Conditions: Healthy Volunteers
Keywords: healthy volunteers
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 38
Healthy volunteers: yes

Brief summary:
Adherence to daily dosing is very important for how well Emtricitabine/Tenofovir Alafenamide (F/TAF) works for treatment of chronic human immunodeficiency virus (HIV), or prevention of HIV acquisition. Methods to measure medication adherence to Tenofovir disoproxil fumarate (tenofovir DF, TDF), a similar but different prodrug of tenofovir, have been developed but cannot be extrapolated to F-TAF. By measuring F-TAF (the drug) and metabolites in the blood cells and dried blood spots, the study plans to see if these results predict adherence to taking the drug. The goal of this study is to vary the amount of F-TAF dosing and see if the drug levels in dried blood spots (DBS) change in a predictable way. This study will mimic different levels of adherence (33%, 67%, and 100% of daily dosing) using directly observed therapy (DOT) to establish the relationship between F-TAF in dried blood spots and adherence. Investigators will also measure drug in hair clippings to see if hair or DBS are a better predictor of adherence.

Detailed description:

Arms:
arm 1: The 33% and 67% dosing regimens will use skipped doses spaced by days (i.e. 67% is two daily doses followed by skipping a day, repeated for 12 weeks; 33% dosing is a daily dose followed by two skipped days, repeated for 12 weeks). arm 2: The 33% dosing regimens will use skipped doses spaced by days (i.e. 33% dosing is a daily dose followed by two skipped days, repeated for 12 weeks). 100% will dose daily for 12 weeks, no skipped doses. arm 3: The 33% and 67% dosing regimens will use skipped doses spaced by days (i.e. 67% is two daily doses followed by skipping a day, repeated for 12 weeks; 33% dosing is a daily dose followed by two skipped days, repeated for 12 weeks). arm 4: 67% dosing regimens will use skipped doses spaced by days (i.e. 67% is two daily doses followed by skipping a day, repeated for 12 weeks. 100% will dose daily for 12 weeks, no skipped doses. arm 5: The 33% dosing regimens will use skipped doses spaced by days (i.e. 33% dosing is a daily dose followed by two skipped days, repeated for 12 weeks). 100% will dose daily for 12 weeks, no skipped doses. arm 6: 67% dosing regimens will use skipped doses spaced by days (i.e. 67% is two daily doses followed by skipping a day, repeated for 12 weeks. 100% will dose daily for 12 weeks, no skipped doses.

Interventions: intervention 1: emtricitabine 200 mg/tenofovir alafenamide 25mg
Intervention descriptions: intervention 1: 1 tablet of Descovy contains emtricitabine 200 mg/tenofovir alafenamide 25mg

Protocol document:
Prot_SAP_000.pdf: 
The Cellular Pharmacology of F-TAF in dried blood spots 
“TAF-DBS” 
 
 
 
 
IDENTIFIERS: 
Colorado Multiple Institutional Review Board: 16-0972 
NCT02962739 
 
 
 
FUNDING SUPPORT:  
Gilead Sciences 
 
PHARMACEUTICAL SUPPORT: 
Study Drug Donated by Gilead Sciences  
 
 
 
IND SPONSOR: 
Exempt 
 
 
 
 
PRINCIPAL INVESTIGATOR 
Peter L. Anderson, Pharm.D. 
 
 
 
 
 Version 2.0 
22 June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL 
 
Full Title: 
The Cellular Pharmacology of F-TAF in dried blood spots 
 
 
Short Title: 
 
TAF-DBS 
 
Clinical Phase:  
I-II 
 
IND Sponsor:  
Exempt 
 
Principal Investigator: Peter L. Anderson, Pharm.D. 
 
Sample Size: 
Approximately 36 who complete the study timeline. IRB approvals will be 
sought for 72 subjects to allow for screen failures and drop outs.  
 
Study population: 
HIV-uninfected adult participants at low risk for HIV infection. All participants 
must have a creatinine clearance  >60 ml/min (MDRD equation) and no 
contraindicated medical conditions or medications. 
 
Participating sites: 
The University of Colorado Anschutz Medical Campus. 
 
 
 
 
 
Study Design: 
Approximately 36 HIV negative subjects will be enrolled. Enrollment will target 
approximately half women and one third African-Americans or Latino. However, 
strict quotas will not be imposed. Enrollment will proceed without the need to 
meet specific race/gender targets. Participants will be randomized to one of 6 
sequences consisting of two directly observed dosing regimens, 33%/67%, 
33%/100%, 67%/33%, 67%/100%, 100%/33%, and 100%/67%, expressed as % 
of daily dosing. Each dose regimen will have a duration of approximately 12 
weeks. DBS/blood will be collected every week and hair will be collected at 3 
week intervals. There will be a 12 week washout period between dose regimens.  
Additional samples will be collected during this washout period to determine 
elimination kinetics in hair and DBS/blood.  
 
The 33% and 67% dosing regimens will skip doses spaced by days (i.e. 67% is 
two daily doses followed by skipping a day, repeated for 12 weeks; 33% dosing 
is a daily dose followed by two skipped days, repeated for 12 weeks).  
 
Study Duration: 
For participants, the study lasts for approximately 36 weeks. Recruitment and 
enrollment will continue for approximately one year, the total study duration is 
approximately two years.  
 
Study Regimen: 
Volunteers will receive 200mg and 25mg of emtricitabine and tenofovir 
alafenamide fumarate (F-TAF) according to the regimens outlined above. This 
medication will be donated by Gilead Sciences, and managed by the University 
of Colorado Hospital Investigational Pharmacy. 
 
 
 
 


 
Primary objectives: 
1)  Define the expected concentrations and dose-proportionality for TFV-DP in 
DBS using directly observed F-TAF therapy at 33%, 67%, and 100% of daily 
dosing.  
 
2) Establish a model to predict adherence rate to F-TAF by level of TFV-DP in 
DBS. 
 
 
 
STATISTICAL CONSIDERATIONS  
Primary outcomes 
 
Primary outcome 1. The study was powered on dose proportionality of TFV-DP in DBS. Means, 
variances and dose proportionality will utilize measured concentrations at steady-state (Css at 12 weeks). 
Measured values will be validated with fitted values from PK modeling approaches (eg NONMEM).(22) 
The sample size was based upon demonstrating dose proportionality. Under the power model, 
Css=a(dosing)be, dose proportionality dictates the 90% CI for b is in (0.8, 1.25).(23) We assume an 
incomplete block design with each subject receiving 2 (of 3) doses, providing 6 permuted dose sequences 
(figure 2). An estimate of within subject CV was 2*max(CV) = 0.20 based on 5 replicate TFV-DP DBS 
samples from 2 subjects. Assuming a significance level of 0.05, we estimate a sample size of n=36 
subjects (6 per dose sequence).(23) If dose proportionality is not shown, we will consider dose as a 
predictor of log(Css) as a linear (b≠1) or a categorical effect interacted with time. Secondary outcomes 
such as the effects of race, gender and genetics, will be evaluated with models utilizing likelihood ratio 
tests and AIC to compare nested and non-nested models. (23-27) 
 
Primary outcome 2. The goal is to determine DBS TFV-DP cut points associated with adherence levels. 
For the primary analyses, we will attempt to discriminate 33%, 67% and 100% dosing based upon TFV-
DP in DBS. Power calculations conservatively assume a single measured Css observation at week 12, 
dose as a categorical predictor and 1 dose regimen per subject. Sample sizes of n=16 for each regimen 
achieve 90% power to detect a difference of 0.27 (0.30) between the area under the ROC curve (AUC) 
under the null hypothesis of 0.50 and an AUC under the alternative hypothesis of 0.77 (0.80) using a two-
sided z-test at a significance level of 0.05. In practice, a proportional odds logistic approach which allows 
for an ordinal outcome (25, 26, 28) and extensions which control for correlations between repeated 
measurements on a subject will be utilized. (29) Finally, we will employ PK models from aim 1 to 
simulate TFV-DP for other dose regimens to estimate cut points for adherence rates other than 33%, 67% 
and 100%. 
 
 
 
Enrollment/Stratification/Randomization/Blinding Procedures 
This is a randomized open label observational study. Each subject will be randomized to one of 6 possible 
dosing regimens shown in the table below (Table 1).  For each study period, block randomization will be 
used to ensure that Dosing Groups are balanced across enrollment time. The randomization will be 
programmed using R software (http://cran.r-project.org/ , The R Foundation for Statistical Computing). 
 
 
 


Table 1: All possible randomization scenarios  
Dosing group 
1 
2 
3 
4 
5 
6 
Period 1 
33 
33 
67 
67 
100 
100 
Period 2 
67 
100 
33 
100 
33 
67 
N (36 total) 
6 
6 
6 
6 
6 
6 
 
Participant Enrollment Follow-Up 
Enrollment will be discussed at PSRT meetings every 6 months.  
 
 
Planned Interim Analyses and Stopping Guidelines  
Because the study is non-therapeutic and relatively small (N<100) the study team will monitor for safety 
as described above, but not efficacy.  
 
Assays will be performed real time for the first 6 participants to evaluate if the half-life of TFV-DP in 
RBC is similar for TAF vs TDF. An analysis will be conducted at week 6 or 8 to assess TFV-DP by 
fitting the following equation:  Ct=Css*(1-e-K*t), where Ct is TFV-DP in DBS at time t, Css is the fitted 
steady state concentration, k is the fitted first-order elimination rate constant. Note the dose is not required 
for this equation. For comparison, we will run simulations of TFV-DP in DBS during TDF therapy using 
data from our ongoing DOT-DBS study (COMIRB 13-0427). If TFV-DP kinetics are similar for TAF and 
TDF, we would expect the fitted k to be similar between DOT-DBS and the present study. This interim 
analysis will only detect very large differences. We will meet as a study team (PSRT and Dr. Sam 
MaWhinney) to assess comparability, and will make decisions about potential study design alterations at 
this meeting. If study alterations are deemed to be needed, they will be submitted to the IRB prior to 
implementation.