Safety, Tolerability & Pharmacokinetics (PK) of Co-administered Single Doses of OZ439 and Mefloquine (MQ) in Healthy Volunteers

• Sponsor: Medicines for Malaria Venture (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01615822
• Collaborator: University of Cape Town (Other)
• Enrollment: 25
• Location: 1
• Arms: 5
• Duration (Months): 8
• Patients Per Site Per Month: 3.1

Study Details

Study Description

Brief Summary

OZ439 is a novel, synthetic trioxolane medicine which is related to artemisinin, but has the advantage of a longer elimination half-life so is being developed to be administered together with a potential partner drug e.g. mefloquine as a single dose cure for uncomplicated malaria. The study findings will be used to inform the dose and design of future studies. The aim of the study is to establish the safety, tolerability and pharmacokinetics of co-administered OZ439 and MQ at a range of doses up to the maximum tolerated dose, in healthy volunteers.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: OZ439 100mg; Drug: OZ439 400mg; Drug: MQ 250 mg, single dose; Drug: MQ 750mg, single dose; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase I Healthy Volunteer Study Investigating the Safety, Tolerability & Pharmacokinetics of Co-administered Single Doses of OZ439 and Mefloquine
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OZ439 100mg single dose OZ439 100mg single dose oral suspension	Drug: OZ439 100mg; OZ439 100mg oral suspension, single dose
Experimental: OZ439 100mg plus MQ 250mg single doses Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet	Drug: OZ439 100mg; OZ439 100mg oral suspension, single dose; Drug: MQ 250 mg, single dose; Mefloquine 250 mg tablet, single dose
Experimental: OZ439 400mg single dose OZ439 400mg single dose oral suspension	Drug: OZ439 400mg; OZ439 400mg oral suspension, single dose
Experimental: OZ439 400mg plus MQ 750mg single doses Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets	Drug: OZ439 400mg; OZ439 400mg oral suspension, single dose; Drug: MQ 750mg, single dose; Mefloquine 750mg oral tablet, single dose
Placebo Comparator: Placebo Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. OZ439 AUC0-t [Up to 42 days post-dose]

   Area under the plasma concentration versus time curve (AUC) of OZ439

Secondary Outcome Measures

1. OZ439 Cmax [Up to 42 days post-dose]

   Peak Plasma Concentration (Cmax) of OZ439

2. MQ AUC0-t [Up to 42 days post-dose]

   Area under the plasma concentration versus time curve (AUC) of MQ

3. MQ Cmax [Up to 42 days post-dose]

   Peak Plasma Concentration (Cmax) of MQ

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male and non-childbearing potential female volunteers of between 18 and 55 years of age

• Female volunteers must have a negative serum pregnancy test at screening

• Females must be of non-childbearing potential

• Male volunteers and their partner(s) must agree to use a double barrier method of contraception for at least 14 days prior to first dose of study drug through 90 days after the last dose.

• Body mass Index between 18 and 30kg/m2, inclusive; and a total body weight >50 kg

• Laboratory tests at screening within normal ranges or not clinically significant as judged by the Investigator.

Exclusion Criteria:

• Received an investigational drug or participated in another research study within 30 days of the first dose of study drug or at any time through the study

• Evidence of current or history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, gastrointestinal, haematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, or clinically significant current infection.

• Any condition that could possibly affect drug absorption, such as gastrectomy, diarrhea and lactose intolerance

• Use of any medications, vitamins, herbal supplements, dietary supplements or vaccinations within 14 days of the first dose of study drug or at any time through the study, unless prior approval is granted. This includes any drugs that are substrates, inhibitors or inducers of CYP3A4. Intermittent use of acetaminophen at doses of up to 2g/day is permitted

• History of drug or alcohol abuse within 2 years of Screening

• History of alcohol consumption within 24 hours of any study visit

• Tobacco users

• Consumption of fruit juices within 7 days prior to dosing

• Participation in unaccustomed strenuous exercise within 7 days prior to

• Positive urine drug screen

• Positive test for HIV-1, HBsAg or HCV

• Known hypersensitivity to MQ or artemisinins

• QTcF greater than 450msec

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Division of Clinical Pharmacology, University of Cape Town	Cape Town		South Africa	7925

Sponsors and Collaborators

• Medicines for Malaria Venture
• University of Cape Town

Investigators

• Principal Investigator: Karen I Barnes, University of Cape Town

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Medicines for Malaria Venture
• ClinicalTrials.gov Identifier: NCT01615822
• Other Study ID Numbers: MMV_OZ439_12_001
• First Posted: Jun 11, 2012
• Last Update Posted: Apr 16, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Medicines for Malaria Venture: Malaria; PK; OZ439; Mefloquine; Healthy Volunteers
• Additional relevant MeSH terms: Malaria; Artefenomel

Study Results

Participant Flow

Arm/Group Title	Cohort 1	Cohort 2	Placebo
Arm/Group Description	Period 1: OZ439 100mg single dose oral suspension Period 2: Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet	Period 1: OZ439 400mg single dose oral suspension Period 2: Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets	Placebo
Period Title: Period 1
STARTED	8	11	6
COMPLETED	7	9	6
NOT COMPLETED	1	2	0
Period Title: Period 1
STARTED	7	9	6
COMPLETED	7	8	4
NOT COMPLETED	0	1	2

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Placebo	Total
Arm/Group Description	Period 1: OZ439 100mg single dose oral suspension Period 2: Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet	Period 1: OZ439 400mg single dose oral suspension Period 2: Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets	Placebo	Total of all reporting groups
Overall Participants	8	10	6	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.1 (10.3)	30.6 (9.42)	26 (4.45)	28.6 (8.06)
Sex: Female, Male (Count of Participants)
Female	1 12.5%	2 20%	0 0%	3 12.5%
Male	7 87.5%	8 80%	6 100%	21 87.5%
Region of Enrollment (participants) [Number]
South Africa	8 100%	10 100%	6 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	OZ439 AUC0-t
Description	Area under the plasma concentration versus time curve (AUC) of OZ439
Time Frame	Up to 42 days post-dose

Outcome Measure Data

Analysis Population Description

Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.

Arm/Group Title	OZ439 100mg Single Dose	OZ439 100mg Plus MQ 250mg Single Doses	OZ439 400mg Single Dose	OZ439 400mg Plus MQ 750mg Single Doses
Arm/Group Description	OZ439 100mg single dose oral suspension OZ439 100mg: OZ439 100mg oral suspension, single dose	Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet OZ439 100mg: OZ439 100mg oral suspension, single dose MQ 250 mg, single dose: Mefloquine 250 mg tablet, single dose	OZ439 400mg single dose oral suspension OZ439 400mg: OZ439 400mg oral suspension, single dose	Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets OZ439 400mg: OZ439 400mg oral suspension, single dose MQ 750mg, single dose: Mefloquine 750mg oral tablet, single dose
Measure Participants	7	7	9	9
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1060 (32)	1060 (32)	8100 (30)	7300 (30)

2. Secondary Outcome

Title	OZ439 Cmax
Description	Peak Plasma Concentration (Cmax) of OZ439
Time Frame	Up to 42 days post-dose

Outcome Measure Data

Analysis Population Description

Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.

Arm/Group Title	OZ439 100mg Single Dose	OZ439 100mg Plus MQ 250mg Single Doses	OZ439 400mg Single Dose	OZ439 400mg Plus MQ 750mg Single Doses
Arm/Group Description	OZ439 100mg single dose oral suspension OZ439 100mg: OZ439 100mg oral suspension, single dose	Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet OZ439 100mg: OZ439 100mg oral suspension, single dose MQ 250 mg, single dose: Mefloquine 250 mg tablet, single dose	OZ439 400mg single dose oral suspension OZ439 400mg: OZ439 400mg oral suspension, single dose	Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets OZ439 400mg: OZ439 400mg oral suspension, single dose MQ 750mg, single dose: Mefloquine 750mg oral tablet, single dose
Measure Participants	7	7	9	9
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	157 (24)	147 (33)	821 (21)	745 (26)

3. Secondary Outcome

Title	MQ AUC0-t
Description	Area under the plasma concentration versus time curve (AUC) of MQ
Time Frame	Up to 42 days post-dose

Outcome Measure Data

Analysis Population Description

Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.

Arm/Group Title	OZ439 100mg Plus MQ 250mg Single Doses	OZ439 400mg Plus MQ 750mg Single Doses
Arm/Group Description	Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet	Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets
Measure Participants	7	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	167 (18)	421 (30)

4. Secondary Outcome

Title	MQ Cmax
Description	Peak Plasma Concentration (Cmax) of MQ
Time Frame	Up to 42 days post-dose

Outcome Measure Data

Analysis Population Description

Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.

Arm/Group Title	OZ439 100mg Plus MQ 250mg Single Doses	OZ439 400mg Plus MQ 750mg Single Doses
Arm/Group Description	Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet	Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets
Measure Participants	7	8
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	0.602 (27)	1.34 (36)

Adverse Events

Time Frame	Up to Day 42 post-dose
Adverse Event Reporting Description	All subjects who received at least one dose of study drug were included in the safety analysis set. Adverse events were collected irrespective of whether or not the patients had received OZ439 alone or in combination with MQ.
Arm/Group Title	Cohort 1		Cohort 2		Placebo
Arm/Group Description	Period 1: OZ439 100mg single dose oral suspension Period 2: Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet		Period 1: OZ439 400mg single dose oral suspension Period 2: Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets		Placebo
All Cause Mortality
	Cohort 1		Cohort 2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1		Cohort 2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		0/10 (0%)		0/6 (0%)
Injury, poisoning and procedural complications
Gun Shot wound	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		9/10 (90%)		5/6 (83.3%)
Cardiac disorders
Palpitations	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Ear and labyrinth disorders
Ear Pain	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Motion Sickness	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Eye disorders
Seasonal Conjunctivitis	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Gastrointestinal disorders
Change of bowel habit	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Diarrhoea	0/8 (0%)	0	2/10 (20%)	2	0/6 (0%)	0
Gastrointestinal sounds abnormal	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Nausea	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
General disorders
Fatigue	0/8 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Medical Device Site Reaction	6/8 (75%)	6	6/10 (60%)	6	4/6 (66.7%)	4
Immune system disorders
Seasonal Allergy	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Infections and infestations
Influenza	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Laryngitis Viral	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Nasopharynigitis	0/8 (0%)	0	2/10 (20%)	2	0/6 (0%)	0
Pneumonia	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Tinea Cruris	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Urinary Tract Infection	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Viral Tonsilitis	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Injury, poisoning and procedural complications
Foreign Body	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Investigations
ECG QT Shortened	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
GGT Increased	1/8 (12.5%)	1	0/10 (0%)	0	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle Fatigue	0/8 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Dizziness	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Headache	2/8 (25%)	2	1/10 (10%)	1	0/6 (0%)	0
Psychiatric disorders
Anxiety	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Confusional Arousal	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Depressive Symptom	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Insomnia	0/8 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Nightmare	1/8 (12.5%)	1	1/10 (10%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/8 (12.5%)	1	1/10 (10%)	1	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Blister	1/8 (12.5%)	1	1/10 (10%)	1	0/6 (0%)	0
Rash	1/8 (12.5%)	1	1/10 (10%)	1	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.