An Open-label Study to Evaluate the Pharmacokinetics (PK) of Darunavir (DRV) and Cobicistat (COBI) After a Single-oral Administration of Darunavir/Cobicistat Fixed-Dose Combination Tablet in Healthy Japanese Adult Subjects
Phase: PHASE4
Conditions: Healthy
Sponsor: Janssen Pharmaceutical K.K.

1 
Status: Approved,  Date: 3 February 2017  
 
Janssen Pharmaceutical K.K.  
 
Clinical Protocol 
 
An open-label study to evaluate the pharmacokinetics (PK) of Darunavir (DRV) and 
Cobicistat (COBI) after a single-oral administration of Darunavir/Cobicistat Fixed-Dose 
Combination Tablet in Healthy Japanese Adult Subjects  
 
  
 
Protocol TMC114FD1HTX4002; Phase 4 
 
 
 TMC114 + JNJ-48763364-AAA Prezcobix® (Darunavir/Cobicistat)  
 
* This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used 
throughout the protocol to represent Janssen Pharmaceutical K.K.  
 
 
Status: 
Approved 
Date: 
3 February 2017 
Prepared by: Janssen Pharmaceutical K.K. 
EDMS number: 
EDMS-ERI-134676387, 1.0 
 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
2 
Approved, Date: 3 February 2017  
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF ATTACHMENTS ............................................................................................................................ 4 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 4 
SYNOPSIS .................................................................................................................................................... 5 
TIME AND EVENTS SCHEDULE ................................................................................................................ 8 
ABBREVIATIONS ...................................................................................................................................... 10 
1. 
INTRODUCTION ................................................................................................................................ 11 
1.1. 
Background .................................................................................................................................... 11 
1.2. 
Overall Rationale for the Study ...................................................................................................... 12 
2. 
OBJECTIVES AND HYPOTHESIS ................................................................................................... 12 
2.1. 
Objectives ...................................................................................................................................... 12 
2.1.1. 
Objectives ................................................................................................................................... 12 
2.2. 
Hypothesis ..................................................................................................................................... 13 
3. 
STUDY DESIGN AND RATIONALE ................................................................................................. 13 
3.1. 
Overview of Study Design .............................................................................................................. 13 
3.2. 
Study Design Rationale .................................................................................................................. 14 
4. 
SUBJECT POPULATION .................................................................................................................. 14 
4.1. 
Inclusion Criteria ............................................................................................................................ 15 
4.2. 
Exclusion Criteria ........................................................................................................................... 17 
4.3. 
Prohibitions and Restrictions ......................................................................................................... 20 
5. 
TREATMENT ALLOCATION AND BLINDING ................................................................................. 21 
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 21 
7. 
TREATMENT COMPLIANCE ............................................................................................................ 22 
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 22 
9. 
STUDY EVALUATIONS .................................................................................................................... 23 
9.1. 
Study Procedures ........................................................................................................................... 23 
9.1.1. 
Overview ..................................................................................................................................... 23 
9.1.2. 
Screening .................................................................................................................................... 24 
9.1.3. 
In-patient period .......................................................................................................................... 25 
9.1.4. 
End of Study ............................................................................................................................... 25 
9.2. 
Efficacy Evaluations ....................................................................................................................... 25 
9.3. 
Initial Subject Characteristics ......................................................................................................... 25 
9.4. 
Pharmacokinetics ........................................................................................................................... 26 
9.4.1. 
Evaluations ................................................................................................................................. 26 
9.4.2. 
Analytical Procedures ................................................................................................................. 26 
9.4.3. 
Pharmacokinetic Parameters ..................................................................................................... 26 
9.5. 
Safety Evaluations ......................................................................................................................... 27 
9.6. 
Sample Collection and Handling .................................................................................................... 30 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 30 
10.1. 
Completion ..................................................................................................................................... 30 
10.2. 
Withdrawal From the Study ............................................................................................................ 30 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
11. 
STATISTICAL METHODS ................................................................................................................. 31 
11.1. 
Subject Information ........................................................................................................................ 31 
11.2. 
Sample Size Determination ........................................................................................................... 31 
11.3. 
Pharmacokinetic Analyses ............................................................................................................. 32 
11.4. 
Safety Analyses ............................................................................................................................. 32 
12. 
ADVERSE EVENT REPORTING ...................................................................................................... 33 
12.1. 
Definitions ...................................................................................................................................... 33 
12.1.1. 
AE Definitions and Classifications .............................................................................................. 33 
12.1.2. 
Attribution Definitions .................................................................................................................. 34 
12.1.3. 
Severity Criteria .......................................................................................................................... 35 
12.2. 
Special Reporting Situations .......................................................................................................... 35 
12.3. 
Procedures ..................................................................................................................................... 36 
12.3.1. 
All Adverse Events ...................................................................................................................... 36 
12.3.2. 
Serious Adverse Events ............................................................................................................. 37 
12.3.3. 
Pregnancy ................................................................................................................................... 37 
12.4. 
Contacting Sponsor Regarding Safety ........................................................................................... 38 
13. 
PRODUCT QUALITY COMPLAINT HANDLING .............................................................................. 38 
13.1. 
Procedures ..................................................................................................................................... 38 
13.2. 
Contacting Sponsor Regarding Product Quality ............................................................................ 38 
14. 
STUDY DRUG INFORMATION ......................................................................................................... 39 
14.1. 
Physical Description of Study Drug(s) ........................................................................................... 39 
14.2. 
Packaging ...................................................................................................................................... 39 
14.3. 
Labeling .......................................................................................................................................... 39 
14.4. 
Preparation, Handling, and Storage ............................................................................................... 39 
14.5. 
Drug Accountability ........................................................................................................................ 39 
15. 
STUDY-SPECIFIC MATERIALS ....................................................................................................... 39 
16. 
ETHICAL ASPECTS ......................................................................................................................... 40 
16.1. 
Study-Specific Design Considerations ........................................................................................... 40 
16.2. 
Regulatory Ethics Compliance ....................................................................................................... 40 
16.2.1. 
Investigator Responsibilities ....................................................................................................... 40 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................... 40 
16.2.3. 
Informed Consent ....................................................................................................................... 42 
16.2.4. 
Privacy of Personal Data ............................................................................................................ 42 
17. 
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 43 
17.1. 
Protocol Amendments .................................................................................................................... 43 
17.2. 
Regulatory Documentation ............................................................................................................ 43 
17.2.1. 
Regulatory Approval/Notification ................................................................................................ 43 
17.2.2. 
Required Prestudy Documentation ............................................................................................. 44 
17.3. 
Subject Identification, Enrollment, and Screening Logs ................................................................ 44 
17.4. 
Source Documentation ................................................................................................................... 45 
17.5. 
Case Report Form Completion ...................................................................................................... 45 
17.6. 
Data Quality Assurance/Quality Control ........................................................................................ 46 
17.7. 
Record Retention ........................................................................................................................... 46 
17.8. 
Monitoring ...................................................................................................................................... 47 
17.9. 
Study Completion/Termination ....................................................................................................... 47 
17.9.1. 
Study Completion/End of Study .................................................................................................. 47 
17.9.2. 
Study Termination ....................................................................................................................... 47 
17.10. On-Site Audits ................................................................................................................................ 48 
17.11. Use of Information and Publication ................................................................................................ 48 
REFERENCES ............................................................................................................................................ 50 
INVESTIGATOR AGREEMENT ................................................................................................................. 74 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
4 
Approved, Date: 3 February 2017  
 
LIST OF ATTACHMENTS 
Attachment 1: 
Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events .......................................................................................................... 51 
Attachment 2: 
Cardiovascular Safety – Abnormalities ...................................................................... 73 
 
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES 
Table 1: 
PK parameter for DRV and COBI in previous study (TMC114IFD1003) .................................. 14 
Table 2: 
Description of Interventions ...................................................................................................... 22 
Table 3: 
Volume of Blood to be Collected from Each Subject ................................................................ 24 
 
FIGURES 
Figure 1: 
Schedule Overview of the Study ............................................................................................... 13 
 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
5 
Approved, Date: 3 February 2017  
SYNOPSIS 
An open-label study to evaluate the pharmacokinetics (PK) of Darunavir (DRV) and Cobicistat (COBI) 
after a single-oral administration of Darunavir/Cobicistat Fixed-Dose Combination Tablet in Healthy 
Japanese Adult Subjects 
DRV inhibits dimerization of human immunodeficiency virus Type 1 (HIV-1) protease and its enzymatic 
activity. DRV selectively inhibits cleavage of Gag-Pol polyprotein coded by HIV-1 in the infected cells 
and thereby suppresses the formation of matured infective viruses. DRV has been shown to have a high 
affinity to the HIV-1 protease with a Kd of 4.5×10−12mol/L and is less likely to be affected by mutations 
associated with resistance to HIV protease inhibitors. 
COBI selectively inhibits CYP3A. COBI is used as a pharmacokinetic enhancer (booster) for drugs which 
CYP3A-mediated metabolism could reduce bioavailability and shorten elimination half-life.  COBI is 
used in combination with such type drugs to increase the exposure of the drug. 
TMC114 + JNJ-48763364-AAA (Prezcobix®) is a combined formulation of two compounds, DRV and 
COBI, and is intended for treating patients naive to anti-HIV drug treatment and patients without DRV-
resistant mutants previously treated with an anti-HIV drug. Normally, one fixed-dose combination tablet 
is orally administered to adult patients once daily and must be used in combination with other types of 
anti-HIV drugs. 
This study will be conducted as a postmarketing study to evaluate the pharmacokinetics of DRV/COBI 
after a single oral administration of Prezcobix to healthy Japanese adult subjects. 
OBJECTIVES AND HYPOTHESIS 
Objectives 
Primary Objective 
The primary objective is to evaluate the PK of DRV and COBI after a single oral administration of 
Prezcobix to healthy Japanese adult subjects. 
Secondary Objective 
The secondary objective is to evaluate the safety after a single oral administration of Prezcobix to healthy 
Japanese adult subjects 
Hypothesis 
No formal statistical hypothesis testing is planned for this study. This study is designed to collect PK data 
in Japanese subjects after a single oral administration of Prezcobix under a fed condition.  
OVERVIEW OF STUDY DESIGN 
This is a single center open-label, single oral dose study in healthy Japanese adult subjects. The study 
consists of 3 phases; a screening phase from Day -21 to Day -2, an in-patient phase from Day -1 to Day 4 
(dosing day is Day 1), and a follow-up assessment phase scheduled 7 to 10 days after the intake of the 
study drug or at the time of early withdrawal. 
SUBJECT POPULATION 
Eight subjects will be enrolled to ensure that at least 6 subjects complete the study up to Day 4. If more 
than 2 subjects withdraw from the study before completion up to Day 4 for reasons other than safety, 
additional subjects will be enrolled to ensure that at least 6 subjects complete the study up to Day 4.  
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
Main Criteria for Inclusion 
Healthy Japanese men and women between 20 and 55 years of age, inclusive; body mass index (BMI) 
between 18.0 and 30.0 kg/m2, inclusive; and body weight not less than 50 kg. 
DOSAGE AND ADMINISTRATION 
One Prezcobix tablet will be taken in the morning on Day 1. The study drug will be taken orally with 
240 mL of noncarbonated water within 30 minutes after start of the standardized breakfast, and the 
breakfast should be fully ingested within 30 minutes. The study drug must be swallowed whole, not 
chewed, divided, dissolved or crushed.  
PHARMACOKINETIC EVALUATIONS 
Venous blood will be collected for the determination of plasma concentrations for each component of 
DRV/COBI at the following time points; 
 
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 20, 24, 36, 48, 60, 72 hours postdose and early 
withdrawal visit 
Based on the individual plasma concentration-time data, using the actual sampling times, the following 
PK parameters will be estimated by noncompartmental analysis. Additional PK parameters may be 
estimated as well. 
PK parameters for DRV and COBI: Cmax, Clast, tmax, AUClast, AUC∞, λz, t1/2,term 
SAFETY EVALUATIONS 
Safety will be evaluated throughout the study. Following evaluations will be performed according to the 
TIME AND EVENTS SCHEDULE. 
 
Adverse Events (AEs) 
 
Clinical Laboratory Tests 
 
- Hematology Panel 
 
- Biochemistry Panel 
 
- Urinalysis 
 
12-lead Electrocardiogram (ECG)  
 
Vital Signs (blood pressure, pulse, temperature [axillary], respiration rate) 
 
Physical Examination 
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigator until resolution or until reaching a clinically stable endpoint. 
STATISTICAL METHODS 
Sample Size Determination 
Eight subjects will be enrolled in the study to ensure that at least 6 subjects complete the study 
assessments up to Day 4. Based on a previous study, TMC114IFD1003, the maximum observed value of 
between subject coefficient of variation (CV) for Cmax, AUClast and AUC∞ for DRV and COBI after intake 
of DRV/COBI as an FDC tablet under fed conditions were 35% for DRV and 44% for COBI in healthy 
nonJapanese adult subjects. Using an estimate of approximately 40% for between subject CV and a 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
sample size of 6 subjects, the true mean Cmax, AUClast and AUC∞ for each component of DRV/COBI are 
estimated to be within 73% to 137% of the observed geometric means with 90% confidence. 
Pharmacokinetics 
All subjects receiving the study drug and having at least one plasma concentration data after 
administration will be included in the pharmacokinetic analysis. Plasma concentration data will be 
tabulated for each component of DRV/COBI. Individual and mean concentration time profiles for each 
analyte will be visually presented on a linear and logarithmic scale. PK parameters for each analyte will 
be calculated using data of all the subjects whose concentration-time profiles allow for accurate 
calculation of PK parameters. The descriptive statistics (eg, number of collected data, mean, standard 
deviation, median, minimum, maximum, CV and geometric means) of plasma concentrations of each 
analyte at each time point will be reported. Individual and descriptive statistics of PK parameters of each 
analyte will be tabulated.  
Safety 
All subjects who received the study drug will be included in the safety and tolerability analysis. Baseline 
for all laboratory evaluations, vital signs and ECG will be defined as the last evaluation done before the 
study drug administration. Safety will be evaluated by examining frequency, severity and type of AEs, 
and changes in clinical laboratory test values (hematology, biochemistry and urinalysis), physical 
examination results, vital signs and ECG measurements. Safety data will be summarized using descriptive 
statistics and frequency tables. 
 
 
 
 
 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
TIME AND EVENTS SCHEDULE  
Phase 
Screening 
In-patient period 
End-of-Study
Study day 
Days -21 to -
2 
Da 
y 
 -1 
Day 1 
Day 2 
Day 3 
Day 4
End of Study
(Day 7 – 10) 
or Early 
Withdrawal
Time 
 
 
Predose 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
2.5 h 
3 h 
4 h 
5 h 
6 h 
9 h 
12 h 
16 h 
20 h 
24 h 
36 h 
48 h 
60 h 
72 h 
 
Informed consent 
(ICF)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking habits 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug/Breath 
alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testa 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
Urine pregnancy test 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense/administer 
study drug 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
X 
X 
Vital signsa,b 
X 
X 
X 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
X
 
 
 
X 
X 
Serologya, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGa 
X 
X 
X 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
X
 
 
 
X 
X 
Clinical Labsd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
X 
X 
Blood sample for PK 
 
 
X 
 
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
X
X 
Xg 
Residence in clinic 
 
 
Concomitant 
medication 
throughout the study 
Adverse events 
throughout the study 
Footnotes: 
a. 
When blood samples are to be collected and 12-lead ECG and/or vital signs are to be checked at the same time point, blood samples will be collected after 
completion of other evaluations. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
b. 
Vital signs include respiration rate, supine blood pressure, pulse and temperature (axillary) after more than 5 minutes rest.  
c. 
Serology tests include HIV antigen/antibody, hepatitis A virus (HAV) antibody immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, and serologic test for syphilis. 
d. 
Clinical labs include hematology, biochemistry and urinalysis. Subjects will fast for at least 10 hours prior to the blood sampling for clinical labs. 
e. 
For postmenopausal women only. 
f. 
For women of childbearing potential only. 
g. 
For the early withdrawal visit only. 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
10 
Approved, Date: 3 February 2017  
ABBREVIATIONS 
 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
alanine aminotransferase 
ARV 
antiretroviral 
AUClast 
area under the plasma concentration-time curve from time zero to time the last quantifiable time, 
calculated by linear trapezoidal summation 
AUC∞ 
area under the plasma concentration-time curve from time zero to infinite time 
BMI 
body mass index 
Clast 
concentration at last quantifiable time point 
Cmax 
maximum plasma concentration 
COBI 
cobicistat 
CRF 
case report form 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DRV 
Darunavir 
ECG 
electrocardiogram 
eDC 
electronic data capture 
FDC 
Fixed-dose combination 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IRB 
Institutional Review Board 
PI 
protease inhibitor 
PK 
pharmacokinetic 
PQC 
Product Quality Complaint 
RBC 
red blood cell 
rtv 
ritonavir 
SAE 
Serious Adverse Event 
t1/2,term 
terminal elimination half-life 
tmax 
time to reach the maximum plasma concentration 
US 
United States 
WBC 
white blood cell 
λz 
elimination rate constant associated with the terminal phase 
 
 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
11 
Approved, Date: 3 February 2017  
1. 
INTRODUCTION 
Darunavir (DRV) / cobicistat (COBI) Fixed-Dose Combination Tablet (Prezcobix®) is a fixed 
dose combination (FDC) tablet containing DRV 800 mg and COBI 150 mg, which enables 
simplification of the regimen for human immunodeficiency virus (HIV) infection. 
For the most comprehensive nonclinical and clinical information regarding Prezcobix, refer to 
the latest version of the package insert and interview form for Prezcobix  
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page (s), which will be provided as a separate document. 
DRV is a protease inhibitor (PI) with potent in vitro activity demonstrated against native human 
immunodeficiency virus (HIV) and multi-resistant clinical isolates. COBI is an investigational 
pharmacokinetic enhancer of CYP3A substrates without intrinsic antiretroviral (ARV) activity. 
1.1. 
Background 
HIV infection and the Acquired Immune Deficiency Syndrome (AIDS) caused by its infection 
have serious impacts to human and socio-economics. In 2014, it was estimated that there are 36.9 
million HIV patients across the world. In 2014, there were 2.0 million patients with new HIV 
infection globally and 1.6 million deaths. As of 27 December 2015, 17,909 HIV-infected patients 
and 8,086 AIDS patients were reported in Japan. In 2015, Japan reported 1,006 new HIV 
infections and 428 new AIDS cases.2 Introduction of combination antiretroviral therapy (ART) 
has led to a dramatic reduction in mortality and morbidity in treated HIV-infected individuals. 
Further improvements in therapy and outcome have been challenged by limitations of the 
commercially available ARV agents, including safety and tolerability, dosing complexity, and 
the emergence of viral resistance resulting in reduced ARV activity. 
DRV 
DRV in combination with low dose ritonavir (rtv), as well as other ARV agents, is currently 
indicated for the treatment of HIV infection in adult patients.  
DRV is a HIV protease inhibitor with potent in vitro activity against wild-type HIV-1. As a 
result of the drug-screening program aimed at activity against resistant strains of HIV-1,  DRV is 
also active against a large panel of viruses resistant to currently licensed protease inhibitor (PI). 
DRV has been developed in combination with low-dose rtv which serves as a pharmacokinetic 
enhancer of DRV. 
COBI 
COBI is an investigational pharmacokinetic enhancer of CYP3A substrates without intrinsic 
ARV activity. COBI is a potential substitute for rtv and also has the advantage of being able to 
be coformulated with DRV resulting in a reduced pill burden and potentially fewer adverse 
effects. This could result in better adherence to the dosing regimen and therefore less risk in the 
development of resistance. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
DRV/COBI Fixed-Dose Combination Tablet (Prezcobix®) 
DRV/COBI FDC (Prezcobix®) tablet is a novel combination tablet containing fixed doses of 
DRV, a PI and COBI which acts as pharmacoenhancer has been developed in a collaboration 
research by Janssen Research & Development and Gilead Sciences Inc. One tablet of 
DRV/COBI combination tablet contains these compounds at the respective recommended dose 
(DRV 800 mg [ethanol additive as 800 mg of darunavir] and COBI 150 mg (150 mg as 
cobicistat): this combination tablet must be administered in combination with other ARV drugs. 
DRV/COBI FDC (Prezcobix®) has been approved in United States (US) and European Union 
(EU) countries. In Japan, the DRV/COBI FDC has been approved under the trade name of 
Prezcobix in November 2016. 
Clinical Studies 
Prezcobix demonstrated its efficacy and tolerability in phase 3 clinical study (Study GS-US-216-
0130) conducted outside Japan involving adult anti-HIV drugs-naïve patients with HIV 
infections or anti-HIV drug-treated patients with HIV infections without mutations associated 
with resistance to DRV. 
1.2. 
Overall Rationale for the Study 
This study is designed to evaluate the Pharmacokinetic (PK) of DRV/COBI after single oral 
administration of Prezcobix combination tablet to healthy Japanese adult subjects.  
In Japan, the applications for approval for anti-infective drugs for HIV which are approved in 
foreign country can be submitted without clinical data in Japanese subjects, and their quality, 
safety and efficacy will be evaluated based on foreign data (ref. “Handling of applications for 
import or manufacturing approval of anti-infective drugs for HIV” [PMSB / ELD Notification 
No.1015 dated November 12,1998]). In this case, it is allowed to conduct a study to evaluate PK 
profiles in Japanese subjects after marketing authorization. 
According to this notification, after approval of Prezcobix in US, Janssen Pharmaceutical K.K. 
submitted the new drug application of Prezcobix only with foreign data, and obtained aproval in 
Japan in November 2016 with the condition that a clinical single-dose PK study in healthy 
Japanese subjects will be conducted as a postmarketing study. 
2. 
OBJECTIVES AND HYPOTHESIS 
2.1. 
Objectives 
2.1.1. 
Objectives 
Primary Objective 
The primary objective is to evaluate the PK of DRV and COBI after a single oral administration 
of Prezcobix to healthy Japanese adult subjects. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
 Secondary Objective 
The secondary objective is to evaluate the safety after a single oral administration of Prezcobix 
to healthy Japanese adult subjects. 
2.2. 
Hypothesis 
No formal statistical hypothesis testing is planned for this study. This study is designed to collect 
PK data in Japanese subjects after a single oral administration of Prezcobix under a fed condition. 
3. 
STUDY DESIGN AND RATIONALE 
3.1. 
Overview of Study Design 
This is a single center open-label, single oral dose study in healthy Japanese adult subjects. Eight 
subjects will be enrolled to ensure that at least 6 subjects complete the study up to Day 4. The 
study consists of 3 phases; a screening phase from Day -21 to Day -2, an in-patient period-phase 
from Day -1 to Day 4 (dosing day is Day 1), and an End of Study phase with a visit scheduled 7 
to 10 days after the intake of study drug or at the time of early withdrawal. 
As depicted in Figure 1, eight subjects who satisfy all inclusion criteria and do not meet any 
exclusion criteria will receive Prezcobix at Day 1. Subjects who met the selection criteria at 
screening will be admitted to the investigational institute on the day before administration 
(Day -1). All enrolled subjects will receive a single oral dose of one Prezcobix tablet on Day 1 
(there is no Day 0) within 30 minutes after start of the standardized breakfast (see Figure 1), and 
the breakfast should be fully ingested within 30 minutes. All subjects will remain in the 
investigational institute for the entire duration of the in-patient phase. Subjects will be discharged 
on Day 4 after the completion of all required assessments. Subjects will visit the investigational 
institute on the days as scheduled until the last follow-up assessment on Day 7 - Day 10. Serial 
blood samples for the determination of plasma concentrations for each component of Prezcobix 
will be collected over a period of 72 hours. Details on the timing of the dose and the PK and 
safety assessments are given in the TIME AND EVENTS SCHEDULE. 
Figure 1: 
Schedule Overview of the Study 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
3.2. 
Study Design Rationale 
This open-label, single-arm, single-dose study design is a commonly used design for required 
postmarketing studies to evaluate PK of anti-HIV drugs in Japan. 
This study is designed to evaluate the pharmacokinetics (PK) of DRV and COBI after single 
dose administration of Prezcobix to healthy Japanese subjects, since there are currently no PK 
data after administration of Prezcobix to Japanese subjects. 
The dose regimen is a single oral dose of Prezcobix taken under a fed condition is selected since 
this dose is approved for once daily use in Japan and is how it is currently being used in clinical 
practice. 
The frequent blood samplings especially on Day 1 are set to accurately evaluate the PK profiles 
of each component with different absorption and elimination rates. A tmax and t1/2 for DRV and 
COBI in previous study (TMC114IFD1003 in healthy nonJapanese adult subjects) are 
summarized in Table 1. 
Table 1: 
PK parameter for DRV and COBI in previous study (TMC114IFD1003) 
PK parameter 
tmax : median (min-max), t1/2,term : mean (standard deviation) 
N=40 
DRV 
COBI 
tmax (h) 
4.03 (1.50 - 9.50) 
4.00 (1.00 - 5.02) 
t1/2,term (h) 
6.7 (3.4) 
3.8 (0.8) 
 
The blood sampling points in this study are decided as in TMC114IFD1003 study. 
Venous blood will be collected for the determination of plasma concentrations for each 
component of DRV/COBI at the following time points; 
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 20, 24, 36, 48, 60 and 72 hours postdose 
4. 
SUBJECT POPULATION 
Screening for eligible subjects will be performed within 21 days before administration of the 
study drug. 
Eight subjects will be enrolled to ensure that at least 6 subjects complete the study up to Day 4. If 
more than 2 subjects withdraw from the study before completion up to Day 4 for reasons other 
than safety, additional subjects will be enrolled to ensure that at least 6 subjects complete the 
study up to Day 4. 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study.   
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Clinical Protocol TMC114FD1HTX4002  
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4.1. 
Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study:  
1. 
Subject must be a Japanese man or woman 20 to 55 years of age, inclusive. 
2. 
Subject must be healthy on the basis of physical examination, medical history, vital 
signs, and 12-lead ECG performed at screening. This determination must be recorded in 
the subject's source documents and initialed by the investigator. 
3. 
Subject must be healthy on the basis of clinical laboratory tests performed at screening. 
If the results of the serum chemistry panel, hematology, or urinalysis are outside the 
normal reference ranges, the subject may be included only if the investigator judges the 
abnormalities or deviations from normal to be not clinically significant or to be 
appropriate and reasonable for the population under study with exception of those 
parameters listed explicitly in the exclusion criteria. This determination must be 
recorded in the subject's source documents and initialed by the investigator. 
4. 
Each subject must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of, and procedures required for, the study and are willing to 
participate in the study.  
5. 
A woman of childbearing potential must have a negative serum (-human chorionic 
gonadotropin [-hCG]) at screening and urine pregnancy test at the time of admission to 
the study site, hospitalization, and must not breast feed from screening onwards.  
6. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subject participating in clinical studies. 
Before study drug administration, a woman must be either: 
a. 
Not of childbearing potential defined as:  
o 
premenarchal 
 
A premenarchal state is one in which menarche has not yet occurred. 
o 
postmenopausal  
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL) in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy, however in the absence of 
12 months of amenorrhea, a single follicle stimulating hormone (FSH) 
measurement is insufficient. 
o 
permanently sterile 
 
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy. 
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Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
b. Of childbearing potential and 
practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly)  
Examples of highly effective contraceptives include 
- user-independent methods: 
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the subject.) 
- user-dependent methods: 
combined (estrogen- and progestogen-containing ) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, and transdermal; progestogen-only hormone 
contraception associated with inhibition of ovulation: oral and 
injectable 
 
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies. 
Hormonal contraception may be susceptible to interaction with the study 
drug, which may reduce the efficacy of the contraceptive method. 
 
If a woman is of childbearing potential, she must agree to remain on a highly effective 
method throughout the study and for at least 30 days after the last dose of study drug.  
7. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for a period of at least 30 days after intake of the 
study drug. 
8. 
In addition to the user independent highly effective method of contraception, a male or 
female condom with or without spermicide is required. Male condom and female 
condom should not be used together (due to risk of failure with friction).  
9. 
During the study and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 90 days) after receiving the dose of study drug, in addition to the highly 
effective method of contraception, a man. 
 
who is sexually active with a woman of childbearing potential must agree to use a 
barrier 
method 
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository). 
 
who is sexually active with a woman who is pregnant must use a condom must 
agree not to donate sperm. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
10. 
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol. 
11. 
Body mass index (BMI; weight [kg]/height2 [m2]) between 18 and 30 kg/m2 (inclusive), 
and body weight not less than 50 kg. 
12. 
Blood pressure (after the subject is supine for 5 minutes) between 90 and 140 mm Hg 
systolic, inclusive, and no higher than 90 mm Hg diastolic. 
13. 
Nonsmoker or subject who habitually smokes no more than 10 cigarettes or equivalent 
of e-cigarettes, or 2 cigars, or 2 pipes of tobacco per day for at least 6 months before 
study drug administration. 
14. 
Subjects must agree to comply with contraceptive measures as mentioned in Section 4.3 
(Prohibitions and Restrictions). 
4.2. 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:  
1. 
Subject has a history of or current clinically significant medical illness including (but 
not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, 
coagulation disorders (including any abnormal bleeding or blood dyscrasias), lipid 
abnormalities, significant pulmonary disease, including bronchospastic respiratory 
disease, diabetes mellitus, liver or renal insufficiency (estimated creatinine clearance 
below 80 mL/min); thyroid disease, neurologic or psychiatric disease, infection, 
significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, 
hematologic, rheumatologic, psychiatric, metabolic disturbances or any other illness that 
the investigator considers should exclude the subject or that could interfere with the 
interpretation of the study results.  
2. 
Subject has a history of malignancy before screening (exceptions are squamous and 
basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, that 
is considered cured with minimal risk of recurrence). 
3. 
Subject has a known allergies, hypersensitivity, or intolerance to Prezcobix or its 
excipients (refer to Package Insert or Interview Form for Prezcobix). 1, 3 
4. 
Subject has a history of or current clinically significant skin reactions (such as but not 
limited to Stevens-Johnson Syndrome [SJS], TEN, and/or erythema multiforme) or any 
history of allergies to drugs, such as, but not limited to, sulfonamides and penicillins. 
5. 
Clinically significant abnormal values for hematology, clinical chemistry, or urinalysis 
at screening as deemed appropriate by the investigator. 
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Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
6. 
Clinically significant abnormal physical examination and vital signs at screening or 
predose on Day 1, as deemed appropriate by the investigator. 
7. 
The following confirmed laboratory abnormalities at screening as defined by the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AEs 
and in accordance with the normal ranges of the clinical laboratory: 
a. 
serum creatinine grade 1 or greater (≥1.1 x upper limit of laboratory normal 
range [ULN]) or calculated creatinine clearance (CrCL) <80 mL/min; 
Creatinine clearance (Ccr) is calculated by the Cockcroft-Gault method. 
b. lipase and/or pancreatic amylase grade 1 or greater (≥1.1 x ULN); 
c. 
hemoglobin grade 1 or greater (≤10.9 g/dL); 
d. platelet count grade 1 or greater (≤124.999 x 109/L); 
e. 
white blood cell (WBC) count grade 1 or greater (≤2.5 x 109/L); 
f. 
absolute neutrophil count grade 1 or greater (≤1.3 x 109/L); 
g. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 
or greater (≥1.25 x ULN); 
h. total bilirubin grade 1 or greater (≥1.1 x ULN); 
i. 
any other laboratory abnormality of grade 2 or above. For proteinuria (spot 
urine) ≥2+, and microscopic hematuria (>10 red blood cell [RBC]/high power 
field), a urine retest should be performed in women after the menstrual period. 
Note: Retesting of abnormal lab values that could lead to exclusion is allowed once. 
Retesting must take place during an unscheduled visit in the screening phase. 
8. 
Subjects with a past history of heart arrhythmias (extrasystole, tachycardia at rest) or, 
history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history 
of long QT syndrome). 
Note: Retesting of abnormal QTcF interval (QTcF > 450msec) value that may lead to 
exclusion will be allowed once without prior approval from the Sponsor. Retesting will 
take place during an unscheduled visit in the screening phase. Subjects with a normal 
value at retest may be included. 
9. 
Subject has been contraindicated DRV and COBI per local prescribing information. 
10. 
Subject has taken any disallowed therapies as noted in Section 8, Prestudy and 
Concomitant Therapy before the planned first dose of study drug.  
11. 
Subject has received an investigational drug (including investigational vaccines) or used 
an invasive investigational medical device within 120 days or within a period less than 
10 times the drug’s half-life, whichever is longer, before the planned dose of study drug 
or is currently enrolled in an investigational study. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
12. 
Subject is a woman, who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study. 
13. 
Subject is a man who plans to father a child while enrolled in this study or within 3 
month after study drug intake. 
14. 
Subject has any condition for which, in the opinion of the investigator, participation 
would not be in the best interest of the subject (eg, compromise the well-being) or that 
could prevent, limit, or confound the protocol-specified assessments. 
15. 
Preplanned surgery or procedures that would interfere with the conduct of the study. 
16. 
Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as 
well as family members of the employees or the investigator . 
17. 
Subject has a history of hepatitis A antibody immunoglobulin M (IgM), hepatitis B 
surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically 
active liver disease, or tests positive for HBsAg or anti-HCV or serologic tests for 
syphilis at Screening. 
18. 
Subject has a history of human immunodeficiency virus (HIV) antibody positive, or 
tests positive for HIV at Screening. 
19. 
History of drug or alcohol abuse according to Diagnostic and Statistical Manual of 
Mental Disorders (4th edition or 5th edition) (DSM-IV or DSM-V) criteria  within 5 
years before Screening or positive test results for alcohol and/or drugs of abuse 
(including methadone, barbiturates, opiates, cocaine, cannabinoids, amphetamines and 
benzodiazepines) at Screening and Day -1. 
20. 
Subject has donated blood or plasma within 60 days preceding the intake of study drug. 
21. 
Subject has previously participated in more than 3 single-dose studies with COBI (GS-
9350) and/or DRV (TMC114). 
22. 
Subject has known allergies to heparin or history of heparin induced thrombocytopenia. 
23. 
Subjects with lack of good/reasonable venous access. 
24. 
Subject who is unable to swallow solid, oral dosage forms whole with the aid of water 
(participants may not chew, divide, dissolve, or crush the study drug). 
 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the dose of study drug is given such that he 
or she no longer meets all eligibility criteria, then the subject should be excluded from 
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Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
participation in the study. Section 9.1.2, Screening, describes options for retesting. Section 17.4, 
Source Documentation, describes the required documentation to support meeting the enrollment 
criteria. 
4.3. 
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation: 
1. 
Refer to Section 8, Prestudy and Concomitant Therapy for details regarding prohibited 
and restricted therapy during the study. 
2. 
Since the effects of DRV and/or COBI on conception and fetal development are 
unknown, subject must comply with the contraceptive requirements as indicated in the 
inclusion criteria. 
For details on the existing data with regard to the reproductive toxicity of DRV, see the 
current Package Insert or Interview Form. 
3. 
Strenuous exercise may affect study specified assessments and safety laboratory results; 
for this reason, strenuous exercise should be avoided within 48 hours before all planned 
study visits and during stays in the investigational institute. 
4. 
Avoid donating blood for at least 90 days after completion (ie, final follow-up visit) of 
the study. 
5. 
Subjects may not consume food or beverages containing alcohol, grapefruit juice, 
Seville oranges, or quinine (eg, tonic water) from 24 hours (72 hours in the case of 
grapefruit juice and Seville oranges) before pharmacokinetic sample collection, until 
after the last pharmacokinetic sample is collected. 
6. 
Subjects may not consume vegetables from the mustard green family (eg, kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard), and charbroiled meats 
from 7 days before the intake of study drug until the last pharmacokinetic sample has 
been taken. 
7. 
If a subject has had a recent febrile illness within 14 days of the scheduled start of study 
drug intake, the start of study drug intake should be postponed until the body 
temperature is normal for at least 72 hours. 
8. 
Subjects must refrain from the use of any methylxanthine-containing products, (eg, 
chocolate bars or beverages, coffee, teas, or colas) from 48 hours before administration 
of study drug and during confinement, and also must avoid excessive use of caffeine (ie, 
no more than approximately 500 mg/day, as contained in 5 cups of tea or coffee or 8 
cans of cola) for outpatient visits during the entire study (including the screening 
period). 
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Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
9. 
Subjects may not consume food containing poppy seeds during the study. 
10. 
Subjects must consume standard institutional meals during the in-patient period. 
11. 
Throughout the study, prescription or nonprescription medication (including any 
systemic herbal medications and dietary supplements) other than the study drug are 
prohibited, except for paracetamol (acetaminophen) or ibuprofen, birth control drugs, 
hormone replacement therapy, vitamins and the drug for treatment of AEs. See Section 8 
for additional information regarding allowed prescription or nonprescription medication.
12. 
Smoking subjects will not change their stable smoking habits for the duration of the 
study. 
13. 
Subjects must avoid extreme exposure to the sun or sunbathing, as well as the use of 
tanning devices (eg, sunbed, solarium) and topical tanning products from screening until 
the last study-related visit. 
14. 
Subjects must remain at the study site from at least 10 hours before study drug 
administration until 72 hours postdose blood sampling for PK and safety assessment on 
Day 4. 
5. 
TREATMENT ALLOCATION AND BLINDING 
As this is an open study, blinding procedures are not applicable. No randomization is planned in 
this study. All the subjects will be assigned to the same treatment. 
6. 
DOSAGE AND ADMINISTRATION 
One Prezcobix FDC Tablet, containing 800 mg DRV and 150 mg COBI, will be taken in the 
morning on Day 1. The study drug will be taken orally with 240 mL of noncarbonated water 
within 30 minutes after start of the standardized breakfast, and the breakfast should be fully 
ingested within 30 minutes. The study drug must be swallowed whole, not chewed, divided, 
dissolved or crushed. 
The actual date and time of the study drug administration will be recorded in the case report form 
(CRF). 
As a rule, subjects are to remain in an upright position from the time of the study drug 
administration until 4 hours after the study drug administration. 
The actual start and end time and date of the breakfast on Day 1 will be recorded in the CRF. 
The start time and date of lunch will also be recorded in the CRF. 
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TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
Standardized breakfast: 
Standardized breakfast (21 g fat, 533 kcal) will be served consisting of (or its equivalent) 4 slices 
of bread, 2 slices of ham and/or cheese, butter, jelly, and 2 cups (up to 480 mL) of decaffeinated 
coffee or tea with milk and/or sugar, if desired. 
Details of DOSAGE AND ADMINISTRATION were shown on the following Table 2. 
Table 2: 
Description of Interventions 
Treatment name 
TMC114 + JNJ-48763364-AAA 
Test articles(s) 
Prezcobix, DRV/COBI 
Description 
FILM-COATED TABLET 
Dose per delivery 
1 tablet (DRV 800 mg/COBI 150 mg) 
Frequency 
1 time on Day 1 
Total daily dose 
DRV 800 mg/ COBI 150 mg 
Delivery method 
oral administration during or immediately after a meal 
7. 
TREATMENT COMPLIANCE 
Study drug will be administered in the controlled environment of the investigational institute and 
the direct observation of the administration of the study drug by investigators or investigational 
staff will ensure compliance with study requirements. 
8. 
PRESTUDY AND CONCOMITANT THERAPY 
All medication including over-the-counter medication, must have been discontinued at least 14 
days before the intake of study drug (Day 1), except for paracetamol (acetaminophen) or 
ibuprofen, birth control drugs, hormone replacement therapy, and vitamins. Subjects must not 
use any medication other than the study drug up to 7 days after the intake of study drug, except 
for paracetamol (acetaminophen) or ibuprofen, birth control drugs, hormone replacement therapy, 
and vitamins. Subjects must also not use any systemic herbal medications or dietary supplements 
including products containing Hypericum perforatum (eg, St. John's Wort) from 28 days before 
the intake of study drug and up to 7 days after the intake of study drug. 
Paracetamol (acetaminophen) or ibuprofen may be used up to 3 days before the intake of study 
drug. After that, the clinical investigator may permit the use of paracetamol (acetoaminophen) or 
ibuprofen from 3 days before the intake of study drug until the day of study drug intake, at no 
more than 500 mg per dose and no more than 1,500 mg per day for paracetamol 
(acetaminophen), or at no more than 200 mg per dose and no more than 600 mg per day for 
ibuprofen. In case paracetamol (acetaminophen) or ibuprofen is used, the dose and dosage 
regimen as well as the indication for use must be recorded in the Concomitant Therapy section of 
the eCRF.  
Female subjects of childbearing potential must use birth-control methods as outlined above in 
Section 4 and must be willing to continue practicing these birth-control methods throughout the 
study and for at least 30 days after the intake of study drug. The use of hormonal contraceptives 
should be recorded in the Concomitant Therapy section of the eCRF. Applicable procedures and 
treatment guidance based on package inserts should be respected.  
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Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
Hormone replacement therapy is allowed in postmenopausal women. The use of hormone 
replacement therapy should be recorded in the Concomitant Therapy section of the eCRF. 
Applicable procedures and treatment guidance based on package inserts should be respected.  
All medications taken by a subject (prescription or nonprescription) that are not the study drug 
must be documented in the concomitant therapy section of the CRF. This includes medications 
taken during the period from the screening to the study drug administration. 
Other concomitant medication is allowed in the following cases:  
 
In case of cutaneous reaction/rash and/or an allergic reaction, the use of (levo) cetirizine, 
topical corticosteroids, topical vitamin A and D ointment, or antipruritic agents in the 
recommended dosing scheme is permitted.  
 
In case of nausea (grade 1 and 2), the use of antiemetics (domperidone and metoclopramide) 
will be permitted. 
 
In case of diarrhea (grade 1 and 2), the use of loperamide will be allowed. 
 
Drugs for treatment of AEs 
In case any of these medications or vitamins is used, the dose and dosage regimen must be 
recorded in the Concomitant Therapy section of the eCRF. 
If a subject requires use of a disallowed medication, a request for such use must be reviewed by 
the Sponsor and if approved, subjects may continue to participate in the study. 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
9. 
STUDY EVALUATIONS 
See TIME AND EVENTS SCHEDULE for details 
9.1. 
Study Procedures 
9.1.1. 
Overview 
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of PK, and safety 
measurements applicable to this study. 
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: Vital signs and ECG assessments must be done before 
blood collection. Actual dates and times of assessments will be recorded in the source 
documentation and CRF. 
The total blood volume for the study is approximately 147 mL. Details were shown on the 
following Table 3. 
 
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Clinical Protocol TMC114FD1HTX4002  
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Approved, Date: 3 February 2017  
Table 3: 
Volume of Blood to be Collected from Each Subject 
Type of Sample 
Volume per 
Sample ( mL) 
No. of Samples 
per Subject 
Approximate  
Total Volume of 
Blood ( mL)a 
Safety (including screening and posttreatment 
assessments) 
 
 
 
-Hematology 
8 mL 
5 
40 mL 
-Serum chemistry 
2 mL 
5 
10 mL 
Serology (HIV, hepatitis, syphilis) 
6 mL 
1 
6 mL 
Serum β-hCG pregnancy testsb 
2 mL 
2 
4 mL 
FSH testc 
2 mL 
1 
2 mL 
Pharmacokinetic samples 
3 mL 
19 
57 mL 
Loss by use of indwelling intravenous cannula 
2 mL 
14 
28 mL 
Approximate Totald 
 
 
147 mL 
a. Calculated as number of samples multiplied by amount of blood per sample. 
b. For women of childbearing potential only 
c. For postmenopausal women only 
d. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples. 
Note: An indwelling intravenous cannula may be used for blood sample collection.  
 
For each subject, the maximum amount of blood drawn from each subject in this study will not 
exceed 147 mL. 
The total blood volume to be collected from each subject will be approximately 147 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
If blood samples are collected via an indwelling cannula, an appropriate amount (ie, 2 mL) of 
fluid slightly greater than the dead space volume of the lock will be removed from the cannula 
and discarded before each blood sample is taken. After blood sample collection, the cannula will 
be flushed with 10 U/mL of sodium heparin and filled to the volume equal to the dead space 
volume of the lock. 
9.1.2. 
Screening 
At the screening visit, after the signing of the ICF, a physical examination will be conducted. 
Concomitant medication will be recorded. The subject’s characteristics (height, weight), 
smoking habits, and demographic data will be recorded. The overall eligibility of the subject to 
participate in the study will be assessed.  
At the screening visit, the results of the laboratory tests must be within the limits specified in 
exclusion criteria 7. Exceptional and limited retesting of abnormal screening values that lead to 
exclusion are allowed only once using an unscheduled visit during the screening period (to 
reassess eligibility). The investigator may consider the subject eligible if the previously abnormal 
laboratory test result is within normal range on a repeat testing in the laboratory. At the screening 
visit, serology tests are including HIV antigen/antibody, hepatitis A virus (HAV) antibody IgM, 
HBsAg, HCV antibody, and serologic test for syphilis, a breath alcohol test and a urine drug 
screening will be performed. A serum pregnancy test will be performed for women of 
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Clinical Protocol TMC114FD1HTX4002  
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childbearing potential only. A FSH test will be performed for postmenopausal women only. A 
blood sample for serology, hematology and biochemistry and a urine sample for urinalysis will 
be taken. Vital signs and a 12-read ECG will be recorded. 
9.1.3. 
In-patient period 
Day -1 
At Day -1, a physical examination will be conducted, a breath alcohol test, and a urine drug 
screening will be performed. A urine pregnancy test will be performed only for women of 
childbearing potential. A blood sample for hematology and biochemistry, and a urine sample for 
urinalysis will be taken. Vital signs and a 12-read ECG will be recorded.  
Day 1 
At Day 1, all subjects participating in the study will receive single-dose of one Prezcobix 
combination tablet, and a physical examination will be conducted predose. At the same time, 
vital signs and a 12-read ECG will be recorded. 
Day 1 - Day 4 
The frequency and timing of the PK and safety assessments during the in-patient period are 
detailed in the TIME AND EVENTS SCHEDULE. 
Day 2 and Day 4 
At Day 2 and Day 4, a physical examination will be conducted on 24h and 72h after 
administration. At the same time, a blood sample for hematology and biochemistry and a urine 
sample for urinalysis will be taken, and vital signs and a 12-read ECG will be recorded. 
Subjects will be discharged on Day 4 after the completion of all required assessments.  
9.1.4. 
End of Study 
At the end of study or early withdrawal, a physical examination will be conducted. A serum 
pregnancy test will be performed for women of childbearing potential only. A blood sample for 
hematology and biochemistry and a urine sample for urinalysis will be taken. Sample PK will be 
performed for early withdrawal visit only. Vital signs and a 12-read ECG will be recorded.  
9.2. 
Efficacy Evaluations  
This item is not applicable in this study. 
9.3. 
Initial Subject Characteristics 
Following information will be collected. 
 
Date of visit (dd/MMM/yyyy) 
 
Date of birth (dd/MMM/yyyy) 
 
Date of informed consent (dd/MMM/yyyy) 
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 
Race 
 
Sex 
 
Weight and height 
9.4. 
Pharmacokinetics 
Following information will be collected. 
9.4.1. 
Evaluations  
Venous blood samples of approximately 3 mL will be collected for measurement of plasma 
DRV/COBI concentrations at the time points indicated in the TIME AND EVENTS 
SCHEDULE. 
Venous blood samples will be collected and each plasma sample will be divided into 2 aliquots 
(1 for PK and 1 for back-up). Samples collected for analyses of plasma DRV/COBI 
concentration may additionally be used to evaluate safety aspects that address concerns arising 
during or after the study period. Genetic analyses will not be performed on these plasma samples. 
Subject confidentiality will be maintained. At visits where plasma DRV/COBI concentration will 
be evaluated, 1 blood draw of sufficient volume can be used. Refer to the separate PK lab 
manual for further information regarding handling and shipment of plasma samples. 
9.4.2. 
Analytical Procedures 
Pharmacokinetics 
Plasma samples will be analyzed to determine concentrations of DRV and COBI using a 
validated, specific, and sensitive LC-MS/MS method by or under the supervision of the sponsor.  
9.4.3. 
Pharmacokinetic Parameters  
Based on the individual plasma concentration-time data, using the actual sampling times, the 
following PK parameters will be derived from the bioanalytical results and will be estimated by 
noncompartmental analysis. Additional PK parameters may be estimated as well. 
 
Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 20, 24, 36, 48, 60, 72 hours postdose and 
early withdrawal visit 
PK parameters to be estimated from each plasma DRV/COBI concentration-time profiles include, 
but not limited to: 
 
Cmax - maximum plasma concentration 
 
Clast - concentration at last quantifiable time point 
 
tmax - time to reach the maximum plasma concentration 
 
AUClast - area under the plasma concentration-time curve from time zero to time the last 
quantifiable time, calculated by linear trapezoidal summation 
 
AUC∞ - area under the plasma concentration-time curve from time zero to infinite time 
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 
λz - elimination rate constant associated with the terminal phase 
 
t1/2,term - terminal elimination half-life 
9.5. 
Safety Evaluations 
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event (AE) section of the CRF. 
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.  
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TIME AND EVENTS SCHEDULE: 
AEs 
AEs will be reported by the subject for the duration of the study. AEs will be followed by the 
investigator as specified in Section 12, AE Reporting. 
Clinical Laboratory Tests  
Blood samples for serum chemistry and hematology and urine samples for urinalysis will be 
collected for evaluation of laboratory safety parameters. The investigator must review the 
laboratory results, document this review, and record any clinically relevant changes occurring 
during the study in the AE Section of the CRF. The laboratory reports must be filed with the 
source documents. 
The following tests will be performed by the investigational institute: 
 
Hematology Panel 
-hemoglobin 
-white blood cell (WBC) count with differential 
-hematocrit 
*neutrophils (fraction, %)  
-RBC count 
*lymphocytes (fraction, %) 
-RBC parameters: 
*monocytes (fraction, %) 
*mean corpuscular hemoglobin (MCH)
*eosinophils (fraction, %) 
*MCH concentration (MCHC) 
*basophils (fraction, %) 
*mean corpuscular volume (MCV) 
-platelet count 
*Note: A WBC evaluation may include any abnormal cells, which will then be reported by 
the laboratory. A RBC evaluation may include abnormalities in the RBC count, RBC 
parameters, or RBC morphology, which will then be reported by the laboratory. 
In addition, any other abnormal cells in a blood smear will also be reported. 
 
 
Serum Chemistry Panel 
-sodium 
-alkaline phosphatase (ALP) 
-potassium 
-creatinine phosphokinase (CPK) 
-chloride 
-lactic acid dehydrogenase (LDH) 
-blood urea nitrogen (BUN) 
-uric acid 
-creatinine  
-calcium (corrected for albumin) 
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-glucose  
-phosphate  
-aspartate aminotransferase (AST) 
-serum albumin  
-alanine aminotransferase (ALT) 
-total protein  
-gamma-glutamyltransferase (GGT) 
-total cholesterol  
-total bilirubin  
-high-density lipoprotein (HDL) cholesterol  
-direct bilirubin 
-low-density lipoprotein (LDL) cholesterol 
-indirect bilirubin 
-triglycerides 
-calculated CrCl* 
-magnesium 
*Creatinine clearance (Ccr) is calculated by the Cockcroft-Gault method. The calculated 
ClCr value is multiplied by 0.85 if female. 
Ccr = (140 - age) × body weight (kg) / (72 × creatinine ) × 0.85 (if female) 
 
 
Urinalysis 
Dipstick 
Sediment  
-glucose 
-RBC 
-protein 
-WBC 
-blood 
-squamous epithelial cells 
-pH 
 
-ketones 
Specific gravity 
 
 
At screening and at end of the study, a serum pregnancy test will be performed for women 
of childbearing potential only.  
 
On Day -1, urine Pregnancy Testing for women of childbearing potential only. 
 
At screening, a FSH test will be performed for postmenopausal women only. 
 
At screening, Serology (HIV antigen/antibody, hepatitis A antibody IgM, hepatitis B surface 
antigen, and hepatitis C virus antibody) and serologic test for syphilis. 
 
At screening and on Day -1, urine Drug Screen (methadone, barbiturates, amphetamines, 
benzodiazepines, cocaine, cannabinoids, and opioids). 
 
At screening and on Day -1, a Breath Alcohol Testing will be performed. 
Presence of changes 
If the value meets any of the following, it will be assessed as “change present”: 
 
The baseline value is within the normal range and the postdose value shows a deviation from 
the normal range. 
 
Both baseline and postdose values show deviations from the normal range and the change 
show a worsening trend. 
 
Both baseline and postdose values are within the normal range; however the change requires 
monitoring. 
Handling of laboratory data assessed as “change present” 
If laboratory value after study treatment is assessed as “change present”, the evaluation will be 
conducted in accordance with any one of the following criteria: 
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 
If the change is considered clinically insignificant because it is within physiologic changes 
or it is a change characteristic of the subject, the change will be judged as “physiologic 
change”. 
 
If the change is considered clinically significant, it will be judged as an abnormal change 
and recorded in the column of AEs in the CRF. 
 
If the reason of the abnormal clinical laboratory test value is obviously not related to the 
subject, the reason (eg, worsening of sample storage conditions or hemolysis) will be 
recorded. 
Electrocardiogram (ECG)  
ECGs will be recorded at the time points as scheduled in the TIME AND EVENTS SCHEDULE. 
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw. 
Clinically relevant abnormalities occurring during the study should be recorded in the AE section 
of the eCRF. 
Vital Signs (temperature, pulse/heart rate, respiratory rate, blood pressure) 
Blood pressure and pulse/heart rate measurements will be assessed in supine position with a 
completely automated device. Manual techniques will be used only if an automated device is not 
available. 
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of 
rest in a quiet setting without distractions (eg, television, cell phones). 
Presence of changes 
If the value meets any of the following, it will be assessed as “change present”: 
 
The baseline value is within the normal range and the postdose value shows a deviation from 
the normal range. 
 
Both baseline and postdose values show deviations from the normal range and the change 
show a worsening trend. 
 
Both baseline and postdose values are within the normal range; however the change requires 
monitoring. 
Handling of vital signs data assessed as “change present” 
If vital sign value after study treatment is assessed as “change present”, the evaluation will be 
conducted in accordance with any one of the following criteria: 
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 
If the change is considered clinically insignificant because it is within physiologic changes 
or it is a change characteristic of the subject, the change will be judged as “clinically 
insignificant physiologic change” and no abnormality will be recorded as AE. 
 
If the change is considered clinically significant, it will be judged as an abnormal change 
and recorded in the column of AEs in the CRF. 
Physical Examination  
Physical examinations will be conducted at times indicated in the TIME AND EVENTS 
SCHEDULE. 
Any clinically significant abnormalities persisting at the end of the study will be followed by the 
investigators until resolution or reaching a clinically stable endpoint. 
9.6. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (ie, 2 mL) of fluid slightly greater than the dead space volume of the lock will be 
removed from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula will be flushed with 10 U/mL of sodium heparin and filled to the volume 
equal to the dead space volume of the lock. 
Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency of all sample 
collections. 
Instructions for the collection, handling, storage, and shipment of samples are found in Method 
for Pharmacokinetics Sample Collection, Handling and Shipping (PK) that will be provided. 
Collection, handling, storage, and shipment of samples must be under the specified, and where 
applicable, controlled temperature conditions as indicated in Method for Pharmacokinetics 
Sample Collection, Handling and Shipping (PK). 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY 
10.1. 
Completion 
A subject will be considered to have completed the study if he or she has completed all the 
required assessments. 
10.2. 
Withdrawal From the Study  
A subject will be automatically withdrawn from the study for any of the following reasons: 
 
subjects who vomit within 6 hours after study drug administration 
 
Lost to follow-up 
 
Withdrawal of consent 
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 
Death 
 
Noncompliance defined as : 
 
subject is not in compliance with requirements of the study, including inclusion criteria, 
exclusion criteria, and prohibitions and restrictions 
If a subject withdraws from the study for any reason before the end of the study, end-of-
treatment assessments should be obtained.  
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. If a subject withdraws from the study before the 
end of the study, end-of-treatment assessments should be obtained. 
If more than 2 subjects withdraw before the completion of all the assessments scheduled on Day 
4 for reason other than safety, additional subjects will be enrolled to ensure at least 6 subjects 
complete all the assessments scheduled on Day 4. 
11. 
 STATISTICAL METHODS 
 No formal hypothesis testing will be conducted. Data will be summarized using descriptive 
statistics. Continuous variables will be summarized using the number of observations, mean, SD, 
coefficient of variation, median, and range as appropriate. Categorical values will be summarized 
using the number of observations and percentages as appropriate. 
11.1. 
Subject Information 
For all subjects who receive at least one dose of study drug descriptive statistics will be provided. 
All demographic (eg, age, height, weight, BMI) and other initial subject characteristics (eg, 
medical history, physical examination) will be tabulated and analyzed descriptively. 
11.2. 
Sample Size Determination 
Eight subjects will be enrolled in the study to ensure that at least 6 subjects complete the study 
assessments up to Day 4. Based on a previous study, TMC114IFD1003, the maximum observed 
value of between subject coefficient of variation (CV) for Cmax, AUClast and AUC∞ for DRV and 
COBI after intake of DRV/COBI as an FDC tablet under fed conditions were 35% for DRV and 
44 % for COBI in healthy nonJapanese adult subjects. Using an estimate of approximately 40% 
for between subject CV and a sample size of 6 subjects, the true mean Cmax, AUClast and AUC∞ 
for each component of DRV/COBI are estimated to be within 73% to 137% of the observed 
geometric means with 90% confidence. 
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11.3. 
Pharmacokinetic Analyses  
All subjects receiving the study drug and having at least one plasma concentration data after 
administration will be included in the pharmacokinetic analysis. Plasma concentration data will 
be tabulated for each component of DRV/COBI. Individual and mean plasma DRV/COBI 
concentration and concentration time profiles for each analyte will be visually presented on a 
linear and logarithmic scale. PK parameters for each analyte will be calculated using the data of 
all the subjects whose concentration-time profiles allow accurate calculation of PK parameters. 
The descriptive statistics (eg, number of collected data, mean, standard deviation, median, 
minimum, maximum, CV, geometric means and 90% confidence intervals) of plasma 
concentrations of each analyte at each time point will be reported. Individual and descriptive 
statistics of PK parameters of each analyte will be tabulated. 
PK parameters will be estimated using a noncompartmental analysis method with Phoenix 
WinNonlin® (Version 6.4).  
11.4. 
Safety Analyses 
All subjects who received the study drug will be included in the safety and tolerability analysis. 
Baseline for all laboratory evaluations and vital signs will be defined as the last evaluation done 
before the first study drug administration. Safety will be evaluated by examining frequency, 
severity and type of AEs, and changes in clinical laboratory test values, physical examination 
results, vital signs and ECG measurements. 
AEs 
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during the 
treatment phase (ie, treatment-emergent AEs, and AEs that have worsened since baseline) will be 
included in the analysis. For each AE, the percentage of subjects who experience at least 1 
occurrence of the given event will be summarized. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a 
serious adverse event (SAE). 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Normal ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and at each scheduled time point. Changes from baseline results will be presented in preversus 
posttreatment cross-tabulations (with classes for below, within, and above normal ranges). A 
listing of subjects with any laboratory results outside the reference ranges will be provided. A 
listing of subjects with any markedly abnormal laboratory results will also be provided. 
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Electrocardiogram (ECG) 
All clinically relevant abnormalities in ECG wave form that are changes from the baseline 
readings will be reported (eg, changes in T-wave morphology or the occurrence of U-waves). 
Vital Signs 
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic, supine position) values and changes from baseline will be summarized at 
each scheduled time point. 
The percentage of subjects with values beyond clinically important limits will be summarized. 
Physical Examination 
Physical examination findings and changes from baseline will be summarized at each scheduled 
time point. 
12. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
12.1. 
Definitions 
12.1.1. 
AE Definitions and Classifications 
AE 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Council 
for Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
AEs, for time of last AE recording). 
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SAE 
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also 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 subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious. 
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality). 
Unlisted (Unexpected) AE/Reference Safety Information 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For Prezcobix, the expectedness of an AE will be 
determined by whether or not it is listed in the Package Insert.  
AE Associated With the Use of the Drug 
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2, Attribution Definitions. 
12.1.2. 
Attribution Definitions 
Not Related 
An AE that is not related to the use of the drug. 
Doubtful 
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
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Possible 
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded. 
Probable 
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s). 
Very Likely 
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors: 
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate: Sufficient discomfort is present to cause interference with normal activity. 
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
 
Overdose of a sponsor study drug 
 
Suspected abuse/misuse of a sponsor study drug 
 
Inadvertent or accidental exposure to a sponsor study drug  
 
Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion) 
 
Exposure to a sponsor study drug from breastfeeding 
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the CRF. 
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12.3. 
Procedures 
12.3.1. 
All Adverse Events 
All AEs and special reporting situations, whether serious or nonserious, will be reported from the 
time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure, which may include contact for follow-up of safety. SAEs, including those 
spontaneously reported to the investigator within 30 days after the last dose of study drug, must 
be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol. 
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments. 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the CRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the CRF their opinion concerning the relationship of the 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSAR). For anticipated 
events reported as individual SAEs the sponsor will make a determination of relatedness in 
addition to and independent of the investigator’s assessment. The sponsor will periodically 
evaluate the accumulating data and, when there is sufficient evidence and the sponsor has 
determined there is a reasonable possibility that the drug caused a serious anticipated event, they 
will submit a safety report in narrative format to the investigators (and the head of the 
investigational institute where required). The investigator (or sponsor where required) must 
report SUSARs to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/IRB.  
The subject must be provided with a "wallet (study) card" and instructed to carry this card with 
them for the duration of the study indicating the following:  
 
Study number 
 
Statement, in the local language(s), that the subject is participating in a clinical study 
 
Investigator's name and 24-hour contact telephone number 
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
 
Name of the site 
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 
Site number 
 
Subject number 
12.3.2. 
Serious Adverse Events 
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax). 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following: 
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility) 
 
Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE. 
The cause of death of a subject in a study within 30 days of the dose of study drug, whether or 
not the event is expected or associated with the study drug, is considered an SAE. 
12.3.3. 
Pregnancy  
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
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the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered 
SAEs and must be reported using the Serious Adverse Event Form. Any subject who becomes 
pregnant during the study must be promptly withdrawn from the study. 
 Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported as noted above. Follow-up information regarding 
the outcome of the pregnancy and any postnatal sequelae in the infant will be required.  
12.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures. 
13.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. 
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor. 
13.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document. 
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14. 
STUDY DRUG INFORMATION 
14.1. 
Physical Description of Study Drug(s) 
The Prezcobix supplied for this study is a FDC tablet that contains 800 mg of DRV and 150 mg 
of COBI. It will be manufactured and provided under the responsibility of the sponsor. Refer to 
the Package Insert for a list of excipients.  
14.2. 
Packaging 
Study drug will be packaged in bulk bottle which contains 30 tablets. 
14.3. 
 Labeling 
Study drug labels will contain information which meets the applicable regulatory requirements. 
14.4. 
Preparation, Handling, and Storage  
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage. 
14.5. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject must be 
documented on the drug accountability form. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor. 
15. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
 
Package Insert for Prezcobix 
 
Interview Form for Prezcobix 
 
Pharmacy manual/study site investigational product and procedures manual 
 
Laboratory manual 
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 
eDC Manual 
 
Sample ICF 
 
Contact information page(s) 
16. 
ETHICAL ASPECTS 
16.1. 
Study-Specific Design Considerations 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled. 
The total blood volume to be collected (147 mL) is considered to be within the normal range 
allowed for healthy adults over the study time frame according to the Japanese blood donation rule. 
16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
GCPis an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations): 
 
Final protocol and, if applicable, amendments 
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
 
Package Insert for Prezcobix 
 
Sponsor-approved subject recruiting materials 
 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
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 
Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB) 
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects 
 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved. Approval for the collection of optional samples for research and for the corresponding 
ICF must be obtained from the IEC/IRB.  
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
 
Revision(s) to ICF and any other written materials to be provided to subjects 
 
If applicable, new or revised subject recruiting materials approved by the sponsor 
 
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug 
 
New information that may adversely affect the safety of the subjects or the conduct of the 
study 
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
 
Report of deaths of subjects under the investigator's care 
 
Notification if a new investigator is responsible for the study at the site 
 
Development Safety Update Report and Line Listings, where applicable 
 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).  
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct). 
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At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution). 
16.2.3. 
Informed Consent  
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive. Finally, they will be told that the investigator will 
maintain a subject identification register for the purposes of long-term follow up if needed and 
that their records may be accessed by health authorities and authorized sponsor personnel 
without violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF the subject is authorizing such access. It also denotes 
that the subject agrees to allow his or her study physician to recontact the subject for the purpose 
of obtaining consent for additional safety evaluations, if needed. 
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject. 
When prior consent of the subject is not possible, enrollment procedures should be described in 
the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights, 
safety, and well-being of the subject and to ensure compliance with applicable regulatory 
requirements. The subject must be informed about the study as soon as possible and give consent 
to continue. 
16.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
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put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries. 
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, 
or when the relevant competent authority has raised any grounds for nonacceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When 
the change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC 
where required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it. 
17.2. 
Regulatory Documentation 
17.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met. 
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17.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before shipment of study drug to the 
study site: 
 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee. 
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study. 
 
Regulatory authority approval or notification, if applicable 
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable 
 
Documentation of investigator qualifications (eg, curriculum vitae) 
 
Completed investigator financial disclosure form from the principal investigator, where 
required 
 
Signed and dated clinical trial agreement, which includes the financial agreement 
 
Any other documentation required by local regulations 
 
The following documents must be provided to the sponsor before enrollment of the first subject: 
 
Completed investigator financial disclosure forms from all subinvestigators 
 
Documentation of subinvestigator qualifications (eg, curriculum vitae) 
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable 
 
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable 
17.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
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reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject did not participate into the study, the date seen and 
date of birth will be used.  
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
17.4. 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety parameters as required by 
the protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.  
The author of an entry in the source documents should be identifiable. 
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document). 
The investigator and sponsor will discuss and agree on the source documentation before the 
receiving consent from the first subject. 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents. 
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the CRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the CRF. Data in this system 
may be considered source documentation. 
17.5. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All CRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the CRF are accurate 
and correct. 
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The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor. 
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit. 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways: 
 
Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool). 
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel. 
17.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory to the sponsor's database. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.  
Guidelines for CRF completion will be provided with study-site personnel before the start of the 
study.  
The sponsor will review CRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.  
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
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agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports. 
17.8. 
Monitoring 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel.  
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documents will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct. 
17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion/End of Study 
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement. 
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study site will be closed upon study completion. A 
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study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of subjects by the investigator  
17.10. On-Site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
17.11. Use of Information and Publication 
All information, including but not limited to information regarding Prezcobix or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, generated as a result of this study, are considered 
confidential and remain the sole property of the sponsor. The investigator agrees to maintain this 
information in confidence and use this information only to accomplish this study, and will not 
use it for other purposes without the sponsor's prior written consent. 
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of Prezcobix, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the sponsor 
with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study and direct transmission of 
clinical laboratory data from a local laboratory into the sponsor's database. Recruitment 
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performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Study subject identifiers will not be 
used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. Authorship of publications resulting from this study will be based on the guidelines 
on authorship, such as those described in the Uniform Requirements for Manuscripts Submitted 
to Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.  
 
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REFERENCES 
1. 
Interview Form for Prezcobix®, Edition 1, November 2016 
2. 
Journal of health and welfare statistics. 2016/2017; 63 (9), suppl 
3. 
Package Insert for Prezcobix®, Edition 1, November 2016 
 
 
 
 
 
 
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Attachment 1: Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(version 2.0, November 2014), or ‘DAIDS grading table’, is a descriptive terminology to be 
utilized for adverse event reporting in this study. A grading (severity) scale is provided for each 
adverse event term. 
General Instructions 
Estimating Severity Grade 
If the need arises to grade a clinical adverse event that is not identified in the DAIDS grading 
table, use the category ‘Estimating Severity Grade’ located at the top of the table on the 
following page. In addition, all deaths related to an adverse event are to be classified as grade 5. 
Grading Adult and Pediatric Adverse Events 
The DAIDS grading table includes parameters for grading both adult and pediatric adverse 
events. When a single set of parameters is not appropriate for grading specific types of adverse 
events for both adult and pediatric populations, separate sets of parameters for adult and/or 
pediatric populations (with specified respective age ranges) are provided. If there is no 
distinction in the table between adult and pediatric values for a type of adverse event, then the 
single set of parameters listed is to be used for grading the severity of both adult and pediatric 
events of that type. 
Determining Severity Grade 
If the severity of an adverse event could fall under either 1 of 2 grades (eg, the severity of an 
adverse event could be either grade 2 or grade 3), select the higher of the 2 grades for the adverse 
event. 
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory 
value. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
52 
Approved, Date: 3 February 2017  
Definitions 
Basic self-care functions 
Adults: activities such as bathing, dressing, toileting, 
transfer/movement, continence, and feeding 
 
Young children: activities that are age and culturally appropriate 
(eg, feeding self with culturally appropriate eating implements) 
Usual social & functional 
activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example:
 
Adults: adaptive tasks and desirable activities, such as going to 
work, shopping, cooking, use of transportation, or pursuing a hobby
 
Young Children: activities that are age and culturally appropriate 
(eg, social interactions, play activities, learning tasks) 
Intervention 
Medical, surgical, or other procedures recommended or provided by 
a healthcare professional for the treatment of an adverse event. 
 
 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Clinical adverse event 
NOT identified 
elsewhere in the 
grading table  
Mild symptoms 
causing no or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated  
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated  
Severe symptoms 
causing inability to 
perform usual social & 
functional activities 
with intervention or 
hospitalization 
indicated  
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-
care functions with 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability, or death  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
53 
Approved, Date: 3 February 2017  
MAJOR CLINICAL CONDITIONS 
CARDIOVASCULAR 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Arrhythmia (by ECG 
or physical 
examination)  
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated  
No symptoms AND 
Non-urgent 
intervention indicated  
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated  
Blood Pressure 
Abnormalities1  
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit)  
≥18 years of age  
 
 
140 to <160 mmHg 
systolic OR 90 to 
<100 mmHg diastolic  
 
 
≥160 to <180 mmHg 
systolic OR ≥100 to 
<110 mmHg diastolic  
 
 
≥180 mmHg systolic 
OR ≥110 mmHg 
diastolic  
 
 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (eg, 
malignant 
hypertension) OR 
Hospitalization 
indicated  
<18 years of age  
>120/80 mmHg  
≥95th to <99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic)  
≥99th percentile + 
5 mmHg adjusted for 
age, height, and gender 
(systolic and/or 
diastolic)  
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (eg, 
malignant 
hypertension) OR 
Hospitalization 
indicated  
Hypotension  
No symptoms  
Symptoms corrected 
with oral fluid 
replacement  
Symptoms AND IV 
fluids indicated  
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure  
Cardiac Ischemia or 
Infarction  
Report only one  
NA  
NA  
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent with 
ischemia  
Unstable angina OR 
Acute myocardial 
infarction  
Heart Failure  
No symptoms AND 
Laboratory or cardiac 
imaging abnormalities 
Symptoms with mild to 
moderate activity or 
exertion  
Symptoms at rest or 
with minimal activity 
or exertion (eg, 
hypoxemia) OR 
Intervention indicated 
(eg, oxygen)  
Life-threatening 
consequences OR 
Urgent intervention 
indicated (eg, 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant)  
Hemorrhage (with 
significant acute blood 
loss)  
NA  
Symptoms AND No 
transfusion indicated  
Symptoms AND 
Transfusion of ≤2 units 
packed RBCs indicated  
Life-threatening 
hypotension OR 
Transfusion of >2 units 
packed RBCs (for 
children, packed 
RBCs >10 cc/kg) 
indicated  
1 Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-
2107C.   
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
54 
Approved, Date: 3 February 2017  
 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Prolonged PR 
Interval or AV Block  
Report only one  
>16 years of age  
PR interval 0.21 to 
<0.25 seconds  
PR interval 
≥0.25 seconds OR 
Type I 2nd degree AV 
block  
Type II 2nd degree AV 
block OR Ventricular 
pause ≥3.0 seconds  
Complete AV block  
≤16 years of age  
1st degree AV block 
(PR interval > normal 
for age and rate)  
Type I 2nd degree AV 
block  
Type II 2nd degree AV 
block OR Ventricular 
pause ≥3.0 seconds  
Complete AV block  
Prolonged QTc 
Interval2  
0.45 to 0.47 seconds  
>0.47 to 0.50 seconds  
>0.50 seconds OR 
≥0.06 seconds above 
baseline  
Life-threatening 
consequences (eg, 
Torsade de pointes, 
other associated 
serious ventricular 
dysrhythmia)  
Thrombosis or 
Embolism  
Report only one  
NA  
Symptoms AND No 
intervention indicated  
Symptoms AND 
Intervention indicated  
Life-threatening 
embolic event (eg, 
pulmonary embolism, 
thrombus)  
2 As per Bazett’s formula.   
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
55 
Approved, Date: 3 February 2017  
DERMATOLOGIC 
PARAMETER  
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3  
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Alopecia (scalp only)  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities  
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
NA  
NA  
Bruising  
Localized to one area  
Localized to more than 
one area  
Generalized  
NA  
Cellulitis  
NA  
Non-parenteral 
treatment indicated 
(eg, oral antibiotics, 
antifungals, antivirals) 
IV treatment indicated 
(eg, IV antibiotics, 
antifungals, antivirals)  
Life-threatening 
consequences (eg, 
sepsis, tissue necrosis) 
Hyperpigmentation  
Slight or localized 
causing no or minimal 
interference with usual 
social & functional 
activities  
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities  
NA  
NA  
Hypopigmentation  
Slight or localized 
causing no or minimal 
interference with usual 
social & functional 
activities  
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities  
NA  
NA  
Petechiae  
Localized to one area  
Localized to more than 
one area  
Generalized  
NA  
Pruritus3 (without skin 
lesions)  
Itching causing no or 
minimal interference 
with usual social & 
functional activities  
Itching causing greater 
than minimal 
interference with usual 
social & functional 
activities  
Itching causing 
inability to perform 
usual social & 
functional activities  
NA  
Rash  
Specify type, if 
applicable  
 
For the rash 
management applicable 
in this study, see 
Section 9.3. 
Localized rash  
Diffuse rash OR Target 
lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site  
Extensive or 
generalized bullous 
lesions OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis  
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section.   
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
56 
Approved, Date: 3 February 2017  
ENDOCRINE AND METABOLIC 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus  
Controlled without 
medication  
Controlled with 
medication OR 
Modification of current 
medication regimen  
Uncontrolled despite 
treatment modification 
OR Hospitalization for 
immediate glucose 
control indicated  
Life-threatening 
consequences (eg, 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end 
organ failure)  
Gynecomastia  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities  
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with usual 
social & functional 
activities  
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social & 
functional activities  
NA  
Hyperthyroidism  
No symptoms AND 
Abnormal laboratory 
value  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (eg, 
thyroid storm)  
Hypothyroidism  
No symptoms AND 
Abnormal laboratory 
value  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (eg, 
myxedema coma)  
Lipoatrophy4  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities  
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
Disfiguring changes  
NA  
Lipohypertrophy5  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with usual 
social & functional 
activities  
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
Disfiguring changes  
NA  
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.  
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.   
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
57 
Approved, Date: 3 February 2017  
GASTROINTESTINAL 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Anorexia  
Loss of appetite 
without decreased oral 
intake  
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss  
Loss of appetite 
associated with 
significant weight loss  
Life-threatening 
consequences OR 
Aggressive 
intervention indicated 
(eg, tube feeding, total 
parenteral nutrition)  
Ascites  
No symptoms  
Symptoms AND 
Intervention indicated 
(eg, diuretics, 
therapeutic 
paracentesis)  
Symptoms recur or 
persist despite 
intervention  
Life-threatening 
consequences  
Bloating or 
Distension  
Report only one  
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA  
Cholecystitis  
NA  
Symptoms AND 
Medical intervention 
indicated  
Radiologic, 
endoscopic, or 
operative intervention 
indicated  
Life-threatening 
consequences (eg, 
sepsis, perforation)  
Constipation  
NA  
Persistent constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated  
Life-threatening 
consequences (eg, 
obstruction)  
Diarrhea  
≥1 year of age  
Transient or 
intermittent episodes of 
unformed stools OR 
Increase of ≤3 stools 
over baseline per 24-
hour period  
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to 6 stools over 
baseline per 24-hour 
period  
Increase of ≥7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated  
Life-threatening 
consequences (eg, 
hypotensive shock)  
<1 year of age  
Liquid stools (more 
unformed than usual) 
but usual number of 
stools  
Liquid stools with 
increased number of 
stools OR Mild 
dehydration  
Liquid stools with 
moderate dehydration  
Life-threatening 
consequences (eg, 
liquid stools resulting 
in severe dehydration, 
hypotensive shock)  
Dysphagia or 
Odynophagia  
Report only one and 
specify location  
Symptoms but able to 
eat usual diet  
Symptoms causing 
altered dietary intake 
with no intervention 
indicated  
Symptoms causing 
severely altered dietary 
intake with 
intervention indicated  
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding  
Not requiring 
intervention other than 
iron supplement  
Endoscopic 
intervention indicated 
Transfusion indicated  
Life-threatening 
consequences (eg, 
hypotensive shock)  
Mucositis or 
Stomatitis  
Report only one and 
specify location  
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding with 
minor trauma  
Life-threatening 
consequences (eg, 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous mucosal 
bleeding  
Nausea  
Transient (<24 hours) 
or intermittent AND 
No or minimal 
interference with oral 
intake  
Persistent nausea 
resulting in decreased 
oral intake for 24 to 
48 hours  
Persistent nausea 
resulting in minimal 
oral intake 
for >48 hours OR 
Rehydration indicated 
(eg, IV fluids)  
Life-threatening 
consequences (eg, 
hypotensive shock)  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
58 
Approved, Date: 3 February 2017  
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Pancreatitis  
NA  
Symptoms with 
hospitalization not 
indicated  
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (eg, 
circulatory failure, 
hemorrhage, sepsis)  
Perforation  
(colon or rectum)  
NA  
NA  
Intervention indicated  
Life-threatening 
consequences  
Proctitis  
Rectal discomfort with 
no intervention 
indicated  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated  
Life-threatening 
consequences (eg, 
perforation)  
Rectal Discharge  
Visible discharge  
Discharge requiring 
the use of pads  
NA  
NA  
Vomiting  
Transient or 
intermittent AND No 
or minimal interference 
with oral intake  
Frequent episodes with 
no or mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (eg, IV 
fluids)  
Life-threatening 
consequences (eg, 
hypotensive shock)  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
59 
Approved, Date: 3 February 2017  
MUSCULOSKELETAL 
PARAMETER  
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3  
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Arthralgia  
Joint pain causing no or 
minimal interference 
with usual social & 
functional activities  
Joint pain causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Joint pain causing 
inability to perform 
usual social & 
functional activities  
Disabling joint pain 
causing inability to 
perform basic self-care 
functions  
Arthritis  
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities  
Stiffness or joint 
swelling causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities  
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-care 
functions  
Myalgia (generalized)  
Muscle pain causing no 
or minimal interference 
with usual social & 
functional activities  
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Muscle pain causing 
inability to perform 
usual social & 
functional activities  
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions  
Osteonecrosis  
NA  
No symptoms but with 
radiographic findings 
AND No operative 
intervention indicated  
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated  
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions  
Osteopenia6  
≥30 years of age  
BMD t-score -2.5 to -1 
NA  
NA  
NA  
<30 years of age  
BMD z-score -2 to -1  
NA  
NA  
NA  
Osteoporosis6  
≥30 years of age  
NA  
BMD t-score <-2.5  
Pathologic fracture 
(eg, compression 
fracture causing loss of 
vertebral height)  
Pathologic fracture 
causing life-
threatening 
consequences  
<30 years of age  
NA  
BMD z-score <-2  
Pathologic fracture 
(eg, compression 
fracture causing loss of 
vertebral height)  
Pathologic fracture 
causing life-
threatening 
consequences  
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of osteoporosis 
at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of 
Sheffield, UK. 2007: Printed by the University of Sheffield.   
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
60 
Approved, Date: 3 February 2017  
NEUROLOGIC 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acute CNS Ischemia  
NA  
NA  
Transient ischemic 
attack  
Cerebral vascular 
accident (eg, stroke 
with neurological 
deficit)  
Altered Mental 
Status (for Dementia, 
see Cognitive, 
Behavioral, or 
Attentional 
Disturbance below)  
Changes causing no or 
minimal interference 
with usual social & 
functional activities  
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Confusion, memory 
impairment, lethargy, 
or somnolence causing 
inability to perform 
usual social & 
functional activities  
Delirium OR 
Obtundation OR Coma 
Ataxia  
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities OR No 
symptoms with ataxia 
detected on 
examination  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions  
Cognitive, 
Behavioral, or 
Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder)  
Specify type, if 
applicable  
Disability causing no 
or minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
not indicated  
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
on part-time basis 
indicated  
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated  
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated  
Developmental Delay 
<18 years of age  
Specify type, if 
applicable  
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either 
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Headache  
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR 
Headache with 
significant impairment 
of alertness or other 
neurologic function  
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy)  
Specify type, if 
applicable  
Minimal muscle 
weakness causing no 
or minimal 
interference with usual 
social & functional 
activities OR No 
symptoms with 
decreased strength on 
examination  
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities  
Muscle weakness 
causing inability to 
perform usual social & 
functional activities  
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation  
 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
61 
Approved, Date: 3 February 2017  
 
PARAMETER  
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3  
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy)  
Specify type, if 
applicable  
Minimal paresthesia 
causing no or minimal 
interference with usual 
social & functional 
activities OR No 
symptoms with 
sensory alteration on 
examination  
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities  
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions  
Seizures  
New Onset Seizure  
≥18 years of age  
 
NA  
 
NA  
 
1 to 3 seizures  
 
Prolonged and 
repetitive seizures (eg, 
status epilepticus) OR 
Difficult to control (eg, 
refractory epilepsy)  
<18 years of age  
(includes new or pre-
existing febrile 
seizures)  
Seizure lasting 
<5 minutes with 
<24 hours postictal 
state  
Seizure lasting 5 to 
<20 minutes with 
<24 hours postictal 
state  
Seizure lasting 
≥20 minutes 
OR >24 hours postictal 
state  
Prolonged and 
repetitive seizures (eg, 
status epilepticus) OR 
Difficult to control (eg, 
refractory epilepsy)  
Pre-existing Seizure  
NA  
Increased frequency 
from previous level of 
control without change 
in seizure character  
Change in seizure 
character either in 
duration or quality (eg, 
severity or focality)  
Prolonged and 
repetitive seizures (eg, 
status epilepticus) OR 
Difficult to control (eg, 
refractory epilepsy)  
Syncope  
Near syncope without 
loss of consciousness 
(eg, pre-syncope)  
Loss of consciousness 
with no intervention 
indicated  
Loss of consciousness 
AND Hospitalization 
or intervention 
required  
NA  
 
 
PREGNANCY, PUERPERIUM, AND PERINATAL 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Fetal Death or 
Stillbirth (report using 
mother’s participant 
ID)  
Report only one  
NA  
NA  
Fetal loss occurring at 
≥20 weeks gestation  
NA  
Preterm Delivery7 
(report using mother’s 
participant ID)  
Delivery at 34 to 
<37 weeks gestational 
age  
Delivery at 28 to 
<34 weeks gestational 
age  
Delivery at 24 to 
<28 weeks gestational 
age  
Delivery at <24 weeks 
gestational age  
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID)  
Report only one  
Chemical pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage  
Complicated 
spontaneous abortion 
or miscarriage  
NA  
7 Definition: A delivery of a live-born neonate occurring at ≥20 to <37 weeks gestational age.  
8 Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.   
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
62 
Approved, Date: 3 February 2017  
PSYCHIATRIC 
PARAMETER  
GRADE 1  
MILD 
GRADE 2 
MODERATE 
GRADE 3  
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Insomnia  
Mild difficulty falling 
asleep, staying asleep, 
or waking up early  
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early  
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early  
NA  
Psychiatric Disorders  
(includes anxiety,  
depression, mania, and  
psychosis)  
Specify disorder  
Symptoms with 
intervention not 
indicated OR Behavior 
causing no or minimal 
interference with usual 
social & functional 
activities  
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms with 
hospitalization 
indicated OR Behavior 
causing inability to 
perform usual social & 
functional activities  
Threatens harm to self 
or others OR Acute 
psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions  
Suicidal Ideation or 
Attempt  
Report only one  
Preoccupied with 
thoughts of death AND 
No wish to kill oneself 
Preoccupied with 
thoughts of death AND 
Wish to kill oneself 
with no specific plan 
or intent  
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated  
Suicide attempted  
 
 
RESPIRATORY 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acute Bronchospasm  
Forced expiratory 
volume in 1 second or 
peak flow reduced to 
≥70 to <80% OR 
Mild symptoms with 
intervention not 
indicated  
Forced expiratory 
volume in 1 second or 
peak flow 50 to <70% 
OR Symptoms with 
intervention indicated 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Forced expiratory 
volume in 1 second or 
peak flow 25 to <50% 
OR Symptoms 
causing inability to 
perform usual social 
& functional activities  
Forced expiratory 
volume in 1 second or 
peak flow <25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation  
Dyspnea or 
Respiratory Distress  
Report only one  
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age  
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities OR 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to <95%  
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry 
<90%  
Respiratory failure with 
ventilator support 
indicated (eg, CPAP, 
BPAP, intubation)  
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
63 
Approved, Date: 3 February 2017  
SENSORY 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Hearing Loss  
≥12 years of age  
NA  
Hearing aid or 
intervention not 
indicated  
Hearing aid or 
intervention indicated  
Profound bilateral 
hearing loss (>80 dB at 
2 kHz and above) OR 
Non-serviceable 
hearing (ie, >50 dB 
audiogram and <50% 
speech discrimination) 
<12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram)  
>20 dB hearing loss at 
≤4 kHz  
>20 dB hearing loss at 
>4 kHz  
>20 dB hearing loss at 
≥3 kHz in one ear with 
additional speech 
language related 
services indicated 
(where available) OR 
Hearing loss sufficient 
to indicate therapeutic 
intervention, including 
hearing aids  
Audiologic indication 
for cochlear implant 
and additional speech-
language related 
services indicated 
(where available)  
Tinnitus  
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities with 
intervention indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA  
Uveitis  
No symptoms AND 
Detectable on 
examination  
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention indicated  
Posterior or pan-
uveitis OR Operative 
intervention indicated  
Disabling visual loss in 
affected eye(s)  
Vertigo  
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities  
Vertigo causing greater 
than minimal 
interference with usual 
social & functional 
activities  
Vertigo causing 
inability to perform 
usual social & 
functional activities  
Disabling vertigo 
causing inability to 
perform basic self-care 
functions  
Visual Changes 
(assessed from 
baseline)  
Visual changes 
causing no or minimal 
interference with usual 
social & functional 
activities  
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Visual changes 
causing inability to 
perform usual social & 
functional activities  
Disabling visual loss in 
affected eye(s)  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
64 
Approved, Date: 3 February 2017  
SYSTEMIC 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acute Allergic 
Reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated  
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm  
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema  
Chills  
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA  
Cytokine Release 
Syndrome9  
Mild signs and 
symptoms AND 
Therapy (ie, antibody 
infusion) interruption 
not indicated  
Therapy (ie, antibody 
infusion) interruption 
indicated AND 
Responds promptly to 
symptomatic treatment 
OR Prophylactic 
medications indicated 
for ≤24 hours  
Prolonged severe signs 
and symptoms OR 
Recurrence of 
symptoms following 
initial improvement  
Life-threatening 
consequences (eg, 
requiring pressor or 
ventilator support)  
Fatigue or Malaise  
Report only one  
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Incapacitating 
symptoms of fatigue or 
malaise causing 
inability to perform 
basic self-care 
functions  
Fever (non-axillary 
temperatures only)  
38.0 to <38.6°C or 
100.4 to <101.5°F  
≥38.6 to <39.3°C or 
≥101.5 to <102.7°F  
≥39.3 to <40.0°C or 
≥102.7 to <104.0°F  
≥40.0°C or ≥104.0°F  
Pain10 (not associated 
with study agent 
injections and not 
specified elsewhere)  
Specify location  
Pain causing no or 
minimal interference 
with usual social & 
functional activities  
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities  
Pain causing inability 
to perform usual social 
& functional activities  
Disabling pain causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated  
Serum Sickness11  
Mild signs and 
symptoms  
Moderate signs and 
symptoms AND 
Intervention indicated 
(eg, antihistamines)  
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(eg, steroids or IV 
fluids)  
Life-threatening 
consequences (eg, 
requiring pressor or 
ventilator support)  
Underweight12  
>5 to 19 years of 
age  
NA  
WHO BMI z-score <-2 
to ≤-3  
WHO BMI z-score <-3  WHO BMI z-score <-3 
with life-threatening 
consequences  
2 to 5 years of age  
NA  
WHO Weight-for-
height z-score  
<-2 to ≤-3  
WHO Weight-for-
height z-score <-3  
WHO Weight-for-
height z-score <-3 with 
life-threatening 
consequences  
<2 years of age  
NA  
WHO Weight-for-
length z-score  
<-2 to ≤-3  
WHO Weight-for-
length z-score <-3  
WHO Weight-for-
length z-score <-3 with 
life-threatening 
consequences  
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.  
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.  
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea.   
12 WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤5 years of age. 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
65 
Approved, Date: 3 February 2017  
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Weight Loss 
(excludes postpartum 
weight loss)  
NA  
5 to <9% loss in body 
weight from baseline  
≥9 to <20% loss in 
body weight from 
baseline  
≥20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated 
(eg, tube feeding, total 
parenteral nutrition)  
 
 
URINARY 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract 
Obstruction  
NA  
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or renal 
dysfunction  
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction  
Obstruction causing 
life-threatening 
consequences  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
66 
Approved, Date: 3 February 2017  
SITE REACTIONS TO INJECTIONS AND INFUSIONS 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain or 
Tenderness  
Report only one  
Pain or tenderness 
causing no or minimal 
limitation of use of 
limb  
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social & 
functional activities  
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated  
Injection Site 
Erythema or 
Redness13  
Report only one  
>15 years of age  
2.5 to <5 cm in 
diameter OR 6.25 to 
<25 cm2 surface area 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities  
≥5 to <10 cm in 
diameter OR ≥25 to 
<100 cm2 surface area 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
≥10 cm in diameter OR 
≥100 cm2 surface area 
OR Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Potentially life-
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤15 years of age  
≤2.5 cm in diameter  
>2.5 cm in diameter 
with <50% surface area 
of the extremity 
segment involved (eg, 
upper arm or thigh)  
≥50% surface area of 
the extremity segment 
involved (eg, upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage  
Potentially life-
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
Injection Site 
Induration or 
Swelling  
Report only one  
>15 years of age  
Same as for Injection 
Site Erythema or 
Redness, >15 years 
of age  
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age  
≤15 years of age  
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, ≤15 years of 
age  
Injection Site Pruritus  Itching localized to 
the injection site that 
is relieved 
spontaneously or in 
<48 hours of 
treatment  
Itching beyond the 
injection site that is not 
generalized OR Itching 
localized to the 
injection site requiring 
≥48 hours treatment  
Generalized itching 
causing inability to 
perform usual social & 
functional activities  
NA  
13 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.   
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
67 
Approved, Date: 3 February 2017  
LABORATORY VALUES 
CHEMISTRIES 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Acidosis  
NA  
pH ≥7.3 to <LLN  
pH <7.3 without life-
threatening 
consequences  
pH <7.3 with life-
threatening 
consequences  
Albumin, Low (g/dL; 
g/L)  
3.0 to <LLN  
30 to <LLN  
≥2.0 to <3.0  
≥20 to <30  
<2.0  
<20  
NA  
Alkaline 
Phosphatase, High  
1.25 to <2.5 x ULN  
2.5 to <5.0 x ULN  
5.0 to <10.0 x ULN  
≥10.0 x ULN  
Alkalosis  
NA  
pH > ULN to ≤7.5  
pH >7.5 without life-
threatening 
consequences  
pH >7.5 with life-
threatening 
consequences  
ALT or SGPT, High  
Report only one  
1.25 to <2.5 x ULN  
2.5 to <5.0 x ULN  
5.0 to <10.0 x ULN  
≥10.0 x ULN  
Amylase (Pancreatic) 
or Amylase (Total), 
High  
Report only one  
1.1 to <1.5 x ULN  
1.5 to < 3.0 x ULN  
3.0 to <5.0 x ULN  
≥5.0 x ULN  
AST or SGOT, High  
Report only one  
1.25 to <2.5 x ULN  
2.5 to <5.0 x ULN  
5.0 to <10.0 x ULN  
≥10.0 x ULN  
Bicarbonate, Low 
(mEq/L; mmol/L)  
16.0 to <LLN  
16.0 to <LLN  
11.0 to <16.0 
11.0 to <16.0  
8.0 to <11.0  
8.0 to <11.0  
<8.0  
<8.0  
Bilirubin  
Direct Bilirubin14, 
High  
>28 days of age  
 
 
NA  
 
 
NA  
 
 
>ULN  
 
 
>ULN with life-
threatening 
consequences (eg, 
signs and symptoms of 
liver failure)  
≤28 days of age  
ULN to ≤1 mg/dL  
>1 to ≤1.5 mg/dL  
>1.5 to ≤2 mg/dL  
>2 mg/dL  
Total Bilirubin, 
High  
>28 days of age  
 
1.1 to <1.6 x ULN  
 
1.6 to <2.6 x ULN  
 
2.6 to < 5.0 x ULN  
 
≥5.0 x ULN  
≤28 days of age  
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates  
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates  
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates  
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates  
Calcium, High 
(mg/dL; mmol/L)  
≥7 days of age  
 
10.6 to <11.5  
2.65 to <2.88  
 
11.5 to <12.5  
2.88 to <3.13  
 
12.5 to <13.5  
3.13 to <3.38  
 
≥13.5  
≥3.38  
<7 days of age  
11.5 to <12.4  
2.88 to <3.10  
12.4 to <12.9  
3.10 to <3.23  
12.9 to <13.5  
3.23 to <3.38  
≥13.5  
≥3.38  
Calcium (Ionized), 
High (mg/dL; 
mmol/L)  
>ULN to <6.0  
>ULN to <1.5  
6.0 to <6.4  
1.5 to <1.6  
6.4 to <7.2  
1.6 to <1.8  
≥7.2  
≥1.8  
Calcium, Low 
(mg/dL; mmol/L)  
≥7 days of age  
7.8 to <8.4  
1.95 to <2.10  
7.0 to <7.8  
1.75 to <1.95  
6.1 to <7.0  
1.53 to <1.75  
<6.1  
<1.53  
<7 days of age  
6.5 to <7.5  
1.63 to <1.88  
6.0 to <6.5  
1.50 to <1.63  
5.50 to <6.0  
1.38 to <1.50  
<5.50  
<1.38  
Calcium (Ionized), 
Low (mg/dL; mmol/L)  
<LLN to 4.0  
<LLN to 1.0  
3.6 to <4.0  
0.9 to <1.0  
3.2 to <3.6  
0.8 to <0.9  
<3.2  
<0.8  
Cardiac Troponin I, 
High  
NA  
NA  
NA  
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory  
14 Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as grade 2, if <10% of the total bilirubin.   
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
68 
Approved, Date: 3 February 2017  
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Creatine Kinase, 
High  
3 to <6 x ULN  
6 to <10 x ULN  
10 to <20 x ULN  
≥20 x ULN  
Creatinine, High  
1.1 to 1.3 x ULN  
>1.3 to 1.8 x ULN OR 
Increase of >0.3 mg/dL 
above baseline  
>1.8 to <3.5 x ULN 
OR Increase of 1.5 to 
<2.0 x above baseline  
≥3.5 x ULN OR  
Increase of ≥2.0 x 
above baseline  
Creatinine 
Clearance15 or 
eGFR, Low  
Report only one  
NA  
<90 to 60 ml/min or 
ml/min/1.73 m2 OR 10 
to <30% decrease from 
baseline  
<60 to 30ml/min or 
ml/min/1.73 m2 OR 
≥30 to <50% decrease 
from baseline  
<30 ml/min or 
ml/min/1.73 m2 OR 
≥50% decrease from 
baseline or dialysis 
needed  
Glucose  
(mg/dL; mmol/L)  
Fasting, High  
110 to 125  
6.11 to <6.95  
>125 to 250  
6.95 to <13.89  
>250 to 500  
13.89 to <27.75  
>500  
≥27.75  
Nonfasting, High  
116 to 160  
6.44 to <8.89  
>160 to 250  
8.89 to <13.89  
>250 to 500  
13.89 to <27.75  
>500  
≥27.75  
Glucose, Low 
(mg/dL; mmol/L)  
≥1 month of age  
55 to 64  
3.05 to 3.55  
40 to <55  
2.22 to <3.05  
30 to <40  
1.67 to <2.22  
<30  
<1.67  
<1 month of age  
50 to 54  
2.78 to 3.00  
40 to < 50  
2.22 to <2.78  
30 to <40  
1.67 to <2.22  
< 30  
<1.67  
Lactate, High  
ULN to <2.0 x ULN 
without acidosis  
≥2.0 x ULN without 
acidosis  
Increased lactate with 
pH <7.3 without life-
threatening 
consequences  
Increased lactate with 
pH <7.3 with life-
threatening 
consequences  
Lipase, High  
1.1 to <1.5 x ULN  
1.5 to <3.0 x ULN  
3.0 to <5.0 x ULN  
≥5.0 x ULN  
Lipid Disorders  
(mg/dL; mmol/L)  
Cholesterol, 
Fasting, High  
≥18 years of age  
 
 
200 to <240  
5.18 to <6.19  
 
 
240 to <300  
6.19 to <7.77  
 
 
≥300  
≥7.77  
 
 
NA  
<18 years of age  
170 to <200  
4.40 to <5.15  
200 to <300  
5.15 to <7.77  
≥300  
≥7.77  
NA  
LDL, Fasting, High  
≥18 years of age  
130 to <160  
3.37 to <4.12  
160 to <190  
4.12 to <4.90  
≥190  
≥4.90  
NA  
>2 to <18 years of 
age  
110 to <130  
2.85 to <3.34  
130 to <190  
3.34 to <4.90  
≥190  
≥4.90  
NA  
Triglycerides, 
Fasting, High  
150 to 300  
1.71 to 3.42  
>300 to 500  
>3.42 to 5.7  
>500 to <1,000  
>5.7 to 11.4  
>1,000  
>11.4  
Magnesium16, Low 
(mEq/L; mmol/L)  
1.2 to <1.4  
0.60 to <0.70  
0.9 to <1.2  
0.45 to <0.60  
0.6 to <0.9  
0.30 to <0.45  
<0.6  
<0.30  
Phosphate, Low 
(mg/dL; mmol/L)  
>14 years of age  
2.0 to < LLN  
0.81 to < LLN  
1.4 to < 2.0  
0.65 to < 0.81  
1.0 to <1.4  
0.32 to <0.65  
<1.0  
<0.32  
1 to 14 years of age  
3.0 to <3.5  
0.97 to <1.13  
2.5 to <3.0  
0.81 to <0.97  
1.5 to <2.5  
0.48 to <0.81  
<1.5  
<0.48  
<1 year of age  
3.5 to <4.5  
1.13 to <1.45  
2.5 to <3.5  
0.81 to <1.13  
1.5 to <2.5  
0.48 to <0.81  
<1.5  
<0.48  
Potassium, High 
(mEq/L; mmol/L)  
5.6 to <6.0  
5.6 to <6.0  
6.0 to <6.5  
6.0 to <6.5  
6.5 to <7.0  
6.5 to <7.0  
≥7.0  
≥7.0  
Potassium, Low 
(mEq/L; mmol/L)  
3.0 to <3.4  
3.0 to <3.4  
2.5 to <3.0  
2.5 to <3.0  
2.0 to <2.5  
2.0 to <2.5  
<2.0  
<2.0  
15 Use the applicable formula (ie, Cockcroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).   
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.   
 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
69 
Approved, Date: 3 February 2017  
 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Sodium, High 
(mEq/L; mmol/L)  
146 to <150  
146 to <150  
150 to <154  
150 to <154  
154 to <160  
154 to <160  
≥160  
≥160  
Sodium, Low 
(mEq/L; mmol/L)  
130 to <135  
130 to <135  
125 to <130  
125 to <135  
121 to <125  
121 to <125  
≤120  
≤120  
Uric Acid, High 
(mg/dL; mmol/L)  
7.5 to <10.0  
0.45 to <0.59  
10.0 to <12.0  
0.59 to <0.71  
12.0 to <15.0  
0.71 to <0.89  
≥15.0 
≥0.89  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
70 
Approved, Date: 3 February 2017  
HEMATOLOGY 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L)  
>5 years of age 
(not HIV infected)  
 
 
300 to <400  
300 to <400  
 
 
200 to <300  
200 to <300  
 
 
100 to <200  
100 to <200  
 
 
<100  
<100  
Absolute Lymphocyte 
Count, Low  
(cell/mm3; cells/L)  
>5 years of age  
(not HIV infected)  
 
 
600 to <650  
0.600 x 109 to <0.650 
x 109  
 
 
500 to <600  
0.500 x 109 to <0.600 
x 109  
 
 
350 to <500  
0.350 x109 to <0.500 x 
109  
 
 
<350  
<0.350 x 109  
Absolute Neutrophil 
Count (ANC), Low  
(cells/mm3; cells/L)  
>7 days of age  
 
 
800 to 1,000  
0.800 x 109 to 1.000 x 
109  
 
 
600 to 799  
0.600 x 109 to 0.799 x 
109  
 
 
400 to 599  
0.400 x 109 to 0.599 x 
109  
 
 
<400  
<0.400 x 109  
2 to 7 days of age  
1,250 to 1,500  
1.250 x 109 to 1.500 x 
109  
1,000 to 1,249  
1.000 x 109 to 1.249 x 
109  
750 to 999  
0.750 x 109 to 0.999 x 
109  
<750  
<0.750 x 109  
≤1 day of age  
4,000 to 5,000  
4.000 x 109 to 5.000 x 
109  
3,000 to 3,999  
3.000 x 109 to 3.999 x 
109  
1,500 to 2,999  
1.500 x 109 to 2.999 x 
109  
<1,500  
<1.500 x 109  
Fibrinogen, 
Decreased (mg/dL; 
g/L)  
100 to <200  
1.00 to <2.00  
OR  
0.75 to <1.00 x LLN  
75 to <100  
0.75 to <1.00  
OR  
≥0.50 to <0.75 x LLN 
50 to <75  
0.50 to <0.75  
OR  
0.25 to <0.50 x LLN  
<50  
<0.50  
OR  
<0.25 x LLN  
OR Associated with 
gross bleeding  
Hemoglobin17, Low 
(g/dL; mmol/L)18  
≥13 years of age 
(male only)  
 
 
10.0 to 10.9  
6.19 to 6.76  
 
 
9.0 to <10.0  
5.57 to <6.19  
 
 
7.0 to <9.0  
4.34 to <5.57  
 
 
<7.0  
<4.34  
≥13 years of age 
(female only)  
9.5 to 10.4  
5.88 to 6.48  
8.5 to <9.5  
5.25 to <5.88  
6.5 to <8.5  
4.03 to <5.25  
<6.5  
<4.03  
57 days of age to 
<13 years of age 
(male and female)  
9.5 to 10.4  
5.88 to 6.48  
8.5 to <9.5  
5.25 to <5.88  
6.5 to <8.5  
4.03 to <5.25  
<6.5  
<4.03  
36 to 56 days of 
age (male and 
female)  
8.5 to 9.6  
5.26 to 5.99  
7.0 to <8.5  
4.32 to <5.26  
6.0 to <7.0  
3.72 to <4.32  
<6.0  
<3.72  
22 to 35 days of 
age (male and 
female)  
9.5 to 11.0  
5.88 to 6.86  
8.0 to <9.5  
4.94 to <5.88  
6.7 to <8.0  
4.15 to <4.94  
<6.7  
<4.15  
8 to ≤21 days of 
age (male and 
female)  
11.0 to 13.0  
6.81 to 8.10  
9.0 to <11.0  
5.57 to <6.81  
8.0 to <9.0  
4.96 to <5.57  
<8.0  
<4.96  
≤7 days of age 
(male and female)  
13.0 to 14.0  
8.05 to 8.72  
10.0 to <13.0  
6.19 to <8.05  
9.0 to <10.0  
5.59 to <6.19  
<9.0  
<5.59  
INR, High  
(not on anticoagulation 
therapy)  
1.1 to <1.5 x ULN  
1.5 to <2.0 x ULN  
2.0 to <3.0 x ULN  
≥3.0 x ULN  
Methemoglobin (% 
hemoglobin)  
5.0 to <10.0%  
10.0 to <15.0%  
15.0 to <20.0%  
≥20.0%  
17 Male and female sex are defined as sex at birth.  
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. For grading hemoglobin 
results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate 
conversion factor for the particular laboratory.   
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
71 
Approved, Date: 3 February 2017  
 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
PTT, High  
(not on anticoagulation 
therapy)  
1.1 to <1.66 x ULN  
1.66 to <2.33 x ULN  
2.33 to <3.00 x ULN  
≥3.00 x ULN  
Platelets, Decreased 
(cells/mm3; cells/L)  
100,000 to <124,999 
100.000 x 109 to 
<124.999 x 109  
50,000 to <100,000  
50.000 x 109 to 
<100.000 x 109  
25,000 to <50,000 
25.000 x 109 to 
<50.000 x 109  
<25,000  
<25.000 x 109  
PT, High  
(not on anticoagulation 
therapy  
1.1 to <1.25 x ULN  
1.25 to <1.50 x ULN  
1.50 to <3.00 x ULN  
≥3.00 x ULN  
WBC, Decreased  
(cells/mm3; cells/L)  
>7 days of age  
 
 
2,000 to 2,499  
2.000 x 109 to 2.499 x 
109  
 
 
1,500 to 1,999  
1.500 x 109 to 1.999 x 
109  
 
 
1,000 to 1,499  
1.000 x 109 to 1.499 x 
109  
 
 
<1,000  
<1.000 x 109  
≤7 days of age  
5,500 to 6,999  
5.500 x 109 to 6.999 x 
109  
4,000 to 5,499  
4.000 x 109 to 5.499 x 
109  
2,500 to 3,999  
2.500 x 109 to 3.999 x 
109  
<2,500  
<2.500 x 109  
 
 
URINALYSIS 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Glycosuria (random 
collection tested by 
dipstick)  
Trace to 1+ or  
≤250 mg  
2+ or ˃250 to ≤500 mg 
>2+ or >500 mg  
NA  
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin)  
6 to <10 RBCs per 
high power field  
≥10 RBCs per high 
power field  
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated  
Life-threatening 
consequences  
Proteinuria (random 
collection tested by 
dipstick)  
1+  
2+  
3+ or higher  
NA  
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
72 
Approved, Date: 3 February 2017  
APPENDIX A: TOTAL BILIRUBIN TABLE FOR TERM AND PRETERM NEONATES 
PARAMETER  
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Total Bilirubin19, 
High (mg/dL; 
μmol/L)20  
Term Neonate21  
<24 hours of age  
 
 
 
 
4 to <7  
68.4 to <119.7  
 
 
 
 
7 to <10  
119.7 to <171  
 
 
 
 
10 to <17  
171 to <290.7  
 
 
 
 
≥17  
≥290.7  
24 to <48 hours of 
age  
5 to <8  
85.5 to <136.8  
8 to <12  
136.8 to <205.2  
12 to <19  
205.2 to <324.9  
≥19  
≥324.9  
48 to <72 hours of 
age  
8.5 to <13  
145.35 to <222.3  
13 to <15  
222.3 to <256.5  
15 to <22  
256.5 to <376.2  
≥22  
≥376.2  
72 hours to 
<7 days of age  
11 to <16  
188.1 to <273.6  
16 to <18  
273.6 to <307.8  
18 to <24  
307.8 to <410.4  
≥24  
≥410.4  
7 to 28 days of age 
(breastfeeding)  
5 to <10  
85.5 to <171  
10 to <20  
171 to <342  
20 to <25  
342 to <427.5  
≥25  
≥427.5  
7 to 28 days of age 
(not breastfeeding)  
1.1 to <1.6 x ULN  
1.6 to <2.6 x ULN  
2.6 to <5.0 x ULN  
≥5.0 x ULN  
Preterm Neonate20  
35 to <37 weeks 
gestational age  
 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age).  
 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age).  
 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age).  
 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age).  
32 to <35 weeks 
gestational age 
and <7 days of age  
NA  
NA  
10 to <14  
171 to <239.4  
≥14  
≥239.4  
28 to <32 weeks 
gestational age 
and <7 days of age  
NA  
NA  
6 to <10  
102.6 to <171  
≥10  
≥171  
<28 weeks 
gestational age 
and <7 days of age  
NA  
NA  
5 to <8  
85.5 to <136.8  
≥8  
≥136.8  
7 to 28 days of age 
(breastfeeding)  
5 to <10  
85.5 to <171  
10 to <20  
171 to <342  
20 to <25  
342 to <427.5  
≥25  
≥427.5  
7 to 28 days of age 
(not breastfeeding)  
1.1 to <1.6 x ULN  
1.6 to <2.6 x ULN  
2.6 to <5.0 x ULN  
≥5.0 x ULN  
19 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of life 
followed by the benign phenomenon of breast milk jaundice after the first week of life. Severity grading in this appendix corresponds 
approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 4.  
20 A laboratory value of 1 mg/dL is equivalent to 17.1 μmol/L.  
21 Definitions: Term is defined as ≥37 weeks gestational age; near-term, as ≥35 weeks gestational age; preterm, as <35 weeks gestational age; and 
neonate, as 0 to 28 days of age.   
AV = atrioventricular; BPAP = bilevel positive airway pressure; CPAB = continuous positive airway pressure; INR = international standardized 
ratio; LLN = lower limit of normal; NA = not applicable; PT = prothrombin time; PTT = partial thromboplastin time; QTc = corrected QT; 
SGPT = serum glutamic pyruvic transaminase; WHO = World Health Organisation 
 
 
 
 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
73 
Approved, Date: 3 February 2017  
Attachment 2: Cardiovascular Safety – Abnormalities 
 
ECG 
All important abnormalities from the ECG readings will be listed. 
Abnormality Code 
ECG parameter 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
Abnormally low 
 45 bpm 
NAP 
 50 ms 
- 
Abnormally high 
 120 bpm 
 210 ms 
 120 ms 
- 
[450 ms, 480 ms] 
- 
- 
- 
450 ms< QTc  480 ms 
[480 ms, 500 ms] 
- 
- 
- 
480 ms< QTc  500 ms 
More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
[30; 60] ms 
- 
- 
- 
[30; 60] ms 
> 60 ms 
- 
- 
- 
> 60 ms 
For absolute QTc parameters the categories are defined based on the ICH E14 Guidance13F13F13F13F13Fa 
 
Vital Signsb 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs parameter 
Pulse 
DBP 
SBP 
Abnormalities on actual values 
Abnormally low 
 45 bpm 50 
bpm 
 50 mmHg 
 90 mmHg 
Grade 1 or mild 
- 
> 90 mmHg - < 100 mmHg 
> 140 mmHg - < 160 mmHg
Grade 2 or moderate 
- 
 100 mmHg - < 110 mmHg
 160 mmHg - < 180 mmHg
Grade 3 or severe 
- 
 110 mmHg 
 180 mmHg 
Abnormally high 
 120 bpm 
- 
- 
 
 
 
 
 
 
 
 
 
 
 
                                                 
 
a The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
CHMP/ICH/2/04, May 2005. 
b The classification of AEs related to hypotension and hypertension will be done according to the DAIDS grading scale (see also 
Attachment 1). 
 
NCT03123848

TMC114 + JNJ-48763364-AAA  Prezcobix® (Darunavir/Cobicistat)  
 
 
 
Clinical Protocol TMC114FD1HTX4002  
74 
Approved, Date: 3 February 2017  
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date:
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
 
Institution: 
Janssen Pharmaceutical K.K. 
Signature: 
electronic signature appended at the end of the protocol 
Date:
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
NCT03123848

 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Akihiro Koh
03Feb2017, 08:45:27 AM, UTC
Document Approval
NCT03123848