCT00928083
First received: June 24, 2009
Last updated: January 7, 2015
Last verified: January 2015
  Purpose

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.


Condition Intervention Phase
Malaria Falciparum
Malaria Vivax
Healthy Volunteers
Drug: OZ439 50mg API capsules
Drug: OZ439 200mg API capsules
Drug: OZ439 400mg aqueous dispersion
Drug: OZ439 800mg aqueous dispersion
Drug: OZ439 100mg API capsules
Drug: OZ439 400mg API capsules
Drug: OZ439 1600mg aqueous dispersion
Drug: OZ439 800mg API capsules
Drug: OZ439 1200mg API capsules
Drug: Placebo
Drug: OZ439 200mg aqueous dispersion
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase I Study To Investigate The Safety, Tolerability And Pharmacokinetic Profile Of OZ439 In Healthy Male and Female Subjects

Resource links provided by NLM:


Further study details as provided by Medicines for Malaria Venture:

Primary Outcome Measures:
  • Adverse Events [ Time Frame: From screening and at 10 (+/-2) days after last dose of study medication ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • OZ439 AUC0-t [ Time Frame: Samples collected from Pre-dose up to 96h post dose ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification (AUC0-t).

  • OZ439 AUC0-∝ [ Time Frame: Samples collected from Pre-dose up to 96h post dose ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve from zero to infinity (AUC0-∝).

  • OZ439 Cmax [ Time Frame: Samples collected from Pre-dose up to 96h post dose ] [ Designated as safety issue: No ]
    Maximum observed plasma drug concentration (Cmax).

  • OZ439 Tmax [ Time Frame: Samples collected from Pre-dose up to 96h post dose ] [ Designated as safety issue: No ]
    Time to maximum observed plasma drug concentration of OZ439

  • OZ439 t1/2 [ Time Frame: Samples collected from Pre-dose up to 96h post dose ] [ Designated as safety issue: No ]
    Apparent terminal half-life (t1/2)

  • OZ439 Rac [ Time Frame: Samples collected from Pre-dose up to 96h post dose ] [ Designated as safety issue: No ]

    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)



Enrollment: 63
Study Start Date: April 2009
Study Completion Date: December 2009
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A - 50 mg Single Dose
OZ439 Single doses of 50mg (capsules)
Drug: OZ439 50mg API capsules
Other Name: OZ439
Experimental: Part A - 100mg Single Dose
OZ439 Single doses of 100mg (capsules)
Drug: OZ439 100mg API capsules
OZ439 100mg (2x50mg API capsules)
Other Name: OZ439
Experimental: Part A - 200mg Single Dose
OZ439 Single doses of 200mg (capsules)
Drug: OZ439 200mg API capsules
Other Name: OZ439
Experimental: Part A - 400mg Single Dose
OZ439 Single doses of 400mg (capsules)
Drug: OZ439 400mg API capsules
OZ439 400mg (2x200mg API capsules)
Other Name: OZ439
Experimental: Part A - 400mg Single Dose + Food
OZ439 Single doses of 400mg (capsules) administered with food.
Drug: OZ439 400mg API capsules
OZ439 400mg (2x200mg API capsules)
Other Name: OZ439
Experimental: Part A - 400mg AD Single Dose
OZ439 Single doses of 400mg (aqueous dispersion)
Drug: OZ439 400mg aqueous dispersion
Experimental: Part A - 800mg Single Dose
OZ439 Single doses of 800mg (capsules)
Drug: OZ439 800mg API capsules
OZ439 800mg (4x200 API capsules)
Other Name: OZ439
Experimental: Part A - 800mg AD Single Dose
OZ439 Single doses of 800mg (aqueous dispersion)
Drug: OZ439 800mg aqueous dispersion
Other Name: OZ439
Experimental: Part A - 1200mg Single Dose
OZ439 Single doses of 1200mg (capsules)
Drug: OZ439 1200mg API capsules
OZ439 1200mg (6x200mg API capsules)
Other Name: OZ439
Experimental: Part A - 1600mg AD Single Dose
OZ439 Single doses of 800mg (aqueous dispersion)
Drug: OZ439 1600mg aqueous dispersion
Other Name: OZ439
Placebo Comparator: Part A - Placebo
Placebo control for Single rising Part A
Drug: Placebo
Experimental: Part B - 800mg AD Single Dose Fed
Single dose of OZ439 800mg aqueous dispersion administered under fed conditions
Drug: OZ439 800mg aqueous dispersion
Other Name: OZ439
Experimental: Part B - 800mg AD Single Dose Fast
Single dose of OZ439 800mg aqueous dispersion administered under fast conditions
Drug: OZ439 800mg aqueous dispersion
Other Name: OZ439
Experimental: Part C - 200mg AD Multiple Dose
200mg aqueous solution OZ439 or placebo once daily for 3 days fasted
Drug: OZ439 200mg aqueous dispersion
Other Name: OZ439
Experimental: Part C - 400mg AD Multiple Dose
400mg aqueous solution OZ439 or placebo once daily for 3 days fasted
Drug: OZ439 400mg aqueous dispersion
Experimental: Part C - 800mg AD Multiple Dose
800mg aqueous solution OZ439 or placebo once daily for 3 days fasted
Drug: OZ439 800mg aqueous dispersion
Other Name: OZ439
Placebo Comparator: Part C - Placebo
Placebo control for Multiple rising Part C
Drug: Placebo

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00928083

Locations
United States, Florida
Comprehensive Phase One Miramar; 3400 Enterprise Way
Miramar, Florida, United States, 33025
Sponsors and Collaborators
Medicines for Malaria Venture
Investigators
Study Director: Joerg Moehrle, PhD Medicines for Malaria Venture
Principal Investigator: Maria Gutierrez, MD Comprehensive Phase One Miramar, 3400 Enterprise Way, Miramar, FL 33025
  More Information

Additional Information:
Publications:
Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT00928083     History of Changes
Other Study ID Numbers: MMV_OZ439_09_001
Study First Received: June 24, 2009
Results First Received: November 10, 2014
Last Updated: January 7, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Medicines for Malaria Venture:
Phase I
Safety and tolerability
Pharmacokinetic
synthetic peroxide
trioxolane
treatment of erythrocytic stages of malaria

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Parasitic Diseases
Protozoan Infections

ClinicalTrials.gov processed this record on July 28, 2015