Trial Outcomes & Findings for Effects of Ledipasvir/Sofosbuvir on the Pharmacokinetics and Renal Safety of Tenofovir Alafenamide (TAF) (NCT NCT03126370)

NCT ID: NCT03126370

Last Updated: 2021-02-11

Results Overview

Compare plasma tenofovir AUC0-24 between TAF with boosted PI vs. TDF with boosted PI (Phase 2 vs. 1), and between TAF with boosted PI and LDV/SOF vs. TDF with boosted PI (Phase 3 vs. 1)

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 10 participants
• Primary outcome timeframe: 12 weeks and 24 weeks and 28 weeks
• Results posted on: 2021-02-11

Participant Flow

Participant milestones

Measure	TAF With a Boosted PI and LDV/SOF Subjects who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease inhibitor for HIV treatment will continue to take their prescribed treatment for 12 weeks after enrollment. Subjects will be switched from tenofovir disoproxil fumarate to tenofovir alafenamide (TAF) 25 mg/emtricitabine (FTC) 200 mg (Descovy) with a boosted protease inhibitor for the next 12 weeks. After taking TAF/FTC for 12 weeks, subjects will then start taking ledipasvir 90mg/sofosbuvir 400mg (Harvoni) in combination with TAF/FTC and a boosted protease inhibitor for 4 weeks. Subjects will then return to taking TAF/FTC with a boosted protease inhibitor for the final 12 weeks of the study. TDF with a boosted protease inhibitor: Subjects who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease
TDF With a Boosted PI STARTED	10
TDF With a Boosted PI COMPLETED	10
TDF With a Boosted PI NOT COMPLETED	0
TAF With a Boosted PI STARTED	10
TAF With a Boosted PI COMPLETED	10
TAF With a Boosted PI NOT COMPLETED	0
TAF With a Boosted PI and LDV/SOF STARTED	10
TAF With a Boosted PI and LDV/SOF COMPLETED	10
TAF With a Boosted PI and LDV/SOF NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effects of Ledipasvir/Sofosbuvir on the Pharmacokinetics and Renal Safety of Tenofovir Alafenamide (TAF)

Baseline characteristics by cohort

Measure	TAF With a Boosted PI and LDV/SOF n=10 Participants Subjects who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease inhibitor for HIV treatment will continue to take their prescribed treatment for 12 weeks after enrollment. Subjects will be switched from tenofovir disoproxil fumarate to tenofovir alafenamide (TAF) 25 mg/emtricitabine (FTC) 200 mg (Descovy) with a boosted protease inhibitor for the next 12 weeks. After taking TAF/FTC for 12 weeks, subjects will then start taking ledipasvir 90mg/sofosbuvir 400mg (Harvoni) in combination with TAF/FTC and a boosted protease inhibitor for 4 weeks. Subjects will then return to taking TAF/FTC with a boosted protease inhibitor for the final 12 weeks of the study. TDF with a boosted protease inhibitor: Subjects who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease
Age, Continuous	50 years STANDARD_DEVIATION 12.3 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants
eGFR	91.5 mL/min/1.73^m2 STANDARD_DEVIATION 26.6 • n=5 Participants
Weight	88.8 kg STANDARD_DEVIATION 16.6 • n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks and 24 weeks and 28 weeks

Compare plasma tenofovir AUC0-24 between TAF with boosted PI vs. TDF with boosted PI (Phase 2 vs. 1), and between TAF with boosted PI and LDV/SOF vs. TDF with boosted PI (Phase 3 vs. 1)

Outcome measures

Measure	TDF With a Boosted PI n=10 Participants Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks	3466 ng*h/mL Geometric Coefficient of Variation 51.4	743 ng*h/mL Geometric Coefficient of Variation 35.8	868 ng*h/mL Geometric Coefficient of Variation 40.8

PRIMARY outcome

Timeframe: 12 weeks, and 24 weeks and 28 weeks

Compare tenofovir-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1).

Outcome measures

Measure	TDF With a Boosted PI n=10 Participants Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks	83.0 fmol/10^6 cells Geometric Coefficient of Variation 66.6	926 fmol/10^6 cells Geometric Coefficient of Variation 23.4	1129 fmol/10^6 cells Geometric Coefficient of Variation 34.9

SECONDARY outcome

Timeframe: 12 weeks and 24 and 28 weeks

Population: Comparisons between study phases were controlled for 3-month adherence. Results reported

Compare tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1)

Outcome measures

Measure	TDF With a Boosted PI n=10 Participants Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS)	36014 fmol/2x7mm punches Geometric Coefficient of Variation 46.4	6735 fmol/2x7mm punches Geometric Coefficient of Variation 45.0	6100 fmol/2x7mm punches Geometric Coefficient of Variation 41.0

SECONDARY outcome

Timeframe: 12 weeks, 24 weeks, and 28 weeks

Change in estimated glomerular filtration rate (eGFR)

Outcome measures

Measure	TDF With a Boosted PI n=10 Participants Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR	86.7 mL/min/1.73 m^2 Geometric Coefficient of Variation 27.6	91.0 mL/min/1.73 m^2 Geometric Coefficient of Variation 23.0	88.1 mL/min/1.73 m^2 Geometric Coefficient of Variation 24.9

SECONDARY outcome

Timeframe: 12 weeks, 24 weeks, and 28 weeks

Change in estimated glomerular filtration rate (eGFR) and renal biomarkers: Urine protein to creatinine ratio (UPCR)

Outcome measures

Measure	TDF With a Boosted PI n=10 Participants Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR	134 mg/g Geometric Coefficient of Variation 65.7	118 mg/g Geometric Coefficient of Variation 50.2	97.3 mg/g Geometric Coefficient of Variation 41.0

SECONDARY outcome

Timeframe: 12 weeks, 24 weeks, and 28 weeks

Change in renal biomarkers: urinary beta-2 microglobulin (B2M)/creatinine (Cr) ratio, and urinary retinol binding protein (RBP)/Cr ratio

Outcome measures

Measure	TDF With a Boosted PI n=10 Participants Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 Participants Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio β2M:Cr ratio	419 ug/g Geometric Coefficient of Variation 176	224 ug/g Geometric Coefficient of Variation 167	178 ug/g Geometric Coefficient of Variation 156
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio RBP:Cr ratio	436 ug/g Geometric Coefficient of Variation 174	242 ug/g Geometric Coefficient of Variation 180	146 ug/g Geometric Coefficient of Variation 91.6

Adverse Events

TDF With a Boosted PI

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

TAF With a Boosted PI

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

TAF With a Boosted PI and LDV/SOF

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	TDF With a Boosted PI n=10 participants at risk Tenofovir disoproxil fumarate with a boosted protease inhibitor	TAF With a Boosted PI n=10 participants at risk Tenofovir alafenamide with a boosted protease inhibitor	TAF With a Boosted PI and LDV/SOF n=10 participants at risk Tenofovir alafenamide with a boosted protease inhibitor and ledipasvir/sofosbuvir
Renal and urinary disorders Renal events deemed possibly, probably or related	20.0% 2/10 • Number of events 3 • 40 weeks Adverse events were graded according to the Division of AIDS AE Reporting Table (July 2017, version 2.1)	20.0% 2/10 • Number of events 3 • 40 weeks Adverse events were graded according to the Division of AIDS AE Reporting Table (July 2017, version 2.1)	10.0% 1/10 • Number of events 1 • 40 weeks Adverse events were graded according to the Division of AIDS AE Reporting Table (July 2017, version 2.1)

Additional Information

Jennifer Kiser, PharmD, PhD

University of Colorado Anschutz Medical Campus

Phone: 3037246131

Email: jennifer.kiser@cuanschutz.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place