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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Medicines for Malaria Venture
ClinicalTrials.gov Identifier:
NCT01713608
First received: October 22, 2012
Last updated: April 19, 2013
Last verified: April 2013
  Purpose

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.

Condition Intervention Phase
Malaria
Drug: OZ439
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
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

Resource links provided by NLM:


Further study details as provided by Medicines for Malaria Venture:

Primary Outcome Measures:
  • • Maximum concentration (Cmax). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Maximum measured plasma concentration derived by non-compartmental analysis of the plasma concentration-time data


Secondary Outcome Measures:
  • • Time to reach maximum plasma concentration (Tmax). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Time to reach maximum measured plasma concentration


Other Outcome Measures:
  • • Area under the plasma concentration vs time curve from time zero to 24 hours post dose (AUCτ,). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Area under plasma concentration time curve from time 0 to the time of the last quantifiable concentration t calculated using a log-linear trapezoidal method

  • • Area under the plasma concentration vs time curve from time zero to the time of the last detectable drug (AUC0-t). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Area under plasma concentration time curve from time 0 to the time of the last quantifiable concentration t calculated using a log-linear trapezoidal method

  • • Area under the plasma concentration-time curve from zero to infinity (AUC0-∞). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Area under plasma concentration time curve from time 0 extrapolated to infinity

  • • Terminal half-life (t½). [ Time Frame: 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. ] [ Designated as safety issue: No ]
  • • The terminal elimination rate constant [ Time Frame: 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. ] [ Designated as safety issue: No ]
    The apparent terminal elimination rate constant, determined by linear regression of terminal points of the ln-linear analyte concentration-time curve

  • Safety assessments [ Time Frame: 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. ] [ Designated as safety issue: Yes ]
    Safety assessments will include standard laboratory safety tests (haematology, biochemistry, and urinalysis), vital signs, physical examinations, 12-lead ECG, telemetry and AE monitoring.


Enrollment: 34
Study Start Date: November 2012
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OZ439 Dose level 1 (300mg)
• 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
OZ439 x mg once daily for 3 days with milk
Experimental: OZ439 Dose level 2
• 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
OZ439 x mg once daily for 3 days with milk
Experimental: OZ439 dose level 3
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
OZ439 x mg once daily for 3 days with milk

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.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusions:

  1. healthy males or females of any race aged 18 - 55 years
  2. BMI of 18 - 30 kg/m2 inclusive at screening
  3. Agree to use acceptable methods of contraception if of childbearing potential
  4. Capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form
  5. 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:

  1. Male subjects with female partner(s) who is (are) pregnant or lactating from the time of the first administration of study medication
  2. Clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion
  3. History of allergic reactions to artemisinin-based compounds or any other clinically relevant allergy to drugs or food
  4. Clinically relevant history of both soya and cow's milk intolerance/allergy
  5. 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
  6. Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening) and/or 24-hour 5 lead Holter ECG (at screening)
  7. Any abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes
  8. Prolonged QTcF >450 ms or shortened QTcF <340 ms, or family history of Long QT Syndrome
  9. History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrinological, metabolic, neurological, psychiatric, or other disease
  10. 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)
  11. 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
  12. 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
  13. Is pregnant or lactating (female subjects who are of childbearing potential must have negative pregnancy tests at screening and admission)
  14. Mentally handicapped
  15. Participation in a drug trial within 90 days prior to first drug administration
  16. 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
  17. Treatment with herbal supplements during the 7 days prior to drug administration, or use of vitamins during 48 hours prior to drug administration
  18. Is not permitted to use strong inhibitors and/or inducers of CYP450 within 21 days prior to the planned first drug administration
  19. 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)
  20. Blood ALT, AST and bilirubin should be in the normal range at screening and on admission
  21. Donation of more than 500 mL of blood within 90 days prior to drug administration
  22. Subjects must be non-smokers for at least three months prior to first drug administration
  23. Any circumstances or conditions, which, in the opinion of the PI, may affect full participation in the trial or compliance with the protocol
  24. Legal incapacity or limited legal capacity at screening
  25. Subjects who are vegetarians, vegans or have any dietary restrictions conflicting with the study standardised menus
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01713608

Locations
United Kingdom
Richmond Pharmacology Ltd
Croydon, United Kingdom, CR77YE
Sponsors and Collaborators
Medicines for Malaria Venture
Investigators
Study Director: Fiona Macintyre, PhD Medicines for Malaria Venture
  More Information

Additional Information:
No publications provided

Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT01713608     History of Changes
Other Study ID Numbers: MMV_OZ439_12_005, 2012-004187-22
Study First Received: October 22, 2012
Last Updated: April 19, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Medicines for Malaria Venture:
malaria
dose escalation
safety
tolerability
maximum tolerated dose

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases

ClinicalTrials.gov processed this record on April 17, 2014