Clinical trial NCT03717129
Conditions: Healthy Volunteers
Sponsor: Johns Hopkins University
Start date: 2019-04-15; Completion date: 2021-11-01
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Step-wise, two sequential, single-dose, bioequivalence study in 12 healthy volunteers to determine whether crushed Genvoya tablet is bioequivalent to whole Genvoya tablet. The first study sequence will involve a directly observed single dose of the fixed dose formulation of whole Genvoya tablet, with semi-intensive pharmacokinetic serum sampling at time points following the dose. After a washout period of seven days, subjects will then receive a directly observed single dose of a crushed tablet of Genvoya with subsequent semi-intensive pharmacokinetic serum sampling.

Detailed description:
Genvoya, a fixed-dose combination of the two Nucleoside Reverse Transcriptase Inhibitors (NRTI) emtricitabine (FTC) 200mg and tenofovir alafenamide (TAF) 10mg, with the integrase inhibitor elvitegravir (EVG) and the boosting agent cobicistat (COBI), is FDA approved for the treatment of HIV-infected patients.

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 oral regimens, all of which can contribute to non-adherence. These observations are especially important because non-adherence to antiretroviral (ARV) medications is highly prevalent and associated with decreased survival. 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.

Many clinical scenarios make the administration of crushed 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 antiretroviral fixed-dose combinations used in the treatment of HIV-infected patients. It is therefore of substantial practical and clinical interest to know whether antiretroviral combinations such as Genvoya can be taken in crushed form with bioequivalence to whole tablet form.

This is a step-wise bioequivalence single-dose and two sequential design study in healthy volunteers to evaluate the combination Genvoya to provide this critical information.

Primary Objective: To investigate the bioequivalence of oral single whole tablet and crushed tablet of Genvoya in healthy volunteers, by characterizing the serum Area Under the Curve 0 to infinity (AUC0-∞) and Cmax of EVG, COBI, FTC, and TAF in plasma, after single doses of whole tablet and crushed tablet of this fixed dose antiretroviral combination in healthy volunteers.

Primary Endpoint:Ratio of serum AUC0-∞ and ratio of Cmax in plasma of EVG, COBI, FTC, and TAF in healthy volunteers after two different dosage forms (whole and crushed tablets).

Secondary Endpoints(s): Ratio of Tmax in plasma of EVG, COBI, FTC, and TAF in healthy volunteers after two different dosage forms (whole and crushed tablets).

Projected Study Design: Step-wise, two sequential, single-dose, bioequivalence study in 12 healthy volunteers. The first study sequence will involve a directly observed single dose of the fixed dose formulation of whole Genvoya tablet, with semi-intensive pharmacokinetic serum sampling at time points following the dose. After a washout period of seven days, subjects will then receive a directly observed single dose of a crushed tablet of Genvoya with subsequent semi-intensive pharmacokinetic serum sampling. Additional information about the proposed pharmacokinetic sampling time points for each of the antiretroviral components of Genvoya and safety evaluations is included in the Study Procedures Section of this proposal. The duration of the washout period of seven days between the two study sequences and proposed pharmacokinetic sampling time points, was selected for convenience and based on the antiretroviral component of Genvoya with the longest half-life (EVG).

Projected Duration of Treatment: Two directly observed doses of one table of Genvoya over two weeks (one single dose of whole and one single dose crushed Genvoya tablets, as specified in the Regimen Section of this proposal).

Study Duration: It will take 6-8 months to complete accrual and follow up of 12 subjects and an additional three months to complete the data analysis.

Regimens - Study Sequence:

Period 1: Product: Genvoya - Dose: 1 tablet PO (whole) - Frequency: Single dose Period 2: Product: Genvoya - Dose: 1 tablet PO (crushed) - Frequency: Single dose

Other Evaluations: Safety will be monitored and evaluated at pre-defined time points (screening and 2 weeks) throughout the study, and assessments will include: monitoring for adverse treatment-related events, clinical examinations with vital signs, and collection of blood for routine safety laboratory tests in accordance with the protocol \[e.g. Complete Blood Count (CBC), chemistry, HIV and hepatitis B (HBV screening, pregnancy test\]. Subjects will receive a single dose of Genvoya whole and crushed tablets. Pharmacokinetic assessment will be performed, with blood drawn for testing at time zero, and at selected time points after dosing with for EVG, COBI, FTC, and TAF, with more intensive sampling surrounding the evidence-based Cmax of each drug, and adequate sampling in the tail to estimate AUC with precision. Plasma will be tested for EVG, COBI, FTC and TAF concentrations using a validated high-performance liquid chromatography- mass spectroscopy (HPLC-MS) assay. The ARV components of Genvoya will be sampled as follows:

EVG -10 time points: 0, 1, 2, 3, 4, 9, 12, 24, 48, 72 hours COBI -11 time points: 0, 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24 hours FTC-14 time points: 0, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 48, 72 hours TAF-10 time points: (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 hours

To determine serum pharmacokinetic parameters of EVG, COBI, FTC, and TAF the Phoenix WinNonLin non-linear curve-fitting software (V 6.4; Pharsight, Mountain View, CA) will be employed using standard non-compartmental analytic methods. Pharmacokinetic parameters calculated will include area under the plasma concentration-time curve from 0 to τ (AUCτ, calculated using the linear trapezoidal rule); the maximum EVG, COBI, FTC, and TAF concentrations in serum after one dose (Cmax); and the time to maximum observed drug concentrations in serum (Tmax).

Hypothesis: there will be a 90% confidence interval between 0.8 and 1.25 for the ratio of Area Under the Curve for the whole tablet (AUCwhole): Area Under the Curve for the crushed tablet (AUCcrushed); and the ratio of Maximum Concentration whole tablet (Cmaxwhole): Maximum Concentration crushed tablet (Cmaxcrushed), for the four antiretroviral components of Genvoya: EVG, COBI, FTC, and TAF.

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.

In order to test the primary hypothesis, log-transformed AUCτ and Cmax after a single dose for crushed versus whole tablets will be compared. The adjusted mean differences and ratios will be estimated and the 90% confidence intervals calculated. In the case of AUCτ and Cmax, the estimated differences and confidence limits will be exponentiated in order to compare ratios between tablet forms. For Tmax, arithmetic means will be calculated, whereas for AUCτ and Cmax, geometric means will be calculated.

Statistical methods. The sample size was calculated according to the formulas for a multiplicative model. Table 2 includes sample size calculations for this proposed study. 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 required to provide 90% power to demonstrate the bioequivalence of Cmax with 90% confidence intervals (CI) of 80% and 125%

Arms: arm 1: Single observed oral dose of Genvoya whole tablet arm 2: Single observed oral dose of Genvoya crushed tablet
Interventions: intervention 1: Genvoya Oral dose intervention 2: Genvoya Crushed Dose
Intervention descriptions: intervention 1: Single Genvoya oral dose directly observed intervention 2: Single Genvoya crushed tablet in water directly observed

Protocol documents:
Prot_SAP_002.pdf: 
 
 
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 
 

ICF_003.pdf: 
 
 
 
Johns Hopkins University 
 Bioequivalence of Crushed and Whole Genvoya Tablets 
(Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fumarate)  
NCT03717129 
5-21-2019 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 1 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
 
 
 
 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
Analysis of Crushed and Whole Genvoya 
(elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) 
Tablets  
 
Application No.: 
IRB00110315 
 
Sponsor: 
Gilead Sciences  
 
Principal Investigator: Craig Hendrix, MD 
 
600 North Wolfe Street, Blalock 569 
Baltimore, MD 21287 
 
Phone: (410) 955-9709 
 
Fax: (410) 955-9708 
 
1. 
What you should know about this study: 
• You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
• You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
• If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors. 
• When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital.  
• Biospecimens will be collected in this study.  Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. 
• A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
If you are using Epic for this study, fax a copy 
of the signed consent form to 410-367-7382. 
 
 
 
 
 
Patient I.D. plate 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 2 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
• If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number.  
• During this study, you will not have access to certain medical information and test results collected 
for study purposes.  If an emergency occurs while you are in the study, medical information needed 
for your treatment can be made available to your study physician and other physicians who treat you.  
When the study is completed, all the information in your medical record will be available to you. 
 
2. 
Why is this research being done? 
This research is being done to see whether whole and crushed/dissolved Genvoya tablets are comparable 
in terms of how they are absorbed, distributed and excreted by the body.  
 
Genvoya is a combination of four antiretroviral medications, medications that target types of viruses, in 
one tablet. It is approved in the United States by the Food and Drug Administration (FDA) to be taken 
daily for the treatment of HIV infection. The four antiretroviral medications included in the Genvoya 
tablet are: elvitegravir, emtricitabine, cobicistat, and tenofovir alafenamide.   
 
Many HIV-infected patients have difficulty swallowing whole tablets of antiretroviral medications such 
as Genvoya. Therefore, it is important to find out whether crushing tablets such as Genvoya, to make it 
easier for patients to swallow, affects the effectiveness of its antiretroviral medications and potentially 
their effect to control HIV infection.  
 
Healthy HIV negative adult men and women, without active hepatitis B may join this study. Since 
participants will only be given two doses of Genvoya in this study, individuals with hepatitis B and/or 
HIV will not be allowed to participate, because they require daily doses of medications for their lifetime 
to treat these infections. In addition, certain commonly prescribed medications can affect and/or may be 
affected by Genvoya. Therefore, only healthy adult subjects not taking medications prohibited in this 
study will be allowed to participate.  
 
Women who screen for the study must not be pregnant or breastfeeding and must use a reliable form of 
contraception for the duration of the study. 
 
How many people will be in this study? 
Up to 20 individuals may be enrolled in the study to assure that 12 healthy men and women adult 
volunteers will be complete the study. 
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Screening Visit: 
This study has one screening visit that will take about 1 - 2 hours. The purpose of the screening visit is 
to confirm if it is safe for you to join the study. The screening visit will take place at the Johns Hopkins 
Drug Development Unit (DDU). The following will take place at the screening visit. 
 
• You will be asked to sign this form after you have reviewed it carefully and had the chance to ask 
questions about the study.  
• You will have a little less than 2 tablespoons of blood collected for the following:  
▪ An HIV test. You may be asked to sign a separate State of Maryland consent form for 
this HIV test. This test must be negative for you to be in the study. If the HIV test is 
positive it does not always mean you are infected with HIV. It does mean you will need 
further testing and you will receive counseling about this issue.  


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 3 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
▪ Hepatitis B antigen. If you have a positive hepatitis B antigen it means that you have 
active hepatitis B virus. This test must be negative for you to be in the study. If you have 
a positive hepatitis B antigen you will be referred back to your primary care clinician for 
further evaluation.  
* The law requires us to report positive HIV and Hepatitis B tests to the health 
department. This reporting will include information that identifies you (for example 
name, date of birth, home address, phone number, etc.) as required by Maryland 
law.  The health department may use this information to contact you for further follow up 
and/or to help conduct health surveillance activities aimed at preventing or controlling 
diseases. 
▪ Blood tests to make sure you do not have other medical problems such as kidney and/or 
liver disease, or anemia. 
• You will be asked questions about your medical and medication history. 
• You will have a physical examination by a study clinician. 
• If you are a woman, you will have a urine pregnancy test performed to see if you are pregnant. 
The test must be negative for you to participate in the study. 
• You will be advised to use the recommended birth control method. 
 
Whole Tablet Period: (Administration of Single Dose of Genvoya Whole Tablet ) – 4 study visits 
on Days 1, 2, 3 and 4 
• If you pass the screening visit you will return for the entry visit (Day 1).  
• All study visits will take place in the Drug Development Unit. 
• The Day 1 Visit will last about 14 hours.  The Day 2, 3 and 4 visits will last about 30 minutes. 
• The purpose of the entry visit is to give you a single dose of Genvoya whole tablet at the research 
unit and start the blood collections to measure all four antiretroviral medications in Genvoya. 
• If you have any new medical problems since your last visit, you will be examined by a study 
clinician at these visits.   
• You will be provided with meals at the Day 1 Visit. 
•  At the Day 1 Visit, you will also have a small intravenous (IV) catheter inserted into your arm or 
hand so that we may draw blood without sticking you repeatedly. We will draw blood from the 
catheter 13 times over the next 14 hours to measure the medications in Genvoya in your blood and 
assess your kidney function. The total amount of blood that will be collected on Day 1 will be about 
7 tablespoons. The catheter will be removed at the end of the visit.  If you are a women, you will 
have a urine pregnancy test prior to taking the Genvoya.  This test must be negative for you to 
continue in the study. 
• You will return to the clinic the following day (Day 2) to have about 2 teaspoons of blood drawn, 
about 24 hours after taking Genvoya. The study team will again ask you questions about your health 
and if you have any new medical problems, you may be examined by a study clinician. 
• You will return to the clinic the following day (Day 3) to have about 2 teaspoons of blood drawn, 
about 48 hours after taking Genvoya. The study team will again ask you questions about your health 
and if you have any new medical problems, you may be examined by a study clinician. 
• You will again return to the clinic the following day (Day 4) to have about 2 teaspoons of blood 
drawn about 72 hours after taking the Genvoya medication. The study team will again ask you 
questions about your health and if you have any new medical problems, you may be examined by a 
study clinician. 
 
You will return 7 days after taking the Genvoya tablet, for the First Safety Visit – see below.  
 
First Safety Visit  


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 4 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
After completing all evaluations for the Whole Tablet Period, and 7 days after taking the whole tablet, 
you will be asked to return to the research unit your first safety visit, to monitor your health during the 
study. During this visit, we will collect about 2 teaspoons of blood to check a number of tests, including 
those to monitor your kidney and liver function, to make sure that Genvoya is not causing any problems.  
If your blood work shows abnormal results that require further action, you will be contacted with 
additional instructions that could require additional evaluations. If all your evaluations are considered 
normal, you will be instructed to return to the research unit 7 days later for your next study visits. 
 
Crushed/Dissolved Tablet Period (Administration of Single Dose of Genvoya Crushed/Dissolved 
Tablet)  - 4 study visits on Days 1, 2, 3 and 4  
After you complete your first study safety visit, and a minimum of 14 days after taking the whole tablet 
of Genvoya, you will be asked to return for of the Crushed/Dissolved Tablet Period.  Genvoya will be 
given to you during this period as a crushed/dissolved tablet mixed with water. You will return to the 
clinic to complete the same blood collections as in the Whole Tablet Period, to measure the four 
antiretroviral medications in Genvoya in your blood (see Whole Tablet Period above). 
 
After completing all the blood collection for this period ,you will be instruct to return 7 days later for 
your final safety and study visit (see below). 
 
Final Safety Visit/Final Study Visit  
After completing all evaluations for the Crushed/Dissolved Tablet Period, and 7 days after taking the 
crushed/dissolved tablet, you will be asked to return to the research unit your final safety/study visit. 
During this visit, we will collect about 2 teaspoons of blood to check a number of tests, including those 
to monitor your kidney and liver function, to make sure that Genvoya is not causing any problems.  If 
your blood work shows abnormal results that require further action, you will be contacted with 
additional instructions that could require additional evaluations. If all your evaluations are considered 
normal, you will be finished with study participation. 
 
How long will you be in the study? 
You will be in this study for about 5 weeks. 
 
Future Contact: 
We would like your permission to contact you about other studies you may be eligible for in the future. 
Please indicate your choice below about being contacted for future research. 
 
□ YES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
 
 
Date 
 
□ NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
 
 
Date 
 
Request to Collect and Store Biospecimens for Future Research: 
As part of this research study, we would like to ask you to let us store your biospecimens and health 
information for future research.  This research could include other diseases. 
 
If you consent to allow us to store your biospecimens for future research and then later change your 
mind, you can withdraw your consent and your biospecimens will be destroyed. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 5 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
The study doctor can provide you with additional information if you have questions. In addition, further 
information about our use of your biospecimens can be found in this consent document under the 
heading “What happens to Data and Biospecimens that are collected in the study?” 
 
□ YES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
 
 
Date 
 
□ NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
 
 
Date 
 
4. 
What are the risks or discomforts of the study? 
Risks of Study Procedures: 
Blood Draw:  The risks and discomforts of blood drawing are slight. The vein may be damaged by the 
needle and cause a temporary black and blue spot; rarely the vein may clot. The risk of infection is 
slight. Some people faint when they blood drawn.  
 
A total of about19 tablespoons (292 milliliters) of blood will be drawn over the entire course of the 
study. The total amount of blood taken for this study will be a little more than half of the amount taken 
for a routine Red Cross blood donation.  
 
Risks of Genvoya: 
Information from previous studies showed that Genvoya can be associated with nausea, headaches, 
diarrhea and fatigue. Most of these side effects were considered mild in nature.  
 
Laboratory abnormalities that have been described with Genvoya include: elevations of blood levels of 
test used to measure kidney (creatinine) and liver function (ALT and AST). Some of these laboratory 
abnormalities were considered severe and occurred in more than 2% of studies participants enrolled in 
clinical trials with Genvoya.  
 
Individuals taking Genvoya can experience an increase in a blood test that measures kidney function, 
known as creatinine. However, the increase in creatinine is not the result of kidney disease caused by 
Genvoya. Instead, Genvoya blocks the elimination of creatinine through the kidneys causing an increase 
in its blood levels. Most of the side effects associated with Genvoya occur when this medication is taken 
for a long time. It is unlikely you will experience toxicities with Genvoya since you will only take a total 
of two doses of this medication. You will also be monitored through the study to make sure that any side 
effect that you might experience is treated.   
 
There may be side effects and discomforts that are not yet known. 
 
5. 
Are there risks related to pregnancy? 
Tenofovir alafenamide, one of the components of Genvoya, has not been evaluated during pregnancy. It 
is not known if some of the components of Genvoya are present in human breast milk. Therefore, pregnant 
women and women who are breast-feeding will not be allowed to participate in this study.   
 
Because of the risks involved, you must use one of the birth control methods that you have discussed 
with the study staff. You must be using birth control when you start taking Genvoya. You must continue 
to use birth control until you stop taking Genvoya.  
 
If you are not willing to prevent pregnancy, you will not be allowed to participate in the study. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 6 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
This research may hurt an embryo or fetus in ways we do not currently know.  
 
6. 
Are there benefits to being in the study? 
There is no direct benefit to you from being in this study. If you take part in this study, you may help 
others in the future. 
 
7. 
What are your options if you do not want to be in the study? 
The alternative is not to take part of the study. You do not have to join this study.  If you do not join, 
your care at Johns Hopkins will not be affected. 
 
8. 
Will it cost you anything to be in this study?   
There are no costs for you if you decide to participate in this study.  
 
9. 
Will you be paid if you join this study? 
You will be paid a total of $900 for successful completion of the study - $80 of this payment is a bonus, 
which you will be eligible to receive if you complete all study visits as scheduled and have taken your 
medicines correctly.  
 
If you leave the study earlier, you will be paid an amount proportional to the amount of the study you 
have completed.  
 
 
All payments are made by check at the final study visit.  
 
You will be provided with parking validation for the long Day 1 study visits, if applicable.  You will 
need to bring your parking ticket with you to the study visit. 
 
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us. 
 
10. 
Can you leave the study early? 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities.  
 
If you decide to leave the study will be asked to complete a final safety monitoring visit that will include 
laboratory tests and clinical evaluation.   
 
11. 
Why might we take you out of the study early?  
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 7 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
• There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities. 
 
12. 
How will your privacy be protected?  
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 
 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records (which may include 
information about HIV status, drug, alcohol or STD treatment, genetic test results, or mental health 
treatment). 
 
The research team will know your identity and that you are in the research study.  Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety.    
 
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study.  
 
If you are in a cancer study that receives federal funding, the National Cancer Institute (NCI) now 
requires that we report identifiable information (such as, zip code) about your participation.  You may 
contact the NCI if you have questions about how this information is used.  
 
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form.  
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
13. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study? 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 8 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
As a part of this study, the researchers may ask to see your health care records from your other health 
care providers.   
 
14. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins does not have a program to pay you if you are hurt or have other bad results from being 
in the study.  However, medical care at Johns Hopkins is open to you as it is to all sick or injured people.   
 
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form you will not give up any rights you have to seek compensation for injury.  
 
15. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
 
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Hendrix at 410-955-9707. If you wish, you may contact the 
principal investigator by letter or by fax.  The address and fax number are on page one of this 
consent form. If you cannot reach the principal investigator or wish to talk to someone else, call the 
IRB office at 410-955-3008.   
 
c. What should you do if you are injured or ill as a result of being in this study?  
If you think you are injured or ill because of this study, call the Principal Investigator Dr. Hendrix at 
410-955-9707 during regular office hours. If you need to reach Dr. Hendrix after regular hours for 
emergencies you can page him at 410-283-1075.  
 
If you have an urgent medical problem related to your taking part in this study, call Dr. Hendrix at 
410-955-9707 during regular office hours and page him at 410-283-5898 after hours and on 
weekends. If you page Dr. Hendrix call 410-283-1075 and after the tone, enter the phone number 
where you can be called, press the # key, and hang up. 
 
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 9 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.    
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 10 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
16. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form, you 
accept the provisions in the form and you agree to join the study. You will not give up any legal rights 
by signing this consent form.  
 
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                                           (Print Name)                                                 
 
Date/Time  
 
 
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                  (Print Name)                                               
 
Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY 
MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-
7382; IF YOU ARE NOT USING EPIC A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO 
MEDICAL RECORD EXISTS OR WILL BE CREATED).  
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT 
OF RESEARCH PARTICIPANTS. 
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: April 24, 2019 
Principal Investigator: Craig Hendrix, MD 
Application No.: IRB00110315 
 
Page 11 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                     
 
Date/Time   
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                    (Print Name)                                                                    
 
Date/Time     
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY 
MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-
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