Assessment of a New "Boosting" Strategy for HIV Pre-exposure Prophylaxis in Healthy Volunteers

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03202511
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 2
• Actual Duration (Months): 12.3
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The study will be a randomized, open-label, cross-over clinical pharmacokinetic trial to investigate a strategy for probenecid "boosting" in the setting of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for HIV pre-exposure prophylaxis (PrEP). The study will be conducted at the Indiana University Clinical Research Center. All samples will be processed and the amount of tenofovir/FTC in plasma, blood, and urine, and tenofovir diphosphate and emtricitabine in peripheral blood mononuclear cells will be determined using validated analytical methods developed by the investigators at the University of Colorado. Probenecid plasma and urine concentrations will also be measured using an in-house assay. Following completion of the study, the secondary aim will be accomplished via analysis of selected samples collected at baseline and following treatment. Those selected samples will be assessed for urinary markers of proximal tubulopathy (urine total protein, albumin, creatinine, phosphorus, retinol binding protein, and beta-2-microglobulin) and serum alkaline phosphatase, osteocalcin, procollagen type 1 N propeptide, cystatin C, and creatinine to determine if the probenecid boosting strategy does indeed lead to less potential renal and bone toxicity.

Condition or Disease	Intervention/Treatment	Phase
Pre-Exposure Prophylaxis	Drug: Probenecid Oral Tablet; Drug: Tenofovir disoproxil fumarate/Emtricitabine	Early Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Subjects will be randomly allocated to enter the study in either the control or treatment arm using a blocked design to ensure equal numbers of subjects in each sequence group (n=8, control to treatment; n=8, treatment to control). Following a washout period of at least 6 weeks, each individual will crossover to the next study phase. The randomization table will be constructed prior to subject enrollment by the Principal Investigator using the Statistical Analysis Software (SAS®) randomization procedure. In the event that an individual is withdrawn from the study, an alternate participant will replace that individual using an identical study sequence to maintain the block design. A total of 16 subjects will be initially enrolled in an effort to ensure that at least 14 subjects complete the entire study. If needed, additional subjects will be screened and enrolled until the target enrollment of n=14 subjects have completed the entire study.Subjects will be randomly allocated to enter the study in either the control or treatment arm using a blocked design to ensure equal numbers of subjects in each sequence group (n=8, control to treatment; n=8, treatment to control). Following a washout period of at least 6 weeks, each individual will crossover to the next study phase. The randomization table will be constructed prior to subject enrollment by the Principal Investigator using the Statistical Analysis Software (SAS®) randomization procedure. In the event that an individual is withdrawn from the study, an alternate participant will replace that individual using an identical study sequence to maintain the block design. A total of 16 subjects will be initially enrolled in an effort to ensure that at least 14 subjects complete the entire study. If needed, additional subjects will be screened and enrolled until the target enrollment of n=14 subjects have completed the entire study.
• Masking: None (Open Label)
• Masking Description: This will be an open-label study.
• Primary Purpose: Basic Science
• Official Title: Assessment of a New "Boosting" Strategy for HIV Pre-exposure Prophylaxis in Healthy Volunteers
• Actual Study Start Date: Jun 23, 2017
• Actual Primary Completion Date: Jul 2, 2018
• Actual Study Completion Date: Jul 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control The control phase will consist of subjects taking 600/400 mg oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on day 1 (2 tablets) followed by 300/200 mg (1 tablet) doses on days 2 and 3.	Drug: Tenofovir disoproxil fumarate/Emtricitabine; Included in arm/group descriptions.; Other Names: TDF/FTC, Truvada
Experimental: Treatment The treatment phase will consist of subjects taking 600/400 mg oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (2 tablets) along with a 2 gram oral probenecid (PRO) dose (4 tablets, 500 mg each) on day 1.	Drug: Probenecid Oral Tablet; Included in arm/group descriptions.; Drug: Tenofovir disoproxil fumarate/Emtricitabine; Included in arm/group descriptions.; Other Names: TDF/FTC, Truvada

Outcome Measures

Primary Outcome Measures

1. Plasma TFV AUC0-INF GMR [The first 72 hours of each phase.]

   The geometric mean ratio (GMR) of the plasma TFV area under the curve (AUC) comparing the test phase (T) to control phase (C) was assessed. PK samples were collected from 0 to 72 hours post-dose.

2. PBMC TFV-DP AUC GMR [The first 72 hours of each phase.]

   The geometric mean ratio (GMR) of the PBMC TFV-DP area under the curve (AUC) comparing the test phase (T) to control phase (C) was assessed. PK samples were collected from 0 to 72 hours post-dose.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. 18 to 55 years old healthy (as decided from a pre-enrollment screening session described above) male participants within 32% of their ideal body weight.

2. Individuals who agree to refrain from taking any prescriptions medications, over-the-counter medications (including salicylates/aspirin), hormonal agents, and herbal, dietary, and alternative supplements that may interact with the metabolism of those study drugs at least 2 weeks prior to the start of the study and until study completion.

3. Nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at least one month prior to and until the completion of the study (the entire study lasts for approximately 49 days).

Exclusion Criteria:

• 1. Are underweight (weigh less than 52 kg or 114 lb) or overweight [body mass index (BMI) greater than 32].

1. Females will be excluded to reduce study variability for this first proof of concept study.

2. Have insufficient renal function (estimated Creatinine Clearance ≤ 90 mL/min).

3. Have history of current alcohol or drug abuse (more than 4 alcoholic drinks per day on a regular basis).

4. Have history of intolerance, allergic reactions (e.g. rash) or other forms of hypersensitivities to any of the study medications (tenofovir disoproxil fumarate/ emtricitabine, probenecid).

5. Have taken TDF or FTC as part of pre-exposure prophylaxis within the past 6 weeks.

6. Any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, diabetes mellitus, gout, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, chronic active hepatitis B virus (HBV) infection, or HIV.

7. History of anemia or any other significant hematologic disorder. 9. Have history or current gastrointestinal disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.

8. Have a serious infection within the last week before study enrollment. 11. Have donated blood within the past two months. 12. Have blood results that do not fall in a healthy range (e.g., blood hemoglobin less than 12.0 mg/dl).

9. Are taking on regular basis substances that may interfere with the metabolism (breakdown) of study medications by the body, including prescription medications, over-the-counter, herbal or dietary supplements, alternative medications, or hormonal agents (i.e. oral contraceptives, intra-uterine device with hormones).

10. Have a life style that places subjects at a higher risk for contracting HIV during the study period (e.g. active illicit drug use, excessive alcohol drinking, sexually transmitted infection (including gonorrhea, chlamydia, syphilis, herpes, human papilloma virus) within the past one year, or having more than one sexual partner in the past 6 months).

11. Positive HIV antibody test. 16. Positive HBV surface antigen test. 17. Have participation in a research study or use of an investigational drug in the last one month.

12. Are employed or are student under supervision of any of the investigators of this study.

13. Cannot state a good understanding of this study including risks and requirements; are unable to follow the rules of this study.

14. Cannot commit the time requested for this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Clinical Research Center at University Hospital	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University

Investigators

• Principal Investigator: Brandon T Gufford, PharmD, PhD, Indiana Unversity School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 5, 2017

More Information

Publications

None provided.

• Responsible Party: Zeruesenay Desta, Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT03202511
• Other Study ID Numbers: 1705315090
• First Posted: Jun 28, 2017
• Last Update Posted: May 7, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Tenofovir; Emtricitabine; Probenecid

Study Results

Participant Flow

Arm/Group Title	Treatment TDF/FTC+PRO Dose First, Then Control TDF/FTC	Control TDF/FTC First, Then Treatment TDF/FTC+PRO Dose
Arm/Group Description	Participants received the treatment phase of 600/400 mg oral TDF/FTC along with a 2 gram oral PRO on day 1, 2-week washout, then the control phase of 600/400 mg oral TDF/FTC on day 1 followed by 300/200 mg oral TDF/FTC on days 2 and 3.	Participants received the control phase of 600/400 mg oral TDF/FTC on day 1 followed by 300/200 mg oral TDF/FTC on days 2 and 3, 2-week washout, then the treatment phase of 600/400 mg oral TDF/FTC along with a 2 gram oral PRO on day 1.
Period Title: Overall Study
STARTED	8	7
COMPLETED	7	7
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All participants received control and/or treatment phase The control phase will consist of subjects taking 600/400 mg oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on day 1 (2 tablets) followed by 300/200 mg (1 tablet) doses on days 2 and 3. The treatment phase will consist of subjects taking 600/400 mg oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (2 tablets) along with a 2 gram oral probenecid (PRO) dose (4 tablets, 500 mg each) on day 1.
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 100%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	26
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	15 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 13.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 13.3%
White	10 66.7%
More than one race	1 6.7%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Plasma TFV AUC0-INF GMR
Description	The geometric mean ratio (GMR) of the plasma TFV area under the curve (AUC) comparing the test phase (T) to control phase (C) was assessed. PK samples were collected from 0 to 72 hours post-dose.
Time Frame	The first 72 hours of each phase.

Outcome Measure Data

Analysis Population Description

Primary result was performed for geometric mean ratio of treatment phase to control phase.

Arm/Group Title	Treatment Phase	Control Phase
Arm/Group Description	The treatment phase will consist of subjects taking 600/400 mg oral TDF/FTC along with a 2 gram oral PRO dose on day 1.	The control phase will consist of subjects taking 600/400 mg oral TDF/FTC on day 1 followed by 300/200 mg TDF/FTC on days 2 and 3.
Measure Participants	14	14
Least Squares Mean (90% Confidence Interval) [ng*h/mL]	8.75	8.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Phase, Control Phase
	Comments
	Type of Statistical Test	Equivalence
	Comments	0.8 to 1.25 equivalence margin was used.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 90%; 1.47 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	PBMC TFV-DP AUC GMR
Description	The geometric mean ratio (GMR) of the PBMC TFV-DP area under the curve (AUC) comparing the test phase (T) to control phase (C) was assessed. PK samples were collected from 0 to 72 hours post-dose.
Time Frame	The first 72 hours of each phase.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Phase	Control Phase
Arm/Group Description	The treatment phase will consist of subjects taking 600/400 mg oral TDF/FTC along with a 2 gram oral PRO dose on day 1.	The control phase will consist of subjects taking 600/400 mg oral TDF/FTC on day 1 followed by 300/200 mg TDF/FTC on days 2 and 3.
Measure Participants	14	14
Least Squares Mean (90% Confidence Interval) [fmol*h/10^6cells]	7.12	7.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Phase, Control Phase
	Comments
	Type of Statistical Test	Equivalence
	Comments	80 to 125% equivalence margin was used.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	77.4
	Confidence Interval	(2-Sided) 90%; 61.4 to 97.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected over 1 year during study conduction.
Adverse Event Reporting Description	All adverse events reported from participant were included and graded for severity by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Adverse events were reviewed per patient by treatment and was not separated individually.
Arm/Group Title	Control Phase		Treatment Phase
Arm/Group Description	The control phase consisted of subjects taking 600/400 mg oral TDF/FTC on day 1 followed by 300/200 mg TDF/FTC on days 2 and 3.		The treatment phase consisted of subjects taking 600/400 mg oral TDF/FTC followed by 2 gram oral PRO on day 1.
All Cause Mortality
	Control Phase		Treatment Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)
Serious Adverse Events
	Control Phase		Treatment Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Control Phase		Treatment Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)		8/15 (53.3%)
Blood and lymphatic system disorders
Nose bleed	0/14 (0%)	0	1/15 (6.7%)	1
Gastrointestinal disorders
Nausea, vomiting, or GERD	2/14 (14.3%)	2	8/15 (53.3%)	8
Nervous system disorders
Headache or loss of appetite	2/14 (14.3%)	2	5/15 (33.3%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.