Conditions: Malaria
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 26
Healthy volunteers: yes

Brief summary:
This study is an open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous \[14C\]-OZ439 microdose/800mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a strong CYP3A4 inhibitor, to healthy subjects in fasted state.

Detailed description:
Primary objectives of this study are:

* to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 dispersion and a simultaneous single intravenous (iv) microdose (100 μg) infusion of \[14C\]-OZ439 under fasted conditions (Part 1)
* To evaluate the effects of a single oral dose of cobicistat, a strong cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetic (PK) profile of a single oral dose of a dispersion of OZ439 simple granules under fasted conditions (Part 2)
* To evaluate the PK of single doses of OZ439 granules when restricting the target dosing volumes to 64.5 or 100 mL (Parts 1 and 2)

Secondary objectives are:

* To assess the safety and tolerability of OZ439 when administered alone, and to assess the safety and tolerability of OZ439 and cobicistat when co-administered as single doses to healthy subjects (Parts 1 and 2)
* To determine the PK parameters of OZ439 single iv microdose (100 μg) infusion of \[14C\]-OZ439 (Part 1)
* To assess the effects of the total dosing volume and of dose to volume ratio on OZ439 PK under fasted conditions (Parts 1 and 2)
* To determine the PK parameters and exposures of cobicistat (Part 2)

Arms:
arm 1: This was an open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\]-OZ439 radiolabeled microdose at the anticipated Tmax of the oral dose. Subjects received the following treatment:

Treatment A: A single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439 (47 kBq \[1.27 μCi\]) beginning 3 hours after the oral dose administration. arm 2: This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) arm 3: This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) arm 4: This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)

Interventions: intervention 1: Single oral dose of 800 mg OZ439 intervention 2: Single oral dose of 400 mg OZ439 intervention 3: Single oral dose of cobicistat intervention 4: iv infusion of [14C]-OZ439
Intervention descriptions: intervention 1: Single oral dose of 800 mg OZ439 intervention 2: Single oral dose of 400 mg OZ439 intervention 3: Single oral dose of 150 mg cobicistat intervention 4: 15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
MMV_OZ439_16_01/MMV508EC-165081 
VERSION 1.0 – 26-JAN-2017 
 
 
Page 1 of 67 
CLINICAL STUDY PROTOCOL 
 
AN OPEN-LABEL, TWO-PART STUDY TO DETERMINE THE ABSOLUTE 
BIOAVAILABILITY (BA) OF OZ439 USING SIMULTANEOUS INTRAVENOUS 
[14C]-OZ439 MICRODOSE/800 MG ORAL DOSING AND TO INVESTIGATE THE 
PHARMACOKINETICS (PK) OF OZ439 GRANULES ADMINISTERED AS SINGLE 
DOSES SUSPENDED IN DIFFERENT VOLUMES AND WHEN CO-ADMINISTERED 
WITH A SINGLE DOSE OF COBICISTAT, A STRONG CYP3A4 INHIBITOR, TO 
HEALTHY SUBJECTS IN FASTED STATE 
 
CONFIDENTIAL 
 
Sponsor code: MMV_OZ439_16_01 
PRA code: MMV508EC-165081 
EudraCT number: 2016-004923-21 
 
Absolute BA and OZ439 PK effect of different OZ439 dose volumes and cobicistat 
co-administration study  
 
Investigational product 
OZ439 
Clinical phase 
Phase 1 study 
Indication to be studied 
Not applicable 
 
SPONSOR 
Medicines for Malaria Venture (MMV) 
 
Route de Pré-Bois 20 
1215 Geneva 15  
Switzerland 
 
 
CONTRACT RESEARCH 
ORGANIZATION 
PRA Health Sciences (PRA) – Early Development Services (EDS) 
 
Van Swietenlaan 6 
 
9728 NZ Groningen 
 
The Netherlands 
 
CLINICAL SITE 
PRA-EDS  
 
University Medical Center Groningen 
 
Entrance 23 
 
Hanzeplein 1 
 
Groningen 
 
The Netherlands 
 
PRA-EDS 
Van Swietenlaan 6 
 
9728 NZ Groningen 
The Netherlands 
 
 
PRINCIPAL INVESTIGATOR 
Jan Jaap van Lier, MD 
 
Phone +31 50 402 2325  
 
Fax 
+31 50 402 2223  
 
E-mail lierjanjaapvan@prahs.com  
 
PROTOCOL AUTHOR 
Noëlle Zweers, PhD, Medical Writer, PRA-EDS 
 
 
Version 1.0, 26 January 2017 
 
This study will be performed in compliance with the principles of Good Clinical Practice. 


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Page 2 of 67 
AUTHORIZATION OF CLINICAL STUDY PROTOCOL 
The Sponsor and the Contract Research Organization agree to conduct the study as outlined in 
this clinical study protocol. Any modification of the clinical study protocol must be agreed upon by 
the Sponsor and the Contract Research Organization and must be documented in writing. 
 
Name/Position: 
Date: 
Signature: 
 
 
Sponsor:  Medicines for Malaria Venture  
 
(MMV) 
 
 
 
Dr Myriam El Gaaloul, PharmD 
…………………… 
……………………… 
Clinical Study Director 
 
 
 
Stephan Chalon, MD, PhD 
…………………… 
……………………… 
Medical Monitor 
 
 
 
Contract Research Organization: PRA Health Sciences – Early Development Services 
 
 
 
Jan Jaap van Lier, MD 
…………………… 
……………………… 
Principal Investigator 
PRA Group B.V., a PRA Health Sciences company 
 
 
 
 
 


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Page 3 of 67 
SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In case of a serious adverse event (See Appendix 9.2), the Principal Investigator will send a 
report within 24 hours of notification to: 
Sponsor 
Stephan Chalon, MD, PhD 
Medical Director - Early Development & Clinical Pharmacology 
Medicines for Malaria Venture 
Route de Pré- Bois 20 
1215 Geneva 15 
Switzerland 
Phone 
+41 79 962 9244 
Fax 
+41 22 555 0379 
E-mail 
chalons@mmv.org 
 
Medical Monitor back-up 
Dr Stephan Duparc, MD 
Chief Medical Officer 
Medicines for Malaria Venture 
Route de Pré- Bois 20 
1215 Geneva 15 
Switzerland 
Phone 
+41 22 555 0351 
Mobile 
+41 79 446 2956 
Fax 
+41 22 799 0369 
E-mail 
duparcs@mmv.org 
 
Quintiles LifeCycle Safety 
Pharmacovigilance supplier phone: +41 612 708 181 
Pharmacovigilance supplier fax: dial access code 0-800-8900; dial universal number 866 618 
0422 
 
 
 


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CONTACT INFORMATION 
Sponsor 
Medicines for Malaria Venture (MMV) 
Route de Pré-Bois 20 
1215 Geneva 15  
Switzerland 
 
Sponsor's Contact 
Dr Myriam El Gaaloul, PharmD 
Clinical Study Director 
Phone 
+41 22 555 0377 
Mobile 
+41 76 442 6502 
E-mail 
elgaaloulm@mmv.org  
 
Sponsor’s Medical Expert  
Stephan Chalon, MD, PhD 
Medical Director - Early Development & Clinical Pharmacology 
Phone 
+41 79 962 9244 
Fax 
+41 22 555 0379 
E-mail 
chalons@mmv.org 
 
Sponsor’s Chief Medical Officer 
Dr Stephan Duparc, MD 
Phone 
+41 22 555 0351 
Mobile 
+41 79 446 2956 
Fax 
+41 22 799 0369 
E-mail 
duparcs@mmv.org 
 
Contract Research Organization and  
PRA-EDS 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 402 2222 
Fax 
+31 50 402 2223 
 
Clinical Site 
PRA-EDS  
University Medical Center Groningen 
Entrance 23 
Hanzeplein 1 
Groningen 
The Netherlands 
Phone: 
+31 50 402 2220 
Fax: 
+31 50 402 2622 


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PRA-EDS  
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 402 2222 
Fax 
+31 50 402 2223 
 
Clinical Site Contacts 
Jan Jaap van Lier, MD 
Principal Investigator 
Phone 
+31 50 402 2325 
Fax 
+31 50 402 2223  
E-mail 
lierjanjaapvan@prahs.com 
 
Mariëlle Jacobs, MSc 
Project Manager 
Phone 
+31 50 402 2466 
Fax 
+31 50 402 2223  
E-mail 
jacobsmarielle@prahs.com 
 
Laboratories 
Clinical Laboratory 
PRA-EDS 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 402 2555 
Fax 
+31 50 402 2223 
 
Laboratory for Analysis of Plasma Samples for OZ439 and Cobicistat 
Swiss Bioquant AG 
Dr. Anita Kress 
Kägenstrasse 18 
4153 Reinach 
Switzerland 
Phone 
+41 61 716 9824 
Fax 
+41 61 716 9815 
E-mail 
anita.kress@swissbioquant.com 
 
Laboratory for Analysis of Plasma Samples for [14C]-OZ439 
Xceleron Inc. 
Mitesh Sanghvi, PhD  
20340 Seneca Meadows Parkway 
Germantown 
MD 20876 
USA 


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Phone 
+1 240 361 1900 
 
Medical Screening Center 
PRA-EDS 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
Phone 
+31 50 850 5798 
Fax 
+31 50 850 5782 
 
Pharmacovigilance Provider 
Quintiles LifeCycle Safety (on behalf of MMV) 
Hochstrasse 50 
CH - 4053 Basel 
Switzerland 
Phone 
+41 61 270 8181 
E-mail 
QLS-MMV@quintiles.com 
 


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SYNOPSIS 
Study Title 
AN OPEN-LABEL, TWO-PART STUDY TO DETERMINE THE ABSOLUTE BIOAVAILABILITY (BA) OF OZ439 
USING SIMULTANEOUS INTRAVENOUS [14C]-OZ439 MICRODOSE/800 MG ORAL DOSING AND TO 
INVESTIGATE THE PHARMACOKINETICS (PK) OF OZ439 GRANULES ADMINISTERED AS SINGLE DOSES 
SUSPENDED IN DIFFERENT VOLUMES AND WHEN CO-ADMINISTERED WITH A SINGLE DOSE OF 
COBICISTAT, A STRONG CYP3A4 INHIBITOR, TO HEALTHY SUBJECTS IN FASTED STATE 
 
Short Study Title 
Absolute BA and OZ439 PK effect of different OZ439 dose volumes and cobicistat co-administration study  
 
Study Codes 
Sponsor code 
: MMV_OZ439_16_01 
PRA code 
: MMV508EC-165081 
EudraCT number 
: 2016-004923-21 
 
Sponsor 
Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, 1215 Geneva 15, Switzerland 
Sponsor’s Contact 
: Dr Myriam El Gaaloul, PharmD, Clinical Study Director 
 
Contract Research Organization  
PRA-EDS, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands 
 
Clinical Site 
PRA-EDS, University Medical Center Groningen, Entrance 23, Hanzeplein 1, Groningen, The Netherlands 
PRA-EDS, Van Swietenlaan 6, 9728 NZ Groningen, The Netherlands 
 
Principal Investigator 
Jan Jaap van Lier, MD 
 
Objectives 
Primary 
: To determine the absolute bioavailability of OZ439 following a single oral dose of 
OZ439 dispersion and a simultaneous single intravenous (iv) microdose (100 µg) 
infusion of [14C]-OZ439 under fasted conditions (Part 1) 
 
: To evaluate the effects of a single oral dose of cobicistat, a strong cytochrome P450 
(CYP) 3A4 inhibitor, on the pharmacokinetic (PK) profile of a single oral dose of a 
dispersion of OZ439 simple granules under fasted conditions (Part 2) 
 
: To evaluate the PK of single doses of OZ439 granules when restricting the target 
dosing volumes to 64.5 or 100 mL (Parts 1 and 2) 
 
Secondary 
: To assess the safety and tolerability of OZ439 when administered alone, and to assess 
the safety and tolerability of OZ439 and cobicistat when co-administered as single 
doses to healthy subjects (Parts 1 and 2) 
 
: To determine the PK parameters of OZ439 single iv microdose (100 µg) infusion of 
[14C]-OZ439 (Part 1) 
 
: To assess the effects of the total dosing volume and of dose to volume ratio on OZ439 
PK under fasted conditions (Parts 1 and 2) 
 
: To determine the PK parameters and exposures of cobicistat (Part 2) 
 
Design and Treatments 
This is a single-center, 2-part clinical study in healthy subjects. 
 


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Part 1 
This is an open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single 
oral dose of OZ439 and a simultaneous single iv infusion of [14C]-OZ439 radiolabeled microdose administered at the 
anticipated tmax of the oral dose. Subjects will receive the following treatment: 
 
Treatment A: 
a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed 
by a 15-minute 10-mL iv infusion of 100 μg [14C]-OZ439 (47 kBq [1.27 µCi]) beginning 3 hours after 
the oral dose administration.  
 
Part 2  
This is an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject will 
participate in 3 treatment periods and each subject will receive a single dose of each of the following 3 treatments in a 
randomized order with a 14-day wash-out period between each treatment: 
 
Treatment B: 
a single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion  
Treatment C:  
a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion  
Treatment D:  
a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and 
co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) 
 
Study Schedule 
Screening 
: Between Day -28 and Day -1 (admission) 
Confinement period 
: Part 1: the subjects will be admitted to the clinical research center in the afternoon of 
Day -1. They will be discharged on Day 2 (24 hours post-dose) after completion of the 
assessments. After discharge, the subjects will return to the clinical research center for 
ambulatory visits on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours post-dose) for PK 
and safety assessments 
 
 Part 2: subjects will be in the clinic for 3 treatment periods. Each period, the subjects 
will be admitted to the clinical research center in the afternoon of Day -1. They will be 
discharged on Day 2 (24 hours post-dose) after completion of the assessments. After 
discharge, the subjects will return to the clinical research center for ambulatory visits 
on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours post-dose) of each period for PK 
and safety assessments. For Treatment D, the subjects will also return to the clinical 
research center for additional ambulatory visits on Days 10, 12 and 14 for PK and 
safety assessments (Day 14 will coincide with Day -1 of the next period when a subject 
is randomized to Treatment D in Period 1 or Period 2) 
Follow-up 
: Part 1: subjects will attend a follow-up visit on Day 15 (± 2 days) for a final safety 
assessment 
 
 Part 2: Subjects will attend a follow-up visit between Day 15 and Day 19 of Period 3 
(14 to 18 days after last drug administration) for a final safety assessment 
 
Subjects 
A total of 26 healthy male subjects and female subjects of non-childbearing potential will be enrolled (excluding any 
replacement subjects). In Part 1, 8 subjects will be enrolled to ensure data in 6 evaluable subjects for the PK 
endpoints. In Part 2, 18 subjects will be randomized to ensure data in 15 evaluable subjects for the PK endpoints. In 
Part 2, a subject will be considered evaluable for the primary analysis if they have sufficient PK data to estimate all of 
the primary endpoints (Cmax, C168h, AUC0-168h and AUC0-inf) for the 3 treatments. 
 
Main Criteria for Inclusion 
Gender 
:  healthy male or female of non-childbearing potential 
Age 
: 18-55 years, inclusive, at screening 
Weight 
: >50 kg, at screening 
Body mass index 
: 18.0-30.0 kg/m2, inclusive, at screening  
 


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Study Drug 
Active medication 
Active substance 
: OZ439 
Activity 
: peroxide anti-malarial agent  
Indication 
: treatment of uncomplicated malaria 
Strength 
: 400 mg/64.5 mL, 800 mg/64.5 mL and 800 mg/100 mL 
Dosage form 
: oral dispersion 
Manufacturer 
: Novasep (Finorga) (drug substance); PRA pharmacy (oral dispersions) 
 
In the table below the OZ439 doses, the vehicle and  volume of vehicle are given for the different treatments. 
 
Treatment 
OZ439 Dose 
Volume of Vehicle 
A 
800 mg granules 
100 
mL 
of 
water 
containing 
Ora-sweet and polysorbate 80 
B 
800 mg granules 
64.5 mL of solution containing 
Ora-sweet and polysorbate 80 
C 
400 mg granules 
64.5 mL of solution containing 
Ora-sweet and polysorbate 80 
D 
400 mg granules 
64.5 mL of solution containing 
Ora-sweet and polysorbate 80 
 
The exact reconstitution procedure and amounts of Ora-sweet and polysorbate 80 will be described in the pharmacy 
manual to be provided by MMV. 
 
Active medication 
Active substance 
: [14C]-OZ439 
Activity 
: peroxide anti-malarial agent 
Indication 
: treatment of uncomplicated malaria 
Strength 
: 10 µg/mL free base containing 4.7 kBq/mL (0.127 µCi/mL) of radioactivity 
Dosage form 
: iv solution for infusion 
Manufacturer 
: Almac (drug substance); PRA Pharmacy (iv solution for infusion) 
 
Reference medication 
Active substance 
: Cobicistat (Tybost®) 
Activity 
: CYP3A4 inhibitor (PK exposure enhancer) 
Indication 
: pharmacokinetic enhancer of atazanavir or darunavir as part of anti-retroviral 
combination therapy in human immunodeficiency virus (HIV)-1 infected adults 
Strength 
: 150 mg 
Dosage form 
: oral tablet 
Manufacturer 
: Gilead Sciences B.V. 
 
Endpoints 
Part 1 
: Primary Endpoint  
 
 - PK: absolute oral bioavailability (Fpo) of OZ439 
 
 Secondary Endpoints  
 
 - PK for iv administration of OZ439: Vd, CL, t1/2, AUC0-t, AUC0-inf and z 
 
 - PK for oral administration of OZ439: Cmax, tmax, t1/2, C168h, AUC0-168h, AUC0-t, AUC0-inf, 
CL/F and z 
 
 - Safety: adverse events (AE), clinical laboratory, vital signs, electrocardiogram (ECG) 
and physical examination  
 
 Exploratory Endpoints 
 
 - Estimation of fraction absorbed, extraction ratio, liver first pass and deconvolution of 
absorption profile over time for OZ439 
 
 - Future OZ439 metabolites analysis may be performed 
Part 2 
: Primary Endpoint  
 
 - PK of OZ439: Cmax, C168h, AUC0-168h and AUC0-inf  


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 Secondary Endpoints  
 
 - PK of OZ439: tmax, t1/2, AUC0-t and z 
 
 - PK of cobicistat: Cmax, tmax, t1/2, AUC0-t, AUC0-inf, CL/F and z 
 
 - Safety: AEs, clinical laboratory, vital signs, ECG and physical examination 
 
 Exploratory Endpoint 
 
 - Future OZ439 metabolites analysis may be performed 
 
Statistical Methods 
PK parameters 
: Descriptive statistics for all relevant PK parameters: n, mean, standard deviation (SD), 
minimum, median, maximum, geometric mean, and coefficient of variation (CV%); A 
statistical analysis will be performed on OZ439 PK parameters Cmax, C168h, AUC0-168h, 
and AUC0-inf. The PK parameters will undergo a natural logarithmic transformation and 
will be analyzed using analysis of variance (ANOVA) techniques. The ANOVA model 
will include treatment as a fixed effect. Adjusted geometric mean ratios (GMRs) and 
90% confidence intervals for the adjusted GMRs will be provided for the comparisons 
between: 
 
 - Treatment C versus Treatment D to assess the effect of cobicistat on OZ439 
 
 - Treatment A versus Treatment B to explore volume effect (for this no within-subject 
comparison is possible) 
 
 - Treatment B versus Treatment C to explore dosing solution concentration effect (dose 
normalized)  
Safety parameters 
: Descriptive statistics 
 
 


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Table 1 
Schedule of Assessments - Part 1 
 
 
Assessment Period1 
 
 
Screening 
Pre-
Treatment 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-
up 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
15 (± 2) 
Hours 
 
 
Pre-
dose 
0 
0.25 
0.5 
0.75 
1 
2 
3 
4 
5 
6 
8 
12 16 
24 
48 
72 
96 
168 
 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Ambulatory visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and height 
(including BMI calculation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X2 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
 
X 
Serology (HBsAg, anti-HCV, 
anti-HIV 1 and 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females 
only) 
X 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory4 
X4 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
12-lead ECG5 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
X 
Vital signs6 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
X 
Eligibility check 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OZ439 oral administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[14C]-OZ439 iv 
administration 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples for 
OZ439 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood samples for 
[14C]-OZ439 
 
 
 
 
 
 
 
 
 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples for OZ439 
metabolites 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Subjects will be in the clinic from Day -1 until 24 hours post-dose (Day 2). Subjects will return for ambulatory visits on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours post-dose) 
2 
A targeted physical examination of applicable body systems will be performed if needed as per the judgment of the PI (eg, if the subject reports AEs) at pre-dose, on Day -1 and at discharge 
3 
Confirmation of negative pregnancy test result required before dosing 


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4 
Clinical laboratory tests (including clinical chemistry, hematology and urinalysis): all results must be available before dosing; out-of-range results judged to be possibly relevant by the PI are to 
be discussed with the medical monitor before dosing  
5 
Triplicate 12-lead ECG only required at pre-dose on Day 1 and at 2 and 4 hours post-dose on Day 1. Individual ECG measurements as part of a triplicate ECG will be recorded 1 minute (and 
no more than 2 minutes) apart. Single 12-lead ECGs will be done at the rest of the time points indicated in the schedule of assessments. 
6 
Vital signs will consist of supine systolic and diastolic blood pressure, pulse and body temperature 
7 
PK blood samples for [14C]-OZ439 will be collected at the start of iv infusion and at 10, 15 (just prior to end of iv infusion), 20, 30 and 45 minutes after start of iv infusion 
AE: adverse event; BMI: body mass index; ECG: electrocardiogram; FSH: follicle stimulating hormone; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; 
iv: intravenous; PK: pharmacokinetic(s); PI: Principal Investigator 
 


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Table 2 
Schedule of Assessments - Part 2 
 
 
Assessment Period 1, 2 or 31 
 
 
Screening 
Pre-
Treatment 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
102 
122 
142 
15-19 of 
Period 3 
Hours 
 
 
Pre-
dose 
0 
0.5 
1 
2 
3 
4 
5 
6 
8 
12 16 
24 
48 
72 
96 
168 
216 
264 
312 
 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Ambulatory visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and height 
(including BMI calculation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X3 
X3 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
X3 
Serology (HBsAg, anti-HCV, 
anti-HIV 1 and 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females 
only) 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory5 
X5 
X5 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
12-lead ECG6 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Vital signs7 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Eligibility check 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples for OZ439 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood samples for 
cobicistat8 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
Blood samples for OZ439 
metabolites9 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Subjects will be in the clinic for 3 periods, each period from Day -1 until 24 hours post-dose (Day 2). Subjects will return for ambulatory visits on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours 
post-dose) of each period 
2 
Additional ambulatory visits on Days 10, 12 and 14 for Treatment D only (a single oral dose of 400 mg OZ439 simple granules administered as a 60-mL dispersion and co-administered with a 
150 mg cobicistat tablet [CYP3A4 inhibitor]). Day 14 will coincide with Day -1 of the next period when a subject is randomized to Treatment D in Period 1 or Period 2. 
3 
A targeted physical examination of applicable body systems will be performed if needed as per the judgment of the PI (eg, if the subject reports AEs) at pre-dose, on Day -1 and at discharge 
4 
Confirmation of negative pregnancy test result required before dosing 


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5 
Clinical laboratory tests (including clinical chemistry, hematology and urinalysis): all results must be available before dosing; out-of-range results judged to be possibly relevant by the PI are to 
be discussed with the medical monitor before dosing  
6 
Triplicate 12-lead ECG only required at pre-dose on Day 1 and at 2 and 4 hours post-dose on Day 1. Individual ECG measurements as part of a triplicate ECG will be recorded 1 minute (and 
no more than 2 minutes) apart. Single 12-lead ECGs will be done at the rest of the time points indicated in the schedule of assessments.  
7 
Vital signs will consist of supine systolic and diastolic blood pressure, pulse and body temperature 
8 
Only applicable for Treatment D (a single oral dose of 400 mg OZ439 simple granules administered as a 60-mL dispersion and co-administered with a 150 mg cobicistat tablet [CYP3A4 
inhibitor]) 
9 
Blood samples for future OZ439 metabolites analysis will be collected in Period 1 only 
AE: adverse event; BMI: body mass index; ECG: electrocardiogram; FSH: follicle stimulating hormone; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; 
PK: pharmacokinetic(s); PI: Principal Investigator 
 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ....................................................................................................................... 1 
AUTHORIZATION OF CLINICAL STUDY PROTOCOL ..................................................... 2 
SERIOUS ADVERSE EVENT CONTACT INFORMATION ................................................ 3 
CONTACT INFORMATION ................................................................................................ 4 
SYNOPSIS .......................................................................................................................... 7 
TABLE OF CONTENTS .................................................................................................... 15 
TABLE OF TABLES ......................................................................................................... 17 
LIST OF ABBREVIATIONS .............................................................................................. 18 
1. INTRODUCTION ........................................................................................................ 20 
1.1 
Background ................................................................................................................. 20 
1.1.1 Summary of Clinical Studies ........................................................................... 21 
1.2 
Risk-Benefit Assessment ........................................................................................... 24 
1.3 
Study Rationale ........................................................................................................... 24 
1.4 
Dose Rationale ............................................................................................................ 25 
2. OBJECTIVES ............................................................................................................. 28 
2.1 
Primary ........................................................................................................................ 28 
2.2 
Secondary.................................................................................................................... 28 
3. INVESTIGATIONAL PLAN ........................................................................................ 29 
3.1 
Overall Study Design and Plan .................................................................................. 29 
3.1.1 Type of Study ................................................................................................... 29 
3.1.2 Screening Period ............................................................................................. 29 
3.1.3 Treatment Period ............................................................................................. 30 
3.1.4 Follow-up.......................................................................................................... 30 
3.2 
Discussion of Study Design ....................................................................................... 30 
3.3 
Selection of Study Population .................................................................................... 31 
3.3.1 Inclusion Criteria ............................................................................................. 31 
3.3.2 Exclusion Criteria ............................................................................................ 32 
3.3.3 Removal and Replacement of Subjects from the Study ............................... 33 
3.4 
Treatments ................................................................................................................... 34 


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3.4.1 Treatments Administered ................................................................................ 34 
3.4.2 Identity of Investigational Products ............................................................... 34 
3.4.3 Method of Assigning Subjects to Treatment Groups .................................... 35 
3.4.4 Selection of Doses in the Study ..................................................................... 36 
3.4.5 Timing of Doses in the Study .......................................................................... 36 
3.4.6 Meals During the Study ................................................................................... 36 
3.4.7 Blinding ............................................................................................................ 36 
3.4.8 Concomitant Medication and Other Restrictions During the Study ............. 36 
3.4.9 Treatment Compliance .................................................................................... 38 
3.5 
Pharmacokinetic and Safety Measurements and Endpoints ................................... 38 
3.5.1 Pharmacokinetic and Safety Measurements Assessed and Schedules 
of Assessments ............................................................................................... 38 
3.5.1.1 
Pharmacokinetic Measurements .................................................... 38 
3.5.1.1.1 
Blood Sampling ............................................................... 38 
3.5.1.2 
Safety and Tolerability Measurements ........................................... 38 
3.5.1.2.1 
Adverse Events ............................................................... 38 
3.5.1.2.2 
Clinical Laboratory ........................................................... 39 
3.5.1.2.3 
Vital Signs ....................................................................... 40 
3.5.1.2.4 
Electrocardiogram ........................................................... 40 
3.5.1.2.5 
Physical Examination ...................................................... 40 
3.5.1.3 
Total of Blood Volume ..................................................................... 41 
3.5.2 Appropriateness of Measurements ................................................................ 41 
3.5.2.1 
Timing of Assessments ................................................................... 41 
3.5.3 Pharmacokinetic, Safety and Exploratory Endpoints ................................... 42 
3.5.3.1 
Endpoints for Part 1 ......................................................................... 42 
3.5.3.2 
Endpoints for Part 2 ......................................................................... 43 
3.5.3.3 
Pharmacokinetic Parameters .......................................................... 43 
3.5.4 Drug Concentration Measurements ............................................................... 44 
3.6 
Statistical Procedures and Determination of Sample Size ....................................... 44 
3.6.1 Analysis Sets ................................................................................................... 44 
3.6.1.1 
Safety Set ......................................................................................... 44 
3.6.1.2 
Pharmacokinetic Set ........................................................................ 44 
3.6.2 Statistical and Analytical Plan for Pharmacokinetic and Safety 
Evaluation ........................................................................................................ 44 
3.6.2.1 
Pharmacokinetic Evaluation ........................................................... 44 
3.6.2.2 
Evaluation of Safety and Tolerability.............................................. 45 
3.6.2.2.1 
Adverse Events ............................................................... 45 
3.6.2.2.2 
Clinical Laboratory ........................................................... 45 
3.6.2.2.3 
Vital Signs and Electrocardiograms ................................. 45 
3.6.2.2.4 
Physical Examination ...................................................... 45 
3.6.3 Determination of Sample Size ......................................................................... 45 
3.7 
Data Quality Assurance .............................................................................................. 46 
4. ETHICS ....................................................................................................................... 47 
4.1 
Independent Ethics Committee .................................................................................. 47 
4.2 
Ethical Conduct of the Study ..................................................................................... 47 


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4.3 
Subject Information and Consent .............................................................................. 48 
4.4 
Privacy ......................................................................................................................... 48 
5. STUDY ADMINISTRATIVE STRUCTURE ................................................................. 49 
5.1 
Distribution of Activities ............................................................................................. 49 
5.2 
Documentation ............................................................................................................ 49 
5.2.1 Archiving .......................................................................................................... 49 
5.2.2 Recording of Data in Source Documents and CRFs ..................................... 50 
6. FINANCE AND INSURANCE ..................................................................................... 51 
7. CONFIDENTIALITY AND PUBLICATION POLICY ................................................... 51 
8. REFERENCES ........................................................................................................... 52 
9. APPENDICES ............................................................................................................. 54 
9.1 
Drug Accountability .................................................................................................... 54 
9.2 
Adverse Events and Serious Adverse Events Evaluation and Reporting ............... 54 
9.2.1 Adverse Events ................................................................................................ 54 
9.2.1.1 
WHO Recommendations for Grading Acute and Subacute 
Toxic Effects .................................................................................... 55 
9.2.2 Serious Adverse Events .................................................................................. 65 
9.2.3 Suspected Unexpected Serious Adverse Reactions ..................................... 66 
9.2.4 Follow-up of Adverse Events .......................................................................... 67 
 
TABLE OF TABLES  
Table 1 
Schedule of Assessments - Part 1 ................................................................................ 11 
Table 2 
Schedule of Assessments - Part 2 ................................................................................ 13 
Table 3 
Key Studies - Drug Exposures OZ439 ........................................................................... 26 
Table 4 
Number and Volume of Blood Samples and Total Blood Volume Collected per 
Subject for Part 1 .......................................................................................................... 41 
Table 5 
Number and Volume of Blood Samples and Total Blood Volume Collected per 
Subject for Part 2 .......................................................................................................... 41 
 


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LIST OF ABBREVIATIONS 
ACPR 
Adequate clinical and parasitological response 
ACT 
Artemisinin-based combination therapy 
ADL 
Activities of daily living 
AE 
Adverse event  
ALT 
Alanine aminotransferase 
AMS 
Accelerator mass spectrometry 
ANOVA 
Analysis of variance 
ART 
Artemisinin 
AST 
Aspartate aminotransferase 
BA 
Bioavailability 
β-hCG 
β-human chorionic gonadotropin 
BMI 
Body mass index 
bpm 
Beats per minute 
CA 
Competent authority 
CI 
Confidence interval 
CPMP 
Committee for Proprietary Medicinal Products; current name: Committee for 
Medicinal Products for Human Use (CHMP) 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Clinical Trial Directive 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDS 
Early Development Services 
eGFR 
Estimated glomerular filtration rate 
EU 
European Union 
FQ 
Ferroquine 
FSH 
Follicle stimulating hormone 
gamma-GT 
Gamma glutamyl transferase 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMR 
Geometric mean ratio 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation (formerly: International Conference on 
Harmonisation) 
IEC 
Independent Ethics Committee 
iv 
Intravenous 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MEB  
Medicine Evaluation Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMV 
Medicines for Malaria Venture 
MPC 
Minimum parasiticidal concentration 
MQ 
Mefloquine 
P. 
Plasmodium 


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PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PIB 
Powder in bottle 
PK 
Pharmacokinetic(s) 
PQ 
Primaquine 
PQP 
Piperaquine phosphate 
PRA 
PRA Health Sciences 
PRA-EDS 
PRA Early Development Services 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TPGS 
α-tocopherol polyethylene glycol 1000 succinate 
WHO 
World Health Organization 
WMA 
 
World Medical Association 
WMO 
Wet medisch-wetenschappelijk onderzoek met mensen (Medical research 
involving human subjects act) 
 
Note: Definitions of pharmacokinetic (PK) parameters are provided in Section 3.5.3 
 


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1. 
INTRODUCTION 
1.1 
Background 
Malaria is a parasitic disease that threatens half of the world’s population. The World 
Health Organization (WHO) reported that since 2000, the number of malaria cases has 
fallen from a range of 205 to 316 million to an estimated 214 million new cases in 
2013, out of 3.2 billion people at risk. In the same year, malaria caused 438,000 
deaths; 90% of the mortality was in the African region. However, even in this region 
mortality rates have fallen by 66% in all groups and by 71% in children under 5 years 
and overall, malaria deaths in children under 5 years have decreased to 306,000 in 
2015.1 In 2015 there were approximately 13.8 million cases of Plasmodium (P.) vivax 
malaria globally with most occurring in the WHO Southeast Asia Region.  
 
While global efforts have led to the significant progress in the prevention, diagnosis, 
and management of malaria, treatment of malarial infections in the face of emerging 
drug resistance among Plasmodium species continues to pose clinical challenges. In 
particular, the widespread resistance of P. falciparum has rendered conventional 
monotherapies such as chloroquine, amodiaquine, and sulfadoxine/pyrimethamine 
ineffective. To combat increasing levels of resistance, the WHO recommends 
artemisinin (ART)-based combination therapy (ACT) as the first-line therapy for the 
treatment of uncomplicated P. falciparum malaria.1 
 
ART and its derivatives are currently the most potent and rapidly acting anti-malarial 
agents available.2 Their anti-malarial activities are characterized by high parasite kill 
rates and broad-stage activity that produce a faster clinical and parasitological 
response than other classes of anti-malarial agents. The peroxidic pharmacophore of 
ARTs is believed to be the main source of their potent activity. However, ART 
derivatives have been associated with high recrudescence rates when used as the 
conventional 3 to 5 days of monotherapy.3 Combination with other agents has allowed 
for shorter courses of ACT therapy, improved treatment outcomes, and enhanced 
patient compliance. 
 
OZ439 is a synthetic trioxolane that has potential value as a peroxide anti-malarial 
agent.4 The first synthetic trioxolane, arterolane (RBx11160/OZ277), was identified in a 
collaborative drug discovery project.5 Arterolane was launched in India in April 2013. 
Trioxolanes such as arterolane react with Fe(II) and are partially cleared by 
blood-mediated degradation. Because of this finding, a program to identify and develop 
new trioxolanes with increased exposure by reducing blood clearance without 
compromising activity was initiated by the Medicines for Malaria Venture (MMV). 
OZ439 is a product of this research, focused on identifying a potential anti-malarial 
curative treatment which may eventually be able to be administered as part of a 
single-dose cure in P. falciparum malaria.6,7 Compared to previous compounds in the 
series, OZ439 shows in in vitro and in vivo models a high prophylactic potential, longer 
half-life (t1/2), higher oral bioavailability, and better metabolic stability. OZ439 was 
selected from a large series of trioxolanes because of its high parasite activity and 
improved stability in blood. It has been found to be effective and safe in animal models 


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of malaria. The mesylate salt of OZ439 was selected as a development candidate due 
to its favorable solid state properties and good solubility in water. 
1.1.1 
Summary of Clinical Studies 
At the data cutoff of 11th January 2017, data were available for 15 completed clinical 
studies (11 Phase Ia studies in healthy volunteers, 1 Phase Ib study in healthy 
volunteers inoculated with P. falciparum [QP12C10], and 2 Phase IIa study 
[MMV_OZ439_10_002 
and 
MMV_OZ439_12_006] 
and 
1 
Phase 
IIb 
study 
[MMV_OZ439_13_003] in malaria patients). In these studies a total of 886 subjects 
have received at least 1 dose of OZ439. Of them, 337 subjects received OZ439 as a 
monotherapy (including 87 subjects in Phase IIa and 250 subjects in Phase I) or in 
combination with either piperaquine phosphate (PQP; 602 subjects), mefloquine (MQ; 
13 subjects), ferroquine (FQ; 39 subjects) or primaquine (PQ; 19 subjects). 
 
In addition, 3 clinical studies have recently been completed (3 Phase 1b challenge 
studies: QPC15C11, QP15C05 and QP14C12) for which reporting is ongoing) and 
1 clinical study is ongoing (Phase IIb study DRI12805 FALCI). Validated data from 
these studies (and MMV_OZ439_12_006) were not available as of the cutoff date of 
the current valid Investigator’s Brochure (IB)8, i.e. 28th of April 2016, and therefore no 
results were presented in the IB, however, none of the results changed the risk-benefit 
ratio of the drug.  
 
In studies in healthy subjects, plasma Cmax in the fasted state was reached 
approximately 3 hours after administration of a single dose, and thereafter, OZ439 
concentrations decreased in a multiphasic way. Concentrations initially dropped about 
100-fold over the first 48 to 60 hours followed by a terminal phase with a t1/2 of about 
120 hours. Tissue distribution was extensive and plasma clearance (CL/F) was 
moderate. Following a single dose, the renal excretion of OZ439 and all metabolites 
was negligible, indicating that renal excretion is a minor pathway in the elimination of 
oral OZ439. Exposure to OZ439 and its metabolites increased in the presence of 
piperaquine, but the extent of this effect was limited (<1.7-fold). 
 
In studies in patients with malaria, the PK for OZ439 was not dose-proportional. The 
apparent CL/F decreased with increasing OZ439 dose: about 50% lower at 800 mg 
versus 100 mg. In addition, the absorption rate constant decreased with an increase in 
actual OZ439 dose administered; about 50% lower at 800 mg versus 100 mg. The 
average exposures after a single dose of 800 mg OZ439 (all patients) were geometric 
mean (coefficient of variation [CV]%): Cmax = 869 (78%) ng/mL; AUC0-inf = 10 (107%) 
μg*hr/mL, and concentration on Day 7 (CDay 7) = 3.0 (147%) ng/mL. The overall 
between subject variability in exposures was considerable. 
 
In vitro metabolism studies have shown that OZ439 is a substrate for CYP3A4; 
thus, the metabolism of OZ439 could be affected by drugs that either inhibit or 
induce CYP3A4. Inhibitory studies (up to 30 μM of OZ439) showed that OZ439 is a 
CYP3A4 inhibitor; thus, there is a potential for PK drug interactions with drugs that 
are CYP3A4 substrates. 


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The anti-malarial activity of OZ439 was investigated in a blood stage P. falciparum 
challenge model in healthy subjects who were inoculated with infected erythrocytes 
(Study QP12C10). Pharmacokinetics/pharmacodynamics modeling of the preliminary 
study data suggested that the minimum parasiticidal concentration of OZ439 is 3 (1 to 
10) ng/mL. 
 
In a Phase IIa study, single oral doses of OZ439 from 200 to 1200 mg demonstrated 
consistent anti-malarial efficacy, with no tailing off in the effect in the lower dose 
cohorts. OZ439 cleared more than 97.8% of P. falciparum and P. vivax parasites by 
36 hours, reducing malaria symptomatology and leading to an estimated parasite 
clearance time of 69 hours or less. 
 
In a Phase IIb study of a single-dose regimen of OZ439 800 mg in combination with 
3 doses of PQP (640 mg, 960 mg, and 1440 mg) in adults and children with 
uncomplicated P. falciparum malaria in Africa and Asia, none of the dose arms of the 
study met the protocol-defined efficacy threshold of 95% efficacy based on the primary 
endpoint of polymerase chain reaction (PCR)-adjusted adequate clinical and 
parasitological response (ACPR) outcome on Day 28 in the per protocol analysis set. 
No clear dose response was observed for crude and PCR-adjusted ACPR on Day 28; 
however, the PQP 1440 mg dose was overall more efficacious than the lower doses. 
 
To date, OZ439 administered either as a monotherapy or in combination with a partner 
anti-malarial, has been generally well tolerated in malaria patients and healthy 
subjects. In a Phase IIa study of OZ439 doses of 200, 400, 800 and 1200 mg in 
malaria patients, increased blood creatine phosphokinase was the most frequently 
reported adverse event (AE); a dose relationship was not seen for this AE. 
Gastrointestinal (GI) AEs, including vomiting, abdominal pain, and diarrhea, and 
nervous system disorders, including dizziness and headache, were reported more 
frequently with 1200 mg OZ439 compared to the other dose cohorts. None of these 
AEs were serious AEs (SAEs).  
 
In a Phase IIb study, where OZ439 was evaluated in combination with PQP, in patients 
with uncomplicated P. falciparum malaria, malaria and electrocardiogram (ECG) QTc 
prolongation were the most frequently reported AEs. Malaria was reported with a 
higher incidence in the OZ439 800 mg:PQP 960 mg and in the OZ439 800 mg:PQP 
640 mg treatment arms than in the OZ439 800 mg:PQP 1440 mg treatment arm. The 
ECG 
QTc 
prolongation 
was 
reported 
with 
a 
higher 
incidence 
in 
the 
OZ439 800 mg:PQP 1440 mg and the OZ439 800 mg:PQP 960 mg treatment arms 
than in the OZ439 800 mg:PQP 640 mg treatment arm. Concentration-related QTc 
prolongation has been widely documented with PQP. Diarrhea and vomiting were the 
most frequently reported AEs of the GI system in patients treated with both OZ439 and 
PQP. None of these AEs were SAEs. 
 
The AE profile for OZ439 in healthy subjects was similar to the AE profile in malaria 
patients. Gastrointestinal AEs, including nausea, vomiting, and diarrhea, were the most 
frequently reported AEs in healthy subjects treated with OZ439 alone or OZ439 in 


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combination with either PQP, MQ, or FQ. A tendency for a dose-response relationship 
was seen for GI events. 
 
No deaths have been reported in any of the clinical studies. 
 
Eight subjects treated with OZ439, including 6 malaria patients and 2 healthy 
volunteers, have had SAEs, including P. vivax relapse, pyelonephritis, increased 
alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), 
decreased neutrophil count, anemia, febrile convulsion and decreased hemoglobin in 
malaria patients; and atrial fibrillation and a gunshot wound in healthy subjects. 
Five SAEs (increased ALT, increased AST, decreased neutrophil count, anemia and 
decreased hemoglobin) in malaria patients were assessed as related to study drug by 
the investigator. 
 
An AE of vomiting led to study drug discontinuation in 1 malaria patient treated with 
OZ439. Ten healthy subjects treated with OZ439 discontinued a Phase Ia study due to 
an AE. Vomiting (5 subjects) was the most frequently reported AE leading to study 
discontinuation in the 10 healthy subjects. Except for a few cases observed with 
α-tocopherol polyethylene glycol 1000 succinate (TPGS) formulation that will not be 
used in further studies, vomiting is not reported in healthy subjects at doses < 800 mg 
OZ439. 
 
No Hy’s law cases have been observed. However, mild to severe and reversible 
increases in ALT and AST were seen in OZ439-treated malaria patients; these 
increases did not appear to be dose-dependent. Decreases in hemoglobin, neutrophils, 
and platelets were also seen in OZ439-treated malaria patients; however, these 
decreases were consistent with those observed in acute malaria. Close monitoring of 
liver function is required in the clinical studies. 
 
In the clinic, a significant effect on placebo-corrected change from baseline QTcF was 
not demonstrated for OZ439. In healthy subjects the effect of OZ439 800 mg alone on 
QTc was minimal, with a maximum mean QTcF increase from baseline and placebo of 
8.5 ms (Study MMV_OZ439_12_002). In Study MMV_OZ439_12_003, 1 healthy 
subject with an undisclosed history of mitral and tricuspid regurgitation was 
discontinued from the study due to asymptomatic supraventricular/junctional 
tachycardia after dosing with 120 mg OZ439. QTc prolongations (both QTcB and 
QTcF) were seen when OZ439 was administered in combination with PQP to malaria 
patients and healthy subjects. Most of the prolongations were in the range of >30 ms 
but <60 ms; however, prolongations >60 ms were observed in malaria patients, with 
QTcF values that exceeded 500 ms in 2 patients (1 hypokalemic patient). Reversible 
right bundle branch block (3 patients), reversible first degree atrioventricular block 
(1 patient), and a mild reversible sinus bradycardia (1 patient) were also observed in 
malaria patients treated with OZ439. Close monitoring of cardiac function is required in 
the clinical studies. 
 


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Additional information on non-clinical and clinical studies conducted with OZ439 is 
provided in the IB and addendum to the IB.8,10 
 
Cobicistat 
Cobicistat (Tybost®) is a potent CYP3A4 inhibitor used as "pharmaco-enhancer" for 
boosting 
exposures 
to 
CYP3A4 
substrates 
and 
more 
particularly 
human 
immunodeficiency virus (HIV) drugs. The mechanism may involve direct as well as 
mechanism-based inhibition. Cobicistat was shown to be well tolerated in healthy 
subjects after both single dose (50-400 mg) and multiple dose (50-300 mg for 14 days) 
administration.9 After single dose administration all the AEs observed were of Grade 1. 
The most frequently reported AEs (in only 2 subjects) were headache, somnolence 
and abnormal dreams. No notable changes in biology parameters, vital signs or ECGs 
(QTc) were detected in the first-in-man study. In subsequent studies with multiple dose 
administration of cobicistat, it was shown that the drug increases serum creatinine 
concentration by decreasing its elimination, resulting in a decrease in estimated 
glomerular filtration rate (eGFR). The rise in serum creatinine concentration and 
decline in eGFR was reversible within 7 days after the discontinuation of cobicistat. 
This artefactual change in creatinine is not expected after single dose administration. 
 
When midazolam, a reference substrate for CYP3A4, was co-administered with 
cobicistat at steady-state conditions of the CYP3A4 inhibitor, the lowest dose of 
cobicistat (50 mg) was associated with a 89% reduction in apparent clearance of oral 
midazolam. The maximal inhibition of CYP3A4 was achieved with 200 mg (95%) and 
with marginal gain over the 100 mg dose (93%). These data have demonstrated that a 
dose ≥100 mg provide near maximal boosting of CYP3A4 substrate and 150 mg was 
subsequently selected as the boosting dose for HIV drugs. 
 
Detailed information can be found in the Summary of Product Characteristics of 
cobicistat (Tybost®).  
1.2 
Risk-Benefit Assessment 
There is no expected clinical benefit for the healthy subjects that will participate in this 
study. The information obtained in this study can be used for the further clinical 
development of OZ439. Overall, on the basis of the available non-clinical and clinical 
data, and prior knowledge, the risk-benefit profile of OZ439 and cobicistat are judged 
acceptable for the proposed clinical study. 
1.3 
Study Rationale 
Work is ongoing to develop a suitable OZ439 formulation to achieve efficacious 
exposures in patients with malaria, and in addition to meet the target product profile 
volume criterion: a maximum suspension volume of 15 mL in infants (6 months to 
2 years old). It is assumed that 64.5 mL is the equivalent volume in adults (to obtain 
the similar dose/volume ratio). An intermediate 25 mL volume in infants may be 
considered and similarly, would translate into approximately 100 mL in adults. 
 


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The determination of the absolute bioavailability of the simple dispersible OZ439 
granules formulation will allow the estimation of the maximum enhancement of 
bioavailability achievable through formulation approaches.  
 
The non-linearity of OZ439 PK is addressed by administering the iv microdose at the 
tmax of the oral dose, thus ensuring that the clearance is the same for both iv and oral 
doses. In order to ensure adequate assay sensitivity for the microdose, OZ439 will be 
radiolabeled and accelerator mass spectrometry (AMS) will be used to determine the 
plasma drug concentrations over time. 
 
In vitro evidence has shown that OZ439 is mainly metabolized through 
cytochrome P450 (CYP) 3A4 in humans. Marketed CYP3A4 inhibitors are indicated to 
increase systemic exposures of anti-retroviral agents in the treatment of HIV-1 
infection, e.g. Tybost® (cobicistat). Further development of OZ439 could include a 
combination strategy with cobicistat in order to maximize exposures of OZ439 in a 
single-dose setting. This approach will be tested in the second part of the study, to 
determine the fractional increase in OZ439 exposure in the presence of the approved 
150 mg pharmaco-enhancer dose of cobicistat which is a strong CYP3A4 inhibitor 
currently used to increase exposure to HIV drugs in patients (Tybost®).  
 
Data collected in previous clinical studies suggested that the total volume of liquid 
administered with OZ439 may alter the exposure of OZ439 (exposure increasing with 
increasing volume). The PK and exposures of OZ439 granules formulation when 
suspended in 2 different target volumes of dosing vehicle will be evaluated under 
fasted conditions. 
 
Included in the primary PK endpoints evaluating the plasma exposures of OZ439 is the 
concentration on Day 7 (C168h). This endpoint is considered relevant since 
concentrations of an effective anti-malarial drug in a combination treatment may be 
required to exceed the minimum parasiticidal concentration (MPC) for at least 7 days 
to achieve full clearance of the original parasitaemia. Furthermore, a relationship 
between C168h and clinical outcome for the combination of OZ439 with PQP has been 
derived based on Phase IIb data (MMV_OZ439_13_003), allowing direct interpretation 
of this endpoint. 
1.4 
Dose Rationale 
Table 3 summarises the maximum drug exposures achieved in relevant OZ439 clinical 
studies, including those studies providing key efficacy and tolerability data supporting 
the dose rationale for this study. These exposures were generally well tolerated and 
the exposures in the current study are predicted not to exceed exposure levels 
investigated in the previous studies. The highest OZ439 exposure (AUC0-inf of 
29,200 ng.h/mL) achieved in healthy subjects to date was in an OZ439 relative 
bioavailability study (MMV_OZ439_11_001) in which 800 mg OZ439 powder in bottle 
(PIB) formulation was administered in the fed state. 
 


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Table 3 
Key Studies - Drug Exposures OZ439 
 
Study 
Design 
OZ439 Dose (mg) 
Cmax (ng/mL) 
(CV%) 
AUC0-inf 
(ng.h/mL) (CV%) 
PQP Dose (mg) 
MMV_OZ439_09_001 
FIH, Part A 
 
FIH, Part B 
 
400 mg PIB fasted 
800 mg PIB fasted 
800 mg PIB fasted 
800 mg PIB fed 
566 (53.9) 
917 (35.6) 
730 (61.1) 
2220 (52.6) 
5540 (71.3) 
9790 (56.7) 
8080 (68.7) 
23100 (48.9) 
NA 
NA 
NA 
NA 
MMV_OZ439_11_001 
BA OZ439 + TPGS prototype BA 
800 mg PIB fasted (Cohort 1) 
800 mg PIB fasted (Cohort 2) 
800 mg PIB fed (reference) 
827 (47.7) 
538 (33.2) 
1910 (32.9) 
10700 (52.8) 
7460 (34.1) 
29200 (31.2) 
NA 
NA 
NA 
MMV_OZ439_10_002 
Phase IIa efficacy 
1200 mg PIB 
1500 (90.0) 
25100 (85.1) 
NA 
MMV_OZ439_12_005 
3-Day dose escalation 
(Exposures on Day 3) 
700 mg PIB milk 
1790 (32.2) 
20500 (32.0)* 
NA 
MMV_OZ439_12_002 
OZ439 + PQP safety/DDI 
800 mg PIB milk 
100 mg PIB milk 
1650 (26) 
199 (27) 
20700 (41) 
1520 (26)** 
1440 mg milk 
1440 mg milk 
MMV_OZ439_13_002 
OZ439 + TPGS Phase IIb 
prototype + PQP BA 
800 mg PIB milk (reference) 
800 mg + TPGS 
1610 (37.2) 
1540 (26.0) 
18600 (45.4) 
17500 (27.9) 
1440 mg milk 
1440 mg 
MMV_OZ439_13_004 
OZ439 + PQP Phase IIb 
formulation BA 
800 mg + TPGS 
800 mg + TPGS 
800 mg + TPGS 
1260 (35) 
1500 (40) 
1270 (29) 
14200 (26) 
15800 (35.7) 
14100 (34.7) 
1440 mg 
960 mg 
960 mg 
MMV_OZ439_13_007 
PQP + OZ439 
PK study in HV 
800 mg Prototype 1 
800 mg Prototype 2 
800 mg Prototype 3 
877 (41.3) 
995 (32.2) 
924 (50.5) 
8780 (43.7)** 
10300 (23.7)** 
9460 (43.0)** 
960 mg 
960 mg 
960 mg 
MMV_OZ439_15_001 
PQP + OZ439 
PK study in HV 
800 mg TPGS 
800 mg Prototype 1 (110 mL) 
800 mg Prototype 3 (110 mL) 
800 mg TPGS 
800 mg Prototype 1 (220 mL) 
800 mg Prototype 3 (220 mL) 
1600 (36.6) 
824 (38.3) 
616 (49.4) 
1530 (13.2) 
999 (40.8) 
730 (35.7) 
15300 (26.1)** 
7920 (26.4)** 
5610 (38.1)** 
14000 (29.6)** 
9550 (57.5)** 
7100 (45.7)** 
960 mg 
960 mg 
960 mg 
960 mg 
960 mg 
960 mg 
 
 
Exposures are given as geometric mean  
 
 
* Day 3 AUC; ** AUC168h 
BA: bioavailability study; DDI: drug-drug interaction study; FIH: first-in-human study; HV: healthy volunteers; NA: not applicable; PIB: powder in bottle; 
PK: pharmacokinetic; PQP: piperaquine phosphate; TPGS: α-tocopherol polyethylene glycol 1000 succinate  
 


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Single OZ439 doses of up to 800 to 1200 mg giving exposures (Cmax and AUC0–inf) of 
up to 2220 ng/mL and 29,200 ng.h/mL, respectively (Table 3) have been shown to be 
generally well tolerated in patient and in healthy subject studies. Administration of 
700 mg OZ439 for 3 days was also well tolerated.  
For OZ439, the dose level of 800 mg is close to the upper limit of what can be 
administered to patients. Even for the best performing, well tolerated but not 
commercially viable formulations (e.g., TPGS or PIB milk) the exposures for 800 mg 
may be sufficient but are still considered suboptimal. Therefore, the likely clinical dose 
level will be 800 mg, and improving the bioavailability is of interest. 
 
Therefore, the bioavailability of OZ439 will be estimated for a basic formulation 
(granules in dispersion) at the dose level of 800 mg. The anticipated exposures for 
800 mg administered as granules in dispersion are about Cmax 900 ng/mL and AUCinf 
10000 ng*hr/mL (studies MMV_OZ439_09_001 and MMV_OZ439_11_001) 
Likewise, when evaluating the impact of reducing the administration volumes the most 
relevant (maximal) dose level is 800 mg. Anticipated exposures are expected to be 
equal to or lower than what has previously been observed. 
For the evaluation of the co-administration of OZ439 and cobicistat, SimCyp 
simulations are suggesting that a mean 1.20 and 2.55 fold increase in OZ439 exposure 
for Cmax and AUCinf, respectively, could be achieved in the presence of an oral 150 mg 
dose of cobicistat. The simulations assumed that for OZ439 the fraction of CYP3A4 
metabolism was 0.9 (from in vitro data) and the cobicistat parameters were derived 
from human PK and interaction with midazolam. The anticipated Cmax and AUC for a 
single dose of 400 mg OZ439 (granules in dispersion) when co-administered with a 
single dose of  150 mg cobicistat are 390 ng/mL and 11,290 ng*hr/mL, respectively 
(mean value of 10 trials simulations with SimCyp), more than 2-fold lower than the 
maximal evaluated well tolerated exposures. Therefore, 400 mg was considered a safe 
dose of OZ439 to be evaluated with cobicistat.  
 
The rationale for the 150 mg cobicistat dose is provided in Section 1.1.1. 
 
 


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2. 
OBJECTIVES 
2.1 
Primary  
 
To determine the absolute bioavailability of OZ439 following a single oral dose of 
OZ439 dispersion and a simultaneous single iv microdose (100 µg) infusion of 
[14C]-OZ439 under fasted conditions (Part 1) 
 
To evaluate the effects of a single oral dose of cobicistat, a strong CYP3A4 
inhibitor, on the PK profile of a single oral dose of a dispersion of OZ439 simple 
granules under fasted conditions (Part 2) 
 
To evaluate the PK of single doses of OZ439 granules when restricting the target 
dosing volumes to 64.5 or 100 mL (Parts 1 and 2) 
2.2 
Secondary  
 
To assess the safety and tolerability of OZ439 when administered alone, and to 
assess the safety and tolerability of OZ439 and cobicistat when co-administered as 
single doses to healthy subjects (Parts 1 and 2) 
 
To determine the PK parameters of OZ439 single iv microdose (100 µg) infusion of 
[14C]-OZ439 (Part 1) 
 
To assess the effects of the total dosing volume and of dose to volume ratio on 
OZ439 PK under fasted conditions (Parts 1 and 2) 
 
To determine the PK parameters and exposures of cobicistat (Part 2) 
 
 
 
 


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3. 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
3.1.1 
Type of Study 
This is a single-center, 2-part clinical study in healthy subjects. 
 
Part 1 
This is an open-label study in 8 healthy subjects to determine the absolute 
bioavailability of OZ439 following a single oral dose of OZ439 and a simultaneous 
single iv infusion of [14C]-OZ439 radiolabeled microdose administered at the 
anticipated tmax of the oral dose. Subjects will receive the following treatment: 
 
Treatment A: 
a single oral dose of 800 mg OZ439 simple granules administered as a 
100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg 
[14C]-OZ439 (47 kBq [1.27 µCi]) beginning 3 hours after the oral dose 
administration.  
 
Part 2  
This is an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy 
subjects. Each subject will participate in 3 treatment periods and each subject will 
receive a single dose of each of the following 3 treatments in a randomized order with 
a 14-day wash-out period between each treatment: 
 
Treatment B: 
a single oral dose of 800 mg OZ439 simple granules administered as a 
64.5-mL dispersion  
Treatment C:  a single oral dose of 400 mg OZ439 simple granules administered as a 
64.5-mL dispersion  
Treatment D:  a single oral dose of 400 mg OZ439 simple granules administered as a 
64.5-mL dispersion and co-administered with a 150 mg cobicistat 
tablet (CYP3A4 inhibitor) 
3.1.2 
Screening Period 
Subjects will report to the medical screening facility/clinical site for the eligibility 
screening (see Section 3.3 for inclusion and exclusion criteria) within 4 weeks prior to 
(the first) drug administration.  
 
Subjects will sign the study-specific informed consent form (ICF) prior to any 
study-specific screening procedures being performed. The written informed consent 
will be obtained for all subjects, regardless of their eligibility for the study; the signed 
ICFs will be retained and archived at PRA Health Sciences (PRA) and a copy will be 
provided to the subject. 
 
Eligibility screening will consist of the assessments as presented in the schedules of 
assessments (Table 1 and Table 2). 


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3.1.3 
Treatment Period 
Part 1 
The subjects will be admitted to the clinical research center in the afternoon of Day -1. 
They will be discharged on Day 2 (24 hours post-dose) after completion of the 
assessments. After discharge, the subjects will return to the clinical research center for 
ambulatory visits on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours post-dose) for PK 
and safety assessments.  
 
Part 2 
Subjects will be in the clinic for 3 treatment periods. Each period, the subjects will be 
admitted to the clinical research center in the afternoon of Day -1. They will be 
discharged on Day 2 (24 hours post-dose) after completion of the assessments. After 
discharge, the subjects will return to the clinical research center for ambulatory visits 
on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours post-dose) of each period for PK 
and safety assessments. For Treatment D, the subjects will also return to the clinical 
research center for additional ambulatory visits on Days 10, 12 and 14 for PK and 
safety assessments (Day 14 will coincide with Day -1 of the next period when a subject 
is randomized to Treatment D in Period 1 or Period 2). 
 
Assessments during the treatment period(s) will be performed as presented in the 
schedules of assessments (Table 1 and Table 2). 
3.1.4 
Follow-up 
Part 1 
Subjects will attend a follow-up visit on Day 15 (± 2 days) for a final safety assessment. 
 
Part 2 
Subjects will attend a follow-up visit between Day 15 and Day 19 of Period 3 (14 to 
18 days after last drug administration) for a final safety assessment. 
 
Assessments during follow-up will be performed as presented in the schedules of 
assessments (Table 1 and Table 2). 
3.2 
Discussion of Study Design 
In the cross-over design that has been chosen for Part 2 of this study the subjects will 
be their own control for treatment comparisons. The wash-out period with a minimum 
of 14 days is considered to be sufficient to avoid a carry-over effect.  
 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous similar studies and taking into account OZ439 moderate 
to high between subject variability, a total of 8 subjects enrolled in Part 1 of the study to 
achieve a minimum of 6 evaluable subjects is considered sufficient. A total of 
8 subjects is also considered sufficient to assess the effects of the total dosing volume 
and of dose to volume ratio on OZ439 PK under fasted conditions (in combination with 
Part 2). In Part 2 of the study a sample size of 18 subjects is considered appropriate to 
estimate the increase in OZ439 exposure in the presence of a single dose of 150 mg 


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cobicistat with sufficient precision, assuming a mean ratio of 2. Based on the 
assumptions of a point estimate (mean ratio) of 2.0 and a CV of 23%, a sample size of 
18 subjects would give a 90% confidence interval (CI) of 1.75 - 2.28 and this number of 
subjects is therefore considered sufficient. 
3.3 
Selection of Study Population 
A total of 26 healthy male subjects and female subjects of non-childbearing potential 
will be enrolled (excluding any replacement subjects).  
 
In Part 1, 8 subjects will be enrolled to ensure data in 6 evaluable subjects for the PK 
endpoints.  
 
In Part 2, 18 subjects will be randomized to ensure data in 15 evaluable subjects for 
the PK endpoints. In Part 2, a subject will be considered evaluable for the primary 
analysis if they have sufficient PK data to estimate all of the primary endpoints (Cmax, 
C168h, AUC0-168h, and AUC0-inf; see Section 3.5.3) for the 3 treatments.  
3.3.1 
Inclusion Criteria 
Note: Restrictions that apply to the period after (the first) admission are described in 
Section 3.4.8, except when they concern a statement of willingness. 
 
The following inclusion criteria must be met for a subject to be eligible for inclusion in 
the study: 
1. 
Gender 
: male or female 
2. 
Age 
: 18-55 years, inclusive, at screening 
3. 
Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening  
4. 
Weight 
: >50 kg, at screening 
5. 
Status 
: healthy subjects 
6. 
Female subjects must be of non-childbearing potential (either surgically sterilized 
or physiologically incapable of becoming pregnant, or post-menopausal [defined 
as spontaneous amenorrhoea for at least 1 year or spontaneous amenorrhoea for 
at least 6 months confirmed by a follicle stimulating hormone (FSH) result 
indicating a post-menopausal status]) and have a negative pregnancy test at 
screening and at (each) admission to the clinical research center. As all female 
subjects must be of non-childbearing potential, they are not required to use any 
contraception during this study. 
7. 
Male subjects must use adequate contraception and not donate sperm from (first) 
admission to the clinical research center until 90 days after the follow-up visit. 
Adequate contraception for the male subject (and his female partner) is defined 
as surgical sterilization (vasectomy), using hormonal contraceptives (implantable, 
patch, oral, injectable) or an intrauterine device or system combined with at least 
1 of the following forms of contraception (barrier method): a diaphragm or cervical 
cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the 
subject is acceptable.   


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8. 
Must have QTcF ≤450 ms and QTcB ≤450 ms (male subjects); QTcF ≤470 ms 
and QTcB ≤470 ms (female subjects), and PR-interval ≤200 ms for screening, 
and Day -1 and pre-dose ECG measurements of the (first) treatment period 
9. 
Ability and willingness to abstain from alcohol and methylxanthine-containing 
beverages or food (coffee, tea, cola, chocolate, energy drinks) from 48 hours prior 
to (each) admission to the clinical research center 
10. Willing and able to communicate and participate in the whole study 
11. Willing and able to sign the ICF 
3.3.2 
Exclusion Criteria 
Note: Restrictions that apply to the period after (the first) admission are described in 
Section 3.4.8, except when they concern a statement of willingness. 
 
A subject who meets any of the following exclusion criteria will not be eligible for 
inclusion in the study: 
1. 
Male subjects who have currently pregnant partners or who have partners 
planning to be pregnant in the 90 days after discharge 
2. 
Evidence or history of clinically significant oncological, pulmonary, chronic 
respiratory, hepatic, cardiovascular, hematological, metabolic, neurological, 
immunological, nephrological, endocrine or psychiatric disease, or current 
infection  
3. 
Clinically relevant (as decided by the Principal Investigator [PI]) abnormalities in 
the 12-lead ECG, including asymptomatic bundle branch block  
4. 
Family history of sudden death or of congenital prolongation of the QTc-interval 
or known congenital prolongation of the QTc-interval or any clinical condition 
known to prolong the QTc-interval  
5. 
History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia, 
heart rate ≤39 beats per minute (bpm)  
6. 
Electrolyte 
disturbances, 
particularly 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia  
7. 
Any condition that could possibly affect drug absorption, e.g. gastrectomy or 
diarrhea  
8. 
History of post-antibiotic colitis  
9. 
History of any drug or alcohol abuse in the past 2 years prior to screening  
10. Subjects who regularly smoke more than 5 cigarettes a day  
11. Receipt of an investigational drug or participation in another clinical research 
study within 90 days prior to the first dose of study drug 
12. Subjects who are PRA employees, or immediate family members of PRA or 
Sponsor employees  
13. Subjects who have previously been enrolled in this study  
14. Use of moderate/strong inhibitors or inducers of CYP cytochromes or transporters 
within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study 
drug 
15. Consumption of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g. 
Seville oranges, pomelos) within 14 days prior to the first dose of study drug 


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16. Use of prescription or non-prescription drugs and dietary supplements within 
7 days or 5 half-lives (whichever is longer) prior to the first dose of study drug. 
With the exception of paracetamol (which may be used incidentally or for a 
short-term treatment at a maximum dose of 2 g per day) and hormone 
replacement therapy  
17. Use of herbal supplements within 30 days prior to the first dose of study drug 
18. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or 
HIV-1 or HIV-2 antibody results  
19. Clinically significant abnormal biochemistry, hematology or urinalysis as judged 
by the PI. In case of doubt the PI will discuss this with the medical monitor 
20. Positive urine drug screen result at screening or admission to the clinical 
research center  
21. Serious adverse reaction or serious hypersensitivity to any drug or the 
formulation excipients  
22. Presence or history of allergy requiring treatment. Hayfever is allowed unless it is 
active  
23. Donation or loss of >100 mL of blood within 90 days prior to drug administration  
24. Regular alcohol consumption in males >21 units per week and females >14 units 
per week (1 unit = 250 mL beer, 25 mL of 40% spirit or 125 mL of wine)  
25. Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the PI or delegate at screening  
26. Failure to satisfy the PI of fitness to participate for any other reason 
 
The Sponsor will not agree to any waiver related to inclusion or exclusion criteria. 
 
Please note that subjects should refrain from consumption of any foods containing 
poppy seeds within 48 hours (2 days) prior to screening and (first) admission to the 
clinical research center to avoid false positive drug screen results. In addition, they 
should refrain from strenuous exercise within 96 hours (4 days) prior to screening and 
(first) admission as this could result in abnormal clinical laboratory values. 
3.3.3 
Removal and Replacement of Subjects from the Study 
Participation in the study is strictly voluntary. A subject has the right to withdraw from 
the study at any time for any reason. 
 
The PI has the right to terminate participation of a subject for any of the following 
reasons: termination of the study, difficulties in obtaining blood samples, major 
deviation of the protocol, severe AEs or SAEs, or for any other reason relating to the 
subject's safety or integrity of the study data (eg, concurrent illness or requirement for 
prohibited medication), at the discretion of the PI. 
 
If a subject is withdrawn from the study, the Sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the subject will remain under the supervision 
of the PI until satisfactory health has returned. 
 


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If a subject is withdrawn from the study for any reason, whether related to the study 
drug or not, or if a subject voluntarily withdraws before or after receiving the study 
drug, such subject will be considered an early-termination subject. 
  
If a subject is withdrawn due to a study drug-related AE or due to termination of the 
study, the early-termination subject will not be replaced. If a subject does not complete 
the study for reasons other than safety, the early-termination subject may be replaced 
after mutual agreement between the Sponsor and PRA. If there are fewer than 
6 evaluable subjects for the PK endpoints in Part 1 of the study, replacement subjects 
may be enrolled to have at least 6 evaluable subjects following discussion between the 
Sponsor and the PI. If there are fewer than 15 evaluable subjects for the PK endpoints 
in Part 2 of the study, up to 2 replacement subjects may be enrolled per treatment 
following discussion between the Sponsor and the PI. 
 
The decision regarding the replacement of subjects will be documented. 
 
PRA will make every effort to ensure that early-termination subjects who have received 
study drug complete the safety follow-up assessments. 
3.4 
Treatments 
3.4.1 
Treatments Administered 
The treatments and dose levels for each part are described in detail in Section 3.1.1. 
3.4.2 
Identity of Investigational Products 
Active medication 
Active substance 
: OZ439 
Activity 
: Peroxide anti-malarial agent 
Indication 
: Treatment of uncomplicated malaria 
Strength 
: 400 mg/64.5 mL, 800 mg/64.5 mL and 800 mg/100 mL 
Dosage form 
: Oral dispersion 
Manufacturer 
: Novasep (Finorga) (drug substance); PRA pharmacy (oral 
dispersions) 
 
In the table below the OZ439 doses, the vehicle and  volume of vehicle are given for 
the different treatments. 
 
Treatment 
OZ439 Dose 
Volume of Vehicle 
A 
800 mg granules 
100 mL of water containing Ora-sweet and 
polysorbate 80 
B 
800 mg granules 
64.5 mL of solution containing Ora-sweet and 
polysorbate 80 
C 
400 mg granules 
64.5 mL of solution containing Ora-sweet and 
polysorbate 80 
D 
400 mg granules 
64.5 mL of solution containing Ora-sweet and 
polysorbate 80 


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The exact reconstitution procedure and amounts of Ora-sweet and polysorbate 80 will 
be described in the pharmacy manual to be provided by MMV. 
 
Active medication 
Active substance 
: [14C]-OZ439 
Activity 
: Peroxide anti-malarial agent 
Indication 
: Treatment of uncomplicated malaria 
Strength 
: 10 µg/mL free base containing 4.7 kBq/mL (0.127 µCi/mL) of 
radioactivity 
Dosage form 
: iv solution for infusion (10 mL)  
Manufacturer 
: Almac (drug substance); PRA Pharmacy (iv solution for 
infusion) 
 
Reference medication 
Active substance 
: Cobicistat 
Activity 
: CYP3A4 inhibitor (PK exposure enhancer) 
Indication 
: Pharmacokinetic enhancer of atazanavir or darunavir as part 
of anti-retroviral combination therapy in HIV-1 infected adults 
Strength 
: 150 mg 
Dosage form 
: Oral tablet 
Manufacturer 
: Gilead Sciences B.V. 
 
OZ439 and [14C]-OZ439 drug substance will be provided by the Sponsor. The OZ439 
oral dispersions and the [14C]-OZ439 iv solution for infusion will be manufactured by 
the PRA Pharmacy. The reference medication cobicistat will be commercially obtained 
by the PRA Pharmacy.  
 
For details concerning drug storage and drug accountability see Appendix 9.1. 
3.4.3 
Method of Assigning Subjects to Treatment Groups 
After obtaining informed consent, subjects will be screened according to the inclusion 
and exclusion criteria. Subjects who have met all eligibility criteria will receive a subject 
number upon inclusion in the study (for Part 1: subject numbers 101-108; for Part 2: 
subject numbers 201-218). They will receive the subject number according to the order 
of enrolment in Part 1 of the study, and according to the randomization code generated 
by the Biostatistics Department of PRA in Part 2 of the study. The subject number will 
ensure identification throughout the study. Replacement subjects will receive the 
number of the subject to be replaced, increased by 1000 (e.g. 1101 replacement 
number for subject number 101), and will be administered the same or remaining 
treatments in the same order. 
 
Subjects who drop out or withdraw for any reason without completing all screening 
evaluations successfully, will be considered “screening failures“. Such subjects will not 
receive a subject number, and only applicable data will be entered in the electronic 
case report forms (eCRFs).  


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3.4.4 
Selection of Doses in the Study 
The rationale for dose selection is described in Section 1.4. 
3.4.5 
Timing of Doses in the Study 
Study drug (OZ439 alone or in combination with cobicistat) will be administered to 
subjects between 08:00 and 11:00 hours in the morning after an overnight fast of at 
least 10 hours. In Part 1, the iv infusion of 100 μg [14C]-OZ439 (47 kBq [1.27 µCi]) will 
begin 3 hours after the oral dose administration. Fasting will continue for a period of 
6 hours after oral drug administration, ie, until scheduled lunch. During fasting, no 
fluids are allowed except water; however, water is not allowed from 2 hours pre-dose 
until 1 hour post-dose (calculated from oral dose administration). 
 
Administration of the study drug will be supervised by the PI or authorized designee. 
After oral drug administration, a mouth and hand inspection will take place. 
3.4.6 
Meals During the Study 
A fasting period of at least 4 hours is required before obtaining clinical laboratory 
samples at all time points. 
 
With the exception of the restrictions with respect to methylxanthine- and alcohol 
containing beverages or food as described in Section 3.4.8 and what has been 
described in Section 3.4.5, there are no special requirements related to food and 
beverage intake. When not fasting, meals and snacks (such as decaffeinated coffee, 
herbal tea, fruit, biscuits) will be provided according to PRA standard operating 
procedures (SOPs). A light supper will be provided on the evening before those days 
where fasting is required until lunch time.  
3.4.7 
Blinding 
This is an open-label study. 
3.4.8 
Concomitant Medication and Other Restrictions During the Study 
Note: Restrictions that apply to the period before (the first) admission are described in 
Section 3.3.1, and Section 3.3.2. 
 
The use of all prescribed medication is not allowed from (first) admission to the clinical 
research center up to follow-up. The use of all over-the-counter medication, vitamin 
preparations and other food supplements, herbal medications (e.g. St. John’s Wort), 
grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g. Seville oranges, 
pomelos)  is not allowed from (first) admission to the clinical research center up to 
follow-up. An exception is made for paracetamol: from (first) admission onwards, the PI 
may permit a limited amount of paracetamol for the treatment of headache or any other 
pain. Other medication to treat AEs may only be prescribed if deemed necessary by 
the PI. If medication is used, the name of the drug, the dose and dosage regimen will 
be recorded in the eCRF.  
 


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The use of alcohol, methylxanthine-containing beverages or food (coffee, tea, cola, 
chocolate, energy drinks) and tobacco products is not allowed during the stay(s) in the 
clinical research center. 
 
Strenuous exercise is not allowed within 96 hours (4 days) prior to (each) admission and 
during the stay(s) in the clinical research center. Strenuous exercise is also not allowed 
within 96 hours (4 days) prior to the ambulatory visits on Day 5 (Parts 1 and 2) and 
Day 10 ( after Treatment D in Part 2), and the follow-up visit. 
 
Subjects should not consume any foods containing poppy seeds within 48 hours 
(2 days) prior to (each) admission to the clinical research center as this could cause a 
false positive drug screen result. 
 
Contraception, sperm donation and pregnancy 
As all female subjects must be of non-childbearing potential, they are not required to 
use any contraception during this study.  
 
Male subjects are required to use at least 2 adequate methods of contraception (see 
description below) and not donate sperm from (first) admission to the clinical research 
center until 90 days after the follow-up visit. 
 
Adequate contraception for male subjects (and his female partner) is defined as 
surgical sterilization (vasectomy), using hormonal contraceptives (implantable, patch, 
oral, injectable) or an intrauterine device or system combined with at least 1 of the 
following forms of contraception (barrier method): a diaphragm or cervical cap, or a 
condom. Also, total abstinence, in accordance with the lifestyle of the subject is 
acceptable. 
 
In addition, male subjects who have been sterilized or have partners of 
non-childbearing potential (including homosexual men) are required to use one barrier 
method of contraception (condom) from (first) admission to the clinical research center 
until 90 days after the follow-up visit. This is to prevent unintended exposure of the 
partner to the study drug via seminal fluid. 
 
Subjects will be instructed that the study drug has known embryotoxicity in rodents and 
that if they or their partner become pregnant during the study this should be reported to 
the PI. The PI should also be notified of pregnancy occurring during the study but 
confirmed after completion of the study. If a subject or subject’s partner is 
subsequently found to be pregnant after the subject is included in the study, then 
consent will be sought from the partner and, if granted, any pregnancy will be followed 
and the status of mother and/or child will be reported to the Sponsor after delivery. Any 
subject reporting a pregnancy during the study will be withdrawn from the study. A 
pregnancy notification form and follow-up will be completed. 


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3.4.9 
Treatment Compliance 
Study drug will be administered in the clinical research center. To ensure treatment 
compliance, administration of the study drug will be supervised by the PI or authorized 
designee. Compliance will be further confirmed by bioanalytical assessment of OZ439 
in plasma samples (see Section 3.5.4). 
 
The exact times of study drug administration and the number of units administered will 
be recorded in the eCRF.  
3.5 
Pharmacokinetic and Safety Measurements and Endpoints  
3.5.1 
Pharmacokinetic and Safety Measurements Assessed and Schedules of 
Assessments  
The schedules of assessments are presented in Table 1 and Table 2. 
3.5.1.1 
Pharmacokinetic Measurements  
3.5.1.1.1 
Blood Sampling  
At the time points defined in the schedules of assessments, blood samples of 3 mL 
and 8 mL each will be taken for the analysis of OZ439 and [14C]-OZ439, respectively, 
in plasma samples for Part 1. For Part 2, blood samples of 3 mL will be taken for the 
analysis of OZ439 and cobicistat. Additional blood samples of 3 mL will be collected for 
future OZ439 metabolites analysis in Part 1 and in Part 2 (Period 1 only). The blood 
samples will be taken via an indwelling iv catheter or by direct venipuncture. 
 
Samples will be shipped to Swiss BioQuant AG for the analysis of OZ439, OZ439 
metabolites and cobicistat, and to Xceleron for the analysis of [14C]-OZ439.  
 
Details on sample collection, handling, storage and shipping will be described in the 
laboratory manual prepared by PRA. 
3.5.1.2 
Safety and Tolerability Measurements 
Safety and tolerability assessments will consist of AEs, clinical laboratory, vital signs, 
12-lead ECG, and physical examination. Assessments will be performed in accordance 
with the schedules of assessments. 
3.5.1.2.1 
Adverse Events 
Adverse events will be recorded from screening until completion of the follow-up visit. 
Any clinically significant observations in results of clinical laboratory, 12-lead ECGs, 
vital signs or physical examinations will be recorded as AEs. 
 
A treatment-emergent AE (TEAE) is defined as any event not present prior to the first 
administration of the study drug or any event already present that worsens in either 
severity or frequency following exposure to the study drug.  
 
An AE which occurs prior to the first administration of the study drug will be considered 
a pre-treatment AE. 


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At several time points before and after drug administration, subjects will be asked 
non-leading questions to determine the occurrence of AEs. Subjects will be asked in 
general terms about any AEs at regular intervals during the study. In addition, all AEs 
reported spontaneously during the course of the study will be recorded. 
 
All answers will be interpreted by the PI using the Medical Dictionary for Regulatory 
Activities (MedDRA; most recent version) for AEs and will be recorded in the eCRF.  
 
The severity of the AEs will be rated by the PI as “Grade 1”, “Grade 2”, “Grade 3”, or 
“Grade 4”, and the relationship between the AEs and the study drug will be assessed 
by the PI as “certain”, “probable/likely”, “possible”, “unlikely”, “conditional/unclassified” 
or “unassessable/unclassifiable”. Details on the rating of the severity of the AEs and 
relationship to the study treatment are given in Appendix 9.2. 
 
Additional details on AEs and information on SAEs and Suspected Unexpected 
Serious Adverse Reactions (SUSARs) are described in Appendix 9.2. 
3.5.1.2.2 
Clinical Laboratory  
Blood and urine samples for clinical laboratory assessments will be collected according 
to PRA SOPs. 
 
The following parameters will be measured: 
 
Clinical chemistry (serum quantitatively): 
 
total bilirubin, direct bilirubin (only if total is elevated), alkaline phosphatase, 
gamma glutamyl transferase (gamma-GT), AST, ALT, lactate dehydrogenase 
(LDH), creatinine, creatine kinase, troponin I (only if creatine kinase is elevated), 
urea, total protein, glucose, inorganic phosphate, sodium, potassium, calcium, 
chloride, magnesium, albumin and bicarbonate  
 
Hematology (blood quantitatively): 
 
leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes, partial automated 
differentiation: lymphocytes, monocytes, eosinophils, basophils, neutrophils, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean 
corpuscular hemoglobin concentration (MCHC) 
 
Urinalysis (urine qualitatively): 
 
hemoglobin, urobilinogen, ketones, glucose, protein, bilirubin, leukocytes, nitrite, 
pH, specific gravity 
 
Serology: 
 
HBsAg, anti-HCV and anti-HIV 
 
Urine drug and alcohol screen: 
 
opiates, methadone, cocaine, amphetamines (including ecstasy), cannabinoids, 
barbiturates, benzodiazepines, tricyclic antidepressants, phencyclidine and alcohol 
 
Pregnancy test (females only): 
 
β-human chorionic gonadotropin (β-hCG) in serum  
 
Hormones (serum quantitatively):  
FSH at screening and for females only  
 


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In case of unexplained or unexpected clinical laboratory test values, the tests will be 
repeated as soon as possible and followed up until the results have returned to the 
normal range and/or an adequate explanation for the abnormality is found. The clinical 
laboratory will clearly mark all laboratory test values that are outside the normal range 
and the PI will indicate which of these deviations are clinically significant. These 
clinically significant deviating laboratory results will then be recorded as AEs and the 
relationship to the treatment will be indicated (see also Appendix 9.2). 
3.5.1.2.3 
Vital Signs 
Systolic and diastolic blood pressure and pulse will be recorded after the subject has 
been resting for at least 5 minutes in the supine position. These assessments will be 
made using an automated device. Tympanic body temperature will be measured 
subsequently. 
 
If a subject shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality will be followed to resolution if required. Additional 
measurements may be taken as deemed necessary by the PI. Any clinically significant 
abnormality, including changes from baseline, must be reported as an AE. 
3.5.1.2.4 
Electrocardiogram 
A standard 12-lead ECG will be recorded after the subject has been resting for at least 
5 minutes in the supine position. Triplicate 12-lead ECGs will be recorded at some time 
points according to the schedules of assessments. Individual ECG measurements as 
part of a triplicate ECG will be recorded 1 minute (and no more than 2 minutes) apart. 
The ECG will be recorded using an ECG machine equipped with computer based 
interval measurements. The following ECG parameters will be recorded: heart rate, 
PR-interval, QRS-duration, QT-interval, QTc-interval (Bazett’s and Fridericia's) and the 
interpretation of the ECG profile by the PI. 
 
If a subject shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality will be   followed to resolution if required. Additional 
measurements may be taken as deemed necessary by the PI. Any clinically significant 
abnormality, including changes from baseline, will be reported as an AE. 
3.5.1.2.5 
Physical Examination 
Physical examination will be performed according to PRA SOPs. In addition, body 
weight and height will be measured according to PRA SOPs. 
 
Any time the protocol indicates that a physical examination will be done, a complete 
physical examination is performed. The following will be examined: general 
appearance, skin/subcutaneous tissue, head, ears, nose and throat, neck and thyroid, 
thorax, lungs, cardiovascular examination, lymph nodes, abdomen, musculoskeletal 
examination, neurological examination. When a ‘targeted’ physical examination is 
required, subject symptoms dictate which systems should be evaluated. 


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3.5.1.3 
Total of Blood Volume 
Table 4 and Table 5 present the number and volume of blood samples and the total 
volume of blood that will be collected throughout the study per subject for Part 1 and 
Part 2, respectively. 
  
Table 4 
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject for Part 1 
Assessment 
Maximum # samples Volume of blood per 
sample (mL) 
Total volume of 
blood (mL) 
Pharmacokinetics 
 - OZ439 in plasma 
 - [14C]-OZ439 in plasma 
 - OZ439 metabolites 
 
 
18 
17 
4 
 
3 
8 
3 
 
54 
136 
12 
Clinical chemistry 
5 
3.5 
17.5 
Hematology  
5 
3 
15 
Serology 
1 
5 
5 
Total volume of blood drawn 
 
 
239.5 
 
Table 5 
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject for Part 2 
Assessment 
Maximum # samples Volume of blood per 
sample (mL) 
Total volume of 
blood (mL) 
Pharmacokinetics 
 - OZ439 in plasma 
 - Cobicistat in plasma 
 - OZ439 metabolites 
 
 
51 
12 
4 
 
3 
0* 
3 
 
153 
0* 
12 
Clinical chemistry 
15 
3.5 
52.5 
Hematology  
15 
3 
45 
Serology 
1 
5 
5 
Total volume of blood drawn 
 
 
267.5 
* No separate blood samples will be collected for cobicistat analysis. At the corresponding time points, 
blood collected for OZ439 analysis will also be used for cobicistat analysis. Details on sample collection, 
handling, storage and shipping will be described in a laboratory manual prepared by PRA.  
3.5.2 
Appropriateness of Measurements 
The assessments, which will be made in this study are standard, and generally 
recognized as reliable, accurate and relevant.  
3.5.2.1 
Timing of Assessments  
For PK blood sampling 
The acceptable deviations from the nominal post-dose blood sampling times are as 
follows: 
 The pre-dose blood sample will be taken ≤1 hour before dosing  
 0 to 1 hour post-dose samples will be taken within  2 minutes of the nominal 
post-dose sampling time  
 >1 to 12 hours post-dose samples will be taken within  10 minutes of the nominal 
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 >12 hours to 24 hours post-dose samples will be taken within  30 minutes of the 
nominal post-dose sampling time if subjects are resident in the clinical research 
center 
 >24 hours post-dose samples will be taken within  2 hours of the nominal 
post-dose sampling time if subjects are attending an ambulatory visit. Follow-up 
visits will be within  2 days. 
 
Vital signs 
The acceptable deviations from the nominal vital signs measurement time points are 
as follows: 
 The pre-dose vital signs measurements will be taken ≤2 hours before dosing 
  Post-dose vital signs measurements will be taken  15 minutes from the nominal 
post-dose time points 
  For ambulatory visits vital signs measurements will be taken  2 hours from the 
nominal ambulatory visit time point. 
 
ECG 
The acceptable deviations from the nominal ECG measurement time points are as 
follows: 
 The pre-dose ECG measurements will be taken ≤2 hours before dosing 
  Post-dose ECG measurements will be taken  10 minutes from the nominal 
post-dose time points 
  For ambulatory visits ECG measurements will be taken  2 hours from the nominal 
ambulatory visit time point 
 
Clinical laboratory 
The acceptable deviations from the nominal blood sampling time points for clinical 
laboratory assessments are as follows: 
 Post-dose blood samples will be taken  1 hour from the nominal blood sampling 
time except when the time point coincides with the PK blood sampling time. In this 
situation, the time window for the PK blood sample applies. 
 Post-dose urine samples will be taken  2 hours from the nominal urine sampling 
time 
 
In the event assessments are planned for the same scheme time, the order of the 
assessments should be arranged in such a way that PK blood sampling will be done 
after the ECG and vital signs recordings have been conducted, with PK blood sampling 
exactly on time. 
3.5.3 
Pharmacokinetic, Safety and Exploratory Endpoints  
3.5.3.1 
Endpoints for Part 1 
 Primary Endpoint  
- PK: absolute oral bioavailability (Fpo) of OZ439 
 Secondary Endpoints  


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- PK for iv administration of OZ439: Vd, CL, t1/2, AUC0-t, AUC0-inf and z 
- PK for oral administration of OZ439: Cmax, tmax, t1/2, C168h, AUC0-168h, AUC0-t, 
AUC0-inf, CL/F and z 
- Safety: AEs, clinical laboratory, vital signs, ECG and physical examination  
 Exploratory Endpoints 
- Estimation of fraction absorbed, extraction ratio, liver first pass and deconvolution 
of absorption profile over time for OZ439 
- Future OZ439 metabolites analysis may be performed 
3.5.3.2 
Endpoints for Part 2 
 Primary Endpoint  
- PK of OZ439: Cmax, C168h, AUC0-168h and AUC0-inf  
 Secondary Endpoints  
- PK of OZ439: tmax, t1/2, AUC0-t and z 
- PK of cobicistat: Cmax, tmax, t1/2, AUC0-t, AUC0-inf, CL/F and z 
- Safety: AEs, clinical laboratory, vital signs, ECG and physical examination 
  Exploratory Endpoint 
- Future OZ439 metabolites analysis may be performed 
3.5.3.3 
Pharmacokinetic Parameters 
The PK parameters to be determined or calculated using non-compartmental analysis 
from the plasma concentration-time data for OZ439 and cobicistat include but are not 
limited to the parameters as given below. A complete list of PK parameters will be 
provided in the Statistical Analysis Plan (SAP). 
 
Parts 1 and 2 
Cmax 
Maximum observed plasma concentration 
C168h 
Observed plasma concentration at 168 hours post-dose 
tmax 
Time to attain maximum observed plasma concentration 
t1/2 
Terminal elimination half-life, calculated as 0.693/kel 
AUC0-t 
Area under the plasma concentration-time curve up to time t, where t 
is the last point with concentrations above the lower limit of 
quantitation (LLOQ)  
AUC0-168h 
Area under the plasma concentration-time curve over a dosing 
interval of 168 hours 
AUC0-inf 
Area under the plasma concentration-time curve from time 0 to 
infinity calculated as: AUC0-inf = AUC0-t + Clast/kel, 
where Clast is the last measurable plasma concentration  
%AUCextra 
Percentage of estimated part for the calculation of AUC0-inf 
([AUC0-inf-AUC0-t]/AUC0-inf)*100% 
z 
Terminal elimination rate constant 
CL/F 
Apparent clearance 
 


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Part 1 only 
CL 
Total systemic clearance 
Vd 
Volume of distribution  
Fpo 
Oral bioavailability 
3.5.4 
Drug Concentration Measurements 
The analysis of OZ439 in plasma samples will be performed at Swiss BioQuant AG 
using a validated liquid chromatography with tandem mass spectrometry method 
(LC-MS/MS). The analysis of [14C]-OZ439 in plasma samples will be performed at 
Xceleron using a validated LC-AMS method. The analysis of cobicistat in plasma 
samples will be performed at Swiss BioQuant AG using a validated LC-MS/MS 
method. The Bioanalytical Reports for the determinations will be included in the clinical 
study report (CSR).  
3.6 
Statistical Procedures and Determination of Sample Size 
3.6.1 
Analysis Sets 
3.6.1.1 
Safety Set 
All subjects who have received at least 1 dose of OZ349. 
3.6.1.2 
Pharmacokinetic Set 
All subjects who have received at least 1 dose of OZ439 and provided sufficient 
bioanalytical assessment results to calculate reliable estimates of at least one of the 
primary endpoints PK parameters. 
3.6.2 
Statistical and Analytical Plan for Pharmacokinetic and Safety Evaluation  
An SAP will be generated by the Biostatistics Department of PRA; the SAP will be 
finalized prior to database lock. Full details of the analysis to be performed will be 
included in the SAP. 
 
Any deviation from the SAP will be reported in the Section “Changes in Planned 
Analysis” in the CSR. 
3.6.2.1 
Pharmacokinetic Evaluation 
The PK parameters and their statistical evaluation will be included in the CSR of this 
study. 
 
All data will be summarized using descriptive statistics and will be listed and 
summarized in tabular and/or graphical form. 
 
A statistical analysis will be performed on OZ439 PK parameters Cmax, C168h, AUC0-168h 
and AUC0-inf. The PK parameters will undergo a natural logarithmic transformation and 
will be analyzed using analysis of variance (ANOVA) techniques. The ANOVA model 
will include treatment as a fixed effect. Adjusted geometric mean ratios (GMRs) and 
90% CIs for the adjusted GMRs will be provided for the comparisons between: 
 Treatment C vs Treatment D to assess the effect of cobicistat on OZ439 


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 Treatment A vs Treatment B to explore volume effect (for this no within-subject 
comparison is possible) 
 Treatment B vs Treatment C to explore dosing solution concentration effect (dose 
normalized) 
3.6.2.2 
Evaluation of Safety and Tolerability 
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, 
ECGs and physical examination findings, and any other parameter that is relevant for 
safety assessment. 
3.6.2.2.1 
Adverse Events 
A listing of all individual AEs will be provided. Summary tables of TEAEs will be 
presented by system organ class based on the MedDRA terminology list (preferred 
terms): 1 containing the number of TEAEs (frequency of occurrence, number of 
subjects experiencing the event) by treatment and 1 containing the number of 
drug-related TEAEs (frequency of occurrence, number of subjects experiencing the 
event) per treatment. Additional tables of total counts by treatment and relationship and 
by treatment and severity will be given. 
3.6.2.2.2 
Clinical Laboratory 
Clinical laboratory data will be listed accompanied by an indication if the parameter is 
outside the reference range. A summary of all data outside the reference range of the 
clinical laboratory will be provided. Clinical laboratory data will be presented 
descriptively, where applicable. 
3.6.2.2.3 
Vital Signs and Electrocardiograms 
Vital signs and ECG parameters will be listed and they will be presented descriptively, 
where applicable. 
3.6.2.2.4 
Physical Examination 
Changes from baseline for physical examination will be described and listed. 
3.6.3 
Determination of Sample Size 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous similar studies and taking into account OZ439 large 
variability, a total of 8 subjects enrolled in Part 1 of the study to achieve a minimum of 
6 evaluable subjects is considered sufficient. A total of 8 subjects is also considered 
sufficient to assess the effects of the total dosing volume and of dose to volume ratio 
on OZ439 PK under fasted conditions (in combination with Part 2). In Part 2 of the 
study a sample size of 18 subjects is considered appropriate to estimate the increase 
in OZ439 exposure in the presence of a single dose of 150 mg cobicistat with sufficient 
precision, assuming a mean ratio of 2. Based on the assumptions of a point estimate 
(mean ratio) of 2.0 and a CV of 23%, a sample size of 18 subjects would give a 90% 
confidence interval (CI) of 1.75 - 2.28 and this number of subjects is therefore 
considered sufficient. In Part 2, 18 subjects will be randomized to ensure data in 
15 evaluable subjects for the PK endpoints. A subject will be considered evaluable for 


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the primary analysis if they have sufficient PK data to estimate all of the primary 
endpoints (Cmax, C168h, AUC0-168h, and AUC0-inf) for the 3 treatments.  
3.7 
Data Quality Assurance 
The study may be audited by the Quality Assurance Department at PRA to assess 
adherence to the clinical study protocol (CSP) and Quality System. During the conduct 
of the study, process-related audits may be performed. An audit certificate will be 
provided in the appendices of the final CSR outlining any audits and other related 
activities performed.  
 
The clinical research site will be monitored by the study monitor to ensure correct 
performance of the study procedures and assure that the study will be conducted 
according to the relevant regulatory requirements. The eCRF entries will be verified 
with the source documentation, if applicable (in some cases there are no source 
pages, therefore verification is not necessary). 
 
Regulatory authorities, the Independent Ethics Committee (IEC) and/or the Sponsor’s 
clinical quality assurance group may request access to all source documents, eCRFs, 
and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the PI, who must provide support at all times for 
these activities. 
 
Quality control principles will be applied throughout the performance of this study. 
Review procedures will be followed at PRA for all documents that are generated in 
relation with the study.  
 
An explanation will be given for all missing, unused and spurious data in the relevant 
sections of the CSR. 


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4. 
ETHICS 
4.1 
Independent Ethics Committee 
The CSP and the ICFs will be submitted for review and approval by IEC of the 
foundation 
“Beoordeling 
Ethiek 
Biomedisch 
Onderzoek” (English 
translation: 
“Evaluation of Ethics in Biomedical Research”) (Stationsstraat 9, 9401 KV Assen, The 
Netherlands) prior to the eligibility screening. The composition of the IEC is in 
accordance with the recommendations of the WHO, the International Conference on 
Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP)11, and the 
European Union (EU) Clinical Trial Directive (CTD) (Directive 2001/20/EC)12 (see 
below). 
 
PRA will keep the IEC informed about the progress of the study. All changes in 
research activities and all unanticipated problems involving risks to human subjects will 
be immediately reported to the IEC. In accordance with Section 10, Subsection 1, of 
the Dutch law on Medical Research in Human Subjects (WMO, revised 
December 2015)13, PRA will inform the subjects and the IEC if anything occurs on the 
basis of which it appears that the disadvantages of participation may be significantly 
greater than was foreseen in the research proposal, or if further recruitment of subjects 
in the study has been put on hold for that reason, whichever occurs first. The study 
may be suspended pending further review by the IEC, except insofar as suspension 
would jeopardize the subjects’ health. PRA will take care that all subjects are kept 
informed.  
 
No changes will be made in the study without IEC approval, except when required to 
eliminate apparent immediate hazards to human subjects. 
 
Before the study is initiated, the Sponsor will also obtain approval to conduct the study 
from the Competent Authority (CA) in The Netherlands. 
 
Notification of the end of the study will be sent by PRA to the CA in The Netherlands 
and to the IEC within 90 days after completion of follow-up for the last subject. In case 
a study is temporarily halted, PRA will notify the IEC immediately, including the reason 
for this. In case a study is ended prematurely, PRA will notify the IEC and the CA in 
The Netherlands within 15 days, including the reasons for the premature termination. 
A summary of the results of the study will be sent by PRA to the CA and the IEC within 
1 year after the end of the study (last patient last visit).  
4.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their 
origin in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964, and subsequent 
amendments.14 
 


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This study is also designed to comply with ICH E6 Guideline for GCP 
(CPMP/ICH/135/95)11, and the EU CTD Directive 2001/20/EC12, as incorporated into 
Dutch Law.13 
 
ICH adopted guidelines and other relevant international guidelines, recommendations 
and requirements will be taken into account as comprehensively as possible, as long 
as they do not violate Dutch law. 
 
The PI will be responsible for the care of the subjects throughout the study. If the PI is 
not present at the clinical site, he will leave instructions for the staff and a telephone 
number where he can be reached. 
 
The PI will be responsible for the medical follow-up of the subjects. 
 
If a subject refuses to follow the instructions of the PI, the latter is released from any 
legal responsibility. 
4.3 
Subject Information and Consent 
All subjects will be informed verbally and in writing regarding the objectives, 
procedures and risks of study participation. The subjects will have to sign the Dutch or 
English version of the ICF before any study-related procedures are started. The ICF 
contains information about the objectives of the study, about the procedures followed 
during the study and about the risks and restrictions of the study, with special 
reference to possible side effects of the medication and potential interactions. In 
addition, insurance cover provided during the study is explained. The elements 
addressed in the ICF are according to the ICH E6 Guideline for GCP 
(CPMP/ICH/135/95).11 
4.4 
Privacy 
All personal details will be treated as confidential by the PI and staff at PRA and 
handling of personal data will be in compliance with the Dutch Data Protection Act. 
Personal details are stored in databases that have been registered with the Dutch Data 
Protection Authority. 
 


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5. 
STUDY ADMINISTRATIVE STRUCTURE 
5.1 
Distribution of Activities 
Preparation of study drug 
OZ439 and [14C]-OZ439 drug substance will be provided by the Sponsor. The OZ439 
oral dispersions and the [14C]-OZ439 iv solution for infusion will be manufactured by 
the PRA Pharmacy.  
 
Laboratory assessments 
The analysis of OZ439 and cobicistat in plasma samples will be performed at Swiss 
Bioquant AG. The analysis of [14C]-OZ439 in plasma samples will be performed at 
Xceleron.  
 
The analysis of clinical laboratory samples will be performed at the PRA Clinical 
Laboratory.  
 
eCRF design 
The eCRF design will be performed with the computer program Oracle Clinical (Oracle, 
Redwood Shores, Redwood City, CA, USA) by the Database Programming 
Department of PRA. 
 
Data management 
Data management will be performed with the computer programs Oracle Clinical 
(Oracle, Redwood Shores, Redwood City, CA, USA), SAS Enterprise Guide® (SAS 
Institute Inc., Cary, NC, USA) and EXACT (Kinship EXACTTM, Kinship technologies, a 
technology subsidiary of PRA) by the Data Management Department of PRA. 
 
Statistics 
Randomization will be performed by the Biostatistics Department of PRA. An SAP will 
be provided by the Biostatistics Department of PRA. The safety analysis and the 
statistical evaluation of PK parameters will be conducted by the Biostatistics 
Department of PRA. Statistical analysis will be performed with the computer program 
SAS for Windows® (SAS Institute Inc., Cary, NC, USA). 
 
CSR writing 
The CSR, structured in accordance with the guideline ‘Structure and Content of Clinical 
Study Reports - ICH E3’15, will be written by PRA. 
5.2 
Documentation 
5.2.1 
Archiving 
All documents concerning the study will be kept on file in the Central Archives of PRA 
for at least 15 years after conduct of the study. The Sponsor will receive the completed 
eCRFs (upon request, as PDF file). 


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5.2.2 
Recording of Data in Source Documents and CRFs 
Wherever possible, all data will be entered directly into the eCRFs. In some cases 
source documents will be used. 
 
A Data Management Plan will be written by the Data Management Department of PRA, 
which will be finalized prior to performing any data validation. An appendix to the Data 
Management Plan (Source Identification List) will identify any data to be recorded 
directly in the eCRF (ie, no prior written or electronic record of data), and which data 
should be considered source data.  
 
 
 


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6. 
FINANCE AND INSURANCE 
The Sponsor (Medicines for Malaria Venture [MMV]) has funded this study. A no-fault 
clinical trials insurance has been obtained by the Sponsor. The Sponsor insurance will 
compensate subjects in accordance with the Dutch law on Medical Research in Human 
Subjects (WMO, revised December 2015).13 
7. 
CONFIDENTIALITY AND PUBLICATION POLICY 
By signing this CSP, the PI reaffirms to the Sponsor that he will maintain in confidence 
all information furnished to him, or resulting from this study. The PI will only divulge 
such information as may be necessary to the IEC, the members of the staff and the 
subjects who are involved in this study. 
 
All relevant aspects regarding publication will be part of the contract (or similar 
document) between the Sponsor and PRA.  
 


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8. 
REFERENCES 
1. 
WHO World Malaria Report 2015a. WHO Global Malaria Programme. 
http://apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf?ua=
1, accessed January 2016. 
2. 
Ashley EA, White NJ. Artemisinin-based combinations. Curr Opin Infect Dis 
2005; 18 (6): 531-6. 
3. 
Bunnag D, Viravan C, Looareesuwan S, Karbwang J, Harinasuta T. Clinical trial 
of artesunate and artemether on multidrug resistant falciparum malaria in 
Thailand. A preliminary report. Southeast Asian J Trop Med Public Health 1991; 
22 (3): 380-5. 
4. 
Phyo AP, Jittamala P, Nosten FH et al. Antimalarial activity of artefenomel 
(OZ439), a novel synthetic antimalarial endoperoxide, in patients with 
Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 
trial. Lancet Infect Dis 2016; 16 (1): 61-9. 
5. 
Vennerstrom JL, Arbe-Barnes S, Brun R et al. Identification of an antimalarial 
synthetic trioxolane drug development candidate. Nature 2004; 430 (7002): 
900-4. 
6. 
Charman SA, Arbe-Barnes S, Bathurst IC et al. Synthetic ozonide drug 
candidate OZ439 offers new hope for a single-dose cure of uncomplicated 
malaria. Proc Natl Acad Sci U S A 2011; 108 (11): 4400-5. 
7. 
Wells TN. Discovering and developing new medicines for malaria control and 
elimination. Infect Disord Drug Targets 2013; 13 (4): 292-302. 
8. 
Investigator’s Brochure of OZ439 (artefenomel), Edition 10, July 2016. 
9. 
Mathias AA, German P, Murray BP et 
al. Pharmacokinetics 
and 
pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without 
anti-HIV activity. Clin Pharmacol Ther 2010; 87 (3): 322-9. 
10. 
Addendum 1 to Investigator’s Brochure of OZ439 (artefenomel), 10 October 
2016. 
11. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E6: Guideline for Good Clinical Practice (CPMP/ICH/135/95), 
January 1997. 
12. 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 
2001 on the approximation of the laws, regulations and administrative 
provisions of the Member States relating to the implementation of good clinical 
practice in the conduct of clinical trials on medicinal products for human use. 
13. 
Medical 
Research 
in 
Human 
Subjects 
Act 
(WMO, 
Wet 
Medisch-Wetenschappelijk Onderzoek met mensen), revision December 2015. 
14. 
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 
64th World Medical Association General Assembly, Fortaleza, Brazil, October 
2013. 
15. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, 
E3: 
Structure 
and 
Content 
of 
Clinical 
Study 
Reports 
(CPMP/ICH/137/95), November 1995. 


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16. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E2A: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, Note for Guidance on Clinical Safety Data 
Management, June 1995. 


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9. 
APPENDICES 
9.1 
Drug Accountability 
Upon receipt of the study drug, it will be inspected and counted by the responsible 
pharmacist. If necessary, all study drug will be re-packed per dosing occasion, and 
labeled according to PRA SOPs. 
 
The study drug will be kept in the PRA Pharmacy or in a locked and secured storage 
facility accessible to the pharmacist and the pharmacy assistant only. 
 
The responsible pharmacist will keep an inventory. This will include a description of the 
formulation and the quantity of study drug received for the study and a record of what is 
dispensed, to whom and when. 
 
On termination of the study the responsible pharmacist will conduct a final inventory of 
the study drug supply and will record the results of this inventory in the Drug 
Accountability Form. Unused study drug will be returned to the Sponsor at the end of 
the study or will be locally destroyed according to PRA standard procedures. 
9.2 
Adverse Events and Serious Adverse Events Evaluation and Reporting 
9.2.1 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical 
treatment or procedure. AE definitions will be followed as stated in the ‘Note for 
Guidance on clinical safety data management: definitions and standards for expedited 
reporting’ (ICH topic E2A).16 
 
All AEs reported by the subjects or apparent from their physical appearance during the 
clinical study will be reported on the AE eCRF page. 
 
The severity of AEs will be graded using the WHO Recommendations for Grading 
Acute and Subacute Toxic Effects as given in Section 9.2.1.1. 
 


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9.2.1.1 
WHO Recommendations for Grading Acute and Subacute Toxic Effects 
 
 
 
 
WHO Recommendations for Grading Acute and 
Subacute Toxic Effects 
 
 
 
 
 
 
 
 
 
 
 
 
Adaptation of WHO Handbook for Reporting Results of Cancer Treatment.  WHO Offset 
Publication No.  48. 
World Health Organization; Geneva, Switzerland.  1979:16–21. 


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Adverse Event Severity Table 
WHO Recommendations for Grading Acute and Subacute Toxic Effects  
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology 
 
 
 
 
Hematocrit 
28.5 to <31.5% 
24 to <28.5% 
19.5 to <24% 
<19.5% 
Hemoglobin 
9.5–10.9 g/dL 
8.0–9.4 g/dL 
6.5–7.9 g/dL 
<6.5 g/dL 
Leukocytes 
2500 to 
<4000/mm3 
1000 to 
<2500/mm3 
800 to 
<1000/mm3 
<800/mm3 
Absolute neutrophil 
count 
1000 to 
<1500/mm3 
750 to 
<1000/mm3 
500 to <750/mm3 
<500/mm3 
Platelets 
75,000–
99,000/mm3 
50,000–
74,999/mm3 
25,000–
49,999/mm3 
<25,000/mm3 or 
diffuse petechiae 
Prothrombin time   
1.01–1.25  ULN 
1.26–1.5  ULN 
1.51–3.0  ULN 
>3.0  ULN 
Partial 
thromboplastin time 
1.01–1.66  ULN 
1.67–2.33  ULN 
2.34–3.0  ULN 
>3.0  ULN 
Fibrinogen 
0.99–0.75  LLN 
0.74–0.50  LLN 
0.49–0.25  LLN 
<0.25  LLN 
Fibrin split product 
20–40 g/mL 
41–50 g/mL 
51–60 g/mL 
>60 g/mL 
Methemoglobin 
5.0–9.9% 
10.0–14.9% 
15.0–19.9% 
20% 
Chemistries 
 
 
 
 
Hyponatremia 
130–132 mEq/L 
123–129 mEq/L 
116–122 mEq/L 
115 mEq/L or 
mental status 
changes or 
seizures 
Hypernatremia 
148–150 mEq/L 
151–157 mEq/L 
158–165 mEq/L 
>165 mEq/L or 
mental status 
changes or 
seizures 
Hypokalemia 
3.0–3.4 mEq/L 
2.5–2.9 mEq/L or 
requires 
replacement Rx 
2.0–2.4 mEq/L, or 
requires intensive 
replacement Rx or 
hospitalization 
<2.0 mEq/L or 
paresis or ileus or 
life-threatening 
arrhythmias 
Hyperkalemia 
5.6–6.0 mEq/L 
6.1–6.5 mEq/L 
6.6–7.0 mEq/L 
>7.0 mEq/L or 
paresis or ileus or 
life-threatening 
arrhythmias 
LLN: lower limit of normal; ULN: upper limit of normal 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistries 
(cont'd) 
 
 
 
 
Hypoglycemia 
55–64 mg/dL 
40–54 mg/dL 
30–39 mg/dL 
<30 mg/dL 
or mental status 
changes or 
coma 
Hyperglycemia 
116–160 mg/dL 
161–250 mg/dL 
251–500 mg/dL 
>500 mg/dL or 
ketoacidosis or 
seizures 
Hypertriglyceridemia 
250–400 mg/dL 
401–750 mg/dL 
751–1250 mg/dL 
>1250 mg/dL 
Hyperuricemia 
 
 
 
 
  13–18 yrs 
9.1–12.0 mg/dL 
12.1–14.0 mg/dL 
14.1–17.0 mg/dL 
>17.0 mg/dL 
  >18 yrs 
9.6–9.9 mg/dL 
10.0–12.0 mg/dL 
12.1–15.0 mg/dL 
>15.0 mg/dL 
Hypocalcemia  
corrected for albumin  
8.4–7.8 mg/dL 
7.7–7.0 mg/dL 
6.9–6.1 mg/dL 
<6.1 mg/dL or 
life-threatening 
arrhythmias or 
tetany 
Hypercalcemia 
corrected for albumin 
10.6–11.5 mg/dL 
11.6–12.5 mg/dL 
12.6–13.5 mg/dL 
>13.5 mg/dL or 
coma or 
cardiac 
arrhythmias 
Hypomagnesemia 
0.8–1.0 mEq/L 
0.5–0.7 mEq/L or 
requires 
replacement Rx 
0.3–0.4 mEq/L or 
requires 
intensive Rx 
involving 
hospitalization 
<0.3 mEq/L or 
life-threatening 
arrhythmias 
Hypophosphatemia 
2.0–2.4 mg/dL 
1.5–1.9 mg/dL or 
requires 
replacement Rx 
1.0–1.4 mg/dL or 
requires 
intensive Rx 
involving 
hospitalization 
<1.0 mg/dL or 
life-threatening 
arrhythmias or 
congestive heart 
failure 
BUN 
1.25–2.5  ULN 
2.6–4.9  ULN 
5.0–10.0  ULN 
>10  ULN 
Creatinine 
1.1–1.5  ULN 
1.6–3.0  ULN 
3.1–6.0  ULN 
>6.0  ULN or 
requires dialysis 
BUN: blood urea nitrogen; ULN: upper limit of normal 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistries 
(cont'd) 
 
 
 
 
Hypocarbia 
(bicarbonate) 
19–21 mEq/L 
15–18 mEq/L 
10–14 mEq/L 
<10 mEq/L 
Hypercarbia 
(bicarbonate) 
33–36 mEq/L 
37–40 mEq/L 
41–45 mEq/L 
>45 mEq/L 
Hypochloremia 
90–93 mEq/L 
85–89 mEq/L 
80–84 mEq/L 
<80 mEq/L 
Hyperchloremia 
113–116 mEq/L 
117–120 mEq/L 
121–125 mEq/L 
>125 mEq/L 
Enzymes 
 
 
 
 
Bilirubin 
1.26–2.5  ULN 
2.6–5.0  ULN 
5.1–10.0  ULN 
>10.0  ULN 
AST/SGOT 
1.26–2.5  ULN 
2.6–5.0  ULN 
5.1–10.0  ULN 
>10.0  ULN 
ALT/SGPT 
1.26–2.5  ULN 
2.6–5.0  ULN 
5.1–10.0  ULN 
>10.0  ULN 
GGT 
1.26–2.5  ULN 
2.6–5.0  ULN 
5.1–10.0  ULN 
>10.0  ULN 
Alkaline 
phosphatase 
1.26–2.5  ULN 
2.6–5.0  ULN 
5.1–10.0  ULN 
>10.0  ULN 
Amylase 
1.10–1.39  ULN 
1.40–2.09  ULN 
2.10–5.0  ULN or 
mild clinical 
pancreatitis 
>5.0  ULN or 
severe clinical 
pancreatitis 
Lipase 
1.10–1.39  ULN 
1.40–2.09  ULN 
2.10–5.0  ULN or 
mild clinical 
pancreatitis 
>5.0  ULN or 
severe clinical 
pancreatitis 
CPK 
2.0–3.0  ULN 
3.1–5.0  ULN; 
mild myalgia 
5.1–10.0  ULN, 
or moderate or 
severe myalgia 
requiring 
nonsteroidals 
>10.0  ULN or 
severe myalgia 
requiring narcotics 
LDH 
1.10–1.39  ULN 
1.40–2.09  ULN 
2.10–5.0  ULN 
>5.0  ULN 
Urinalysis 
 
 
 
 
Proteinuria 
3 g loss/day 
>3–10 g loss/day 
>10 g loss/day 
Nephrotic 
syndrome 
Hematuria 
Microscopic only; 
10 cells/HPF 
Gross; no clots; 
11–100 cells/HPF 
Gross plus clots; 
101 cells/HPF 
Obstructive or 
requires 
catheterization 
ALT: alanine aminotransferase; AST: aspartate aminotransferase CPK: creatine phosphokinase; GGT: 
gamma glutamyl transferase; LDH: lactate dehydrogenase; SGOT: serum glutamic oxaloacetic 
transaminase; SGPT: serum glutamic pyruvic transaminase; ULN: upper limit of normal 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
 
 
 
 
Cardiac rhythm 
_a 
Asymptomatic, 
transient signs; 
no Rx required 
Recurrent or 
persistent; 
no Rx required 
Requires 
treatment 
Hypertension 
Transient; 
increase >20 mm; 
no Rx required 
Recurrent; 
chronic >20 mm; 
Rx required 
Requires 
outpatient care; 
requires 
acute Rx 
Requires 
hospitalization 
Hypotension 
Transient 
orthostatic 
hypotension; 
no Rx required 
Symptoms 
correctable with 
oral fluid Rx 
Requires IV 
fluids; 
no 
hospitalization 
required 
Requires 
hospitalization 
Pericarditis 
Asymptomatic 
effusion 
Symptomatic; 
no tap required 
Requires 
tamponade tap 
Requires 
tamponade or 
surgery 
Hemorrhage,  
blood loss 
Microscopic or 
occult 
Mild; 
no transfusion 
required 
Gross; 1–2 units 
transfused 
Massive; 3 units 
transfused 
Respiratory 
 
 
 
 
Cough 
 
Transient; 
no Rx required 
Requires local 
nonnarcotic Rx 
Requires 
narcotic Rx 
Uncontrolled 
Shortness of 
breath 
Mild; does not 
interfere with 
routine activities 
Moderate; 
interferes with 
routine activities; 
requires 
intermittent Rx 
Moderate; 
debilitating; 
requires nasal 
oxygen 
Severe; requires 
ventilatory 
assistance 
Bronchospasm 
(acute) 
Transient; FEV1 or 
peak flow >70% 
NL; no Rx 
required 
Normalizes with 
bronchodilator; 
FEV1 or peak flow 
49–70% NL; 
requires Rx 
No 
normalization 
with 
bronchodilator; 
FEV1 or peak 
flow 25–50% NL 
retractions 
Cyanosis; FEV1 or 
peak flow <25% 
NL; intubated 
Gastrointestinal 
 
 
 
 
Stomatitis 
Mild discomfort; 
no limits on 
activity 
Some limits on 
eating or talking 
Eating or talking 
very limited 
Cannot drink 
fluids; 
requires IV fluids 
Nausea 
Mild discomfort; 
maintains 
reasonable intake 
Moderate 
discomfort; 
significant decline 
of intake; some 
limit of activity 
Severe 
discomfort; no 
significant food 
intake; activities 
limited 
Minimal fluid 
intake 
a: no criteria listed for this grade; IV:intravenous 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Gastrointestinal  
(cont'd) 
 
 
 
 
Vomiting 
Transient emesis 
Occasional or 
moderate vomiting 
Orthostatic 
hypotension or 
requires IV 
fluids 
Hypotensive 
shock; 
hospitalization; 
requires IV fluids 
Constipation 
Mild 
Moderate; requires 
Rx 
Severe; 
vomiting; 
requires Rx 
Distension with 
vomiting 
Diarrhea 
Transient or 
nocturnal loose 
stools, or 
3–4 loose 
stools/day, or both; 
requires Rx 
5–7 loose 
stools/day 
or nocturnal loose 
stools, or both; 
requires Rx 
Orthostatic 
hypotension of 
>7 loose 
stools/day or 
requiring IV 
fluids 
Hypotensive 
shock or 
hospitalization for 
IV fluids 
Abdominal pain 
Mild; occasional, 
transient 
Moderate; transient 
Severe or 
requiring 
analgesic 
Severe with 
guarding; 
peritoneal signs 
Neuropsychological 
 
 
 
 
Level of 
consciousness 
Mildly inattentive to 
outside stimuli 
Drowsy, but readily 
responds to verbal 
or uncomfortable 
stimuli 
Stuporous; can 
be aroused by 
vigorous stimuli, 
but verbal 
responses are 
slow or absent; 
can make some 
effort to avoid 
painful stimuli 
Comatose; cannot 
be aroused by 
vigorous stimuli; 
makes no 
purposeful 
attempt to avoid 
painful stimuli 
Confusion 
Oriented to person, 
place, and time, 
but has difficulty 
performing tasks 
requiring logic, 
math, or spatial 
organization 
Oriented to person 
and place, but not 
time; cannot 
perform complex 
tasks requiring 
logic or math 
Oriented to 
person only; 
cannot focus 
attention or care 
for bodily needs 
Delerious; 
not oriented to 
person, place, or 
time; agitated 
Neurocerebellar 
Slight 
incoordination; 
dysdiadokinesia 
Intention tremor; 
dysmetria; slurred 
speech; nystagmus 
Locomotor 
ataxia 
Incapacitated 
Mood 
Mild anxiety or 
depression 
Moderate anxiety 
or depression; 
requires therapy 
Severe anxiety, 
depression, or 
mania (needs 
assistance) 
Acute psychosis; 
incapacitated; 
requires 
hospitalization 
IV: intraevous 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuromuscular 
 
 
 
 
Muscle strength 
Subjective 
weakness; no 
objective 
symptoms or 
signs 
Mild objective 
weakness; no 
decrease in function 
Objective 
weakness; function 
limited 
Paralysis 
Painful neuropathy 
Mild discomfort; 
no therapy 
required 
Moderate 
discomfort 
persisting for 
>72 hours; 
requires analgesia 
Severe discomfort; 
marked antalgic 
gait; 
requires narcotic 
analgesia with 
symptomatic 
improvement 
Incapacitating, 
intolerable 
discomfort;  not 
improved or 
cannot walk 
despite narcotic 
analgesics 
"Pins & needles" 
Mild; does not 
interfere with 
routine activities 
Moderate; interferes 
with some ADL, but 
responds to 
symptomatic 
therapy 
Severe; 
significantly impairs 
ability to perform 
ADL despite 
symptomatic 
therapy; interferes 
with patient's sleep 
Very severe; 
incapacitates 
patient 
Numbness 
Mild decrease in 
sensation 
reported by 
patient, but 
pinprick and 
vibration exams 
are normal; does 
not interfere with 
ADL 
Moderate decrease 
in sensation 
reported by patient; 
reduced pinprick 
and vibratory 
sensation on exam; 
interferes with some 
ADL, but responds 
to symptomatic 
therapy 
Severely impaired 
sensation with 
inability to perceive 
pinprick or 
vibration; 
significantly impairs 
ability to perform 
ADL despite 
symptomatic 
therapy 
Total lack of 
sensation on 
exam; 
incapacitates 
patient despite 
symptomatic 
therapy 
Myalgias 
Mild discomfort; 
no Rx required 
Moderate 
discomfort 
persisting for 
>72 hours; 
requires analgesia 
Severe discomfort; 
requires narcotic 
analgesia with 
symptomatic 
improvement 
Severe discomfort 
not relieved by 
narcotic analgesia 
ADL: activities of daily living 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuromuscular  
(cont'd) 
 
 
 
 
Myositis 
Minimal 
findings 
Patients must have 
some measures of 
myositis (positive 
EMG or muscle 
biopsy) and one of 
the following: 
 
1.  Mild to moderate 
myalgias; 
 
requires >4 weeks  
non-steroidal 
anti-inflammatory 
agents 
 
2. Difficulty climbing 
stairs or rising 
from a sitting 
position, but can 
ambulate without 
assistance 
Patients must have 
some measures of 
myositis (positive 
EMG or muscle 
biopsy) and one of 
the following: 
 
1. Moderate or 
severe myalgias 
or muscle 
tenderness 
 
>4 weeks; 
 
requires non-
steroidal anti-
inflammatory 
agents 
 
2. Requires some 
assistance with 
ambulation or 
general activities 
Patients must have 
some measures of 
myositis (positive EMG 
or muscle biopsy) and 
one of 
the following: 
 
1. Severe muscle pain 
(myalgias) unrelated 
to exercise; 
requires narcotics 
 
2. Muscle weakness 
resulting in inability 
to ambulate; 
requires special care 
and assistance with 
mobilization 
 
3. Acute rhabdo-
myolysis with muscle 
necrosis and edema; 
moderate to severe 
muscle weakness 
resulting in inability 
to ambulate or 
mobilize self without 
assistance 
 
4. Acute rhabdo-
myolysis associated 
with electrolyte 
imbalance or renal 
failure 
EMG: electromyography 


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WHO Recommendations for Grading Acute and Subacute Toxic Effects (cont’d) 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Other Parameters 
 
 
 
Fever (oral, without 
infection, >12 hours) 
37.7–38.5 oC or 
100.0–101.5 oF 
38.6–39.5 oC or  
101.6–102.9 oF 
39.6–40.5 oC or 
103.0–105.0 oF 
>40.5 oC or 
>105.0 oF 
Headache 
Mild; 
no Rx required 
Transient; 
requires moderate 
Rx 
Severe; responds 
to initial narcotic 
therapy 
Intractable; 
requires repeated 
narcotic therapy 
Fatigue 
No decrease in 
daily activities 
Normal activity 
decreased 25–49% 
Normal activity 
decreased 50%; 
cannot work 
Cannot care for 
self 
Allergic reaction 
Pruritus without 
rash 
Localized urticaria; 
angioedema 
Generalized 
urticaria; 
angioedema 
Anaphylaxis 
Local reaction 
Tenderness or 
erythema 
Induration <10 cm 
or phlebitis or 
inflammation 
Induration >10 cm 
or ulceration 
Necrosis 
Mucocutaneous 
Erythema; pruritis 
Diffuse, 
maculopapular 
rash; dry 
desquamation 
Vesiculation; 
moist 
desquamation; 
ulceration 
Exfoliative 
dermatitis, with 
suspected 
involvement of 
mucous 
membrane; 
Stevens-Johnson 
syndrome or 
erythema 
multiforme; 
necrosis requiring 
surgery 
Alopecia 
Minimal 
Patchy 
Complete, but 
reversible 
Irreversible 
 
For toxicities not listed above, grade as follows: 
 
Intensity Grades: 
1. Mild = does not interfere with routine activity 
2. Moderate = interferes with performance of some activities of daily living (ADL), but responds to 
symptomatic therapy or rest 
3. Severe = significantly limits ability to perform ADL despite symptomatic therapy 
4. Very severe = incapacitates patient despite symptomatic therapy; requires hospitalization 


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If an AE has multiple aspects, the aspect with the highest severity will be graded. 
It is emphasized that the term severe is a measure of severity; thus, a severe AE is not 
necessarily serious. For example, itching for several days may be rated as severe, but 
may not be clinically serious. 
 
In addition, clinically significant changes in physical examination findings and abnormal 
objective test findings (eg, laboratory, x-ray, ECG) should also be recorded as AEs. 
Test findings and physical examination findings can result in AEs if they:  
 
Are associated with accompanying symptoms, and/or 
 
Require additional diagnostic testing or medical/surgical intervention, and/or 
 
Lead to a change in study dosing or discontinuation from the study; result in the 
addition of significant additional concomitant drug treatment or other therapy, 
and/or 
 
Lead to any of the outcomes included in the definition of an SAE, and/or 
 
Are considered to be an AE by the PI or Sponsor. 
 
Reporting as an AE should not be triggered by: 
 
Merely repeating an abnormal test or  
 
Any abnormal test result that is determined to be an error. 
 
The relationship of any AE to the study drug will be assessed and graded on a 6-point 
scale: 
certain, 
probable/likely, 
possible, 
unlikely, 
conditional/unclassified, 
unassessable/unclassifiable. 
  
Causality term 
Assessment criteria 
Certain 
a clinical event, including laboratory test 
abnormality, occurring in a plausible time 
relationship to drug administration, and which 
cannot be explained by concurrent disease or 
other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary 
Probable/likely 
a clinical event, including laboratory test 
abnormality, with a reasonable time sequence to 
administration of the drug, unlikely to be attributed 
to concurrent disease or other drugs or 
chemicals, and which follows a clinically 
reasonable response on withdrawal 
(dechallenge). Rechallenge information is not 
required to fulfil this definition 
Possible 
a clinical event, including laboratory test 
abnormality, with a reasonable time sequence to 
administrations of the drug, but which could also 


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be explained by concurrent disease or other 
drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear 
Unlikely 
a clinical event, including laboratory test 
abnormality, with a temporal relationship to drug 
administration which makes a causal relationship 
improbable, and in which other drugs, chemicals 
or underlying disease provide plausible 
explanations 
Conditional/unclassified 
a clinical event, including laboratory test 
abnormality, reported as an adverse reaction, 
about which more data is essential for a proper 
assessment, or the additional data is under 
examination 
Unassessable/unclassifiable 
a report suggesting an adverse reaction which 
cannot be judged because information is 
insufficient or contradictory, and which cannot be 
supplemented or verified 
 
9.2.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that, on the basis of medical and scientific 
judgment: 
 
Results in death, or 
 
Is life-threatening (This refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe), or  
 
Requires inpatient hospitalization for a medical reason or prolongation of existing 
hospitalization (This refers to hospital admission required for treatment of the AE). 
(Note: this does not include confinement in, for example, a respite unit; a skilled 
nursing unit; rehabilitation facility; the clinical research center; or confinement due 
to planned or unplanned reason unrelated to study), or 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. 
 
SAEs will be collected from admission until the final study visit. SAEs that are related to 
the investigational drug and continue beyond the normal collection period (ie, are 


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ongoing at the time a subject exits the study) will be followed until resolution or until 
stabilized with sequelae. SAEs that begin after the subject’s participation in the study is 
complete, but that the PI considers to be related to study drug, may be reported at any 
time.  
 
The PI or clinical site personnel must notify the MMV Medical Monitor or his back-up, 
and to the pharmacovigilance provider (Quintiles LifeCycle Safety) of all SAEs, 
regardless of relationship to the investigational drug, within 24 hours of clinical site 
personnel becoming aware of the event. The PI will provide the initial notification by 
sending a completed “SAE Notification Form”, which must include the PI’s assessment 
of the relationship of the event to investigational drug, and must be signed by the PI. 
 
In addition, notification is sent by PRA to the IEC, and the subject’s General 
Practitioner. 
 
Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to the MMV Medical Monitor or his back-up, and to the pharmacovigilance 
provider (Quintiles LifeCycle Safety). The initial report will be followed up by a full 
written report within 3 working days or 5 calendar days, whichever comes first, unless 
no further information is available. A follow-up report and any subsequent reports will 
be provided as soon as possible when new information becomes available. 
 
All SAE reports should be sent to the contacts provided on Page 3: SAE Contact 
Information. 
 
All SAEs must be recorded and reported whether or not the PI considers the SAE to be 
related to the study drug. Photocopies of results, consultant report(s), a summary of the 
outcome of the reaction and the PI's opinion of study drug relationship to the SAE will 
accompany the SAE form if and when available. 
9.2.3 
Suspected Unexpected Serious Adverse Reactions 
An SAE that is also an unexpected adverse drug reaction is called a SUSAR. 
Unexpected adverse reactions are adverse reactions, of which the nature, or severity, 
is not consistent with the applicable product information (eg, IB for an unapproved 
investigational medicinal product or the Summary of Product Characteristics for an 
authorized medicinal product). It is the responsibility of the Sponsor to determine 
whether a reported SAE fits the classification of a SUSAR and to notify the PI of their 
decision as soon as possible. 
 
The Sponsor’s pharmacovigilance provoider (Quintiles LifeCycle Safety) will report 
expedited the following SUSARs to the IEC: 
 
SUSARs that have arisen in the current clinical study that was assessed by the IEC 
 
SUSARs that have arisen in other clinical studies of the same Sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the current clinical study that was assessed by the IEC 


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The Sponsor’s pharmacovigilance provoider (Quintiles LifeCycle Safety) will report in 
an expedited manner all SUSARs to the CA and the Medicine Evaluation Board (MEB) 
of the country where this study is conducted and to the CAs in other Member States, as 
applicable. 
 
SUSARs that have already been reported to the European Medicines Agency 
Eudravigilance database do not have to be reported again to the CA and the MEB 
because they have direct access to the Eudravigilance database. 
 
It is the responsibility of the Sponsor to determine whether an event requires expedited 
reporting and to notify the PI of their decision as soon as possible. The expedited 
reporting will occur no later than 15 calendar days after the Sponsor or its 
representative has first knowledge of the adverse reactions. For fatal or life-threatening 
cases the term will be maximally 7 calendar days for a preliminary report with another 
8 days for completion of the report. 
 
SUSARs must be recorded and reported whether or not the PI considers the SUSAR to 
be related to the study drug.  
9.2.4 
Follow-up of Adverse Events 
Follow-up of AEs will continue until resolution, stabilization or death. In case of ongoing 
AEs at the moment of database closure, the data obtained at the moment of database 
closure will be used in the statistical analysis. The follow-up of the AE will be 
documented in the source documents and will be described in the final CSR only if 
considered relevant by the PI. 
 
 

SAP_001.pdf: 


Statistical Analysis Plan 
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2.0 Table of Contents 
1.0 Approvals .....................................................................................................................................1 
2.0 Table of Contents..........................................................................................................................2 
3.0 Introduction...................................................................................................................................4 
4.0 Changes from Previous Version of Approved SAP ..........................................................................4 
5.0 Study Objectives ...........................................................................................................................4 
5.1 Primary .....................................................................................................................................4 
5.1.1 Primary Endpoints ...............................................................................................................4 
5.2 Secondary ................................................................................................................................4 
5.2.1 Secondary Endpoints ..........................................................................................................5 
5.2.2 Exploratory Endpoints .........................................................................................................5 
6.0 Study Design ................................................................................................................................5 
6.1 Sample Size Considerations ......................................................................................................5 
6.2 Randomization ..........................................................................................................................6 
7.0 Overview of Planned Analysis ........................................................................................................6 
7.1 Changes from Protocol ..............................................................................................................6 
7.2 Interim Analysis and Key Results................................................................................................6 
7.3 Final Analysis............................................................................................................................6 
8.0 Data Review .................................................................................................................................6 
8.1 Data Management .....................................................................................................................6 
8.2 Acceptance of Data for Summarization .......................................................................................6 
9.0 Definitions and General Analysis Methods ......................................................................................7 
9.1 Analysis Data Presentation ........................................................................................................7 
9.1.1 Rounding ............................................................................................................................7 
9.1.2 Imputation ..........................................................................................................................7 
9.1.3 Descriptive Statistics ...........................................................................................................7 
9.1.4 Pooling ...............................................................................................................................7 
9.1.5 Unscheduled Measurements................................................................................................7 
9.2 Analysis Data Definitions ...........................................................................................................7 
9.2.1 Baseline Definition ..............................................................................................................7 
9.2.2 Treatment/Subject Grouping Definition .................................................................................7 
9.2.3 Other Definitions .................................................................................................................7 
9.2.4 Critical Data ........................................................................................................................8 
9.2.5 QC .....................................................................................................................................8 
9.3 Software ...................................................................................................................................8 
9.4 Statistical Methods ....................................................................................................................8 
9.4.1 Statistical Outlier Determination ...........................................................................................8 
9.4.2 Predetermined Covariates and Prognostic Factors ................................................................8 
9.5 TFL Layout ...............................................................................................................................8 
10.0 Analysis Sets ..............................................................................................................................9 
10.1 Randomized............................................................................................................................9 
10.2 Safety .....................................................................................................................................9 
10.3 Pharmacokinetic ......................................................................................................................9 
10.4 Pharmacokinetic Summary.......................................................................................................9 
11.0 Subject Disposition .................................................................................................................... 10 
12.0 Protocol Deviations and Violations.............................................................................................. 10 
13.0 Demographic and Baseline Characteristics ................................................................................. 10 
13.1 Demographics ....................................................................................................................... 10 
13.2 Medical History...................................................................................................................... 10 
13.3 Other Baseline Characteristics ............................................................................................... 10 
14.0 Prior/Concomitant Medications ................................................................................................... 10 
15.0 Treatment Compliance and Exposure ......................................................................................... 10 
16.0 Pharmacokinetic Analyses ......................................................................................................... 10 
16.1 Pharmacokinetic Variables ..................................................................................................... 11 


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16.2 Pharmacokinetic Concentrations ............................................................................................ 12 
16.3 Pharmacokinetic Parameters.................................................................................................. 13 
16.3.1 Calculation Exploratory Endpoints .................................................................................... 13 
16.3.2 Statistical Analysis........................................................................................................... 14 
17.0 Safety Analyses ........................................................................................................................ 14 
17.1 Safety Variables .................................................................................................................... 14 
17.1.1 Adverse Events ............................................................................................................... 15 
17.1.2 Deaths and Serious Adverse Events................................................................................. 15 
17.1.3 Laboratory Data .............................................................................................................. 15 
17.1.4 Vital Signs ...................................................................................................................... 15 
17.1.5 Electrocardiograms ......................................................................................................... 16 
17.1.6 Physical Examination ...................................................................................................... 16 
18.0 References ............................................................................................................................... 16 
Appendix 1: Glossary of Abbreviations ............................................................................................... 17 
Appendix 2: Schedule of Assessments – Part 1 .................................................................................. 18 
Appendix 3: Schedule of Assessments – Part 2 .................................................................................. 20 
Appendix 4: List of In-Text Outputs .................................................................................................... 22 
Appendix 5: List of End of Text Tables and Figures............................................................................. 23 
Appendix 6: List of End of Text Listings .............................................................................................. 25 
Document History ............................................................................................................................. 26 
 


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3.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and 
reporting 
of 
data 
collected 
under 
Medicines 
for 
Malaria 
Venture 
(MMV) 
Protocol 
MMV_OZ439_16_01. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the SAP has been developed using the protocol version 2.0 dated 16-Mar-2017 (including all 
amendments up to this protocol date) and the final CRF(s) dated 24-Mar-2017. 
An approved and signed SAP is a requirement for database hard lock. 
This SAP only covers the results that will be processed by the PRA Early Development Services (EDS) 
Biostatistics Department. 
PRA EDS will perform the pharmacokinetic (PK) (except the exploratory endpoint), safety and tolerability 
evaluation. Estimation of fraction absorbed, extraction ratio, liver first pass and deconvolution of 
absorption profile over time for OZ439 will be performed by BEL Pharm Consulting and reported in the 
clinical study report (CSR). Future OZ439 metabolites analysis that may be performed will not be reported 
in the CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant 
changes from the planned analysis in this SAP performed to provide results for inclusion in the CSR but 
not included in this SAP, will be clearly identified in Section 9.8.2 of the CSR. Changes to planned 
analyses do not require an updated SAP but should be included in the CSR if significant. 
4.0 Changes from Previous Version of Approved SAP 
This is the first version of the SAP. 
5.0 Study Objectives 
5.1 Primary 
• 
To determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 
dispersion and a simultaneous single intravenous (iv) microdose (100 µg) infusion of [14C]-OZ439 
under fasted conditions (Part 1) 
• 
To evaluate the effects of a single oral dose of cobicistat, a strong cytochrome P450 (CYP) 3A4 
inhibitor, on the PK profile of a single oral dose of a dispersion of OZ439 simple granules under 
fasted conditions (Part 2) 
• 
To evaluate the PK of single doses of OZ439 granules when restricting the target dosing volumes 
to 64.5 or 100 mL (Parts 1 and 2) 
5.1.1 Primary Endpoints 
• 
Part 1: PK: absolute oral bioavailability (Fpo) of OZ439 
• 
Part 2: PK of OZ439: Cmax, C168h, AUC0-168h and AUC0-inf 
5.2 Secondary 
• 
To assess the safety and tolerability of OZ439 when administered alone, and to assess the safety 
and tolerability of OZ439 and cobicistat when co-administered as single doses to healthy subjects 
(Parts 1 and 2) 
• 
To determine the PK parameters of OZ439 single iv microdose (100 µg) infusion of [14C]-OZ439 
(Part 1) 


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• 
To assess the effects of the total dosing volume and of dose to volume ratio on OZ439 PK under 
fasted conditions (Parts 1 and 2) 
• 
To determine the PK parameters and exposures of cobicistat (Part 2) 
5.2.1 Secondary Endpoints 
Part 1: 
• 
PK for iv administration of OZ439: Vd, CL, t1/2, AUC0-t, AUC0-inf and λz 
• 
PK for oral administration of OZ439: Cmax, tmax, t1/2, C168h, AUC0-168h, AUC0-t, AUC0-inf, CL/F and λz 
• 
Safety: adverse events (AE), clinical laboratory, vital signs, electrocardiogram (ECG) and physical 
examination 
Part 2: 
• 
PK of OZ439: tmax, t1/2, AUC0-t and λz 
• 
PK of cobicistat: Cmax, tmax, t1/2, AUC0-t, AUC0-inf, CL/F and λz 
• 
Safety: AEs, clinical laboratory, vital signs, ECG and physical examination 
5.2.2 Exploratory Endpoints 
• 
Part 1: Estimation of fraction absorbed, extraction ratio, liver first pass and deconvolution of 
absorption profile over time for OZ439 
• 
Future OZ439 metabolites analysis may be performed (Part 1 and Part 2) 
6.0 Study Design 
Part 1 
This is an open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 
following a single oral dose of OZ439 and a simultaneous single iv infusion of [14C]-OZ439 radiolabeled 
microdose administered at the anticipated tmax of the oral dose. Subjects will receive the following 
treatment: 
Treatment A: a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion 
followed by a 15-minute 10-mL iv infusion of 100 μg [14C]-OZ439 (47 kBq [1.27 µCi]) beginning 3 hours 
after the oral dose administration.  
Part 2  
This is an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each 
subject will participate in 3 treatment periods and each subject will receive a single dose of each of the 
following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: 
Treatment B: a single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion  
Treatment C: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion  
Treatment D: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion 
and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) 
6.1 Sample Size Considerations 
The study is exploratory and no formal sample size calculation has been made. Based on experience 
from previous similar studies and taking into account OZ439 large variability, a total of 8 subjects enrolled 
in Part 1 of the study to achieve a minimum of 6 evaluable subjects is considered sufficient. A total of 8 
subjects is also considered sufficient to assess the effects of the total dosing volume and of dose to 
volume ratio on OZ439 PK under fasted conditions (in combination with Part 2). In Part 2 of the study a 
sample size of 18 subjects is considered appropriate to estimate the increase in OZ439 exposure in the 


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presence of a single dose of 150 mg cobicistat with sufficient precision, assuming a mean ratio of 2. 
Based on the assumptions of a point estimate (mean ratio) of 2.0 and a CV of 23%, a sample size of 18 
subjects would give a 90% confidence interval (CI) of 1.75 - 2.28 and this number of subjects is therefore 
considered sufficient. In Part 2, 18 subjects will be randomized to ensure data in 15 evaluable subjects for 
the PK endpoints. A subject will be considered evaluable for the primary analysis if they have sufficient 
PK data to estimate the primary endpoints Cmax and AUC0-inf for the 3 treatments. Note: the primary 
analysis refers to the statistical analysis of the treatment comparisons defined in Section 16.3.1. 
6.2 Randomization 
Subjects who have met all eligibility criteria will receive a subject number upon inclusion in the study (for 
Part 1: subject numbers 101-108; for Part 2: subject numbers 201-218). They will receive the subject 
number according to the order of enrolment in Part 1 of the study, and according to the randomization 
code generated by the Biostatistics Department of PRA in Part 2 of the study. The subject number will 
ensure identification throughout the study. Replacement subjects will receive the number of the subject to 
be replaced, increased by 1000 (e.g. 1101 replacement number for subject number 101), and will be 
administered the same or remaining treatments in the same order. 
In Part 2, subjects were randomized to 1 of 6 treatment sequences (BCD, BDC, CBD, CDB, DBC, or 
DCB), with 3 subjects per sequence (balanced randomization). 
7.0 Overview of Planned Analysis 
7.1 Changes from Protocol 
In the protocol it was stated that a subject will be considered evaluable for the primary analysis if they 
have sufficient PK data to estimate all of the primary endpoints (Cmax, C168h, AUC0-168h, and AUC0-inf) for 
the 3 treatments. This was changed in the SAP to: ‘a subject will be considered evaluable for the primary 
analysis if they have sufficient PK data to estimate the primary endpoints Cmax and AUC0-inf for the 3 
treatments’. 
7.2 Interim Analysis and Key Results 
Interim PK results of Part 1 will be provided to the Sponsor. The interim Tables, Figures and Listings 
(TFLs) will include a PK concentration table (Table 15.2.1), individual values and descriptive statistics of 
PK parameters (Table 15.2.2), a summary of the statistical analysis of bioavailability (Table 15.2.3), plots 
of combined individual PK profiles (Figure 15.2.6), and plots of geometric mean PK profiles (Figure 
15.2.5). 
7.3 Final Analysis 
Draft TFLs will be provided with the draft CSR. After Sponsor comments have been incorporated, the 
TFLs will be finalized and incorporated in the final CSR. 
8.0 Data Review 
8.1 Data Management 
Data handling and transfer will take place under the PRA Data Management Plan for the study. 
8.2 Acceptance of Data for Summarization 
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) 
after database lock. Only quality assured (QA’d) results released by the Safety Laboratory, Bioanalytical 
Laboratory, or other external data source will be used for the programming of analysis datasets and TFLs 
for the final report. Any data values requiring investigation or corrections that are identified while 
programming the analysis datasets and TFLs will be sent to the project Data Manager. Database will not 


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be locked until the identified issues are resolved. If the issue affects the TFLs the Programmer or 
Statistician who identified the issue will follow it to resolution. 
9.0 Definitions and General Analysis Methods 
9.1 Analysis Data Presentation 
9.1.1 Rounding 
In listings, data will be presented with the same precision as the original data.  Derived data will be 
rounded for presentation purposes.  
For all non-PK summaries, mean, Standard Deviation (SD), median, minimum and maximum will be 
presented with the same precision as the original data (i.e., the same number of decimals). The derived 
PK parameters, except tmax, will be listed and summarized with a precision of 3 significant digits or as 
integers when the value is >1000; tmax values will be presented with 2 decimals, %AUC extra will be 
presented with 1 decimal. 
CV% will be presented with 1 decimal and frequency percentages will be presented as whole numbers. 
P-values will be reported to 4 decimal places; p-value less than 0.0001 will be reported as p <0.0001. 
9.1.2 Imputation 
Unless otherwise noted data will not be imputed. Exceptions are missing start and end times of AEs, see 
Section 17.1.1 and PK concentrations under lower limit of quantification (LLOQ), see Section 16.2. 
9.1.3 Descriptive Statistics 
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: n (number of observations), (arithmetic) mean, SD, minimum (min) value, median, and 
maximum (max) value. For PK parameters the geometric mean (except for tmax) and the coefficient of 
variation (CV%) will also be presented. 
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of subjects exposed within a treatment. 
9.1.4 Pooling 
Summary statistics will be calculated by treatment (and time point, if applicable). 
9.1.5 Unscheduled Measurements 
Unscheduled measurements will be included in the listings. With the exception of unscheduled 
measurements used for baseline, unscheduled measurements will be excluded from the descriptive 
statistics and statistical analysis. 
9.2 Analysis Data Definitions 
9.2.1 Baseline Definition 
Unless otherwise stated, baseline for post-dose evaluations within each period is defined as the last 
observation recorded before the first study drug administration in each period. The last observation can 
be an unscheduled / repeated measurement. 
9.2.2 Treatment/Subject Grouping Definition 
Throughout this SAP treatment refers to Treatment A, B, C, and D (see Section 6.0). 
9.2.3 Other Definitions 
 


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Variable 
Data Type 
Definition/Calculation 
Change from Baseline 
All 
Post-dose Observation minus 
Baseline Observation 
Study Day (Prior to 
Dose) 
All 
Date of Measurement minus first 
Dose Date for each period 
Study Day (Post-Dose) 
All 
Date of Measurement minus first 
Dose Date +1 for each period 
TEAE 
Adverse Events 
AE is a TEAE if the AE Date/Time 
is greater than the first OZ439 or 
cobicistat Dose Date/Time 
Time post dose 
PK 
Time relative to drug adminstration. 
For the iv treatment time post dose 
will be relative to the iv drug 
administration (3 hours after the 
oral administration) 
9.2.4 Critical Data 
As the primary objective of this study is to determine bioavailability and to characterize the PK, the 
datasets considered critical are Pharmacokinetic Parameters Analysis Dataset (ADPP) and Subject Level 
Analysis Dataset (ADSL). 
The analysis datasets that will be created are ADSL, ADAE, ADLB, ADVS, ADEG, ADPC and ADPP. The 
analysis datasets will be generated in accordance with Clinical Data Interchange Standard Consortium 
(CDISC) Analysis Data Model (ADaM) Version 2.1 (ADaM Implementation Guide v1.1). ADaM compliant 
datasets will be delivered to the Sponsor, including a define.xml (not including analysis results metadata). 
9.2.5 QC 
The analysis datasets and the TFLs will be QC’d according to the general PRA EDS QC plan. 
9.3 Software 
The statistical analysis and reporting will be done using SAS® for WindowsTM Version 9.4 or higher (SAS 
Institute, Inc.). 
PK parameter calculations will be done using Phoenix® WinNonlin® Version 6.3 or higher (Pharsight, Inc.).  
9.4 Statistical Methods 
9.4.1 Statistical Outlier Determination 
No statistical outlier analysis is planned. 
9.4.2 Predetermined Covariates and Prognostic Factors 
There are no predetermined covariates or prognostic factors. 
9.5 TFL Layout 
Report layout will be according to the PRA EDS – ICH E3 compliant – CSR Template. The layout of TFLs 
will be according to the PRA EDS standards. 
No table shells will be provided. The TFLs will be provided in Adobe PDF format (in A4 Format). 
Format: 
• 
Data in listings will be sorted by subject number, period and time point. 


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• 
Data in tables will be sorted by treatment and time point. 
• 
Column titles will be in title case letters. 
• 
All tables and listings will be in landscape format. For figures, the portrait format may be used as 
well. 
• 
The treatment labels A, B, C, and D will be used in the TFLs, with footnotes explaining the 
abbreviations. 
10.0 Analysis Sets 
 
Analyses 
Randomized Set 
Safety Set 
Pharmacokinetic Set 
Disposition 
Summaries 
 
 
 
Safety Assessments 
 
 
 
Baseline 
Characteristics 
 
 
 
Primary Analysis 
 
 
 
PK Concentrations 
 
 
 
PK Parameters 
 
 
 
10.1 Randomized 
The randomized set will consist of subjects who are assigned a randomization number in the study. This 
set will be used for disposition summaries. 
10.2 Safety 
The safety set will consist of subjects who receive at least 1 dose of OZ439. This set will be used for the 
safety data summaries, baseline characteristic summaries, and PK concentration summaries. 
10.3 Pharmacokinetic 
The PK set will consist of all subjects who receive at least 1 dose of OZ439 and provided sufficient 
bioanalytical assessment results to calculate reliable estimates of at least one of the primary endpoints 
PK parameters or secondary endpoint parameters. This set will be used for descriptive statistics of PK 
parameters. 
10.4 Pharmacokinetic Summary 
The PK summary set will consist of all subjects who are considered evaluable for the primary statistical 
analysis, defined as follows: 
For Part 2, a subject will be considered evaluable for the primary statistical analysis if they have sufficient 
PK data to estimate the primary endpoints Cmax and AUC0-inf for the 3 treatments. 
For Part 1, a subject will be considered evaluable for the primary statistical analysis (bioavailability) if they 
have sufficient PK data to estimate the primary endpoint Fpo. 
This set will be used for the statistical analysis of the treatment comparisons defined in Section 16.3.1. 


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11.0 Subject Disposition 
A listing containing the information for each subject with regard to completing the study and study 
withdrawal will be presented. 
The number and percentage of subjects randomized, dosed, and members of each analysis set will be 
presented. The number and percentage of subjects who withdrew from the study prematurely and a 
breakdown of the corresponding reasons for withdrawal will also be presented. 
A listing containing study dates by subject will be presented, containing the following dates: informed 
consent, screening, dose administration in each period, follow-up and last assessment. 
12.0 Protocol Deviations and Violations 
Protocol deviations/violations will be included in the CSR. 
13.0 Demographic and Baseline Characteristics 
13.1 Demographics 
Individual demographic data will be listed. 
Subject demographics will be summarized descriptively for all subjects by study part. The summary will 
include the subjects’ age at informed consent (in years), gender, race, ethnicity, weight (in kg), height (in 
cm), and body mass index (BMI) (in kg/m2). Demographics will be summarized for the safety and PK 
sets. 
13.2 Medical History 
Medical history will be listed. 
13.3 Other Baseline Characteristics 
The results of drug and alcohol screen at screening and admission will be listed.  
The results of serology at screening will be listed.  
The results of pregnancy tests at screening and admission will be listed (females only).  
The results of hormone tests (follicle stimulating hormone [FSH]) at screening for females only will be 
listed. 
14.0 Prior/Concomitant Medications 
Concomitant medication will be listed. Medications with an end date prior to the first dose of study drug 
will be considered prior medications and will be listed separately. If a partial date allows a medication to 
be considered concomitant it will be categorized as such. 
15.0 Treatment Compliance and Exposure 
Study drug administration data will be listed by subject. 
16.0 Pharmacokinetic Analyses  
The plasma samples for OZ439 and Cobicistat will be analyzed by Swiss Bioquant AG and concentration 
data will be transferred to PRA. 
The plasma samples for [14C]-OZ439 will be analyzed by transferred Xceleron Inc and concentration data 
will be transferred to PRA. 


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16.1 Pharmacokinetic Variables 
• 
Plasma concentrations of OZ439 (Part 1 and Part 2) 
• 
Plasma concentrations of [14C]-OZ439 (Part 1) 
• 
Plasma concentrations of cobicistat (part 2) 
• 
Plasma concentrations of total radioactivity (Part 1) 
• 
PK parameters for OZ439 in plasma (Part 1 and Part 2) 
• 
PK parameters for [14C]-OZ439 in plasma (Part 1) 
• 
PK parameters for total radioactivity in plasma (Part 1) 
• 
PK parameters for cobicistat (Part 2) 
 
 
Parameter 
Description 
SAS Programming 
Notes 
Part 1 
OZ439 iv/ 
oral 
Part 2 
OZ439/ 
cobicistat  
Cmax 
Maximum plasma concentration. 
Observed peak analyte concentration 
obtained directly from the 
experimental data without 
interpolation, expressed in 
concentration units 
 
Cmax from WNL 
iv and oral  OZ439 and 
cobicistat 
C168h 
Observed plasma concentration at 
168 hours post-dose 
 
oral 
OZ439 
Tmax 
Time to maximum plasma 
concentration. First observed time to 
reach peak analyte concentration 
obtained directly from the 
experimental data without 
interpolation, expressed in time units. 
Tmax from WNL 
iv and oral 
OZ439 and 
cobicistat 
AUCs 
Calculated using linear up / log down, 
expressed in units of concentration x 
time. 
 
 
 
AUC0-t 
Area under the concentration-time 
curve (time 0 to time of last 
quantifiable concentration). 
AUClast from WNL 
iv and oral 
OZ439 and 
cobicistat 
AUC0-inf 
Area under the plasma concentration-
time curve (time 0 to infinity). Percent 
extrapolation less than or equal to 
20% is required to retain AUCinf. 
AUCINF_obs from 
WNL 
If AUC_%Extrap_obs 
>20% then 
parameter is flagged 
iv and oral 
OZ439 and 
cobicistat 
%AUCextra 
Percentage of estimated part for the 
calculation of AUC. 
%AUCextra = ((AUC0-inf-AUC0-t)/AUC0-
inf)*100%.  
AUC_%Extrap_obs 
from WNL 
iv and oral 
OZ439 and 
cobicistat 
AUC0-168 
Area under the serum concentration-
time curve from time 0 to 168 hours 
post-dose. 
AUC0-168 from WNL 
where partial time 
=168 
oral 
OZ439 
λz 
Terminal phase rate constant 
Lambda_z from WNL 
iv and oral 
OZ439 and 


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Parameter 
Description 
SAS Programming 
Notes 
Part 1 
OZ439 iv/ 
oral 
Part 2 
OZ439/ 
cobicistat  
calculated by linear regression of the 
terminal log-linear portion of the 
concentration vs. time curve. Linear 
regression of at least three is required 
(regression of two points will be 
flagged). 
If adjusted Rsq ≤ .80 
then parameter is 
flagged 
cobicistat 
t1/2 
Terminal phase half-life expressed in 
time units. 
HL_Lambda_z from 
WNL 
If adjusted Rsq ≤ .80 
then parameter is 
flagged 
iv and oral 
OZ439 and 
cobicistat 
CL/F 
Apparent oral clearance, calculated 
Cl_F_obs from WNL 
oral 
cobicistat 
CL 
Clearance, calculated as dose/AUC0-
inf 
Cl_obs from WNL 
iv 
OZ439 
Vd 
Volume of distribution at terminal 
phase, calculated as CL/λz 
Vz_F_obs from WNL 
iv 
OZ439 
Fpo 
Absolute bioavailability, calculated as: 
F=(AUCoral*Div)/ (AUCiv*Doral), where 
AUCoral is the AUC0-inf  of OZ439 and 
AUCiv  is the AUC0-inf  of [14C]-OZ439; 
Doral is the oral dose and Div  is the iv 
microdose  
 
 
 
OZ439 
 
16.2 Pharmacokinetic Concentrations 
Plasma concentrations for total radioactivity, [14C]-OZ439, OZ439 or cobicistat below the quantifiable limit 
(BQL) will be set to ½ LLOQ in the computation of mean concentration values. Descriptive statistics 
(number of subjects, arithmetic mean, geometric mean, SD, CV%, median, minimum, and maximum) will 
be used to summarize the plasma concentrations by treatment at each scheduled time point. If over ½ the 
subjects in a given cell have values BQL then the descriptive statistics will not be presented except for the 
minimum and maximum and the mean will be displayed as BQL. 
Linear and semi-logarithmic plots of the geometric mean total radioactivity, OZ439 and cobicistat plasma 
concentration by scheduled sampling time will be provided by treatment. These plots will show time in 
hours. The plots will match the summary table results and will not have an observation at a given time 
point if more than half of the subjects have values BQL. The following mean plots will be provided: 
• 
Geometric mean oral OZ439 concentration, iv total radioactivity and OZ439 specific radioactivity 
versus time plot (in the same plot). A linear plot including SD bars, and a semi-logarithmic plot will 
be provided [treatment A, Part 1]. 
• 
Geometric mean oral OZ439 concentration vs time plot for treatments C and D in the same plot. 
A linear plot including SD bars, and a semi-logarithmic plot will be provided [Part 2]. 
• 
Geometric mean oral OZ439 concentration vs time plot for treatments A, B  and C (with C dose-
normalized to 800mg) in the same plot. A linear plot including SD bars, and a semi-logarithmic 
plot will be provided [Part 1 and 2]. 
• 
Mean plot of oral cobicistat concentration vs time (linear) [treatment D, Part 2]. 


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Linear and semi-logarithmic plots of the combined individual plasma concentration by actual sampling 
time will be provided in a single plot by treatment and analyte (total radioactivity, OZ439, [14C]-OZ439 and 
cobicistat).  
Linear and semi-logarithmic plots of the individual plasma concentration by actual sampling time will be 
provided by subject (1 subject per page). For Part 1, total radioactivity, OZ439 and [14C]-OZ439 
concentration-time profiles will be shown in the same plot; For Part 2, OZ439 concentration-time profiles 
for Treatments B, C and D will be shown in the same plot. The cobicistat concentration-time profiles (Part 
2, Treatment D only) will be presented separately. In all plots, colours will be used to distinguish between 
treatments. 
All individual subject plasma concentration data will be listed. 
16.3 Pharmacokinetic Parameters 
PK parameters for total radioactivity, OZ439 and cobicistat will be estimated using non-compartmental 
methods with Phoenix WinNonlin® Version 6.3.  
The plasma PK parameters will be estimated from the concentration-time profiles for all subjects in the 
safety population. In estimating the PK parameters, BQL values at the beginning of the profile will be set 
to zero. BQL values that occur after the first quantifiable point will be considered missing. Values that are 
embedded between BQLs, or quantifiable values occurring after 2 or more BQLs, will be set to missing at 
the discretion of the pharmacokineticist.  
Actual blood sampling times will be used in the PK parameter calculations. If the actual time or dose time 
is missing, the scheduled time may be substituted in order to calculate the PK parameter. 
The terminal elimination rate constant (λz) will be determined by plotting the concentration data versus 
time on a semi-logarithmic scale. The time interval of the terminal elimination phase will be determined by 
visual inspection. Linear regression on log-transformed concentrations within this interval will be used to 
calculate the terminal elimination rate constant. At least 3 data points are required to obtain a reliable λz 
and associated parameters. Points prior to and including Cmax will not be used to estimate λz. Terminal 
half-life and λz values (and derived parameters) will be flagged if λz cannot be accurately estimated 
(adjusted r2 < 0.8). In calculations of AUC parameters, the linear up / log down trapezoidal method will be 
used. For AUC0-inf, if the %extrapolation from last quantifiable concentration to infinity >20%, then the data 
will be flagged. 
Descriptive statistics (number of subjects, mean, geometric mean, SD, CV%, median, minimum, and 
maximum) will be used to summarize the calculated PK parameters by treatment. For tmax, the geometric 
mean will not be presented. 
16.3.1 Calculation Exploratory Endpoints 
Assuming little or no extra-hepatic clearance of OZ439 and under the assumptions of the well-stirred 
model, the following exploratory endpoints will be calculated [Yang et al, 2007]: 
• 
Extraction ratio (ER) = CLiv/(Qh*BPratio), where 
o 
CLiv is the average IV plasma clearance (ml/min) estimated in Part 1 of the study 
o 
Qh is an estimation of the liver blood flow: Qh= 1450 [Davis & Morris, 1993] * (mean 
BW/70kg)^0.75 ml/min; mean BW is the mean bodyweight of the subjects in Part 1. 
o 
BPratio is the Blood:Plasma ratio=1.2 as reported in the CIB [CIB v3.0 2011] 
• 
Liver First Pass (Fh) = 1-ER 
• 
Fraction absorbed (Fa = Ftot/Fh), where 
o 
Ftot is the average total bio-availability estimated in Part 1 of the study 
The deconvolution of absorption profile over time for OZ439 will be performed using appropriate software. 


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16.3.2 Statistical Analysis 
Part 1: 
To determine the absolute bioavailability, an analysis of variance (ANOVA) will be performed on OZ439 
PK parameter AUC0-inf using the SAS procedure for mixed effect models (PROC MIXED). The PK 
parameter will be natural logarithm transformed prior to analysis. The model will include a fixed effect for 
treatment (i.e. OZ439 oral or OZ439 iv), and a random effect for subject.  
From the ANOVA model the back-transformed least-squares means (LSMeans) for test (OZ439 oral) and 
reference (OZ439 iv) treatments will be presented. The ratio of the LSMeans for the comparison of oral 
and iv OZ439 (i.e. the absolute bioavailability) will be obtained by exponentiating the difference of the 
LSMeans on the log scale. The absolute bioavailability and the corresponding 90% CI will be presented. 
The individual bioavailability values will also be reported for each subject. 
Part 2: 
An analysis of variance (ANOVA) will be performed on OZ439 PK parameters Cmax, C168h, AUC0-168 and 
AUC0-inf using the SAS procedure for mixed effect models (PROC MIXED). The PK parameters will be 
natural logarithm transformed prior to analysis. The model will include fixed effects for treatment, period, 
and sequence, and a random effect for subject within sequence (comparisons D vs C and B vs C; for 
comparison B vs A only a fixed effect for treatment will be included).  
From the ANOVA model the back-transformed least-squares means (LSMeans) for test and reference 
treatments will be presented. The ratios of the LSMeans for the comparison of the treatments D vs C, B 
vs A and B vs C will be obtained by exponentiating the difference of the LSMeans on the log scale. This 
ratio and the corresponding 90% CI will be presented for the comparisons between: 
• Treatment D vs Treatment C to assess the effect of cobicistat on OZ439 
• Treatment B vs Treatment A to explore volume effect (for this no within-subject comparison is 
possible) 
• Treatment B vs Treatment C to explore dosing solution concentration effect (Treatment C will be 
dose normalized to 800 mg (only for this comparison)) 
17.0 Safety Analyses  
17.1 Safety Variables 
The following safety variables will be summarized: 
• 
AEs 
• 
Vital Signs 
o 
Supine Blood Pressure  
 
Systolic Blood Pressure 
 
Diastolic Blood Pressure 
o 
Pulse rate 
o 
Tympanic body temperature 
• 
Electrocardiograms (ECG) 
o 
Heart Rate 
o 
PR Interval 
o 
QRS Duration 
o 
QT Interval 
o 
QTc (Bazett and Fridericia) Interval 
o 
Interpretation of the ECG profile by the PI 
• 
Clinical Laboratory Evaluations 
o 
Clinical Chemistry  
o 
Hematology 


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o 
Urinalysis 
17.1.1 Adverse Events 
All AEs reported during the study will be reported and coded using Medical Dictionary for Regulatory 
Activities (MedDRA), Version 20.0 or higher. 
A treatment-emergent AE (TEAE) is defined as an event not present prior to the first administration of the 
study drug (first administration of OZ439 or cobicistat) or an event already present that worsens in either 
severity or frequency following exposure to the study drug (first administration of OZ439 or cobicistat). An 
AE which occurs prior to the first administration of the study drug will be considered a pre-treatment AE. 
All AEs (including non-treatment-emergent events) and all AEs leading to study discontinuation will be 
listed, including the AE description (verbatim term), MedDRA system organ class (SOC) and preferred 
term (PT), start date and time, end date and time, severity, intervention, relation to study drug, 
seriousness, action taken, and outcome. 
All AE summaries will include only TEAEs. The incidence of TEAEs will be summarized (number of 
TEAEs, number and percentage of subjects) by SOC and PT by treatment, for all causalities and for only 
related events. An overview of TEAEs will be presented by treatment, relationship and severity (number 
of TEAEs, number and percentage of subjects). 
TEAEs of which the relationship of the test drug was classified as “possible”, “probable/likely” or ‘’certain” 
will be assessed as related, whereas AEs that will be assessed as “unlikely” will be considered not to be 
related. Missing AE severity or relationship will be assumed to be severe or related, respectively. 
TEAEs occurring following dosing in a specific period but before dosing in the next period will be 
attributed to that specific period. If the time is missing for an AE on a dosing day then the AE will be 
attributed to the treatment given on that day. 
The following missing data will be imputed as defined: 
• 
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times 
• 
Missing AE severity or relationship will be assumed to be severe or related, respectively 
• 
Missing AE start times  for the determination of treatment emergence will be assumed to occur 
after treatment unless partial date documents the AE as happening prior to treatment 
• 
Missing AE start times for the determination of treatment assignment will be assumed to occur 
after treatment on the recorded date 
• 
Missing AE start date will be assumed to be after treatment for the determination of TEAE and on 
treatment for single treatment studies but will not be attributed to treatment in studies with 
multiple treatments 
17.1.2 Deaths and Serious Adverse Events 
A listing of deaths and other serious adverse events will be provided (if applicable). 
17.1.3 Laboratory Data 
Clinical laboratory data will be presented using Système International (SI) units (also used in the Study 
Data Tabulation Model (SDTM) Controlled Terminology). 
All laboratory data will be listed. Listings will be split into clinical chemistry, hematology and urinalysis. In 
addition, a summary listing of all data outside the reference range(s) will be presented. 
Descriptive statistics of clinical chemistry and hematology parameters (original values and change from 
baseline) will be provided to summarize continuous laboratory results by treatment and scheduled time. 
17.1.4 Vital Signs 
Vital signs parameters will be listed and descriptive statistics of original values and change from baseline 
will be provided to summarize vital signs by treatment and scheduled time. 


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17.1.5 Electrocardiograms 
ECG parameters will be listed and descriptive statistics of original values and change from baseline will 
be provided to summarize ECG parameters by treatment and scheduled time. At some time points 
triplicate 12-lead ECGs will be recorded. The average of these triplicate values will be used in the 
calculation of descriptive statistics and change from baseline, and the average of the triplicate values at 
pre-dose will be used as baseline. The individual triplicate values will be listed. 
A frequency table of QTc (Bazett and Fridericia) values will be presented by treatment and scheduled 
time. The number of incidences (number of subjects) and percentage of subjects will be presented. The 
following categories will be used: 
• 
<  450 ms 
• 
>= 450 - 480 ms 
• 
>= 480 - 500 ms 
• 
>= 500 ms 
A frequency table of QTc (Bazett and Fridericia) change from baseline values will be presented by 
treatment and scheduled time. The number of incidences (number of subjects) and percentage of 
subjects will be presented. The following categories will be used: 
• 
<  30 ms 
• 
>= 30 - 60 ms 
• 
>= 60 ms 
17.1.6 Physical Examination 
Abnormalities and changes from baseline will be listed. 
18.0 References 
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC. 
Clinical Study Protocol. AN OPEN-LABEL, TWO-PART STUDY TO DETERMINE THE ABSOLUTE 
BIOAVAILABILITY 
(BA) 
OF 
OZ439 
USING 
SIMULTANEOUS 
INTRAVENOUS 
[14C] 
OZ439 
MICRODOSE/800 MG ORAL DOSING AND TO INVESTIGATE THE PHARMACOKINETICS (PK) OF 
OZ439 GRANULES ADMINISTERED AS SINGLE DOSES SUSPENDED IN DIFFERENT VOLUMES 
AND WHEN CO-ADMINISTERED WITH A SINGLE DOSE OF COBICISTAT, A STRONG CYP3A4 
INHIBITOR, TO HEALTHY SUBJECTS IN FASTED STATE. Version 2.0, 16 Mar 2017. 
Davis & Morris, Physiological parameters in laboratory animals and humans. Pharmaceutical Res 10, 
1093, 1993. 
OZ439_Investigator’s Brochure Version FINAL 3.0, July 2011. 
Yang J, Masoud J Yeo KR, Rostami-Hodjegan A and Tucker GT. Misuse of the well-stirred model of 
hepatic drug clearance. Drug Metabolism and Disposition, 2007, vol. 35, No.3, 501-502. 
 
 


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Appendix 1: Glossary of Abbreviations 
Glossary of Abbreviations: 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
BQL 
Below the Quantifiable Limit 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CV 
Coefficient of Variation 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
EDS 
Early Development Services 
FSH 
Follicle Stimulating Hormone 
ICH 
International Conference on Harmonization 
IV 
Intravenous 
LLOQ 
Lower Limit of Quantification 
LSMeans 
Least Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QA’d 
Quality Assured 
QC’d 
Quality Controlled 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SI 
Système International 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TFL(s) 
Tables, Figures and Listings 
WNL 
WinNonlin 
 


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Appendix 2: Schedule of Assessments – Part 1 
 
 
Assessment Period1 
 
 
Screenin
g 
Pre-
Treatment 
Treatmen
t 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow
-up 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
15 (± 
2) 
Hours 
 
 
Pre-
dose 
0 
0.25 
0.5 
0.75 1 
2 
3 
4 
5 
6 
8 
1
2 
16 
24 
48 
72 
96 
168 
 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
 
 
 
 
 
Ambulatory visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and height 
(including BMI 
calculation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X
2 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
2 
 
 
 
 
X 
Serology (HBsAg, anti-
HCV, anti-HIV 1 and 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females 
only) 
X 
X
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory4 
X4 
X
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
12-lead ECG5 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
X 
Vital signs6 
X 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
X 
Eligibility check 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OZ439 oral administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[14C]-OZ439 iv 
administration 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples for 
OZ439 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood samples for 
[14C]-OZ439 
 
 
 
 
 
 
 
 
 
X
7 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 19 of 26 
Blood samples for OZ439 
metabolites 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Subjects w ill be in the clinic from Day -1 until 24 hours post-dose (Day 2). Subjects w ill return for ambulatory visits on Days 3, 4, 5 and 8 (at 48, 72, 96 and 168 hours post-
dose) 
2 
A targeted physical examination of applicable body systems w ill be performed if needed as per the judgment of the PI (eg, if the subject reports AEs) at pre-dose, on Day -1 
and at discharge 
3 
Confirmation of negative pregnancy test result required before dosing 
4 
Clinical laboratory tests (including clinical chemistry, hematology and urinalysis): all results must be available before dosing; out-of-range results judged to be possibly 
relevant by the PI are to be discussed w ith the medical monitor before dosing  
5 
Triplicate 12-lead ECG only required at pre-dose on Day 1 and at 2 and 4 hours post-dose on Day 1. Individual ECG measurements as part of a triplicate ECG w ill be 
recorded 1 minute (and no more than 2 minutes) apart. Single 12-lead ECGs w ill be done at the rest of the time points indicated in the schedule of assessments. 
6 
Vital signs w ill consist of supine systolic and diastolic blood pressure, pulse and body temperature 
7 
PK blood samples for [14C]-OZ439 w ill be collected at the start of iv infusion and at 10, 15 (just prior to end of iv infusion), 20, 30 and 45 minutes after start of iv infusion 
AE: adverse event; BMI: body mass index; ECG: electrocardiogram; FSH: follicle stimulating hormone; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human 
immunodeficiency virus; iv: intravenous; PK: pharmacokinetic(s); PI: Principal Investigator 
 
 
 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 20 of 26 
Appendix 3: Schedule of Assessments – Part 2 
 
 
Assessment Period 1, 2 or 31 
 
 
Screenin
g 
Pre-
Treatment 
Treatme
nt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-
up 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
102 
122 
142 
15-19 of 
Period 3 
Hours 
 
 
Pre-
dose 
0 
0.
5 
1 
2 
3 
4 5 
6 
8 12 16 24 48 72 
96 
16
8 
216 264 
31
2 
 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
 
 
 
 
 
 
 
 
Ambulatory visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and height 
(including BMI calculation) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X
3 
X3 
 
 
 
 
 
 
 
 
 
 
 
X
3 
 
 
 
 
 
 
 
X3 
Serology (HBsAg, 
anti-HCV, anti-HIV 1 and 
2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (females 
only) 
X 
X
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory5 
X5 
X
5 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
12-lead ECG6 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Vital signs7 
X 
X 
X 
 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Eligibility check 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples for 
OZ439 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood samples for 
cobicistat8 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X X 
X 
 
X 
X 
 
 
 
 
 
 
 
Blood samples for OZ439 
metabolites9 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 21 of 26 
1 
Subjects w ill be in the clinic for 3 periods, each period from Day -1 until 24 hours post-dose (Day 2). Subjects w ill return for ambulatory visits on Days 3, 4, 5 and 8 (at 48, 72, 
96 and 168 hours post-dose) of each period 
2 
Additional ambulatory visits on Days 10, 12 and 14 for Treatment D only (a single oral dose of 400 mg OZ439 simple granules administered as a 60-mL dispersion and co-
administered w ith a 150 mg cobicistat tablet [CYP3A4 inhibitor]). Day 14 w ill coincide w ith Day -1 of the next period w hen a subject is randomized to Treatment D in Period 1 
or Period 2. 
3 
A targeted physical examination of applicable body systems w ill be performed if needed as per the judgment of the PI (eg, if the subject reports AEs) at pre-dose, on Day -1 
and at discharge 
4 
Confirmation of negative pregnancy test result required before dosing 
5 
Clinical laboratory tests (including clinical chemistry, hematology and urinalysis): all results must be available before dosing; out-of-range results judged to be possibly 
relevant by the PI are to be discussed w ith the medical monitor before dosing  
6 
Triplicate 12-lead ECG only required at pre-dose on Day 1 and at 2 and 4 hours post-dose on Day 1. Individual ECG measurements as part of a triplicate ECG w ill be 
recorded 1 minute (and no more than 2 minutes) apart. Single 12-lead ECGs w ill be done at the rest of the time points indicated in the schedule of assessments.  
7 
Vital signs w ill consist of supine systolic and diastolic blood pressure, pulse and body temperature 
8 
Only applicable for Treatment D (a single oral dose of 400 mg OZ439 simple granules administered as a 60-mL dispersion and co-administered w ith a 150 mg cobicistat 
tablet [CYP3A4 inhibitor]) 
9 
Blood samples for future OZ439 metabolites analysis w ill be collected in Period 1 only 
AE: adverse event; BMI: body mass index; ECG: electrocardiogram; FSH: follicle stimulating hormone; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human 
immunodeficiency virus; PK: pharmacokinetic(s); PI: Principal Investigator 
 
 
 
 
 
 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 22 of 26 
Appendix 4: List of In-Text Outputs 
The planned tables, figures and subject data listings for the CSR are listed below. The placement and 
numbering presented is for tracking / development purpose and may deviate from the placement order 
and numbering listed in the CSR. 
This list defines the tables to be produced by programming. The MW can decide to insert any of the 
figures or create more tables for the CSR text independently of this SAP. 
 
List of CSR In-Text Outputs: 
Output 
Title  
Population Set 
10.1 
Subject Disposition and Data Sets Analyzed 
Table 1 
Summary with Number of Subjects Included and the 
Number of Subjects Evaluated 
All Subjects 
10.3 
Demographic and Other Baseline Characteristics 
Table 2 
Summary of Demographics 
Safety 
11 
Pharmacokinetic Results 
Figure 1 
Mean OZ439 Concentration vs Time Plot – iv, oral and 
total radioactivity in the same plot (linear with SD and 
semi-log) [Part 1] 
PK 
Figure 2 
Mean Oral OZ439 Concentration vs Time Plot - 
treatments C and D in the same plot (linear with SD 
and semi-log) [Part 2] 
PK 
Figure 3 
Mean Oral  OZ439 Concentration vs Time Plot - 
treatments A, B  and C (with C dose-normalized to 
800mg) in the same plot (linear with SD and semi-log) 
[Part 1 and 2] 
PK 
Table 3 
Summary of OZ439 and Cobicistat PK Parameters 
PK 
Table 4 
Statistical Analysis of Absolute Bioavailability (Part 1) 
PK 
Table 5 
Statistical Analysis of OZ439 PK Parameters (Part 2) 
PK 
12 
Safety Results 
Table 6 
Summary of all TEAEs by System Organ Class and 
Preferred Term 
Safety 
Table 7 
Summary of TEAEs by Relationship and Severity 
Safety 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 23 of 26 
Appendix 5: List of End of Text Tables and Figures 
List of End of Text Tables and Figures: 
Output 
Title  
Population Set 
15.1 
Demographic Data 
Table 15.1.1 
Summary of Subject Disposition 
Safety 
Table 15.1.2 
Summary of Demographics 
Safety 
Table 15.1.3 
Summary of Dosing  
Safety 
15.2 
Pharmacokinetic Data 
Table 15.2.1 
Summary and Listing of OZ439 and 
Cobicistat Plasma Concentrations 
PK 
Table 15.2.2 
Summary and Listing of OZ439 and 
Cobicistat PK Parameters 
PK 
Table 15.2.3 
Statistical Analysis of Absolute 
Bioavailability (Part 1) 
PK 
Table 15.2.4 
Statistical Analysis of OZ439 PK 
Parameters (Part 2) 
PK 
Figure 15.2.5 
Mean Plot of Oral OZ439 Concentration, 
IV Total Radioactivity and OZ439 
Radioactivity versus Time (Linear and 
Semi-logarithmic) 
PK 
Figure 15.2.6 
Mean Plot of Oral Cobicistat 
Concentration vs Time (Linear) 
PK 
Figure 15.2.7 
Plot of Combined Individual OZ439 and 
Cobicistat Plasma Concentrations versus 
Time (Linear and Semi-Logarithmic) 
PK 
Figure 15.2.8 
Plot of Individual OZ439 and Cobicistat 
Plasma Concentrations versus Time 
(Linear and Semi-Logarithmic) 
PK 
15.3 
Safety Data 
15.3.1 Adverse Events 
Table 15.3.1.1   
Summary of TEAEs by System Organ 
Class and Preferred Term 
Safety 
Table 15.3.1.2 
Summary of Related TEAEs by System 
Organ Class and Preferred Term 
Safety 
Table 15.3.1.3 
Summary of TEAEs by Relationship and 
Severity 
Safety 
15.3.2 Lists of Deaths, Other Serious and Significant Adverse Events 
Table 15.3.2 
Listing of Deaths and Other Serious 
Adverse Events  
Safety 
15.3.3 Clinical Laboratory 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 24 of 26 
Table 15.3.3.1 
Listing of Abnormal Laboratory Values 
Safety 
Table 15.3.3.2 
Summary of Clinical Laboratory Data - 
Clinical Chemistry 
Safety 
Table 15.3.3.3 
Summary of Clinical Laboratory Data - 
Hematology 
Safety 
 
 
 
15.3.4 Other Safety Parameters 
Table 15.3.4.1 
Summary of Vital Signs 
Safety 
Table 15.3.4.2 
Summary of 12-Lead Electrocardiogram 
Safety 
Table 15.3.4.3 
Frequency Table of QTc Values 
Safety 
Table 15.3.4.4 
Frequency Table of QTc Change from 
Baseline Values 
Safety 
 
 
 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 25 of 26 
Appendix 6: List of End of Text Listings 
List of End-of-Text Listings: 
Output 
Title  
16.1.7 Randomization Scheme and Codes 
Appendix 16.1.7 
Randomization 
16.2.1 Discontinued Subjects 
Listing 16.2.1.1 
Subject Disposition 
16.2.2 Protocol Deviations 
Listing 16.2.2.1 
Protocol Deviations (reference to Clinical Study Report only) 
16.2.3 Subjects Excluded from the Analysis 
Listing 16.2.3.1 
Overview of Analysis Sets 
16.2.4 Demographics Data and Other Baseline Characteristics 
Listing 16.2.4.1 
Demographic Data 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Previous Medication 
Listing 16.2.4.4 
Alcohol and Drug Screen Results 
Listing 16.2.4.5 
Serology Results 
Listing 16.2.4.6 
Pregnancy Test and FSH (Females Only) 
16.2.5 Compliance and Drug Concentration Data 
Listing 16.2.5.1 
Study Dates 
Listing 16.2.5.2 
Study Drug Administration 
Listing 16.2.5.3 
PK Blood Sampling Time Deviations and Comments 
16.2.6 Adverse Events and Concomitant Medication 
Listing 16.2.6.1 
Adverse Events 
Listing 16.2.6.2 
Concomitant Medication 
16.2.7 Clinical Laboratory Data 
Listing 16.2.7.1 
Clinical Laboratory Results – Clinical Chemistry 
Listing 16.2.7.2 
Clinical Laboratory Results – Hematology 
Listing 16.2.7.3 
Clinical Laboratory Results – Urinalysis 
Listing 16.2.7.4 
Clinical Laboratory Results – Comments (depending on amount of data, 
comments may be listed together with the results) 
16.2.8 Other Safety Parameters 
Listing 16.2.8.1 
Vital Signs 
Listing 16.2.8.2 
12-Lead Electrocardiogram Results 
Listing 16.2.8.3 
Physical Examinations 


Statistical Analysis Plan 
MMV_OZ439_16_01/MMV508EC-165081 
Version Date: 14-Jun-2017  
EDSREP 009 T 01 F 
Page 26 of 26 
Document History 
Version Date 
Modified/Reviewed 
By 
Brief Summary of Changes (if created from a template, 
include template code) 
15-May-2017 
Gerk Rozema 
First Draft 
01-Jun-2017 
Gerk Rozema 
Sponsor comments incorporated 
14-Jun-2017 
Gerk Rozema 
Sponsor comments incorporated