Conditions: HIV/AIDS Adherence, Medication Drug Use
Keywords: HIV PrEP biosensor tenofovir
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: yes

Brief summary:
Truvada®, an oral pill comprised of two anti-retroviral compounds, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), is currently the only drug combination approved for pre-exposure prophylaxis (PrEP) in women exposed to high HIV risk through vaginal acquisition. Adherence to the one pill per day regimen is crucial for its effectiveness in reducing the risk of acquiring HIV. Currently, there is no available point of care diagnostic test to quickly measure blood levels of tenofovir in the clinic. This study will determine whether a tenofovir (TFV) aptamer-based biosensor (aptasensor) can detect TFV in biological fluids from women randomized to different dosing regimens representing high and low adherence.

Detailed description:
Project ADHERE is a pilot, prospective, randomized study which will screen approximately 20 healthy, non-pregnant, HIV negative, premenopausal women (aged 18-50) at Eastern Virginia Medical School (EVMS) who are not at risk of pregnancy and are at low risk for sexually transmitted infections (STIs) in order to have approximately 14 women complete all study visits. The women will be randomized to one of two different dosing regimens of Truvada for up to 14 days. The low adherence cohort will take a total of 3 Truvada pills per week while the high adherence cohort will be assigned to take daily dosing, 7 pills per week. At screening (visit 1), we will screen women for HIV-1 and perform STI tests and serum screening for Hepatitis B and creatinine clearance prior to commencing oral PrEP, consistent with oral PrEP initiation guidelines. After screening labs return, they will come to the clinic for visit 2 when baseline blood, urine, and vaginal fluid will be collected, randomize participants to the dosing regimen, watch the participants ingest the first dose, and then direct to them to take subsequent doses in their homes. Reminder text messages will be sent to the participants to facilitate doses being taken at the same time of day upon which they will text message the coordinator after ingesting the pill. Participants will return 24 hours, 7 days, and 14 days after visit 2 for pre-dose collection of blood, urine, and vaginal fluid samples (visits 3, 4, and 5, respectively). For all visits, participants will not to take the next prescribed dose before coming to the clinic. Once samples are collected, participants will ingest the next scheduled pill. However, for the high adherence regimen, the women will take their last dose on day 14 and then come to the clinic 24 hours later on day 15 for collection of samples. Regardless of regimen, sample collection will take place no earlier than 24 hours after last dosing to prevent white coat effects. Samples will be brought to the laboratory for processing and eventual measurement of TFV levels by the TFV aptasensor. Aliquots of plasma and urine will also be analyzed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) so sensitivity and specificity of the aptasensor can be determined. The ability of the TFV aptasensor to distinguish levels associated with high and low adherence will also be assessed.

Arms:
arm 1: TDF/FTC (300/200 mg), 7 pills/week. Total of 14 pills arm 2: TDF/FTC (300/2200 mg), 3 pills/week. Total of 6 pills

Interventions: intervention 1: Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC)
Intervention descriptions: intervention 1: Women will take 1 pill orally according the dosing regimen of the arm to which they are assigned

Protocol document:
Prot_SAP_000.pdf: 
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TITLE PAGE 
 
 
 
Project ADHERE: Clinical Proof-of-Concept of a Tenofovir (TFV) 
Aptamer-Based Biosensor for Determing Adherence Using 
Different Dosing Regimens of Disoproxil Fumarate/Emtricitabine 
(TDF/FTC) 
 
VERSION 2.0 
 
29 AUG 2019 
 
 
Prepared By: 
Terry Jacot PhD and Andrea Thurman MD 
 
 


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INVESTIGATOR’S AGREEMENT 
Project ADHERE: Clinical Proof-of-Concept of a Tenofovir (TFV) 
Aptamer-Based Biosensor for Determining Adherence Using 
Different Dosing Regimens of Disoproxil Fumarate/Emtricitabine 
(TDF/FTC) 
29 Aug 2019 
VERSION 2.0 
 
This document may contain confidential information. It is understood that persons to whom this 
information is disclosed will not disclose it further without permission from Dr. Jacot, unless such 
information is published or otherwise becomes public knowledge. 
I have received and read:  
 
Package insert for Emtricitabine/ Tenofovir disoproxil fumarate (Truvada) tablets. I have read 
the protocol and agree to conduct the study as outlined. I will comply with all requirements 
regarding the obligations of clinical investigators as fully outlined in 21 Code of Federal 
Regulations (CFR) Parts 50, 56, and 312.60 and in the Statement of Investigator (1572), which I 
have also signed. I will ensure that all associates, colleagues, and employees assisting in the 
conduct of this study are informed about the obligations incurred by their contribution to the 
study. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
Date 
 
 
 


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EMERGENCY CONTACTS 
 
Table 1: 
Emergency Contact Information 
Study Role  
Name 
Email and Telephone number 
Site Principal Investigator 
Andrea Thurman MD 
thurmaar@evms.edu 757-446-8931 
R21 Principal Investigator and 
Laboratory Lead 
Terry Jacot PhD 
jacotta@evms.edu 757-446-7056 


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1. 
SYNOPSIS 
Name of Sponsor: 
National Institutes of Allergy and Infectious Disease (R21) RFA PA-19-054 
Name of Study Products: 
TDF/FTC [tenofovir disoproxil fumarate / emtricitabine] (Truvada) 
Name of Active Ingredients: 
emtricitabine; tenofovir disoproxil fumarate 
Title of Study: 
Project ADHERE: Clinical Proof-of-Concept of a Tenofovir (TFV) Aptamer-Based Biosensor for 
Determining Adherence Using Different Regimens of Disoproxil Fumarate/Emtricitabine 
Principal Investigators and Study Centers: 
 
Terry A. Jacot, PhD, CONRAD, Eastern Virginia Medical School, Norfolk, VA, US (R21 Grant PI) 
 
Andrea Thurman, MD, Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA, USA 
(Clinical Site PI) 
Study period:  
Estimated date first patient enrolled: Q4 2020 
Estimated date last patient completed: Q2 2021 
Phase of development:  
Pilot 


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Background and Rationale: Truvada®, is an oral pill comprised of two anti-retroviral compounds, 
emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). Gilead Sciences reported a total of nearly 100,00 
individuals in the US starting Truvada for pre-exposure prophylaxis (PrEP) between the years 2012-2016 1, and 
this number is growing in the US and globally. Adherence to the one pill per day regimen is crucial for its 
effectiveness in reducing the risk for sexual transmission of human immunodeficiency virus (HIV) infection by 
90%, and by 70% from injection drug use 2. Two landmark safety and effectiveness trials which supported the 
FDA approval of Truvada for PrEP were the iPrEX trial, which investigated Truvada use in HIV-negative men 
or transgender women, and the Partners PrEP trial, conducted in serodiscordant couples 3, 4. Both showed 
Truvada reduced risk of HIV infection by 42% (iPrEX) and 72% (Partners PrEP), noting that risk reduction was 
highly correlated with drug adherence. Another important study supporting PrEP was the TDF2 trial, which 
showed an HIV risk reduction of 62% 5. Although other clinical studies did not show efficacy, the results 
correlating poor drug efficacy with low plasma drug levels did confirm the importance of adherence 6, 7. 
Adherence measured by self-report did not correlate with effectiveness 6, 7. Although adherence is key to 
effectiveness, physicians and other health care providers (HCPs) do not have objective tools to monitor drug 
adherence and be able to tailor counselling to the actual needs of their patients and clients. The evidence 
supporting the association between adherence and effectiveness is strong, but only objective assessment of 
adherence is reliable and correlates with effectiveness. The scientific premise supporting our work is based on 
this evidence, as well as the absence of a point-of-care objective diagnostic test for drug adherence. The most 
objective measure of adherence currently available to detect and quantify drug levels in plasma is liquid 
chromatography tandem mass spectrometry (LC-MS/MS). This method, however, requires a specialized lab and 
does not qualify as a point-of-care (POC) test. Therefore, our project is aimed at filling this gap by developing 
and validating an aptasensor (aptamer-based biosensor), capable of detecting tenofovir (TFV) in various 
biological fluids at a point-of-care/clinic with a simple-to-use procedure, which will empower HCPs to provide 
real-time adherence feedback with each prescription renewal. Ultimately, real-time monitoring of adherence 
will lead to better counselling, resulting in higher effectiveness and improved success rates for treatment and 
prevention of HIV infection.  
Given the importance of adherence to the efficacy of TDF/FTC it is of clinical significance to have a reliable 
metric for adherence levels. Self-reporting of adherence, a non-invasive and simple method of assessment does 
not reliably correlate with effectiveness and blood serum levels. Currently, the most objective measure of 
adherence available is to detect and quantify plasma levels of tenofovir diphosphate (TFV-DP), the active 
metabolite of TDF, using LC-MS/MS. Although this method of quantification is reliable, it requires a specialized 
lab and equipment which comes at a significant cost and does not qualify as POC test. Other recently developed 
methods of measuring TFV levels in urine, ELISA and lateral flow assays, have shown promise, but are limited 
by inadequate sensitivity to detect levels observed in plasma and the inability to distinguish high adherence from 
white coat effects. The lack of a POC test to measure adherence leaves a critical gap for physicians and other 
HCPs when tailoring counseling to improve adherence and ultimately HIV prevention of their patients and 
communities.  
As such, there is an opportunity to evaluate a new method of measuring adherence in a reliable, objective, and 
cost-effective manner. Aptamers are DNA- or RNA-based ligands capable of binding practically any molecular 
target with high specificity, including small molecules such as antiretroviral drugs 8. Aptamers have advantages 
over antibodies. They are more stable and made through a process that is more economical and reproducible, 
which increases the aptamer’s potential capability of being more specific than its antibody counterpart. 
Therefore, aptamers are being used as capture molecules for biosensor platforms, which are becoming smaller 
than previous models, more portable, more sensitive and quantitative (rivaling LC-MS/MS), require less sample 
volume, and simpler to use. Therefore, aptamer-based biosensors or “aptasensors”, have great potential for real-


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time therapeutic drug monitoring. We will be utilizing a previously validated DNA aptamer specific for TFV 
and applying it to a biosensor platform. 
This study will focus on determining the sensitivity and specificity of the TFV aptasensor and assess its ability 
to distinguish TFV concentrations associated with low and high adherence using biological fluids collected 
from women taking TDF/FTC at different dosing regimens. 
Objectives:  
Compare plasma, urine, and vaginal fluid TFV concentrations measured by the aptasensor with those values 
quantitated by LC-MS/MS to determine agreement between the two methodologies, sensitivity, specificity, 
negative predictive value (NPV), and positive predictive value (PPV). 
Primary Objectives:  
 
Compare plasma TFV concentrations measured by the aptasensor with those values quantitated by 
LC-MS/MS to determine agreement between the two methodologies, sensitivity, specificity, NPV and 
PPV 
 
Determine if the TFV aptasensor can detect differences in the plasma TFV concentrations between 
high and low adherence dosing regimens and compare the mean difference to the difference calculated 
from values generated by LC-MS/MS 
Secondary Objectives: 
 
Compare urine TFV concentration measured by the aptasensor with those values quantitated by LC-
MS/MS to determine agreement between the two methodologies, sensitivity, specificity, NPV, and 
PPV 
 
Determine if the TFV aptasensor can detect differences in the urine concentrations of TFV between 
high and low adherence dosing regimens and whether these levels correlate with adherence 
 
Compare vaginal fluid TFV concentrations measured by the aptasensor with preclinical 
determinations of the range of detectable TFV levels and the aptasensor’s limit of detection 


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 
Determine if differences in adherence dosing regimens can be correlated to differences in vaginal fluid 
TFV levels 
 
Endpoints: 
Primary Endpoints:  
 
TFV concentrations in plasma at baseline (pre-dose), 24 hours, 7 days and 14 days after dosing 
Secondary Endpoints:  
 
TFV concentrations in urine and vaginal fluid at baseline (pre-dose), 24 hours, 7 days, 14 days 
after dosing 
Study Design:  
This pilot, prospective, randomized study will screen approximately 20 healthy, non-pregnant, HIV negative, 
premenopausal women (aged 18-50) at Eastern Virginia Medical School (EVMS) who are not at risk of 
pregnancy and are at low risk for sexually transmitted infections (STIs) in order to have approximately 14 
women complete all study visits. This study will examine the plasma, urine, and vaginal fluid from women in 
two dosing regimens of oral tablets: High adherence (HA): TDF/FTC (300/200 mg), 7 pills per week versus 
low adherence (LA): TDF/FTC (300/200mg), 3 pills per week. Participants will be randomized to regimen as 
per the following schemata: 
Randomization Assignments 
Regimen 
N 
Dose 
LA 
7 
TDF/FTC (300/2200 mg), 3 pills/week. Total of 6 pills 
HA 
7 
TDF/FTC (300/200 mg), 7 pills/week.  Total of 14 pills 
 
Participants will undergo the low adherence (LA) regimen or a high adherence (HA) regimen for two weeks, 
consisting of 5 visits.  
Visit 1: At screening/enrollment, volunteers will be consented and undergo procedures to confirm they are 
eligible to continue in the study. Eligible participants will proceed to Visit 2. 
Visit 2: Baseline blood, urine, and vaginal fluid will be collected. Participants will be randomized to dosing 
regimen and the first dose of TDF/TFC will be ingested in the clinic. Participants will be instructed to take 
subsequent doses at home. 
Dosing Contact: Participants will be sent reminder text messages to facilitate dosing occurring at the same 
time of day. Participants will text message the study coordinator to confirm ingestion of tablet.  If the 
participant does not respond to a text within approximately 4 – 6 hours after it is sent, a reminder text will be 
sent. 
Visits 3 - 5: Participants will return at 24 hours, 7 days, and 14 days after visit 2 for the pre-dose collection of 
blood, urine, and vaginal samples.  


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Follow Up Contact: A final follow up site contact will be conducted approximately 1 – 2 weeks after the last 
visit to ask the participant about adverse events and concomitant medications. The participant will be exited 
unless there are symptoms that require follow up. 
Number of patients (planned): 
Approximately 20 women may be consented and undergo assessment procedures in order to have approximately 
14 women who meet eligibility criteria complete the study. All 14 women will be randomly assigned to undergo 
either LA dosing or HA dosing. All randomized participants will be included in the analysis. 
Diagnosis and main criteria for inclusion: 
Healthy, non-pregnant, premenopausal, HIV-uninfected women aged 18-50 (showing regular menstrual 
cycles), with a BMI ≥18 and <35 kg/m2, and either sexually abstinent or in a monogamous relationship with a 
healthy partner. Protected from pregnancy by effective contraception, same-sex relationship, or abstinence.  
Study product, dosage and mode of administration: 
Study Products: tenofovir disoproxil fumarate / emtricitabine (TDF/FTC) tablet 
Dosage: tenofovir disoproxil fumarate (300 mg) with emtricitabine (200 mg)  
Mode of administration: oral 
Control therapy, dosage and mode of administration: HA regimen (7 pills/week) versus LA regimen (3 
pills/week). 
Duration of treatment:  
Low Adherence (LA) Group: 14 days consisting of 3 pills/week (one tablet/dose) for a total of 6 pills ingested 
High Adherence (HA) Group: 14 days consisting of 7 pills/week (one tablet/dose) for a total of 14 pills 
ingested 
Criteria for evaluation: 
Safety: It is expected that there will be no clinically significant concerns. 
Statistical methods: 
Sample size is based on feasibility rather than statistical considerations; thus, analysis will be primarily 
descriptive. Participant flowchart (e.g. number screened, number with sampling) will be provided. 
The Full Analysis Set (FAS) will consist of all subjects who are randomized and have at least one post-
baseline assessment.  
All populations will be defined based on the adherence regimen. 
Evaluation of Study Objectives: Study objectives will be evaluated by presentation of descriptive summaries 
and graphical displays.  


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Primary analysis of this study will evaluate the performance of the TFV aptasensor by comparing its 
measurements of the concentrations of TFV in clinical samples from all women with those values obtained 
from LC-MS/MS. Correlation and agreement between the TFV levels measured by the aptasensor and LC-
MS/MS will be analyzed using scatterplot and linear regression.  Continuous variables will be compared 
between values measured with the aptasensor versus LC-MS/MS using paired comparisons. From this 
comparison, sensitivity, specificity, NPV, and PPV of the aptasensor will also be determined. Confidence 
intervals will be calculated to assess precision and margin of error of those measures. Using the14 baseline 
pre-dose samples, each woman will be her own control, and these pre-dose samples will be used for the 
assessment of specificity and NPV.  
The secondary analysis of this study will evaluate whether the aptasensor can detect differences in TFV levels 
between the two independent cohorts of women taking TDF/FTC at different dosing regimens representing 
high (7 pills/week) and low adherence (3 pills/week). We will compare the two independent cohorts using an 
independent samples t test for normally distributed data or a Wilcoxon-Mann-Whitney test for non-parametric 
data. TFV concentrations from the LA and HA cohorts will be characterized using descriptive statistics (mean, 
median, interquartile range, minimum and maximum). The values will be compared between the high 
adherence and low adherence groups as well as comparing the mean difference between groups generated by 
the aptasensor to that difference generated by LC-MS/ MS. Distributions will be checked for normality so as 
to determine the appropriate statistical test. 
Descriptive Statistics: Categorical variables will be summarized by frequencies and percentages. Continuous 
variables will be summarized by means, standard deviations, medians, quartiles, minima and maxima.  
Control of Type I Error: This pilot study is descriptive in nature. P-values and confidence intervals around 
estimates of treatment differences will not be adjusted for multiplicity and are descriptive in nature. These 
statistics will be provided to guide further future development of the aptasensor; caution must be used as these 
statistics will not have a controlled Type I error.  
Definition of Baseline: For both adherence regimens baseline is defined as the Visit 2 pre-dose measurement.  


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
 
TITLE PAGE ................................................................................................................... 1 
EMERGENCY CONTACTS ........................................................................................... 3 
1. 
SYNOPSIS .................................................................................................... 4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............. 14 
4. 
INTRODUCTION ....................................................................................... 16 
5. 
TRIAL PURPOSE, OBJECTIVES AND ENDPOINTS ............................ 17 
5.1. 
Purpose ........................................................................................................ 17 
5.2. 
Objectives .................................................................................................... 17 
5.2.1. 
Primary Objectives ................................................................................ 17 
5.2.2. 
Secondary Objectives ............................................................................ 17 
5.3. 
Endpoints ..................................................................................................... 17 
5.3.1. 
Primary Endpoint .................................................................................. 17 
5.3.2. 
Secondary Endpoint .............................................................................. 18 
6. 
INVESTIGATIONAL PLAN ..................................................................... 19 
6.1. 
Overall Study Design .................................................................................. 19 
6.2. 
Anticipated Length of Study ....................................................................... 21 
6.3. 
Number of Subjects ..................................................................................... 21 
6.4. 
Treatment Assignment ................................................................................ 21 
6.5. 
Criteria for Study Termination .................................................................... 21 
7. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ..................... 22 
7.1. 
Inclusion Criteria ......................................................................................... 22 
7.2. 
Exclusion Criteria ........................................................................................ 22 
7.3. 
Participant Withdrawal ................................................................................ 23 
7.3.1. 
Withdrawal Criteria ............................................................................... 23 
7.3.2. 
Target Enrollment ................................................................................. 23 
7.3.3. 
Follow-up .............................................................................................. 23 
8. 
STUDY PROCEDURES ............................................................................ 24 


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8.1. 
Visit 1: Screening/Enrolment ...................................................................... 24 
8.2. 
Visit 2: Baseline Pre-Dose Sample Collection ............................................ 24 
8.3. 
Visits 3 – 5: 24 hours , 7 days, and 14 days after first dose ........................ 25 
8.4. 
Final Follow Up Contact ............................................................................. 26 
8.5. 
Unscheduled Visits ...................................................................................... 26 
8.6. 
Early Discontinuation .................................................................................. 26 
9. 
TREATMENT OF PARTICIPANTS ......................................................... 27 
9.1. 
Study Products ............................................................................................ 27 
9.2. 
Concomitant Medications ........................................................................... 27 
9.3. 
Treatment Compliance ................................................................................ 27 
9.4. 
Randomization and Blinding ....................................................................... 27 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ............................ 28 
10.1. 
Description of Study Drug .......................................................................... 28 
10.1.1. 
Emtricitabine/tenofovir disoproxil fumarate (F/TDF) .................... 28 
10.2. 
Study Drug Packaging and Labeling ........................................................... 28 
10.3. 
Study Drug Storage ..................................................................................... 28 
10.4. 
Study Drug Preparation ............................................................................... 28 
10.5. 
Administration ............................................................................................. 28 
10.6. 
Study Drug Accountability ......................................................................... 28 
10.7. 
Study Drug Handling and Disposal ............................................................. 29 
11. 
BIOANALYTICAL AND BIOCHEMICAL ASSESSMENTS ................. 30 
12. 
ASSESSMENT OF SAFETY ..................................................................... 31 
12.1. 
Medical History ........................................................................................... 31 
12.2. 
Physical Examination .................................................................................. 31 
12.3. 
Laboratory Assessments .............................................................................. 31 
12.3.1. 
Blood Samples ................................................................................ 31 
12.4. 
Pregnancy Screen ........................................................................................ 31 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ................................... 32 
13.1. 
Definition of Adverse Event (AE) .............................................................. 32 
13.1.1. 
Suspected Adverse Reaction ........................................................... 32 
13.1.2. 
Adverse Reaction ............................................................................ 32 


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13.1.3. 
Serious Adverse Event (SAE) or Serious Suspected Adverse 
Reaction ........................................................................................... 32 
13.1.4. 
Unexpected Adverse Event or Unexpected Suspected Adverse 
Reaction ........................................................................................... 33 
13.1.5. 
Serious and Unexpected Suspected Adverse Reaction ................... 33 
13.2. 
Relationship to Study Product ..................................................................... 33 
13.3. 
Recording and Grading Adverse Events for Severity ................................. 33 
13.4. 
Reporting Serious Adverse Events .............................................................. 35 
13.5. 
Temporary Product Hold/Permanent Discontinuation in Response to 
Adverse Events ...................................................................................... 35 
13.5.1. 
Grade 1 or 2 ..................................................................................... 35 
13.5.2. 
Grade 3 or 4 ..................................................................................... 35 
14. 
STATISTICS ............................................................................................... 36 
14.1. 
Sample Size Justification ............................................................................ 36 
14.2. 
General Statistical Issues ............................................................................. 36 
14.3. 
Analysis Populations ................................................................................... 36 
14.4. 
Statistical Analysis ...................................................................................... 36 
14.5. 
Interim Analysis .......................................................................................... 37 
15. 
MANAGEMENT OF INTERCURRENT EVENTS .................................. 38 
15.1. 
Loss to Follow-up ....................................................................................... 38 
15.2. 
Protocol Adherence and Sampling Windows ............................................. 38 
15.3. 
Protocol Violations ...................................................................................... 38 
15.4. 
Modification of Protocol ............................................................................. 38 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ......................... 39 
16.1. 
Study Monitoring ........................................................................................ 39 
16.2. 
Institutional Review Board (IRB) ............................................................... 39 
17. 
ETHICS ....................................................................................................... 40 
17.1. 
Ethics Review .............................................................................................. 40 
17.2. 
Ethical Conduct of the Study ...................................................................... 40 
17.3. 
Written Informed Consent ........................................................................... 40 
17.3.1. 
Procedure for Obtaining Informed Consent .................................... 40 
17.3.2. 
Subject Confidentiality .................................................................... 41 


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18. 
DATA HANDLING AND RECORDKEEPING ........................................ 42 
18.1. 
Method of Data Capture .............................................................................. 42 
18.2. 
Inspection of Records .................................................................................. 42 
18.3. 
Retention of Records ................................................................................... 42 
19. 
INVESTIGATOR RESPONSIBILITIES ................................................... 43 
19.1. 
Prior to Starting Study ................................................................................. 43 
19.1.1. 
Signing of Investigator’s Agreement and Amendments ................. 43 
19.1.2. 
Forms and Records .......................................................................... 43 
19.2. 
During the Study: Forms and Records ........................................................ 43 
19.3. 
During the Study: Progress Reports ............................................................ 44 
20. 
PUBLICATION POLICY ........................................................................... 45 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ................................................................... 3 
Table 2: 
Abbreviations .............................................................................................. 14 
Table 3: 
Randomization Assignments ....................................................................... 19 
Table 4:  
Schedule of Evaluations .............................................................................. 20 
Table 5:  
Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF 200/300 mg) ....... 27 
Table 6:  
PK Samples for High Adherence Dosing Regimen (total of 14 doses) ...... 30 
Table 7:  
PK Samples for Low Adherence Dosing Regimen (Total of 6 doses) ....... 30 
Table 8: 
Grading the Severity of Adverse Events ..................................................... 34 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
Abbreviations  
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Act 
STI 
Case report form 
CV 
Cervicovaginal 
EVMS 
Eastern Virginia Medical School 
FAS 
Full analysis set 
FDA 
U.S. Food and Drug Administration 
TDF/FTC 
Emtricitabine + TDF (Truvada®) 
GCP 
Good Clinical Practice 
HA 
High Adherence 
HCPs 
Health Care Providers 
HIPAA 
The Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LA 
Low Adherence 
LC-MS/MS 
Liquid Chromatography tandem Mass Spectrometry 
LLOQ 
Lower limit of quantification 
NIH 
National Institutes of Health 
NPV 
Negative Predictive Value 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
POC 
Point of Care 
PPV 
Positive Predictive Value 
PrEP 
Pre-exposure prophylaxis 
PSA 
Prostate Specific Antigen 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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STI 
Sexually transmitted infection 
TFV 
Tenofovir 
TP 
Treated Population 


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4. 
INTRODUCTION 
Nearly 35 million people worldwide have died from acquired immunodeficiency syndrome (AIDS) -
related causes, and approximately 77 million people have become infected with HIV since the epidemic 
began 9. This epidemic continues to grow with almost 2 million new infections occurring every year, and 
significant increases in youth populations in developing countries will only compound the problem. 
Tenofovir disoproxil fumarate / Emtricitabine (TDF/FTC - Truvada®) is the only oral pill that is 
approved for prevention of HIV acquisition in the United States 10. Two landmark safety and 
effectiveness trials which supported the FDA approval of TDF/FTC showed TDF/FTC reduced risk of 
HIV infection by 42% (iPrEX) and 72% (Partners PrEP), noting that risk reduction was highly correlated 
with drug adherence 4, 5. Although other clinical studies did not show efficacy, the results correlating 
poor drug efficacy with low plasma drug levels did confirm the importance of adherence 6, 7. The 
approved one pill per day regimen TDF/FTC reduces the risk for sexual transmission of HIV by 90% 
suggesting that with proper adherence a much greater reduction in risk of infection is achievable.  
Given the importance of adherence to the efficacy of TDF/FTC it is of clinical significance to have a 
reliable metric for adherence levels. Self-reporting of adherence, a non-invasive and simple method of 
assessment, does not reliably correlate with effectiveness and blood serum levels 6, 7. Currently, the most 
objective measure of adherence available is to detect and quantify plasma levels of tenofovir (TFV), the 
first metabolite of TDF, using liquid chromatography tandem mass spectrometry (LC-MS/MS). 
Although this method of quantification is reliable, it requires a specialized lab and equipment which 
comes at a significant cost and does not qualify as point-of-care (POC) test. Other recently developed 
methods of measuring TFV levels in urine, ELISA and lateral flow assays, have shown promise, but are 
limited by inadequate sensitivity to detect levels observed in plasma and the inability to distinguish high 
adherence from white coat effects. This lack of a POC test to measure adherence leaves a critical gap for 
physicians and other health care providers (HCPs) when tailoring counseling to improve adherence and 
ultimately HIV prevention of their patients and communities.  
As such, there is an opportunity to evaluate a new method of measuring adherence in a reliable, 
objective, and cost-effective manner. Aptamers are DNA- or RNA-based ligands capable of binding 
practically any molecular target with high specificity, including small molecules such as antiretroviral 
drugs 8. Aptamers have advantages over antibodies. They are more stable and made through a process 
that is more economical and reproducible, which increases the aptamer’s potential capability of being 
more specific than its antibody counterpart.  Therefore, aptamers are being used as capture molecules for 
biosensor platforms, which are becoming smaller than previous models, more portable, more sensitive 
and quantitative (rivaling LC-MS/MS), require less sample volume, and simpler to use. Therefore, 
aptamer-based biosensors or “aptasensors,” have great potential for real-time therapeutic drug 
monitoring. We will be utilizing a previously validated DNA aptamer specific for TFV and applying it to 
a biosensor platform. 
This study will focus on determining the sensitivity and specificity of the TFV aptasensor and assess its 
ability to distinguish TFV levels associated with low and high adherence using biological fluids 
collected from women taking TDF/FTC at different dosing regimens.  


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5. 
TRIAL PURPOSE, OBJECTIVES AND ENDPOINTS 
5.1. 
Purpose 
The purpose of this study is to assess the sensitivity and specificity of the TFV aptamer-based biosensor 
measuring TFV levels in plasma, urine, and vaginal fluid and its ability to monitor adherence to 
antiretroviral therapy. The concentrations measured with aptamer-based biosensor will be compared to 
concentrations measured via LC-MS/MS, which is currently the gold standard for pharmacokinetic analysis 
of TFV. 
5.2. 
Objectives 
Compare plasma, urine, and vaginal fluid TFV concentrations measured by the aptasensor with those 
values quantitated by LC-MS/MS to determine agreement between the two methodologies, sensitivity, 
specificity, NPV, and PPV. 
5.2.1. 
Primary Objectives 
 
Compare plasma TFV concentrations measured by the aptasensor with those values 
quantitated by LC-MS/MS to determine agreement between the two methodologies, 
sensitivity, specificity, NPV, and PPV 
 
Determine if the TFV aptasensor can detect differences in the plasma TFV concentrations 
between high and low adherence dosing regimens and compare the mean difference to the 
difference calculated from values generated by LC-MS/MS 
5.2.2. 
Secondary Objectives 
 
Compare urine TFV concentration measured by the aptasensor with those values quantitated 
by LC-MS/MS to determine agreement between the two methodologies, sensitivity, 
specificity, NPV, and PPV 
 
Determine if the TFV aptasensor can detect differences in the urine concentrations of TFV 
between high and low adherence dosing regimens and whether these levels correlate with 
adherence 
 
Compare vaginal fluid TFV concentrations measured by the aptasensor with preclinical 
determinations of the range of detectable TFV levels and the aptasensor’s limit of detection 
 
Determine if differences in adherence dosing regimens can be correlated to differences in 
vaginal fluid TFV levels 
5.3. 
Endpoints 
5.3.1. 
Primary Endpoint 
 
TFV concentrations in plasma at baseline (pre-dose), 24 hours, 7 days and 14 days after 
dosing 


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5.3.2. 
Secondary Endpoint 
 
TFV concentrations in urine and vaginal fluid at baseline (pre-dose), 24 hours, 7 days and 
14 days after dosing 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This pilot, prospective, randomized study will screen approximately 20 healthy, non-pregnant, HIV 
negative, premenopausal women (aged 18-50) at EVMS who are not at risk of pregnancy and are at low 
risk for sexually transmitted infections (STIs) in order to have approximately 14 women complete all 
study visits. This study will examine the plasma, urine, and vaginal fluid from women in two dosing 
regimens of oral tablets: TDF/FTC (300/200 mg), 7 pills per week and TDF/FTC (300/200mg), 3 pills 
per week. Participants will be randomized to regimen as per the following schemata: 
Table 3: 
Randomization Assignments 
Regimen 
N 
Dose 
Low Adherence (LA) 
Regimen  
7 
TDF/FTC (300/2200 mg), 3 pills/week, for a 
total of 6 ingested pills 
High Adherence (HA) 
REgimen 
7 
TDF/FTC (300/200 mg), 7 pills/week, for a total 
of 14 ingested pills 
Participants will undergo the low adherence (LA) regimen or a high adherence (HA) regimen for two 
weeks, consisting of 5 visits.  
Visit 1: At screening/enrollment, volunteers will be consented and undergo procedures to confirm they 
are eligible to continue in the study. Eligible participants will proceed to Visit 2. 
Visit 2: Baseline blood, urine, and vaginal fluid will be collected. Participants will be randomized to 
dosing regimen and the first dose of TDF/TFC will be ingested in the clinic under direct observation. 
Participants will be instructed to take subsequent doses at home. 
Dosing Contact: Participants will be sent reminder text messages to facilitate dosing occurring at the 
same time of day. Participants will text message the study coordinator to confirm ingestion of tablet. If 
the participant does not respond to a text within approximately 4 – 6 hours after it is sent, a reminder text 
will be sent. 
 
Visits 3-5: Participants will return at 24 hours, 7 days, and 14 days after visit 2 for the pre-dose (for 
visits 3 and 4) collection of blood, urine, and vaginal samples. 
Follow Up Contact: A final follow up site contact will be conducted approximately 1 – 2 weeks after the 
last visit to ask the participant about adverse events and concomitant medications. The participant will be 
exited unless there are symptoms that require follow up. 
 
 


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Table 4:  
Schedule of Evaluations  
Single Dose Phase (EVMS only) 
 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3-5 
24h, 7 days, 
and 14 days 
after Visit 2 
Follow 
Up 
Contact 
Informed consent 
 
 
 
 
Review eligibility criteria, interval history 
 
 
 
 
Demographic info/medical history 
 
 
 
 
Height, weight, and blood pressure 
 
 
 
 
Ask about compliance with study 
instructions/restrictions 
 
 
 
 
Ask about AEs, CMs 
 
 
 
 
Directed Physical Exam, pelvic exam 
() 
() 
() 
() 
Urine 
Urine Pregnancy test 
 
() 
() 
() 
PK (Urine): TFV 
 
 
 
 
Blood 
and 
Genital 
Fluids 
Safety: HIV, HBsAg and serum 
creatinine 
 
 
 
 
PK (Plasma): TFV 
 
 
 
 
PK (CV Fluid): TFV 
 
 
 
 
Randomize to dosing regimen (HA versus LA)  
 
 
 
 
Single Dose in clinic 
 
 
() 
 
Provide relevant instructions (e.g., adverse 
events)  
 
 
 
 
() = if indicated 


 
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6.2. 
Anticipated Length of Study 
Recruitment for the study is expected to take approximately 2-3 months. Each participant is expected to 
complete the study in approximately 2 months from time of enrollment with all participants complete 
within a total of 6 months. Lab assays will begin once the first participant completes all visits and will 
continue until the last participant. Data analysis is expected to take approximately 3 months and 
preparation of the final report 2 additional months. 
6.3. 
Number of Subjects 
Approximately 20 women may be consented and undergo assessment procedures in order to have 
approximately 14 women who meet eligibility criteria complete the study. All 14 women will be randomly 
assigned to undergo either a low adherence dosing or high adherence dosing. All randomized participants 
will be included in the analysis.  
6.4. 
Treatment Assignment 
Women will be randomized to one of two in two dosing regimens of oral tablets: TDF/FTC (300/200 
mg), 7 pills per week and TDF/FTC (300/200mg), 3 pills per week.  
6.5. 
Criteria for Study Termination 
Recruitment for the study or a treatment arm may be stopped if, in the opinion of the grant principle 
investigator: 
 
The site has failed to enroll participants at an acceptable rate 
 
The protocol requirements have not been adhered to, and/or 
 
Administrative reasons 


 
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7. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
The volunteers for this study will be recruited primarily through word of mouth and by using existing 
databases of previous study participants (as protected health information permits.) 
Only women will be recruited since the endpoints require vaginal sampling. The NIH has mandated that 
children, defined as younger than 18 years old, be included in research trials when appropriate. This 
study meets “Justifications for Exclusion” criteria for younger children as set forth by the NIH 
(specifically, “insufficient data are available in adults to judge potential risk in children” and “children 
should not be the initial group to be involved in research studies”). As such, this study does not plan to 
enroll children. Efforts will be made by the sites to recruit participants so that the racial and ethnic 
characteristics of the subject population will reflect the demographics of the study sites. No selection 
criteria shall be based on race or ethnicity.  
7.1. 
Inclusion Criteria 
Volunteers must meet all of the following criteria prior to baseline sampling at visit 2: 
1. Age 18 to 50 years, inclusive 
2. General good health (by volunteer history and per investigator judgment) without any clinically 
significant systemic disease (including, but not limited to significant liver disease/hepatitis, 
gastrointestinal disease, kidney disease, thyroid disease, osteoporosis or bone disease, and 
diabetes) and with an intact gastrointestinal tract, uterus and cervix. 
3. Estimated calculated creatinine clearance (eCcr) of at least 80 mL/min 
4. Body Mass Index (BMI) of ≥18 and <35kg/m2; and a total body weight >45 kg (99.2 lbs) 
5. Willing to give voluntary consent and sign an informed consent form  
6. Willing and able to comply with protocol requirements, including swallowing tablets 
7. Must be protected from pregnancy by: 
o Condoms 
o Hormonal contraceptives  
o Copper or Levonorgestrel IUD 
o Sterilization of either partner 
o Heterosexual abstinence  
o Same sex relationship 
8. If in a relationship, must be in a mutually monogamous relationship with a partner who is not 
known to be HIV positive and has no known risk of STIs 
7.2. 
Exclusion Criteria 
Volunteers must not meet any of the following criteria prior to baseline sampling: 
1. Currently pregnant  
2. Currently breastfeeding or planning to breastfeed during the course of the study 
3. In the last three months, diagnosed with or treated for any STI  


 
Page 23 of 45 
 
4. Positive test for HIV, or Hepatitis B surface antigen (HBsAg) 
 
5. Systemic use in the last two weeks or anticipated use during the study of any of the following: 
antiretrovirals (e.g. Viread®, Atripla®, Emtriva®, or Complera®), or drugs that may interact with 
TFV (e.g., protease inhibitors, anticonvulsants, antimycobacterials, St. John’s Wort).  
6. Participation in any other investigational trial with use of a drug/device within the last 30 days or 
planned participation in any other investigational trial with use of a drug/device during the study 
7. Grade 2 or higher laboratory abnormality, per the 2014 update of the Division of AIDS, National 
Institute of Allergy and Infectious Disease (DAIDS) Table for Grading the Severity of Adverse 
Events, or clinically significant laboratory abnormality as determined by the clinician  
8. Abnormal finding on laboratory or physical examination or a social or medical condition in the 
volunteer which, in the opinion of the investigator, would make participation in the study unsafe 
or would complicate interpretation of data 
7.3. 
Participant Withdrawal 
7.3.1. 
Withdrawal Criteria 
Participants who sign the informed consent and agree to participate in the study, but do not meet 
eligibility criteria will not undergo baseline sampling and will not continue in the study. Once a 
participant undergoes baseline genital/rectal sampling, she may be withdrawn from the study for the 
following reasons: 
 
Failure to follow protocol requirements that is judged severe enough by the investigator to 
significantly affect study outcomes 
 
Pregnancy or desire to become pregnant 
 
Medical reasons, including diagnosis of an STI  
 
Personal reasons (participant request) 
 
Discontinuation of treatment adherence arm, or of entire study (Section 6.5) 
7.3.2. 
Target Enrollment  
Participants who initiate product use but discontinue the study prior to completion may not re-enroll. 
Participants will be screened and enrolled so that approximately 14 women (7 per adherence cohort) 
complete all study visits. 
7.3.3. 
Follow-up 
If a participant chooses to discontinue the study after baseline sampling, the site may ask the participant 
to return for the next visit’s study procedures, if she is willing and if relevant. She will be asked about 
medications taken and adverse events (AEs) since the last visit. She will be exited from the study during 
her last contact with the site. 


 
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8. 
STUDY PROCEDURES 
Prospective participants may be pre-screened by telephone or in person: the study will be explained, the 
inclusion/exclusion criteria reviewed, volunteers’ questions answered, and Visit 1 scheduled.  
8.1. 
Visit 1: Screening/Enrolment 
The following will take place to confirm the volunteer is eligible to continue in the study. Note that if the 
participant is not able to complete any of the study procedures at this visit, she may return for an 
unscheduled visit prior to Visit 2. 
 
The study and informed consent form will be reviewed and all volunteer questions will be 
answered. If the volunteer is eligible and wishes to participate in the study, she will be asked to 
sign an informed consent form. The Principal Investigator (PI) or designee will sign the form and 
offer a copy to the participant. Permission may be requested as part of the informed consent 
process for storage of the biologic samples obtained during the study for possible future testing, 
as allowed by the site. 
 
The informed consent process will include an explanation of adherence support (e.g., text 
message reminders) and a request for permission to contact the participant for this purpose.  
 
The participant will be interviewed to obtain medical history and demographic information. 
 
Height, weight, and blood pressure will be measured and recorded. 
 
A urine specimen will be obtained for a urine pregnancy test. If the pregnancy test is positive, the 
participant will be referred as necessary and will not continue in the study. 
 
If the participant’s history is significant for a medical condition, a directed physical exam and or 
pelvic exam will be performed as necessary. 
 
Blood samples (approximately 4 teaspoons) will be collected for HIV and HBsAg testing as well 
as serum creatinine to calculate a creatinine clearance. Participants who test HIV or HBsAg 
positive at screening are not eligible to continue in the study. They will be counseled and given 
referrals for medical and social services.  
Eligible participants will be scheduled for the next visit and directed to refrain from vaginal intercourse 
for 48 hours prior to visit 2. 
8.2. 
Visit 2: Baseline Pre-Dose Sample Collection 
This visit will be scheduled for the early follicular phase of the menstrual cycle (for cycling women).  
 
An interval history will be collected. 
 
Eligibility criteria will be reviewed. If any lab tests reveal that the participant is not eligible, the 
visit should not proceed and the participant will not continue in the study.  
 
If indicated by signs or symptoms or history, a directed physical exam and/or urine pregnancy test 
will be performed. If pregnancy is diagnosed, the participant will be referred as necessary and 
will be discontinued. 


 
Page 25 of 45 
 
 
A vaginal swab for prostate specific antigen (PSA) will be obtained, if the PSA test indicates 
semen exposure, the visit will be re-scheduled.   
 
A urine sample will be obtained. 
 
Vaginal swabs will be obtained 
 
A blood sample (approximately 2 teaspoons) will be obtained. 
 
The participant will be randomized to the HA versus LA regimen and will take her first does of 
TDF/FTC in the clinic under direct observation and the time of product ingestion will be recorded 
in the source document. The pill will be ingested after urine, vaginal and blood samples are 
obtained. 
 
The participant will confirm her contact information for the medication text reminder. 
 
Participants will be instructed to refrain from vaginal intercourse for 48 hours prior to visits 3 – 5. 
8.3. 
Visits 3 – 5: 24 hours , 7 days, and 14 days after first dose 
Visits 3, 4, and 5 will be scheduled for 24 hours, 7 days, and 14 days after initial dosing at Visit 2, 
respectively. The time of the visit will assure that it has been at least 24 hours since the participant’s last 
dose of TDF/FTC. At each visit, the following procedures will be performed: 
 
The study staff will ask the participant if she followed the instructions from the previous visit, 
and ask about adverse events and concomitant medications. 
 
If indicated, a directed physical exam, pelvic exam and/or pregnancy test will be performed. If 
pregnancy is diagnosed, the participant will be referred as necessary and will be discontinued.  
 
Visits 4 and 5: Study staff will count the number of pills remaining and query the participant on 
compliance with her assigned dosing regimen. 
 
A vaginal swab for PSA will be obtained, if the PSA test indicates semen exposure, the 
participant will be reminded of the restrictions on vaginal intercourse, but the visit will proceed. 
 
A urine sample will be obtained. 
 
Vaginal swabs will be obtained 
 
A blood sample (approximately 2 teaspoons) will be obtained. 
 
Visits 3 and 4: The participant will take her dose of medication in the clinic, under direct 
observation, if applicable to her dosing regimen, after urine, vaginal and blood samples are 
obtained.  
 
Visits 3 and 4: Study staff will dispense the appropriate number of TDF/FTC pills in a pill 
carrying case, so that the participant has enough pills to take her to before her next scheduled 
visit. 


 
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8.4. 
Final Follow Up Contact 
The site will contact the participant approximately 1 - 2 weeks after the last visit. The participant will be 
asked about any AEs and concomitant medications since her last visit. The participant will be exited 
from the study unless symptoms require further follow up or she is appropriately referred. 
8.5. 
Unscheduled Visits 
The participant will be instructed to contact the site if she experiences moderate to severe symptoms 
(e.g. gastrointestinal symptoms). 
Unscheduled visits or procedures (e.g. urinalysis, vital sign measurements) may be performed at the 
participant’s request or as deemed necessary by the investigator at any time during the study. The 
participant will be asked to come in for an evaluation, as indicated. Unscheduled visits that require 
examination or interview due to symptoms will be in the study database. 
When an unscheduled visit occurs in response to an AE experienced by a study participant, study staff 
will assess the reported event clinically and provide or refer the participant to appropriate medical care, 
as necessary. All AEs will be evaluated and follow-up of any observed abnormalities will proceed 
according to the study manual. 
8.6. 
Early Discontinuation 
If the participant discontinues from the study prior to the final visit, the site may ask the participant to 
return for study procedures and/or sample collection, if she is willing and if relevant. At a minimum, the 
site may ask participants to return for safety assessments. She will be asked about medications taken and 
adverse events including symptoms since the last visit. She will be exited from the study during her last 
contact with the site.  
 


 
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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Study Products  
Table 5 provides a summary of the treatment to be administered, including the doses and route of 
administration. 
Table 5:  
Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF 200/300 mg) 
Product Name 
emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (Truvada®) 
Unit Dose 
200 mg FTC / 300 mg TDF 
Dosage Form 
Tablet 
Route of Administration 
Oral 
Physical Description 
The tablets are blue, capsule-shaped, film-coated, and debossed 
with “GILEAD” on one side and with “701” on the other side 
Manufacturer 
Gilead Sciences, Inc. (Foster City, CA USA) 
 
9.2. 
Concomitant Medications 
All concomitant medications will be recorded on source documents and the study database for 
participants who have undergone baseline genital/rectal sampling. 
Antriretrovirals (e.g., Viread®, Atripla®, Emtriva®, or Complera®), or drugs that may interact with TFV 
(e.g., protease inhibitors, anticonvulsants, antimycobacterials, St. John’s Wort) should not be used during 
the study (see Section 7.2). 
9.3. 
Treatment Compliance 
Treatment compliance will be evaluated by directly observed therapy (in-clinic dosing) at visits 2, 3 and 
4, as appropriate to the participant’s dosing regimen, participant report and returned tablet count. 
9.4. 
Randomization and Blinding 
This is a prospective, randomized trial. Participants and clinical study staff will not be blinded to the 
adherence dosing regimen. The laboratories and statistical/data analysts will be blinded to study 
treatment. Participants will be randomized 1:1 to the HA versus LA regimen, by simple randomization. 


 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
10.1.1. 
Emtricitabine/tenofovir disoproxil fumarate (F/TDF) 
The F/TDF tablet is marketed as Truvada®. Each tablet contains 200 mg of emtricitabine and 300 mg of 
tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are 
blue, capsule-shaped, film-coated with a length of 19 mm and a width of 8.5 mm, and are debossed with 
“GILEAD” on one side and with “701” on the other side. Excipients include: [Tablet Core] 
croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and [Film 
Coating] polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide black. Thirty (30) 
tablets are packaged in 75 ml, white, high density polyethylene bottles with a three-gram desiccant 
canister (without patent number) present in each bottle. Each bottle is enclosed with a white, continuous 
thread, child-resistant polypropylene screw cap with an induction-sealed, aluminum-faced liner. 
Participants will receive enough study drug at visits 3 and 4 to take them to their next follow up 
appointment. Study drug will be dispensed in accordance with the Clinical Research Center standard 
operating procedure.  
10.2. 
Study Drug Packaging and Labeling 
The site will manage the distribution of TDF/FTC according to the CRC SOP. The study drug will be 
purchased from a local licensed pharmacy and stored in a secure, temperature controlled space.   
10.3. 
Study Drug Storage 
Study products will be stored at room temperature (15° - 30°C) (59° - 86°F) in a locked, secure, 
temperature monitored area in the clinic prior to dispensing. 
10.4. 
Study Drug Preparation 
These study products are ready to use and require no preparation other than packaging as described in 
Section 10.2. 
10.5. 
Administration 
Each of the doses is to be administered orally by the participant. In-clinic doses will include the dose on 
Day 1 (visit 2), Day 2 (visit 3) and Day 7 (visit 4). Participants will be asked to self-administer the other 
doses at home; participants may also come to the clinic to take their daily doses. The time of visits will 
be scheduled so it has been at least 24 hours since the participant’s last dose. 
10.6. 
Study Drug Accountability 
Dispensation of doses, doses taken by the participant, and returned unused doses will be recorded in the 
source documents. 


 
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10.7. 
Study Drug Handling and Disposal 
All un-dispensed and returned study drug remaining at the end of the study will be recorded by the site 
and reconciled by the investigator. After reconciliation, any remaining study drug will be properly 
disposed of.  


 
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11. 
BIOANALYTICAL AND BIOCHEMICAL ASSESSMENTS 
Blood, Urine and CV swabs will be taken to PK as detailed below in Tables 6 and 7. 
Table 6:  
Example of Schedule for PK Samples for High Adherence Dosing Regimen (total of 
14 doses) 
Day of 
Week 
Mon 
Tues 
Wed 
Thurs 
Fri 
Sat 
Sun 
Mon 
Tues 
Wed  
Thurs 
Fri 
Sat 
Sun 
Mon 
Visit 
2 
3 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
24 hour 
Post Dose 
Procedures 
Blood, 
Urine, 
Vaginal 
Fluid 
Blood, 
Urine, 
Vaginal 
Fluid 
 
 
 
 
 
Blood, 
Urine, 
Vaginal 
Fluid 
 
 
 
 
 
 
Blood, 
Urine, 
Vaginal 
Fluid 
Day of 
Study 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Table 7:  
Example of Schedule for PK Samples for Low Adherence Dosing Regimen (Total 
of 6 doses) 
Day of 
Week 
Mon 
Tues 
Wed 
Thurs 
Fri 
Sat 
Sun 
Mon 
Tues 
Wed  
Thurs 
Fri 
Sat 
Sun 
Mon 
Visit 
2 
3 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
Dose 
1 
 
2 
 
3 
 
 
4 
 
5 
 
6 
 
 
 
24 hour 
Post Dose 
Procedures 
Blood, 
Urine, 
Vaginal 
Fluid 
Blood, 
Urine, 
Vaginal 
Fluid 
 
 
 
 
 
Blood, 
Urine, 
Vaginal 
Fluid 
 
 
 
 
 
 
Blood, 
Urine, 
Vaginal 
Fluid 
Day of 
Study 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
  


 
Page 31 of 45 
 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Medical History 
A medical history will be completed at Visit 1. Height, weight, and blood pressure will be measured.  
As part of AE data collection, participant AEs will be assessed at each study visit starting after baseline 
sample collection at Visit 2 as applicable; participant report of symptoms will be documented and may 
result in follow-up assessments. 
12.2. 
Physical Examination 
A physical exam and pelvic exam will be performed at Visit 1 as necessary, based on participant history, 
signs and symptoms. If indicated, a directed physical exam will be performed at each study visit, with 
changes on physical exam documented. 
12.3. 
Laboratory Assessments 
12.3.1. 
Blood Samples 
HIV and HBsAg tests will be performed at Visit 1. A serum creatinine will be performed to calculate a 
creatinine clearance at visit 1.  
12.4. 
Pregnancy Screen 
A pregnancy test is required at Visit 1. Note that participants must be protected from pregnancy as 
described in Section 7.1 in order to be eligible for study participation. A pregnancy test will be done at 
subsequent visits, if indicated by participant signs and symptoms. 


 
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13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1. 
Definition of Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of an investigational or approved 
product in humans, whether or not considered product related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
investigational product. Pre-existing events that increase in frequency or severity in nature during or as a 
consequence of use of an investigational product in human clinical trials will also be considered as AEs. 
Any AE with an onset date after the first date of study product administration is considered to be 
treatment-emergent. 
All AEs with onset at or after baseline sampling, whether or not related to the study product, will be 
recorded in the study database.  
According to 21 CFR 312.32 “IND Safety Reports” the following definitions of terms apply to AEs 
occurring in clinical studies involving drugs. 
13.1.1. 
Suspected Adverse Reaction 
A suspected adverse reaction is “any AE for which there is a reasonable possibility that the study product 
caused the event.” An AE is considered to be a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the study product and the AE. Examples of a causal relationship 
include: 
 
A single occurrence of an event that is uncommon and known to be strongly associated with 
product exposure (e.g., not necessarily applicable to this study, include angioedema, hepatic 
injury, Stevens-Johnson Syndrome) 
 
One or more occurrences of an event that is not commonly associated with product 
exposure, but is otherwise uncommon in the population exposed to the study product (e.g., 
tendon rupture) 
 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of product exposure) that indicates 
those events occur more frequently in the product exposure group than in a concurrent or 
historical control group. 
13.1.2. 
Adverse Reaction 
An adverse reaction is any AE caused by the study product. Adverse reactions are a subset of suspected 
adverse reactions where there is reason to conclude that the product caused the event. 
13.1.3. 
Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
the sponsor, it: 
 
Results in death 


 
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 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Results in a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
All SAEs starting from baseline until the last contact with the site, whether or not they are related to the 
study product, must be recorded on in the source documents and study database. Reporting of SAEs is 
outlined in Section 13.4. 
13.1.4. 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the drug packet 
insert, is not listed at the specificity or severity that has been observed. For example (not necessarily 
applicable to this study), under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the package referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
package insert listed only cerebral vascular accidents. “Unexpected,” as used in this definition, also 
refers to AEs or suspected adverse reactions that are mentioned in the package insert as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
13.1.5. 
Serious and Unexpected Suspected Adverse Reaction 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The sponsor 
must report an AE as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the product and the AE as described above. 
13.2. 
Relationship to Study Product 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE. Relatedness is an assessment made by a study clinician of whether 
or not the event is related to the study agent. Degrees of relatedness will be categorized according to 
current DAIDS-approved guidelines. Per the Manual for Expedited Reporting of Adverse Events to 
DAIDS (Version 2.0, January 2010), the relationship categories that will be used for this study are: 
 
Related: There is a reasonable possibility that the AE is related to the study product(s) 
 
Not related: There is not a reasonable possibility that the AE is related to the study 
product(s) 
13.3. 
Recording and Grading Adverse Events for Severity 
Adverse events spontaneously reported by the participant and/or in response to an open question from 
the study personnel or revealed by observation will be recorded during the study at the clinical site. The 
AE term should be reported in standard medical terminology when possible. For each AE, the 
investigator will evaluate and report the date of onset, date of resolution, severity, relatedness, action 


 
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taken, serious outcome (if applicable), and whether or not it caused the patient to discontinue the study. 
Each AE will be graded for severity using the applicable DAIDs tables for grading the severity of 
adverse events (see Table 8 ), which can also be found at http://rsc.tech-
res.com/safetyandpharmacovigilance/.  
Table 8: 
Grading the Severity of Adverse Events 
Adult and Pediatric AEs 
http://rsc.tech-res.com/Document/safetyandpharmacovigilance/ 
DAIDS_AE_Grading_Table_v2_NOV2014.pdf 
Female Genital AEs 
http://rsc.tech-res.com/Document/safetyandpharmacovigilance/ 
Addendum_1_Female_Genital_Grading_Table_v1_Nov_2007.pdf 
Rectal Grading Table 
http://rcc.tech-res.com/docs/default-source/safety/rectal-tox-table-
updates-05-11-2012.pdf?sfvrsn=6 
 
For clinical AEs NOT identified in the DAIDS AE Grading Tables, the following scale (as listed in the 
DAIDS Table for Grading the Severity of Adult and Pediatric AEs) should be used to grade severity: 
 
Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
 
Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
 
Severe: Symptoms causing inability to perform usual social and functional activities 
 
Potentially Life-Threatening: Symptoms causing inability to perform basic self-care 
functions OR medical or operative intervention indicated to prevent permanent impairment, 
persistent disability, or death 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity whereas 
seriousness is defined by the criteria under Section 13.1.3. An AE of severe intensity may not necessarily 
be considered serious. 
Participants must be protected from pregnancy to participate in the study. Should a pregnancy occur after 
baseline sampling, it must be reported as soon as possible to the study investigators. The participant will 
be discontinued from the study and appropriate exit procedures will be followed. Note that pregnancy in 
itself is not regarded as an AE. If the participant has been exposed to study product, the course of the 
pregnancy should be followed until it has an outcome (e.g., spontaneous miscarriage, elective 
termination, normal birth, congenital abnormality). If the participant seeks care outside the site, every 
effort should be made to obtain her consent for the site to receive a copy of her medical records related 
to the pregnancy, its outcome and the health of the neonate, if applicable. 
Reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be reported as AEs. 


 
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13.4. 
Reporting Serious Adverse Events 
Any SAE, including those listed in the protocol or package insert must be reported to the EVMS IRB 
within 72 hours of discovery. If there is any question whether the event meets the criteria for “serious” it 
should be reported anyway. In addition, a completed SAE form must be filled out as soon as possible. 
The investigator must complete, sign and date the SAE pages, verifying the accuracy of the information 
recorded on the SAE pages and the corresponding source documents. 
Additional follow-up information, if required or available, should all be sent to the EVMS IRB within 
one business day of receipt and this should be completed on an SAE form and placed with the original 
SAE information and kept with the appropriate section of the study database and/or study file. 
The investigator will notify the EVMS IRB of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible, but in no case later than 7 calendar days after she initially receives the 
information. 
The site will promptly investigate and follow up on all safety information it receives, with the 
cooperation of the investigator.  
The investigator is responsible for complying with IRB requirements for AE reporting. 
13.5. 
Temporary Product Hold/Permanent Discontinuation in Response 
to Adverse Events  
13.5.1. 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE, regardless of relationship to study product, 
may continue product use. If the PI/designee opts to temporarily hold study product, reasons for product 
hold must be documented in the study source documents. 
Follow-up testing for Grade 2 laboratory test results should be performed at scheduled study visits, as 
clinically relevant. More frequent testing may be performed at any time if required to properly monitor 
and/or manage participant safety, at the discretion of the PI/designee. 
13.5.2. 
Grade 3 or 4 
A participant who develops a Grade 3 or a Grade 4 AE that is product-related should have the product 
temporarily withheld. If a participant develops a Grade 3 or Grade 4 AE that is not product-related, the 
PI/designee may temporarily withhold product. In either case, the PI/designee must continue the 
temporary product hold until resolution of the AE. If product use is resumed and the same AE recurs at 
the same (or worse) grade level at any time during the study, study product must then be permanently 
discontinued.  


 
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14. 
STATISTICS 
14.1. 
Sample Size Justification 
Sample size is based on feasibility rather than statistical considerations; thus, analysis will be primarily 
descriptive and graphical. Participant flowchart (e.g. number screened, number with genital sampling) 
will be provided.  
14.2. 
General Statistical Issues 
All attempts will be made to avoid missing data. However, missing values will remain as missing, i.e., 
no attempt will be made to impute. In general, only observed values will be used in data analyses and 
presentations. 
14.3. 
Analysis Populations 
The population includes healthy, non-pregnant, HIV negative women. The analysis population will 
include all participants who undergo baseline genital/rectal sampling.  
The Full Analysis Set (FAS) will consist of all subjects who are randomized and have at least one post-
baseline assessment. The FAS will be used to summarize study disposition, baseline characteristics, and 
all non-safety endpoints.  
Evaluation of safety endpoints will be conducted using the Treated Population (TP), consisting of 
women with at least one dose of product use. If all subjects in the TP have at least one post-baseline 
assessment, then the TP will be identical to the FAS. 
All populations will be defined based on the adherence regimen assigned (HA versus LA). 
Additional populations or refinements to these definitions, if needed due to unanticipated circumstances, 
will be described in the SAP or statistical report. 
14.4. 
Statistical Analysis  
Sample size is based on feasibility rather than statistical considerations; thus, analysis will be primarily 
descriptive. Participant flowchart (e.g. number screened, number with sampling) will be provided. All 
populations will be defined based on the adherence regimen. 
Evaluation of Study Objectives: Study objectives will be evaluated by clinical review of descriptive 
summaries and graphical displays.  
Primary analysis of this study will evaluate the performance of the TFV aptasensor by comparing its 
measurements of the concentrations of TFV in clinical samples from all women with those values 
obtained from LC-MS/MS. Correlation and agreement between the TFV levels measured by the 
aptasensor and LC-MS/MS will be analyzed using scatterplot and linear regression. Continuous variables 
will be compared between values measured with the aptasensor versus LC-MS/MS using paired 
comparisons. From this comparison, sensitivity, specificity, NPV, and PPV of the aptasensor will also be 
determined. Confidence intervals will be calculated to assess precision and margin of error of those 


 
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measures. Using the14 baseline pre-dose samples, each woman will be her own control, and these pre-
dose samples will be used for the assessment of specificity and NPV.  
The secondary analysis of this study will evaluate whether the aptasensor can detect differences in TFV 
levels between the two independent cohorts of women taking TDF/FTC at different dosing regimens 
representing high (7 pills/week) and low adherence (3 pills/week). We will compare the two independent 
cohorts using an independent samples t test for normally distributed data or a Wilcoxon-Mann-Whitney 
test for non-parametric data. TFV concentrations from the LA and HA cohorts will be characterized 
using descriptive statistics (mean, median, interquartile range, minimum and maximum). The values will 
be compared between the high adherence and low adherence groups as well as comparing the mean 
difference between groups generated by the aptasensor to that difference generated by LC-MS/ MS. 
Distributions will be checked to determine normality so as to determine the appropriate statistical test. 
Descriptive Statistics: Categorical variables will be summarized by frequencies and percentages. 
Continuous variables will be summarized by means, standard deviations, medians, quartiles, minima and 
maxima.  
Control of Type I Error: This pilot study is descriptive in nature. P-values and confidence intervals 
around estimates of treatment differences will not be adjusted for multiplicity and are descriptive in 
nature. These statistics will be provided to guide clinical judgment; caution must be used as these 
statistics will not have a controlled Type I error.  
Definition of Baseline: For both adherence regimens baseline is defined as the Visit 2 pre-dose 
measurement.  
14.5. 
Interim Analysis 
No interim analysis will be conducted.  


 
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15. 
MANAGEMENT OF INTERCURRENT EVENTS 
15.1. 
Loss to Follow-up 
If a participant fails to appear for a scheduled visit, at least three attempts to contact her should be made 
over the subsequent 30 days. These attempts should be documented in the participant’s study file. The 
final attempt must be a certified letter to the participant with return-receipt requested, or an outreach 
attempt. A copy of this letter or documentation of the final outreach attempt should be in her file. After 
these three attempts, no further efforts need to be made to find her, but her file should remain open until 
study closeout. 
If the participant does not contact the clinic before the study is closed, her final disposition will be 
recorded at the time of study closeout, to indicate that she was lost to follow-up. The lost to follow-up 
designation cannot be made for any participant until study close out. 
15.2. 
Protocol Adherence and Sampling Windows 
Visits 3, 4 and 5 should be scheduled so that it has been at least 24 hours since the participant’s last dose 
of study medication. Visit 3 should be conducted 24 hours + 4 hours from the ingestion of the first dose 
at Visit 2. Visit 4 should be conducted 7 days + 6 hours from the ingestion of the first dose at visit 2. 
Visit 5 should be conducted 14 days + 6 hours from the ingestion of the first dose at visit 2.  
The study site should carefully record the date and time of each collection of blood, urine and CV swabs. 
The site should carefully record the date and time of each ingestion of medication in the clinic. 
15.3. 
Protocol Violations 
If a protocol violation is required to protect the life or physical well-being of a participant in an 
emergency, it may be carried out without prior approval from the IRB. The investigator must, however, 
report the violation to the IRB as soon as possible, no later than 5 working days after the emergency 
occurred. 
Other violations from the protocol may not be carried out without prior approval from the IRB if the 
change involves the rights, safety, or welfare of participants; and without prior approval from the grant 
PI (Terry Jacot, PhD) if the change involves the validity of the data, the study's scientific soundness or 
the rights, safety, or welfare of participants. 
All protocol violations should be recorded in a protocol violation log. 
15.4. 
Modification of Protocol 
No modification of this protocol may be made without written approval of Dr. Jacot. 


 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
The study site may be monitored by the EVMS IRB at any time. This monitoring may include: 
 
Confirm that facilities remain acceptable 
 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs, and that investigational product accountability checks are 
being performed 
 
Confirm all volunteers have been properly consented 
 
Record and report any protocol violations not previously sent to the IRB 
 
Confirm AEs and SAEs have been properly documented and confirm any SAEs have been 
forwarded to the IRB and those SAEs that met criteria for reporting have been forwarded to 
the IRB 
16.2. 
Institutional Review Board (IRB) 
The Principal Investigator (PI) must obtain IRB approval for the investigation. Initial IRB approval, and 
all materials approved by the IRB for this study including the patient consent form and recruitment 
materials must be maintained by the Investigator and made available for inspection. 


 
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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the informed consent form, must be approved or 
given a favorable opinion in writing by an IRB or IEC as appropriate. The study must be conducted in 
accordance with all conditions of approval by the IRB. 
The PI is responsible for informing the IRB or IEC of any amendment to the protocol in accordance with 
local requirements. In addition, the IRB or IEC must approve all advertising used to recruit patients for 
the study. The protocol must be re-approved by the IRB or IEC upon receipt of amendments and 
annually, as local regulations require. 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP, and applicable regulatory requirements. In 
addition, the PI will follow U.S. Department of Health and Human Services regulations regarding the 
Health Information Portability and Accountability Act (HIPAA 45, CFR 164). The PI will ensure that 
appropriate health care or referral is provided for the participants throughout the study. 
17.3. 
Written Informed Consent 
17.3.1. 
Procedure for Obtaining Informed Consent 
No volunteer may be admitted into this study until the PI (or designee) has obtained her legally effective 
informed consent. The PI (or designee) shall seek such consent only under circumstances that provide 
the prospective participant with sufficient opportunity to consider whether or not to participate in the 
study. Informed consent must be obtained without coercion, undue influence, or misrepresentation of the 
potential benefits or risks that might be associated with participation in the study.  
Informed consent encompasses all oral and written information given to the volunteer about the study 
and the study materials. This includes the consent form signed by the participant, the instructions for use 
of study materials that are provided to the participant, recruitment advertising, and any other information 
provided to the participant. All such information that is given to the participant will be in a language that 
is understandable to her. The information will not include any language in which the participant is made 
to waive any of her rights or which releases or appears to release the PI or the PI’s institution from 
liability for negligence. 
Informed consent will be documented by the use of a written consent form that is signed by the 
participant and the PI (or designee). A copy of the consent form will be offered to each participant. The 
original signed consent form for each participant will be kept at the site. The consent form must include 
each of the basic and additional elements of informed consent described in 21 CFR Part 50.25 and must 
describe each of the risks or discomforts to the participant that have been identified as reasonably 
foreseeable.  


 
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17.3.2. 
Subject Confidentiality 
The confidentiality of all subjects consented into this clinical study will be protected to the fullest extent 
possible. Study subjects will not be identified by name on any database, or on any other documentation 
sent to the IRB or other organizations involved in this study, and will not be reported by name in any 
report or publication resulting from data collected in this study. 


 
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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Method of Data Capture 
Clinical data will initially be recorded on source documents at the clinical site. The source documents, 
including signed informed consent forms, laboratory reports, and participant records, should be 
maintained at the site, and should be available for review during monitoring visits. 
Information from the source documents will then be entered in to an electronic study database.  The 
electronic database will be stored on a password protected computer in a locked office. 
18.2. 
Inspection of Records 
The IRB or funding agency (NIH) will be allowed to conduct site visits to the clinical site for the 
purpose of monitoring any aspect of the study. The PI agrees to allow the monitor or designee to inspect 
the storage area, inventory, and accountability records for study product; subject charts and study source 
documents, and other records relative to study conduct. 
18.3. 
Retention of Records 
The signed original informed consent documents for each participant and originals of all study 
documentation (e.g., study product inventory forms, participant clinic records, original laboratory 
reports) will be retained by the PI for a minimum of 2 years at the site. No records may be destroyed 
without written permission from the grant PI (Terry Jacot PhD). 


 
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19. 
INVESTIGATOR RESPONSIBILITIES 
19.1. 
Prior to Starting Study 
19.1.1. 
Signing of Investigator’s Agreement and Amendments 
Prior to study start the clinical site PI is responsible for signing and dating the Investigator’s Agreement 
for this study protocol. The signed and dated original must be submitted to Dr. Jacot, and a copy must be 
maintained by the PI at the site with the study files. 
All protocol amendments must be signed and dated by the PI. The signed and dated original must be 
submitted to Dr. Jacot, and a copy must be maintained by the PI at the site. Amendments must be 
approved by Dr. Jacot and the IRB before implementation. 
19.1.2. 
Forms and Records 
Prior to study activation, Dr. Jacot, the grant PI, will review the electronic database and source 
documents with the site PI, Dr. Thurman. The following forms will be kept in a regulatory binder for the 
study: 
 
Statement of the Investigator (FDA Form 1572) 
 
Financial Disclosure Statement (completed by each staff member listed on FDA Form 
1572). Note that this form will also need to be provided for each staff person at the end of 
the study and one year following completion of the study, as possible. 
 
IRB information consisting of: 
o Copy of IRB approval letter for protocol, consent form, and other written materials 
provided to participants 
o Copy of IRB-approved consent form, and other written materials provided to 
participants, as applicable 
 
Laboratory information including: 
o Name of laboratories to be used to process study specimens 
o Curriculum vitae of laboratory director(s) 
o Current license(s) and/or laboratory certification (such as the Clinical Laboratory 
Improvement Act [CLIA] certification), with expiration date 
o Copy of normal values for tests done by each laboratory for this study 
19.2. 
During the Study: Forms and Records 
The following forms and records will be maintained at the study site, including but not limited to: 
 
Package insert for TDF/FTC 
 
Subject Status Log(s) 
 
Subject Identification Code List 
 
Delegation of Responsibilities Log 
 
Study Supplies Accountability Logs and packing slips 
 
Protocol Violation Log 


 
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 
Source documents 
 
Signed and dated informed consent forms 
 
IRB documents: 
o Submission and approval letters for protocol and any protocol amendments 
o Submission and approval letters for original and any revised consent forms and any 
other written material provided to participants 
o Annual submission and approval letters 
o Other IRB correspondence 
 
Updates on curricula vitae and laboratory information 
 
General correspondence 
Copies of all correspondence between the site and its IRB should be sent to Dr. Jacot. 
The PI is responsible for obtaining any updates to these documents, including certification renewals, and 
sending them to Dr. Jacot in a timely fashion. 
19.3. 
During the Study: Progress Reports 
During the study, a monthly report will be sent to Dr. Jacot and will include: 
 
Participant status 
 
Protocol violations 
 
AEs that are serious and/or related to product use 
Annual progress reports and a final report will be submitted by the site to the IRB or IEC according to 
local regulations or guidelines. 


 
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20. 
PUBLICATION POLICY 
All information concerning the study supplied by the PI and not previously published is considered 
confidential. 
No data collected in this study will be presented or published without prior approval from the laboratory 
lead.  
21. 
 
REFERENCES 
1. Giler RM, Magnuson D, Trevor H, Bush S, Rawlings K, McCallister S. Changes in truvada 
(TVD) for HIV pre-exposure prophylaxis (PrEP) utilization in the United States:  (2012-2016).  
9th International AIDS Society Conference on HIV Science. Paris; 2017. 
2. AIDSinfo. PrEP vs. PEP. 2017. https://aidsinfo.nih.gov/understanding-hiv-
aids/infographics/46/prep-vs--pep (accessed 7/30/18. 
3. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV 
prevention in men who have sex with men. The New England journal of medicine 2010; 
363(27): 2587-99. 
4. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in 
heterosexual men and women. The New England journal of medicine 2012; 367: 399-410. 
5. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis 
for heterosexual HIV transmission in Botswana. The New England journal of medicine 2012; 
367(5): 423-34. 
6. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection 
among African women. The New England journal of medicine 2012; 367(5): 411-22. 
7. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis 
for HIV infection among African women. The New England journal of medicine 2015; 372(6): 
509-18. 
8. Ruscito A, DeRosa MC. Small-Molecule Binding Aptamers: Selection Strategies, 
Characterization, and Applications. Frontiers in chemistry 2016; 4: 14. 
9. UNAIDS. Fact Sheet-Latest Statistics on the status of the AIDS epidemic. 
www.aidsorg/en/resources/factsheet (accessed 7/26/19). 
10. AIDSinfo. FDA approves first drug for reducing the risk of sexually acquired HIV infection. 
2012. https://aidsinfo.nih.gov/news/1254/fda-approves-first-drug-(truvada)-for-reducing-the-
risk-of-hiv-infection (accessed 7/26/19).