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Safety Tolerability & Pharmacokinetics of Co-administered Single Doses of OZ439 & Piperaquine to Healthy Subjects

A Phase I Study to Investigate the Safety, Tolerability & Pharmacokinetics of Co-administered Single Doses of OZ439 and Piperaquine to Healthy Subjects

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01660022
Enrollment
59
Registered
2012-08-08
Start date
2012-09-30
Completion date
2013-05-31
Last updated
2015-01-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Keywords

Healthy, Volunteers

Brief summary

A Phase I Study to investigate the safety, tolerability & pharmacokinetics of co-administered single doses of OZ439 and Piperaquine to healthy subjects.

Detailed description

Placebo-controlled, double-blind, five-cohort, 2-period (per cohort) dose-escalation study. For each subject, the study included a screening evaluation (within 21 days of the 1st dose), dosing on 2 separate occasions (Period 1 and Period 2) and a follow-up visit (6 weeks following the final dose). Within each cohort, subjects were randomised into two sequences to receive OZ439 in Period 1 and OZ439 plus piperaquine in Period 2 (sequence 1, 8 subjects) or OZ439-matching placebo in Period 1 and OZ439/piperaquine matching placebos in Period 2 (sequence 2, 4 subjects). Safety and tolerability were evaluated: Physical examination, ECG assessments including a full baseline matched profile of ECG tracings, vital signs, laboratory evaluations, in particular liver function tests and adverse events.

Interventions

DRUG100mg OZ439 single oral dose

100mg OZ439 oral suspension single dose

DRUGPlacebo

Placebo

DRUG300 mg OZ439 single oral dose

300mg OZ439 oral suspension single dose

DRUG160mg Piperaquine single oral dose

160 mg Piperaquine tablet

DRUG480mg Piperaquine single oral dose

480 mg Piperaquine tablet

DRUG1440mg Piperaquine single oral dose

1440 mg Piperaquine tablet

DRUG800 mg OZ439 single oral dose

800mg OZ439 oral suspension single dose

Sponsors

Cross Research S.A.
CollaboratorINDUSTRY
Medicines for Malaria Venture
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes

Inclusion criteria

* Healthy males & females, 18-55 years old * BMI 18 to 30kg/m2; total body weight \>50kg * Healthy, determined by pre-study medical history, physical examination vital signs, 12 Lead ECG * Females of non-childbearing potential. * Males must agree to use a double barrier method of contraception * Lab tests at screening within the reference ranges

Exclusion criteria

* Any condition that could affect drug absorption, e.g. gastrectomy, diarrhea * Clinically relevant abnormalities in ECG * Family history of sudden death or of congenital prolongation of QTc interval - History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia * Electrolyte disturbances * History of drug or alcohol abuse, tobacco users * Participation in evaluation of any drug for 3 months before the study * Administration of ANY systemic medication/herbal product within 14 days of first dose of study drug. * unaccustomed strenuous exercise within 7 days of any study visit * Alcohol consumption within 24 hours of any study visit * Consumption of any fruit juice or food containing grapefruit within 7 days * Positive test for HIV-1, HBsAg or HCV * Positive urine drug screen at Screening or admission * Severe allergies/multiple drug allergies * Volunteers who have donated blood or experienced significant blood loss within 90 days of screening * Hemoglobin below lower limit of the reference range * Clinically relevant abnormal lab values indicative of physical illness

Design outcomes

Primary

MeasureTime frameDescription
OZ439 CmaxUp to 168 hours post-doseOZ439 Maximum concentration level
Piperaquine CmaxUp to 1008 hours post-dose (Day 43)Piperaquine Maximum concentration level
OZ439 AUC(0-168)Up to 168 hours post-doseArea under the plasma concentration versus time curve to 168 hours post-dose.
OZ439 t1/2Up to 168 hours post-doseOZ439 Elimination half-life
Piperaquine AUC(0-168)Up to 1008 hours post-dose (Day 43)Piperaquine area under the plasma concentration versus time curve to 168 hours post-dose
Piperaquine t1/2Up to 1008 hours post-dose (Day 43)Piperaquine Elimination half-life (t1/2).

Countries

Switzerland

Participant flow

Recruitment details

Date of first enrolment: 11SEP2012 Date last volunteer completed: 07MAY2013 Phase 1 Clinical Research Unit

Participants by arm

ArmCount
Cohort 1
Sequence 1: OZ439 100mg Sequence 2: OZ439 100 mg / PQP 160 mg
8
Cohort 2
Sequence 1: OZ439 100mg Sequence 2: OZ439 100 mg / PQP 480 mg
7
Cohort 3
Sequence 1: OZ439 100mg Sequence 2: OZ439 100 mg / PQP 1440 mg
8
Cohort 4
Sequence 1: OZ439 300mg Sequence 2: OZ439 300 mg / PQP 1440 mg
7
Cohort 5
Sequence 1: OZ439 800mg Sequence 2: OZ439 800 mg / PQP 1440 mg
6
Placebo
Cohorts 1, 2, 3, 4 and 5
20
Total56

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003FG004FG005
First Sequence (7 Days)Adverse Event000013
First Sequence (7 Days)Protocol Violation000001
First Sequence (7 Days)Withdrawal by Subject010100

Baseline characteristics

CharacteristicCohort 1Cohort 2Cohort 3Cohort 4Cohort 5PlaceboTotal
Age, Continuous36.0 years
STANDARD_DEVIATION 9.4
41.7 years
STANDARD_DEVIATION 7.1
35.4 years
STANDARD_DEVIATION 10
32.1 years
STANDARD_DEVIATION 8.4
35.7 years
STANDARD_DEVIATION 11.7
37.3 years
STANDARD_DEVIATION 10.3
36.43 years
STANDARD_DEVIATION 8.7
Region of Enrollment
Switzerland
8 participants7 participants8 participants7 participants6 participants20 participants56 participants
Sex: Female, Male
Female
0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants1 Participants
Sex: Female, Male
Male
8 Participants7 Participants8 Participants7 Participants6 Participants19 Participants55 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
EG006
affected / at risk
EG007
affected / at risk
EG008
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —— / —— / —— / —— / —— / —— / —
other
Total, other adverse events
3 / 243 / 82 / 72 / 80 / 71 / 83 / 71 / 68 / 20
serious
Total, serious adverse events
0 / 240 / 80 / 70 / 80 / 70 / 80 / 70 / 61 / 20

Outcome results

Primary

OZ439 AUC(0-168)

Area under the plasma concentration versus time curve to 168 hours post-dose.

Time frame: Up to 168 hours post-dose

Population: All randomised subjects who fulfilled the study protocol requirements in terms of study drug intake and PK samplings, with no major deviations that could affect the PK results.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Cohort 1 - OZ439 100mgOZ439 AUC(0-168)862 ng.h/mLGeometric Coefficient of Variation 33.9
Cohort 1 - OZ439 100mg / PQP 160mgOZ439 AUC(0-168)920 ng.h/mLGeometric Coefficient of Variation 26.6
Cohort 2 - OZ439 100mgOZ439 AUC(0-168)1130 ng.h/mLGeometric Coefficient of Variation 41.7
Cohort 2 - OZ439 100mg / PQP 480mgOZ439 AUC(0-168)1390 ng.h/mLGeometric Coefficient of Variation 47
Cohort 3 - OZ439 100mgOZ439 AUC(0-168)909 ng.h/mLGeometric Coefficient of Variation 21.4
Cohort 3 - OZ439 100mg / PQP 1440mgOZ439 AUC(0-168)1520 ng.h/mLGeometric Coefficient of Variation 26.1
Cohort 4 - OZ439 300mgOZ439 AUC(0-168)5740 ng.h/mLGeometric Coefficient of Variation 29.9
Cohort 4 - OZ439 300mg / PQP 1440mgOZ439 AUC(0-168)7410 ng.h/mLGeometric Coefficient of Variation 30.3
Cohort 5 - OZ439 800mgOZ439 AUC(0-168)15300 ng.h/mLGeometric Coefficient of Variation 47.6
Cohort 5 - OZ439 800mg / PQP 1440mgOZ439 AUC(0-168)18600 ng.h/mLGeometric Coefficient of Variation 36.8
Primary

OZ439 Cmax

OZ439 Maximum concentration level

Time frame: Up to 168 hours post-dose

Population: All randomised subjects who fulfilled the study protocol requirements in terms of study drug intake and PK samplings, with no major deviations that could affect the PK results.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Cohort 1 - OZ439 100mgOZ439 Cmax142 ng/mLGeometric Coefficient of Variation 39.2
Cohort 1 - OZ439 100mg / PQP 160mgOZ439 Cmax139 ng/mLGeometric Coefficient of Variation 33.1
Cohort 2 - OZ439 100mgOZ439 Cmax146 ng/mLGeometric Coefficient of Variation 43.2
Cohort 2 - OZ439 100mg / PQP 480mgOZ439 Cmax198 ng/mLGeometric Coefficient of Variation 47.4
Cohort 3 - OZ439 100mgOZ439 Cmax127 ng/mLGeometric Coefficient of Variation 22.9
Cohort 3 - OZ439 100mg / PQP 1440mgOZ439 Cmax199 ng/mLGeometric Coefficient of Variation 26.8
Cohort 4 - OZ439 300mgOZ439 Cmax590 ng/mLGeometric Coefficient of Variation 31.5
Cohort 4 - OZ439 300mg / PQP 1440mgOZ439 Cmax778 ng/mLGeometric Coefficient of Variation 31.5
Cohort 5 - OZ439 800mgOZ439 Cmax1500 ng/mLGeometric Coefficient of Variation 42.2
Cohort 5 - OZ439 800mg / PQP 1440mgOZ439 Cmax1650 ng/mLGeometric Coefficient of Variation 25.6
Primary

OZ439 t1/2

OZ439 Elimination half-life

Time frame: Up to 168 hours post-dose

Population: All randomised subjects who fulfilled the study protocol requirements in terms of study drug intake and PK samplings, with no major deviations that could affect the PK results.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Cohort 1 - OZ439 100mgOZ439 t1/2NA hour—
Cohort 1 - OZ439 100mg / PQP 160mgOZ439 t1/2NA hour—
Cohort 2 - OZ439 100mgOZ439 t1/2NA hour—
Cohort 2 - OZ439 100mg / PQP 480mgOZ439 t1/2NA hour—
Cohort 3 - OZ439 100mgOZ439 t1/2NA hour—
Cohort 3 - OZ439 100mg / PQP 1440mgOZ439 t1/2NA hour—
Cohort 4 - OZ439 300mgOZ439 t1/290.6 hourGeometric Coefficient of Variation 19.4
Cohort 4 - OZ439 300mg / PQP 1440mgOZ439 t1/2112 hourGeometric Coefficient of Variation 45.2
Cohort 5 - OZ439 800mgOZ439 t1/265.4 hourGeometric Coefficient of Variation 23.2
Cohort 5 - OZ439 800mg / PQP 1440mgOZ439 t1/2135 hourGeometric Coefficient of Variation 53.2
Primary

Piperaquine AUC(0-168)

Piperaquine area under the plasma concentration versus time curve to 168 hours post-dose

Time frame: Up to 1008 hours post-dose (Day 43)

Population: All randomised subjects who fulfilled the study protocol requirements in terms of study drug intake and PK samplings, with no major deviations that could affect the PK results.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Cohort 1 - OZ439 100mgPiperaquine AUC(0-168)1340 ng.h/mL—
Cohort 1 - OZ439 100mg / PQP 160mgPiperaquine AUC(0-168)3420 ng.h/mLGeometric Coefficient of Variation 22.8
Cohort 2 - OZ439 100mgPiperaquine AUC(0-168)17500 ng.h/mLGeometric Coefficient of Variation 25.7
Cohort 2 - OZ439 100mg / PQP 480mgPiperaquine AUC(0-168)17200 ng.h/mLGeometric Coefficient of Variation 12.8
Cohort 3 - OZ439 100mgPiperaquine AUC(0-168)13200 ng.h/mLGeometric Coefficient of Variation 53.8
Primary

Piperaquine Cmax

Piperaquine Maximum concentration level

Time frame: Up to 1008 hours post-dose (Day 43)

Population: All randomised subjects who fulfilled the study protocol requirements in terms of study drug intake and PK samplings, with no major deviations that could affect the PK results.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Cohort 1 - OZ439 100mgPiperaquine Cmax8.59 ng/mLGeometric Coefficient of Variation 34.7
Cohort 1 - OZ439 100mg / PQP 160mgPiperaquine Cmax46.6 ng/mLGeometric Coefficient of Variation 44.3
Cohort 2 - OZ439 100mgPiperaquine Cmax393 ng/mLGeometric Coefficient of Variation 43.8
Cohort 2 - OZ439 100mg / PQP 480mgPiperaquine Cmax271 ng/mLGeometric Coefficient of Variation 30.9
Cohort 3 - OZ439 100mgPiperaquine Cmax356 ng/mLGeometric Coefficient of Variation 53.6
Primary

Piperaquine t1/2

Piperaquine Elimination half-life (t1/2).

Time frame: Up to 1008 hours post-dose (Day 43)

Population: All randomised subjects who fulfilled the study protocol requirements in terms of study drug intake and PK samplings, with no major deviations that could affect the PK results.

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Cohort 1 - OZ439 100mgPiperaquine t1/2294 hour—
Cohort 1 - OZ439 100mg / PQP 160mgPiperaquine t1/2283 hourGeometric Coefficient of Variation 64.4
Cohort 2 - OZ439 100mgPiperaquine t1/2515 hourGeometric Coefficient of Variation 36.3
Cohort 2 - OZ439 100mg / PQP 480mgPiperaquine t1/2632 hourGeometric Coefficient of Variation 26.5
Cohort 3 - OZ439 100mgPiperaquine t1/2509 hourGeometric Coefficient of Variation 15.9

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026