Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I

HIV-1 Infection Clinical Trial

Official title:

A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adult Subjects Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02616029
• Other study ID #: GS-US-292-1824
• Secondary ID: 2015-002710-74
• Status: Completed
• Phase: Phase 3
• Start date: December 17, 2015
• Est. completion date: July 11, 2019

Study information

• Verified date: July 2020
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the study is to evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) after switching from a stable regimen consisting of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) plus a third antiretroviral (ARV) agent in participants harboring the archived nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V and/or M184I in human immunodeficiency virus (HIV) -1 reverse transcriptase.

This is a two part study. If the rate of virologic failure in Part 1 is deemed acceptable, once the internal data monitoring committee officially completes the interim review, the study will continue to Part 2.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 66
• Est. completion date: July 11, 2019
• Est. primary completion date: October 11, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Documented historical genotype report showing mutation M184V and/or M184I (mixtures are acceptable) in reverse transcriptase. Individuals must not have any primary integrase strand transfer inhibitor (INSTI) or primary protease inhibitor (PI) resistance mutations present on historical genotype; non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations are allowed.

• Proviral deoxyribonucleic acid (DNA) test must not have additional exclusion resistance mutations against PIs, NRTIs and INSTIs

• Part 1: Historical genotype report must show mutation M184V and/or M184I in reverse transcriptase WITHOUT any other NRTI resistance mutation (including thymidine analogue-associated mutations [TAMs] [TAMs are: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion, and Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M])

• Part 2 (after the interim efficacy review): Historical genotype report must show M184V and/or M184I in reverse transcriptase WITH or WITHOUT 1 or 2 TAMs. Evidence of K65R, K70E, T69 insertion and/or Q151M mutation complex will not be eligible

• Currently receiving an ARV regimen consisting of FTC/TDF or ABC/3TC in combination with one third ARV agent for = 6 consecutive months preceding the screening visit

• Documented plasma HIV-1 ribonucleic acid (RNA) levels < 50 copies/mL for = 6 months preceding the screening visit

• Plasma HIV-1 RNA levels < 50 copies/mL at screening visit

• Estimated glomerular filtration rate (GFR) = 30 mL/min according to the Cockcroft-Gault formula for creatinine clearance

• A female individual is eligible to enter the study if it is confirmed that she is:

• not pregnant

• of non-childbearing potential

• stopped menstruating for = 12 months

• of childbearing potential and agrees to utilize the protocol-specified method of contraception or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following discontinuation of study drugs

• Male individuals must agree to use the protocol-specified method(s) of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from screening throughout the study period and for 30 days following the last study drug dose

• Male individuals must agree to refrain from sperm donation from first dose until at least 30 days after the last study drug dose

Key Exclusion Criteria:

• Individuals will have no evidence of previous virologic failure on a PI/r or INSTI-based regimen (with or without resistance to either class of ARV). Individuals may have evidence of prior virologic failure on only an NNRTI plus 2 NRTI-based regimen

• Individuals on a current PI/r-based regimen will have no evidence of previous use of any approved or experimental integrase strand transfer inhibitor (INSTI) (for any length of time)

• Hepatitis C infection that would require therapy during the study

• Hepatitis B surface antigen (HBsAg) positive

• Individuals with clinical evidence of decompensated cirrhosis (eg, ascites, encephalopathy, variceal bleeding)

• Have an implanted defibrillator or pacemaker

• A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non invasive cutaneous squamous carcinoma. Individuals with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 and must not be anticipated to require systemic therapy during the study

• Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1

NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• E/C/F/TAF
150/150/200/10 mg FDC tablets administered orally once daily

Locations

Country	Name	City	State
France	Hopital Sainte Marguerite - Hospital	Marseille
France	CHU de Nantes	Nantes
France	CHU de Nice-l Archet	Nice
France	CHR Orleans la Source	Orleans
France	Hopital Saint Louis	Paris Cedex 10
France	Hopital Necker les Enfants Malades	Paris Cedex 15
France	CHU Tours Service de Médecine Internes et Maladies Infectieuses	Tours
Germany	Universitatsklinikum Essen	Essen
Germany	ICH Study Center- Dedicated Research	Hamburg
Germany	Universitat Mainz	Mainz
Italy	IRCCS A.O.U. San Martino	Genova
Italy	ASST Fatebenefratelli Sacco - Ospedale Luigi Sacco	Milano
Italy	Fondazione IRCCS San Raffaele del Monte Tabor	Milano
Italy	Comprensorio Amedeo Di Savoia Birago Di Vische	Torino
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Hospital Clinic de Barcelona - Hospital	Barcelona
Spain	Hospital Universitario 12 de Octubre - Hospital	Madrid
Spain	Hospital Universitario La Paz	Madrid
United States	Midway Immunology & Research Center, LLC	Fort Pierce	Florida
United States	Orlando Immunology Center	Orlando	Florida
United States	Triple O Research Institute PA	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Spain, 

References & Publications (3)

Perez-Valero I, Llibre JM, Lazzarin A, di Perri G, Pulido F, Molina JM, Esser S, Margot N, Shao Y, Piontkowsky D, Das M, McNicholl IR, Haubrich R. A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) in Virologically-Suppressed HIV-1 Infected Adults Harboring the NRTI Resistance Mutation M184V/I (GS-US-292-1824): Week 24 Results [Poster PE13/20]. 17th European AIDS Conference (EACS), 6-9 November 2019, Basel, Switzerland.

Perez-Valero I, Llibre JM, Lazzarin A, di Perri G, Pulido F, Molina JM, Esser S, McNicholl IR, Lorgeoux RP, Margot N, Shao Y, Piontkowsky D, Das M, Haubrich R. A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Single Tablet Regimen in Virologically-Suppressed HIV-1 Infected Adults Harboring the NRTI Resistance Mutation M184V and/or M184I (GS-US-292-1824): Week 12 Results [Poster]. XXVI International Workshop on HIV Drug Resistance and Treatment Strategies, 6-8 November 2017, Johannesburg, South Africa.

Perez-Valero I, Llibre JM, Lazzarin A, di Perri G, Pulido F, Molina JM, Esser S, McNicholl IR, Lorgeoux RP, Margot N, Shao Y, Piontkowsky D, Das M, Haubrich R. A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Single-Tablet Regimen in Virologically-Suppressed HIV-1 Infected Adults Harboring the NRTI Resistance Mutation M184V and/or M184I (GS-US-292-1824): Week 24 Results [Oral abstract]. 22nd International AIDS Conference, 23-27 July 2018, Amsterdam, The Netherlands.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/mL at Week 12 as Defined by Pure Virologic Response (PVR)	The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 12 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values = 50 copies/mL or the last available HIV-1 RNA value = 50 copies/mL during the study followed by premature discontinuation from the study.	Week 12
Secondary	Percentage of Participants With Emergence of New Mutations in HIV-1 Reverse Transcriptase and Integrase	Development of new resistance mutations was assessed in participants who developed virologic failure, defined as 2 consecutive HIV-1 RNA result = 50 copies/mL at any point in the study or with HIV-1 RNA = 50 copies/mL at last visit.	Day 1 up to 48 weeks
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using PVR	The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 24 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values = 50 copies/mL or the last available HIV-1 RNA value = 50 copies/mL during the study followed by premature discontinuation from the study.	Week 24
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using PVR	The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 48 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values = 50 copies/mL or the last available HIV-1 RNA value = 50 copies/mL during the study followed by premature discontinuation from the study.	Week 48
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 71 and 98 (inclusive).	Week 12
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 24 window was between Day 141 and 210 (inclusive).	Week 24
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 295 and 378 (inclusive).	Week 48
Secondary	Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 12 Using the FDA Snapshot Analysis	The percentage of participants with HIV-1 RNA < 20 copies/mL at Week 12 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 71 and 98 (inclusive).	Week 12
Secondary	Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 24 Using the FDA Snapshot Analysis	The percentage of participants with HIV-1 RNA < 20 copies/mL at Week 24 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 24 window was between Day 141 and 210 (inclusive).	Week 24
Secondary	Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 Using the FDA Snapshot Analysis	The percentage of participants with HIV-1 RNA < 20 copies/mL at Week 48 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 295 and 378 (inclusive).	Week 48
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Failure (M = F) Approach	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was analyzed using the M = F approach. In this approach, all missing data was treated as HIV-1 RNA = 50 copies/mL.	Week 12
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = F Approach	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the M = F approach. In this approach, all missing data was treated as HIV-1 RNA = 50 copies/mL.	Week 24
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = F Approach	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the M = F approach. In this approach, all missing data was treated as HIV-1 RNA = 50 copies/mL.	Week 48
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Excluded (M = E) Approach	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was also analyzed using the M = E approach. In this approach, all missing data was excluded in the computation of the proportions.	Week 12
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = E Approach	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was also analyzed using the M = E approach. In this approach, all missing data was excluded in the computation of the proportions.	Week 24
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = E Approach	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was also analyzed using the M = E approach. In this approach, all missing data was excluded in the computation of the proportions.	Week 48
Secondary	Change From Baseline in Cluster Determinant 4+ (CD4+) Cell Count at Week 12		Baseline (Day 1); Week 12
Secondary	Change From Baseline in CD4+ Cell Count at Week 24		Baseline (Day 1); Week 24
Secondary	Change From Baseline in CD4+ Cell Count at Week 48		Baseline (Day 1); Week 48
Secondary	Change From Baseline in CD4 Percentage (%) at Week 12		Baseline (Day 1); Week 12
Secondary	Change From Baseline in CD4 % at Week 24		Baseline (Day 1); Week 24
Secondary	Change From Baseline in CD4 % at Week 48		Baseline (Day 1); Week 48