Bioequivalence of Crushed and Whole Genvoya Tablets (Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fumarate)
Phase: PHASE4
Conditions: Healthy Volunteers
Sponsor: Johns Hopkins University

 
 
Protocol:  Bioequivalence of Crushed and Whole Genvoya Tablets 
(Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fumarate) ________ 
NCT03717129 
Date: 1/17/2019 
 

 
1 
 
Protocol Title: 
 
Bioequivalence of Crushed and Whole Genvoya Tablets 
(Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fumarate) 
 
 
Co-Principal Investigators: Craig W. Hendrix, MD 
 
 
 
Study Site: 
 
 
Johns Hopkins University  
 
 
Study Sponsor: 
 
Gilead Sciences, Inc. 
 
 
Protocol Version: 
 
2.0 
 
 
Date:  
 
 
January 17, 2019 

 
2 
 
TABLE OF CONTENTS 
Page 
PROTOCOL TEAM ROSTER 
 
 
 
 
 
 
3 
SCHEMA  
 
 
 
 
 
 
 
 
 
4 
 
 
1 
INTRODUCTION  
 
 
 
 
 
 
 
5 
 
 
1.1 
Background 
 
 
 
 
 
 
 
5 
1.2 
Study Drugs: Clinical Pharmacology and Safety 
 
 
5 
2 
RATIONALE  
 
 
 
 
 
 
 
7 
3 
HYPOTHESIS AND STUDY OBJECTIVES  
 
 
 
7 
 
3.1 
Hypothesis  
 
 
 
 
 
 
 
7 
 
3.2 
Primary Objective  
 
 
 
 
 
 
8 
 
3.3 
Secondary Objective   
 
 
 
 
 
8 
4 
STUDY DESIGN 
 
  
 
 
 
 
 
8 
 
 
5 
STUDY DRUGS, ADMINISTRATION, AND DURATION 
 
9 
6 
STUDY POPULATION  
 
 
 
 
 
 
10 
7 
SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS 
10 
 
7.1 
Inclusion Criteria 
 
 
 
 
 
 
10 
 
7.2 
Exclusion Criteria 
 
 
 
 
 
 
10 
8  
CONCOMITANT AND PROHIBITED MEDICATIONS  
 
11 
9 
CLINICAL AND LABORATORY EVALUATIONS  
 
 
11 
 
9.1 
Study Schedule 
 
 
 
 
 
 
11 
 
9.2 
Definitions for Study Schedule 
 
 
 
 
11 
10 
TOXICITY MANAGEMENT  
 
 
 
 
 
15 
11 
CRITERIA FOR TREATMENT DISCONTINUATION  
 
 
15 
 
 
12 
CRITERIA FOR PREMATURE STUDY DISCONTINUATION  
16 
13 
STATISTICAL CONSIDERATIONS 
 
 
 
 
16 
 
14 
HUMAN SUBJECTS  
 
 
 
 
 
 
17 
 
14.1 
IRB and Informed Consent 
 
 
 
 
 
17 
 
14.2 
Subject Confidentiality 
 
 
 
 
 
18 
 
14.3 
Definition of Adverse Events  
 
 
 
 
18 
 
14.4 
Reporting of Adverse Events  
 
 
 
 
19 
 
14.5 
Steps to Minimize the Risks  
 
 
 
 
19 
 
14.6 
Potential Benefits of the Proposed Research  
 
 
19 
 
14.7 
Importance of the Knowledge to be Gained  
 
 
19 
 
14.8 
Inclusion of Women, Minorities, and Children 
 
 
19 
 
15 
REFERENCES  
 
 
 
 
 
 
 
20 
16  
APPENDIX 
 
 
 
 
 
 
 
 
21 
 

 
3 
 
 
 
PROTOCOL TEAM ROSTER 
 
Co-Principal Investigators 
 
Adriana Andrade, MD, M.P.H. FACP 
National Institute o Health (NIH) 
National Institute of Allergy and Infectious 
Diseases (NAID) 
5601 Fishers Lane, BG 5601FL, RM 9E42 
Rickville, MD 20852 
Phone: (301) 761-7362 
Email: adriana.andrade@nih.gov 
 
Craig Hendrix, MD  
Johns Hopkins University  
600 North Wolfe Street, Blalock 569  
Baltimore, MD 21287 
Phone: (410) 955-9707 
Fax: (410) 955-9708 
Email: chendrix@jhmi.edu 
 
Co-Investigators 
 
Edward Fuchs, PA-C 
The Johns Hopkins University 
School of Medicine 
Division of Clinical Pharmacology  
600 N Wolfe St, Blalock 569 
Phone:  (410) 614-8762   
Fax: (410)955-9708 
Email: ejfuchs@jhmi.edu 
 
Ethel Weld, MD  
Johns Hopkins University   
1830 East Monument Street,  
Baltimore, MD 21205 
Phone: (410) 502-2326 
Fax: (410) 955-9708 
Email: eweld@jhmi.edu  
 
 
 
 
 
 
 
 
 
Mark Marzinke, PhD 
Johns Hopkins University 
4940 Eastern Avenue; Mason F Lord 
Building Center Tower, Room 603 
Phone: 410-550-9702 
Email: mmarzin1@jhmi.edu 
 
 
Protocol Pharmacist 
 
Andrea Weiss, RPh 
Investigational Drug Service, Osler 100 
Johns Hopkins Hospital 
600 N. Wolfe St. 
Baltimore, MD  21287 
Phone: (410) 955-4505 
Fax: (410) 614-8074 
Email: aweiss@jhmi.edu 
 
Study Coordinators  
 
Jennifer Breakey, RN, MPH, CCRP 
Division of Clinical Pharmacology 
600 N. Wolfe Street, Blalock 569 
Baltimore, MD  21287 
Phone: (410) 955-5370 
Fax: (410)  955-9708 
email: jbreake1@jhmi.edu 
 
Danielle Signer 
Division of Clinical Pharmacology 
600 N. Wolfe Street, Blalock 569 
Baltimore, MD 21287 
Phone: (443) 287-7156 
Fax: (410) 955-9708 
email: dsigner1@jhmi.edu 
 
 
 
 
 
 

 
4 
 
SCHEMA 
 
 
Table 1: Pharmacokinetic Sampling Schedule 
 
 
 
Rationale 
Genvoya, a once-daily single fixed-dose combination tablet for treatment of HIV-infection, consists 
of two nucleoside reverse transcriptase inhibitors (NRTIs), emtricitabine (FTC) and tenofovir 
(TFV) alafenamide fumarate (TAF), the integrase strand transfer inhibitor (InSTI) elvitegravir 
(EVG), and the boosting agent cobicistat (COBI). It is unknown whether Genvoya, taken as a 
crushed/dissolved tablet, is bioequivalent to when taken as a whole tablet. This is crucial 
information since a substantial number of HIV-infected individuals suffer from pill aversion that 
could lead to non-adherence and treatment failure. 
Design 
Within-subject, fixed-order, two-period, open label study to determine the  bioequivalence of oral 
single dose of whole and crushed/dissolved tablets of Genvoya in healthy adult male and female 
research participants administered under direct observation.   
Population 
Up to 20 adult male and female healthy research participants will be enrolled to complete 12. 
Intervention Whole Tablet Period: Single observed oral dose of Genvoya whole tablet  
Crushed/dissolved Tablet Period: Single observed oral dose of Genvoya crushed/dissolved tablet  
Outcome 
Measures 
Primary:  To investigate the bioequivalence of oral single whole tablet and crushed/dissolved tablet 
of Genvoya by characterizing the plasma AUC0-∞ and Cmax of EVG, COBI, FTA, TAF, and TFV in 
plasma, after single doses of whole tablet and crushed/dissolved tablet in healthy male and female 
adult research participants. 
Secondary: To compare other pharmacokinetic parameters of oral single whole tablet and 
crushed/dissolved tablet of Genvoya by characterizing the plasma Tmax and terminal elimination 
half-life of EVG, COBI, FTA, TAF, and TFV after single doses of whole tablet and 
crushed/dissolved tablet in healthy male and female adult research participant. 
Procedures 
Screening: Potential research participants provide written informed consent and undergo evaluation 
of inclusion and exclusion criteria. 
Whole Tablet Period (3 days): Research participants will swallow, under direct observation, a 
single dose of a whole Genvoya tablet, followed by plasma sampling for 72 hours as indicated in 
Table 1 below.  
Safety Visit: Participants will return approximately 7 days after the whole-tablet dosing for clinical 
and laboratory safety assessment visit. 
Washout: A minimum of 14  will elapse between the two Genvoya doses. 
Crushed/dissolved Tablet Period (3 days): Research participants will swallow, under direct 
observation, a single dose of a crushed/dissolved Genvoya tablet, followed by plasma sampling 
for 72 hours, as indicated in Table 1 below. 
Final Safety Visit: Participants will return approximately 7 days after the crushed/dissolved-tablet 
dosing for a final clinical and laboratory safety assessment visit.  
* Adverse events will be monitored at all study visits and graded using the DAIDS Adverse Events 
Grading Table (Version 2.1, July 2017) as outlined in the protocol. 
Sampling 
Hour 
Pre-
dose 
0.25 
0.5 
0.75 
1.0 
1.5 
2 
3 
4 
5 
6 
10 
14 
24 
48 
72 
EVG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COBI 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
FTC 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
TAF 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
TFV 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 

 
5 
 
1     
INTRODUCTION 
1.1 
Background 
 
Genvoya, a fixed-dose combination of the two non-nucleosides reverse transcriptase inhibitors (NRTIs) 
emtricitabine (FTC) and tenofovir (TFV) alafenamide fumarate (TAF), with the integrase strand transfer 
inhibitor (InSTI) elvitegravir (EVG) and the EVG-boosting agent cobicistat (COBI), is FDA approved for 
the treatment of HIV-infected patients (1). 
 
Despite the availability of Genvoya, allowing for a single tablet fixed-dose combination and once-daily 
dosing, a substantial number of individuals living with HIV suffer from pill aversion, dysphagia, 
odynophagia, or problems swallowing their oral regimens - all of which can contribute to non-adherence 
(2). These observations are especially important because non-adherence to antiretroviral (ARV) 
medications is highly prevalent and associated with decreased survival (3). Non-adherence has been 
estimated at 55% in North American pooled cohorts, and is a vital public health concern, as it leads to 
treatment failure and transmission of drug-resistant virus (4-6). 
 
Many clinical scenarios make the administration of crushed/dissolved tablets desirable as a potential 
strategy to overcome pill aversion. However, there is a theoretical concern that the systemic absorption of 
the active ingredients of tablets may be altered by crushing the pills. In fact, pharmacokinetic and 
bioequivalence data are lacking for most ARV fixed-dose combinations used in the treatment of HIV-
infected patients. It is therefore of substantial practical and clinical interest to know whether ARV 
combinations such as Genvoya can be taken in crushed/dissolved form with bioequivalence to whole tablet 
form.  
 
A recent study reported the bioavailability results from crushing and splitting the single fixed-dose 
formulation tablet containing darunavir (DRV), cobicistat (COBI), emtricitabine (FTC), and TAF (7). This 
was an open-label, randomized, cross-over study in 30 HIV healthy research participants, using a single 
dose of this fixed dose formulation as whole tablet, crushed/dissolved tablet, and halved tablet. Plasma 
concentrations for each method of administration were comparable for DRV, FTC, and COBI. Although 
TAF was bioequivalent for the whole versus split tablet, the crushed/dissolved tablet resulted in 20% 
reduced TAF AUC. Therefore, further studies are needed to confirm these results. Also, it is crucial to 
conduct a bioequivalence study with the Genvoya tablet, since this fixed-dose formulation includes EVG, a 
different ARV class than DRV in the previous bioavailability study (7). 
 
The national treatment guidelines recommend that treatment-naive HIV-infected patients receive an initial 
combination regimen with InSTI-based therapy (8). Thus, InSTIs are a relevant class of ARV drugs for the 
treatment of HIV infection, and showing whether these medications can be taken in a crushed/dissolved 
tablet form can be a lifesaving intervention for individuals who cannot tolerate ingesting a whole tablet 
formulation.  
 
In this short pharmacokinetic study we will investigate whether an oral single-dose of whole tablets of 
Genvoya is bioequivalent to a crushed/dissolved form of this medication in healthy research participants.   
 
 
 
 

 
6 
 
 
 
1.2  
STUDY DRUGS: CLINICAL PHARMACOLOGY AND SAFETY 
 
Genvoya (EVG/COBI/FTC/TAF)  
 
Genvoya is a once-daily single fixed-dose combination tablet for treatment of HIV-infection. One tablet 
consists of two NRTIs, FTC 200 mg and TAF 10 mg, the InSTI EVG 150 mg, and the EVG-boosting agent 
COBI 150 mg (1). The FDA recommended dosage of Genvoya in patients ≥12 years old is one tablet daily 
taken with food (1). Genvoya should not be used in patients with a creatinine clearance (CrCl) <30 mL/min 
(1). EVG and COBI are highly bound to plasma proteins (1).  
 
 
Safety. The most common adverse effects with Genvoya are diarrhea, nausea, fatigue, and headaches (1). 
Most of these adverse events are self-limited and resolve spontaneously. COBI is known to inhibit 
creatinine secretion that leads to an increase in serum creatinine, and a corresponding reduction in GFR and 
creatinine clearance although actual GFR is not affected (1). In addition, more patients treated with 
Genvoya had LDL levels >190 mg/dL compared to Stribild, 5% and 2%, respectively (1).  
 
Cardiac electrophysiology studies showed that EVG and TAF did not prolong or affect the PR and QT/QTc 
intervals, respectively, while COBI prolonged the PR interval in one study (1). However, the dose of COBI 
in the Genvoya tablet is lower than doses evaluated in cardiac electrophysiology study. Therefore, it is 
unlikely that treatment with Genvoya will lead to clinically important prolongation of the PR interval (1). 
The effect of the combination regimen Genvoya or FTC on the QT interval is unknown. Genvoya has been 
giving to healthy research participants in a number of studies with minimal reported toxicity (1). It is also 
important to underscore that most of the side effects associated with Genvoya occur with chronic use of this 
ARV medication and, thus, less likely to occur with the short-term term dosing proposed in this 
bioavailability study.  
 
Genvoya is a category B drug for use during pregnancy (1). No adverse developmental effects were 
observed in animal studies when the components of Genvoya were administered separately during the 
period of organogenesis (1). TAF use in women during pregnancy has not been evaluated, while EVG, 
COBI, and FTC use during pregnancy has been evaluated in a limited number of women (1). Current data 
showed no birth defects reported for COBI or EVG and no difference in the overall risk of major birth 
defects for FTC compared with a U.S. reference population (1). It is unknown if COBI, EVG, and TAF are 
present in human breast milk; FTC has been shown to be present in human breast milk (1).  
 
Clinical Pharmacology. The PK parameters of individual components of Genvoya are listed in Table 2. 
All PK parameter data are taken from the GenvoyaTM package insert for EVF, COBI, FTC, and TAF. Data 
for TFV, which results from the conversion of TAF, is taken from the VemlidyTM package insert with 
adjustment of PK parameters for 10 mg dose of TAF in Genvoya vs. 25 mg in Vemlidy, assuming dose 
proportionality (Cmax, AUC0-∞, and Ctrough) and the Genvoya package insert (TFV half-life only which 
differs significantly from TFV half-life when administered as TDF).  
 
 
 
 
 

 
7 
 
 
 
Table 2.  Summary of Genvoya constituent drugs pharmacokinetic parameters after oral administration in 
HIV-infected adults. Mean (SD). 
 
Parameter 
Units 
EVG 
COBI 
FTC 
TAF 
TFV (from TAF) 
Dose 
mg 
150 
150 
200 
10 
NA 
Cmax 
mg/mL 
1.7 (0.4) 
1.1 (0.4) 
1.9 (0.5) 
0.16 (0.08) 
0.012 
AUC0-∞ 
mg/hr/mL 
23.0 (7.5) 
8.3 (3.8) 
12.7 (4.5) 
0.21 (0.15) 
0.16 
Ctrough 
mg/mL 
0.45 (0.26) 
0.05 (0.13) 
0.14 (0.25) 
NA 
0.04 
Half-life 
hours 
12.9 
3.5 
10 
0.51 
32 
 
 
COBI and EVG are metabolized by CYP3A4 enzyme; therefore, concomitant use of these two drugs with 
CYP3A4 inhibitors could substantially increase their plasma concentration (1). COBI is also metabolized 
by CYP2D6. CYP3A4 inducers on the other hand, lower COBI and EVG plasma concentrations which may 
lead to loss of therapeutic effect of Genvoya and development of treatment failure and viral resistance (1). 
COBI is also an inhibitor of CYP3A4 and CYP2D6 in addition to drug transporters such as breast cancer 
resistance protein (BCRP), p-glycoprotein (P-gp), and organic anion transporting peptide (OATP) 1B1 and 
1B3 (1). Therefore, co-administration of Genvoya with CYP3A4, CYP2D6, P-gp, BCRP, OATP1B1 or 
OATP1B3 substrates can significantly increase their plasma concentrations.  
 
EVG, a CYP2C9 inducer, can lower plasma concentrations of substrates metabolized through this pathway 
(1). TAF is a weak inhibitor of CYP3A in vitro but not an inhibitor or inducer of CYP3A in vivo;  TAF is 
also a substrate of P-gp, BCRP, OATP1B1 and OATP1B3 (1). Therefore, inhibitors of these drug 
transporters may increase the absorption of TAF. Conversely, drugs that induce the activity of these drug 
transporters could lead to a reduction TAF absorption and decrease TAF plasma concentrations (1). FTC is 
renally eliminated and does not undergo biotransformation through the cytochrome P450 pathway (1). 
Coadministration of Genvoya with drugs that can affect renal function can lead to a reduction of renal 
elimination of FTC and consequently an increase in FTC concentrations and potential adverse events. Other 
mechanism of drug interactions with the components of Genvoya besides drug transporters and hepatic 
drug metabolizing enzymes, include diminished absorption when EVG is coadministered with drugs 
containing polyvalent cations (e.g., Mg, Al, Fe, or Ca; 1).  
 
2 
RATIONALE  
 
Despite the availability of Genvoya, a single tablet once-daily fixed-dose formulation, a substantial number 
of individuals living with HIV infection still have difficulty swallowing whole tablets of ARV 
combinations. Therefore, crushed/dissolved tablet oral formulations are highly desirable as a potential 
strategy to overcome pill aversion. However, there is a theoretical concern that the systemic absorption of 
the active ingredients of the whole tablet formulation may be altered by crushing the tablets. We propose a 
study in healthy adult women and men research participants to determine whether Genvoya in 
crushed/dissolved form is bioequivalent with the whole tablet form.  
 
The FDA recommended dosage of Genvoya is one tablet daily for the treatment of HIV infection (1). Since 
participants in this bioequivalence study will be dosed with Genvoya for only one dose on two occasions, 
we will only enroll healthy HIV-uninfected individuals in order to prevent the development of potential 

 
8 
 
viral resistance that could occur with this short-term drug exposure. In addition, healthy research 
participants are less likely to be using other medications that could affect the metabolism, absorption or 
elimination of the components of Genvoya and consequently interfere with the proposed study endpoints.  
 
Genvoya was selected for this bioavailability study because this fixed combination InSTI-based therapy is 
included in the national treatment guidelines as a first line therapy for the treatment of HIV infection (8). 
Therefore, Genvoya is frequently prescribed for treatment-naïve patients initiating ART.  
 
3 
HYPOTHESIS and STUDY OBJECTIVE 
 
3.1 
Hypothesis  
 
3.1.2    Genvoya crushed/dissolved tablet will be bioequivalent to the whole tablet. 
 
3.2. 
Primary Objective  
 
3.2.1  To investigate the bioequivalence of oral single whole tablet and crushed/dissolved tablet of 
Genvoya in healthy research participants by characterizing the plasma AUC0-∞ and Cmax of 
EVG, COBI, FTC, TAV, and TFV after single doses of a whole  and crushed/dissolved 
tablet of this fixed-dose ARV combination in healthy adult research participants.  
 
3.3 
Secondary Objective 
 
3.3.1 To compare other pharmacokinetic parameters of oral single whole tablet and 
crushed/dissolved tablet of Genvoya in healthy adult research participants, Tmax, and 
terminal elimination half-life, in plasma of EVG, COBI, FTC, TAF, and TFV.  
 
4 
STUDY DESIGN 
 
The proposed bioequivalence study will have two pharmacokinetic observation periods:   
 
Whole Tablet Period: Research participants will be asked to swallow a single whole Genvoya 
tablet under direct observation. The first 72-hour pharmacokinetic sampling period for each of the 
ARV components of Genvoya will occur as outlined in Table 3. Participants will return for a safety 
visit for clinical and laboratory assessments seven days after whole tablet dosing. A minimum 14 
day washout period will take place between the whole tablet dosing and the crushed/dissolved tablet 
dosing. 
 
Crushed/Dissolved Tablet Period: Research participants will be asked to swallow a single 
crushed/dissolved Genvoya tablet under direct observation. The second and final Genvoya 
pharmacokinetic sampling will occur as outlined in Table 3.  
 
Pharmacokinetic Sampling. Plasma sampling for estimating pharmacokinetic parameters were 
selected to optimize information content of each sample for each drug (and TFV metabolite of TAF) 
for robust estimates of Tmax, Cmax, AUC0-∞, and terminal elimination half-life. These are based on 
prior observations of Tmax and half-life.   
 

 
9 
 
 
 
 
Table 3. Pharmacokinetic sampling schedule 
 
The proposed pharmacokinetic sampling visits will be conducted at the Drug Development Unit 
(DDU) in the Division of Clinical Pharmacology at the Johns Hopkins Hospital. The DDU staff has 
extensive experience conducting pharmacokinetic studies in healthy research participants. The DDU 
will provide study coordinators and other administrative research support, and recruit participants 
for this study.   
 
Plasma samples will be processed and analyzed at the Clinical Pharmacology Analytical Laboratory 
(CPAL) within the Division of Clinical Pharmacology. Genvoya tablets will be donated by Gilead 
and will be stored and dispensed by the Johns Hopkins Investigational Pharmacy. Approximately 
8ml of blood will be collected in each dosing period, on the time points outlined in Table 3. The 
plasma concentrations of EVG, COBI, FTC TFV, and TAF will be quantified using validated liquid 
chromatographic-tandem mass spectrometric (LC-MS/MS) methods (UPLC-MS/MS). Assay 
validation reports are peer-reviewed and approved by the DAIDS-sponsored Clinical Pharmacology 
Quality Assurance program.   
 
Safety Assessments. Safety will be assessed by monitoring physical examinations, vital signs, and 
laboratory and clinical adverse events. Safety laboratory tests will be performed at the two safety 
visits post dose with whole and crushed/dissolved Genvoya tablets. Laboratory tests will include 
hematology and chemistry. A negative HIV-1/2 Antigen/Antibody (Ag/Ab) screening test and 
negative hepatitis B surface antigen test in addition to chemistry, and hematology results as 
specified in the inclusion criteria section are required to meet study eligibility criteria.   
 
 
5 
STUDY DRUGS, ADMINISTRATION AND DURATION 
 
 
The protocol-specified ARV regimens are: 
 
• Whole Tablet Period: Single observed oral dose of Genvoya whole tablet (EVG 150mg/COBI 
150mg/FTC 200mg/TAF 10mg) under direct observation.  
 
• Crushed/Dissolved Tablet Period: Single observed oral dose of Genvoya crushed/dissolved 
tablet (EVG 150mg/COBI 150mg/FTC 200mg/TAF 10mg) under direct observation.  
 
Genvoya will be administered with a light meal. Crushed/dissolved Genvoya tablet solution will be 
Sampling 
Hour 
Pre-
dose 0.25 
0.5 
0.75 
1.0 
1.5 
2 
3 
4 
5 
6 
10 
14 
24 
48 
72 
EVG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COBI 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
FTC 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
TAF 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
TFV 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 

 
10 
 
prepared at the Johns Hopkins Investigational Pharmacy.   
 
Genvoya tablets will be donated by Gilead Sciences and will be dispensed by the Johns Hopkins 
Investigational Pharmacy. The Johns Hopkins Investigational Pharmacy will also maintain complete 
records of all study medications. All unused study medications must be returned to the Johns 
Hopkins Investigational Pharmacy after the study is completed or terminated. Unused or returned 
study medications will be destroyed.  
 
6 
STUDY POPULATION   
 
Up to twenty male and female health research participants will be enrolled in this study to assure 
twelve individuals complete the trial. All participants will meet inclusion/exclusion criteria as 
outlined in this protocol. Healthy research participants will be recruited by the Johns Hopkins DDU 
staff.  
 
7 
SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS 
 
7.1 
Inclusion Criteria  
 
7.1.1 Healthy adults ≥18 years of age.  
7.1.2 Negative HIV-1/2 Ag/Ab serology documented within 30 days prior to study entry.  
7.1.3 Negative Hepatitis B surface antigen within 30 days prior to study entry. 
7.1.4 Ability and willingness of subject to provide a signed informed consent and comply 
with study requirements.  
7.1.5 Negative POCT qualitative urine pregnancy test (female participants only).  
7.1.6 All subjects must not participate purposely in a conception process (e.g., active 
attempt to impregnate, sperm donation, or in vitro fertilization). If participating in 
sexual activity that could lead to pregnancy subjects must take every precaution to 
avoid risk of pregnancy by using a reliable contraception for the duration of the study 
therapy (e.g., condoms, hormonal, barrier).  
7.1.7 Laboratory values and physical examination as judged by the principal investigator to 
be safe to participate including normal renal function.  
7.1.8 Good peripheral venous access for proposed pharmacokinetic sampling.  
7.1.9 Willingness and ability to take oral medications.  
 
 
7.2 
Exclusion Criteria 
 
7.2.1 History of chronic or acute medical conditions that in the opinion of the investigator 
would jeopardize safety of subjects participating in this study.  
7.2.2 Known or suspected hypersensitivity to the components of Genvoya. 
7.2.3 Currently taking or having taken oral PrEP or PEP (e.g. Truvada®) within 30 days of 
study entry, or anticipated use of PrEP/PEP during study participation 
7.2.4 Use of prescription or over-the-counter medications, including agents containing 
polyvalent cations (e.g., Mg, Al, Fe, or Ca), or any other drugs that in the opinion of 
the investigator could interfere with the pharmacokinetics of any of the ARV 
components of Genvoya within 2 weeks prior to either study dose.  
7.2.5 Pregnant or breast feeding.  

 
11 
 
7.2.6 Active drug or alcohol use or dependence that, in the opinion of the investigator, 
would interfere with adherence to study requirements.  
7.2.7 Hospitalization or therapy for serious illness within 30 days prior to study entry as 
judged by the investigator.  
7.2.8 Participation in any investigational drug study within 30 days prior to study entry that 
in the opinion of the investigator would preclude study participation. 
7.2.9 Taking any medication listed in the package insert that is contraindicated with 
Genvoya. 
7.2.10 Any other condition or prior therapy that, in the opinion of the investigator, would 
preclude informed consent, make study participation unsafe, make the individual 
unsuitable for the study or unable to comply with the study requirements. Such 
conditions may include, but are not limited to, current or recent history of severe, 
progressive, or uncontrolled substance abuse, or renal, hepatic, hematological, 
gastrointestinal, endocrine, pulmonary, neurological, or cerebral disease. 
 
8 
CONCOMITANT AND PROHIBITED MEDICATIONS 
 
Use of any licensed drugs during the study is prohibited unless medically required for the safety of 
the subjects, and requires prior approval by the study investigators. If a concomitant medication is 
needed and approved by the study investigators, the package insert will be reviewed to ensure that 
the team has the most current information on drug interactions. Concomitant use of herbals, dietary 
supplements, nutritional supplements, or any other complementary and alternative medicine 
compounds containing polyvalent cations (e.g., Mg, Al, Fe, or Ca) is not allowed from the 14 days 
prior to,  and 3 days following each study dose. Investigational medications are also prohibited.   
 
9 
CLINICAL AND LABORATORY EVALUATIONS 
 
Study Schedule  
 
The study visits are described below as to their timing, procedures, and sample collections and 
summarized in Table 3 Schedule of Events.   
 
9.2 
Definitions for Study Schedule 
 
9.2.1 Screening (Visit 1) 
 
Screening will be scheduled at the Johns Hopkins DDU and must occur prior to the subject 
taking any study medication. At the beginning of the screening visit, subjects will be asked 
to read and sign the informed consent approved by the Johns Hopkins IRB, and will undergo 
screening laboratory and clinical evaluation. Eligibility of study participation will be 
determined by screening evaluations. Screening evaluations to determine eligibility must be 
completed within 30 days prior to study entry and administration of study drugs.  
 
The following assessment and procedures will be performed at screening visit:  
 
• Medical/Medications history  
• Physical examination (including vital signs, weight and height) 

 
12 
 
• HIV-1/2 Ag/Ab serology and Hepatitis B surface antigen testing 
• POCT qualitative urine pregnancy test (female participants only) 
• CBC with differential 
• Complete Metabolic Panel (sodium, potassium, chloride, carbon dioxide, glucose, urea 
nitrogen, creatinine, calcium, total protein albumin, total bilirubin, alkaline phosphatase, 
AST, ALT) 
• Serum Phosphorus  
• Estimated creatinine clearance (Cockcroft-Gault Formula) 
 
Medical history should include current or recent use of illicit drugs, alcohol, and tobacco; 
any prescription medications within the last 30 days; all diagnoses active within the 
preceding 30 days; past medical history; and current contraception method if participants are 
engaging in sexual activity.  
 
The medication history should consist of the following: all prescription, nonprescription 
medications, alternative therapies, vitamins and dietary supplements taken within 30 days of 
entry, including actual or estimated start and stop dates. Following entry, all prescription and 
nonprescription medications taken since the last clinic visit should be recorded. 
 
Weight will be measured and recorded on the source document at screening to calculate 
creatinine clearance at entry, at each dosing visit, and at the final safety visit. Height will be 
measured and recorded once at screening.  
 
Blood pressure, temperature, and pulse rate will be collected at all visits and recorded on the 
source documents.  
 
Complete physical examination is required at screening. The complete physical exam does 
not include genital, breast, and rectal examinations. 
  
9.2.2 Day 1 (Visits 2 and 7) Genvoya Dosing Under Direct Observation followed by 
pharmacokinetic sampling.  
 
 
Participants who satisfy the inclusion criteria will be asked to return to the DDU on Day 1.  
Individuals will be given a single oral dose of Genvoya whole tablet (Whole Tablet Period) 
or a crushed/dissolved Genvoya tablet mixed in water (crushed/dissolved Tablet Period) 
under direct observation. They will undergo pharmacokinetic sampling at the DDU for the 
components of Genvoya as outlined in Table 2 (Pharmacokinetic sampling schedule) and 
Table 3 (Schedule of Events). Approximately 8 mL will be collected at all pharmacokinetic 
time points. Serum creatinine will be collected once, pre-dose, for estimated creatinine 
clearance.  Female participants will have a POCT qualitative urine pregnancy test prior to 
dosing and negative test results are required for participants to continue with dosing/the 
study visit.  Any positive POCT qualitative urine pregnancy test results will be confirmed 
with a serum quantitative pregnancy test. 
 
At entry, all signs, symptoms, and diagnoses within 30 days prior to entry will be recorded, 
including actual and estimated dates of onset and resolution. After entry, all new diagnoses, 

 
13 
 
signs and symptoms will be recorded at the visit they are reported and should include status, 
date of onsent, date of discovery and date of resolution, if applicable. 
 
For the WholeTablet Period, subjects will be given a single oral dose of a whole Genvoya 
tablet under direct observation. Participants will be asked to return to the DDU 
approximately 7 days after receiving the whole tablet dose, in order to complete the first 
study safety evaluation. Participants will be required to undergo a minimum 14-day washout 
period following receipt of the Genvoya whole tablet.  
 
For the Crushed/Dissolved Tablet Period, subjects will be given a single oral dose of a 
crushed/dissolved Genvoya tablet under direct observation. The solution of 
crushed/dissolved Genvoya tabled mixed in water will be prepared at the Johns Hopkins 
Investigational Drug Pharmacy. Participants will be asked to return to the DDU 
approximately 7 days after receiving the crushed/dissolved tablet dose, in order to complete 
the final study safety evaluation.  

 
14 
 
Table 3. Schedule of Events 
1Screening within 30 days of entry 
2Serum creatinine only 
3Creatinine Clearance estimated by Cockcroft-Gault formula 
4A targeted physical exam will only be completed if clinically indicated
Evaluations 
1Screening 
Whole Tablet Period2 
Safety  
Visit 
Crushed/Dissolved Tablet Period2 
Safety 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Day -30 
Day 1 
Day 2 
Day 3 
Day 4 
Day 8 
Day 1 
Day 2 
Day 3 
Day 4 
Day 8 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, Temp) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
HIV-1/2 Ag/Ab 
X 
 
 
 
 
 
 
 
 
 
 
HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
CBC w/ Diff 
X 
 
 
 
 
 
 
 
 
 
X 
Complete Metabolic Panel 
X 
X2 
 
 
 
X 
X2 
 
 
 
X 
Serum Phosphorus 
X 
 
 
 
 
X 
 
 
 
 
X 
POCT Qualitative Urine HCG 
(female participants only) 
X 
X 
 
 
 
 
X 
 
 
 
 
3Estimated Creatinine Clearance 
X 
X 
 
 
 
 
X 
 
 
 
X 
Medical /Medication History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical Exam4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Observed whole dose Genvoya 
 
X 
 
 
 
 
 
 
 
 
 
Observed crushed/dissolved 
dose Genvoya 
 
 
 
 
 
 
X 
 
 
 
 
Plasma Pharmacokinetics5 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 

 
15 
 
 
5Pharmacokinetic sampling time points pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 10, 14, 24, 48, and 72 hours after each dose.  There is a 
+/- 5 min window for 0.25hr to 1.5hr PK  specimen collection and a +/- 15 min window for 2hr to 14hr PK specimen collection.  Windows for 
24, 48 and 72 hr PK specimen collection outlined in section 9.2.3-9.2.5. 
 
9.2.3 Day 2 (Visits 3 and 8) – 24 hour PK sampling 
 
 
Participants will return to the clinic for a 24 + 1 hour pharmacokinetic blood sample. They 
will be asked about any new or continuing adverse events and concomitant medications. A 
targeted physical examination will be performed if any adverse event is reported. 
 
9.2.4 Day 3 (Visits 4 and 9) – 48 hour PK sampling 
 
Participants will return to the clinic for a 48 + 2 hours pharmacokinetic blood sample. They 
will be asked about any new or continuing adverse events and concomitant medications. A 
targeted physical examination will be performed if any adverse event is reported. 
 
9.2.5 Day 4 (Visits 5 and 10) – 72 hour PK sampling 
 
Participants will return to the clinic for a 72 + 4 hours pharmacokinetic blood sample. They 
will be asked about any new or continuing adverse events and concomitant medications. A 
targeted physical examination will be performed if any adverse event is reported. 
 
9.2.6 Day 8 (Visits 6 and 11) - Safety Visit   
 
Subjects will return to the DDU 7 days + 3 days following the direct observed dose of 
Genvoya for a safety study visit. Subjects will undergo clinical and laboratory evaluations as 
outlined in the schedule of events. A targeted physical examination is to be driven by any 
signs or symptoms previously identified that the subject has experienced since the last visit, 
or newly occurring that the subject has experienced since the previous visit. A targeted 
physical examination is not necessary if the subject does not have new symptoms. In the 
absence of new symptoms, a target physical examination may still be require to document 
resolution of previous findings on physical examination.  
 
Study subjects will be reminded that they must not participate in a conception process. 
Participants will also be advised regarding HIV prevention during the study. 
 
Adverse events will be monitored throughout the study according to the DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events. Participants experiencing grade 
≥3 toxicity that is deemed by the investigator as associated with Genvoya will be 
discontinued from the study. These subjects will be followed until resolution, return to 
baseline values, stabilization, or an adequate explanation can be given for their condition. 
They will complete the last safety evaluation visit outlined in the schedule of events. 
Patients experiencing grades 1 or 2 toxicity will continue in the study at the discretion of the 
investigator.  
 

 
16 
 
At visit 6, participants will be scheduled to return to the DDU to start the Crushed/Dissolved 
Tablet Period of the study.   
 
The final safety evaluation visit is also the premature study drug discontinuation visit. They 
will undergo clinical and laboratory assessments as outlined in the schedule of events.  
 
9.2.7 Evaluations for Subjects Who Do Not Start Study Drugs 
 
 
No follow up evaluations are required for study subjects who do not start study drugs.  
 
9.2.8  Completion of Protocol  
 
A subject is considered to have completed the study if he/she completed the two study 
periods for whole and crushed/dissolved Genvoya plasma pharmacokinetic sampling.  
 
9.2.9 Study Drug Modifications  
 
Dose modifications/reductions/interruptions of study medications to manage toxicity are not 
allowed in this study. Subjects requiring dose modifications/reductions/interruptions for the 
management of toxicities at any time during the study will be taken off study.  
 
10 
TOXICITY MANAGEMENT 
 
Dose modifications/reductions/interruptions of study medications to manage toxicity are not 
allowed in this study. Subjects requiring dose modifications/reductions/interruptions for the 
management of toxicities at any time during the study will be taken off study and complete the 
safety evaluation. Adverse events will be graded according to the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events.  
 
• Grade 1 Toxicities  
For all Grade 1 toxicities study participants may continue on study at the discretion of the study 
investigator and will be followed carefully.   
 
• Grade 2 Toxicities  
For all Grade 2 toxicities the participant may continue on study at the discretion of the site 
investigator.  
 
• Grade ≥3 Toxicity 
If a participant has a Grade 3 or greater toxicity attributed to the study drug, the participant will not 
receive any further Genvoya dosing. These individuals will be followed until resolution, 
stabilization, return to baseline values or an adequate explanation can be given for their condition. 
They will complete the evaluations scheduled for the safety visit. Additional clinic visits and 
evaluations might be necessary as medically indicated.   
 

 
17 
 
11 
CRITERIA FOR DISCONTINUING FURTHER GENVOYA DOSING 
 
• Requirement of concomitant medication that is judged by the site investigator to interfere with 
study continuation.  
• Request by the subject to withdraw. 
• Clinical reasons believed life threatening by the investigator, even if not addressed in the toxicity 
management of the protocol. 
• Subject judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of the 
study results. 
• Drug toxicity as defined in Section 10.  
• At the discretion of the investigator, regulatory agencies, or pharmaceutical sponsor. 
• Failure by the subject to take study medications as instructed.   
• Failure to complete a pharmacokinetic sampling visit within the allowable timeframe.  
 
12 
CRITERIA FOR PREMATURE STUDY DISCONTINUATION  
 
• Request by the study subjects to withdraw. 
• Drug toxicity as defined in Section 10. 
• Request of the primary care provider if s/he is no longer in the best interest of the subject. 
• Subject judged by the investigator to be at significant risk for falling to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of the 
study results. 
• Imprisonment or the compulsory detention for treatment of either psychiatric or physical illness. 
• At the discretion of the investigator, regulatory agencies, or pharmaceutical sponsor.  
• Toxicities as outlined in Section 10 of the protocol.  
 
13 
STATISTICAL CONSIDERATIONS  
 
An equivalence approach with no-effect 
boundaries of 80 to 125% will be 
employed, in accordance with the FDA 
guidance on bioequivalence studies, 
which define bioequivalence as “the 
absence of a significant difference in 
the rate and extent to which the active 
moiety becomes available at the site of 
action when administered at the same 
molar dose under similar conditions 
(11).  
In order to test the primary hypothesis, 
log-transformed AUC0-∞ and Cmax after 
a single dose for crushed/dissolved 
Table 4 

 
18 
 
versus whole tablets will be compared. The adjusted mean differences will be estimated and their 
90% confidence intervals calculated. In the case of AUC0-∞ and Cmax, the estimated differences and 
confidence limits will be exponentiated in order to compare ratios between tablet forms.  
Statistical Methods  
The sample size was calculated according to the formulas for a multiplicative model (12). Table 4 
includes sample size calculations for this proposed study (13). If the mean Cmax ratio or AUC ratio 
is 1, a sample size of 5 subjects produces a two-sided 90% confidence interval (0.952, 1.048) (i.e., a 
distance from the mean to the limits that is equal to 0.048, when the estimated standard deviation is 
0.050). A sample size of 10 subjects produces a two-sided 90% confidence interval (0.855, 1.145) if 
the mean Cmax ratio or AUC ratio is 1, and the estimated standard deviation is 0.25. Assuming a 
dropout rate of 10%, a sample size of 12 subjects will be required to provide 90% power to 
demonstrate the bioequivalence of Cmax with 90% confidence intervals (CI) of 80% and 125%. 
 
13.1 
Data Management  
 
The investigator will maintain and securely store complete, accurate, and current study records 
throughout the study.  Pharmacokinetic data will be entered into Excel files and imported into 
WinNonlin for analysis. Non-compartmental PK will be performed for all ARVs. Cmax and AUC will be 
compared across study arms consistent with FDA bioequivalence guidance. Laboratory data will be 
received electronically from the clinical laboratory. Laboratory data will be reviewed in printed format for 
clinically significant lab abnormalities with the paper copy serving as the source document. Clinical data 
will be collected on paper source documents with data being entered into a web-based password-secure 
database with an audit trail (e.g. REDCap).  Data for ineligible subjects will be retained for purposes 
of improving recruitment strategies and to help understand why potential participants are not 
eligible to participate. 
13.2 
Accrual 
 
The team expects to accrue 2-3 subjects per month. Expected time to reach full accrual of 12 
evaluable participants, is 6-9 months.  
 
14 
HUMAN SUBJECTS 
 
Education in the protection of human research participants has been met by certified completion of 
the Johns Hopkins University School of Medicine Web-based Research Compliance course, Human 
Subjects Research Training, by the study staff.  
 
14.1 
IRB and Informed Consent  
 
The protocol and informed consent document and any subsequent modifications will be reviewed 
and approved by the JHU IRB. Written informed consent will be obtained by the study coordinators 
at the DDU unit during the screening visit. The purpose of the study, the procedures to be followed, 
risks, and benefits of participation will be explained. Subjects will be given as much time as they 
need to read, ask questions, and receive satisfactory answers about the consent form. A subject must 

 
19 
 
understand and give written consent to participate in the study. Comprehension of the consent form 
will be assessed by querying the patient about the study. A copy of the signed informed consent will 
be given to the participant, and the original retained by the investigator as part of the study.   
 
14.2 
Subject Confidentiality  
 
All research materials will be obtained by the investigators strictly for research purposes. Each 
subject will be assigned a confidential study number. Data will be stored in a database on IBM PC 
compatible computers using only the confidential study number, without reference to participant’s 
name. Access to subject study identification codes will be restricted to the principal investigator and 
study staff and upon request, to the JHU IRB or other regulatory agencies in compliance with 
HIPAA regulations. Data collected from the study containing PHI, will be stored on a secure 
password protected network accessible only to the study staff.   
 
 
14.3 
Definition of Adverse Events  
 
The safety of all participants enrolled in this study will be monitored throughout the study. Safety 
monitoring will include history and physical examination, with vital signs, adverse event reporting, 
and laboratory evaluations. In addition, participants will be instructed to notify the study staff of any 
problems that occur between visits and, if necessary, will be evaluated by the investigator or study 
staff at an unscheduled interim visit.  
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. For the 
purposes of this protocol, all adverse events will be collected from the time of informed consent, but only 
those occurring following exposure to a dose of Genvoya will be analyzed.  
 
Other adverse event Definitions: The following definitions of terms guided by the International 
Conference on Harmonization and the US Code of Federal Regulations apply to this section:  
 
• Unexpected Adverse Event: An event in which the specificity or severity is not consistent with 
the current investigator’s brochure, consent form, or other risk information. “Unexpected”, as 
used in this definition, refers to an adverse drug experience that has not been previously 
observed.  
 
• Related Adverse Event: Any event for which there is a reasonable possibility that the adverse 
experience may have been caused by the study drug but there is insufficient information to 
determine the likelihood of this possibility.   
 
• Serious Adverse Event: Includes death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 

 
20 
 
disability/incapacity, or any medical event that requires treatment to prevent one of the medical 
outcomes listed above.  
 
• Life-threatening, for the purpose of reporting adverse events, refers to an event in which the 
patient was, in the view of the initial reporter, at immediate risk of death at the time of the event 
as it occurred (i.e., it does not include an event that, had it occurred in a more serious form, 
might have caused death).  
 
14.4 
Reporting of Adverse Events 
 
All events will be reported to the JHU IRB and to other regulatory agencies as needed. Serious 
adverse other than death and immediately lifer threatening events will be reported within 10 
business days after sponsor initial receipt of the information. Death and immediately lifer 
threatening events will be reported within 3 business days Non serious adverse events will be 
reported to the JHU IRB in the annual review report.  
 
14.5 
Steps to Minimize the Risks  
 
Subjects will be evaluated as indicated in the schedule of events, or more frequently if medically 
indicated. If clinically indicated, directed physical examination, vital signs andsafety laboratory tests 
will be performed during outpatient visits. Additional laboratory tests may be undertaken for a 
participant, if medically indicated. Subjects experiencing toxicity will be followed until resolution, 
return to baseline values, stabilization, or an adequate explanation can be given for their condition.  
 
Genvoya is a FDA approved medication for the treatment of HIV infection. This fixed combination 
of ARV drugs is known to be well tolerated. This is a short duration study with only two doses of 
Genvoya. Side effects observed with Genvoya are usually associated with long term administration 
of this ARV medication. Participants in this study will be healthy research participants that will be 
given only two doses of Genvoya. Therefore, the short duration of this study and short medication 
exposure in health research participants makes it less likely that participants will experience 
clinically important adverse events.  
 
14.6 
Potential Benefits of the Proposed Research 
 
There are no benefits for the participants enrolled in this study.  
 
14.7 
Importance of the Knowledge to be Gained  
 
This study will determine whether crushed/dissolved Genvoya tablet is bioequivalent to the whole tablet 
formulation. Confirming bioequivalence between these two tablet forms will provide HIV-infected 
subjects with the option of using the crushed/dissolved Genvoya tablet if they have difficulty 
swallowing the whole tablet formulation.  
 
 

 
21 
 
 
14.8 
Inclusion of Women, Minorities, and Children   
 
This bioequivalence study will focus on adult men and women healthy research participants. All 
efforts will be made to enroll minorities in this study.  
 
14.9 
Compensation 
 
This study will be conducted at no cost to the participant.  Participants will be compensated up to 
$900 to complete the study and parking validation will be provided for the long Day 1 PK study 
visits, if applicable.  There are no financial penalties for not completing the study. All costs for the 
study will be covered for by the study. 
 

 
22 
 
15 
REFERENCES  
 
1. 
Genvoya [Package Insert]. Foster City, CA: Gilead Sciences, Inc; 2015.  
2. 
Golub SA, Indyk D, Wainberg ML. Reframing HIV adherence as part of the experience of illness. 
Soc Work Health Care. 2006;42(3-4):167-88. 
3. 
Bangsberg DR, Perry S, Charlebois ED, Clark RA, Roberston M, Zolopa AR, Moss A. Non-
adherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS. 
2001;15(9):1181-1183. 
4. 
García de Olalla P, Knobel H, Carmona A, Guelar A, López-Colomés JL, Caylà JA. Impact of 
adherence and highly active antiretroviral therapy on survival in HIV-infected patients. J Acquir 
Immune Defic Syndr. 2002; 30(1):105-110. 
5.  
Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, Wagener MM, Singh N. 
Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern 
Med.2000; 133(1):21-30. 
6. 
Mills EJ, Nachega JB, Buchan I, Orbinski J, Attaran A, Singh S, Rachlis B, Wu P, Cooper C, 
Thabane L, et al. Adherence to antiretroviral therapy in Sub-Saharan Africa and North America: a 
meta-analysis. JAMA 2006, 296(6):679-690. 
7. 
Brown K et al. Relative bioavailability of darunavir/cobicistat/emtricitabine/tenofovir alafenamide 
(D/C/F/TAF) single-tablet regimen when administered as a whole, split, or crushed tablet. 16th 
European AIDS Conference (EACS 2017), 25–27 October 2017, Milan. Oral abstract PS8/3. 
8. 
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of 
Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human 
Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.  
Stribild [Package Insert]. Foster City, CA: Gilead Sciences, Inc; 2016. 
9. 
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, Pozniak A, Thompson M, Podzamczer D, 
Molina JM, Oka S, Koenig E, Trottier B, Andrade-Villanueva J, Crofoot G, Custodio JM, Plummer 
A, Zhong L, Cao H, Martin H, Callebaut C, Cheng AK, Fordyce MW, McCallister S; Tenofovir 
alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and 
emtricitabine, for initial treatment of HIV-1 infection: two randomized, double-blind, phase 3, non-
inferiority trials. Lancet 2015; 385:2606. 
10. 
Wohl D, Oka S, Clumeck N, Clarke A, Brinson C, Stephens J, Tashima K, Arribas JR, Rashbaum 
B, Cheret A, Brunetta J, Mussini C, Tebas P, Sax PE, Cheng A, Zhong L, Callebaut C, Das M, 
Fordyce M; GS-US-2,92-01040111 and Study Team.A randomized, double-blind comparison of 
tenofovir alafenamide (TAF) vs. tenofovir disoproxil fumarate (TDF), each coformulated with 
elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: week 96 results. J 
Acquir Immune Defic Syndr 2016 January 29 (epub).  
11. 
Chow, SC, Liu JP. 2000. Design and analysis of bioavailability and bioequivalence studies, 2nd ed., 
revised and expanded. Marcel Dekker, Inc., New York, NY. 
12. 
Guidance for Industry. Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs 
General Considerations. 2014. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389
370.pdf 
13. 
Hahn, G. J. and Meeker, W.Q. 1991. Statistical Intervals. John Wiley & Sons. New York.

 
23 
 
APPENDIX  
 
Table S1. Estimated fractional change of sequential samples relative to Tmax during rise before and decay after Cmax. 
 
Drugs 
PK 
Parameters 
Sampling Hour 
Samples relative to Tmax 
Half-
life 
Tmax 0.25 
0.5 
0.75 
1 
1.5 
2 
3 
4 
5 
6 
10 
14 
24 
48 
72 
Before After 
Half-lives 
After 
EVG 
12.9 
4 
0.25 
0.50 0.75 
Tmax 0.06 
0.06 0.24 0.24 0.71 
2.63 2.63 
3 
7 
5.6 
COBI 
3.5 
3 
0.17 
0.25 
0.67 
Tmax 0.22 
0.49 1.21 1.21 6.25 114.93 
. 
3 
6 
13.7 
FTC 
10 
3 
0.17 
0.25 
0.67 
Tmax 0.07 
0.15 0.32 0.32 1.00 
4.28 4.28 
3 
7 
7.2 
TAF 
0.51 
1 0.25 0.50 0.75 
Tmax 0.97 0.97 2.89 2.89 2.89 14.15 
. 
. 
. 
. 
. 
3 
6 
11.8 
TFV 
32 
1.5 0.17 0.33 0.50 0.67 
Tmax 0.01 0.02 0.02 
0.04 0.09 
. 0.35 
0.68 0.68 
4 
8 
2.3