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

• ClinicalTrials.gov Identifier: NCT02616029
• Recruitment Status: Completed
• First Posted: November 26, 2015
• Results First Posted: November 4, 2019
• Last Update Posted: July 23, 2020
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: November 24, 2015
• First Posted Date: November 26, 2015
• Results First Submitted Date: October 10, 2019
• Results First Posted Date: November 4, 2019
• Last Update Posted Date: July 23, 2020
• Actual Study Start Date: December 17, 2015
• Actual Primary Completion Date: October 11, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 9, 2020)

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) [ Time Frame: Week 12 ]

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.

• Original Primary Outcome Measures (submitted: November 24, 2015): Proportion of participants with HIV-1 RNA < 50 copies/mL at Week 12 as defined by pure virologic response (PVR) [ Time Frame: Week 12 ]

Current Secondary Outcome Measures (submitted: July 9, 2020)

• Percentage of Participants With Emergence of New Mutations in HIV-1 Reverse Transcriptase and Integrase [ Time Frame: Day 1 up to 48 weeks ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using PVR [ Time Frame: Week 24 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using PVR [ Time Frame: Week 48 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis [ Time Frame: Week 12 ]
  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).
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis [ Time Frame: Week 24 ]
  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).
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis [ Time Frame: Week 48 ]
  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).
• Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 12 Using the FDA Snapshot Analysis [ Time Frame: Week 12 ]
  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).
• Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 24 Using the FDA Snapshot Analysis [ Time Frame: Week 24 ]
  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).
• Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 Using the FDA Snapshot Analysis [ Time Frame: Week 48 ]
  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).
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Failure (M = F) Approach [ Time Frame: Week 12 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = F Approach [ Time Frame: Week 24 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = F Approach [ Time Frame: Week 48 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Excluded (M = E) Approach [ Time Frame: Week 12 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = E Approach [ Time Frame: Week 24 ]
  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.
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = E Approach [ Time Frame: Week 48 ]
  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.
• Change From Baseline in Cluster Determinant 4+ (CD4+) Cell Count at Week 12 [ Time Frame: Baseline (Day 1); Week 12 ]
• Change From Baseline in CD4+ Cell Count at Week 24 [ Time Frame: Baseline (Day 1); Week 24 ]
• Change From Baseline in CD4+ Cell Count at Week 48 [ Time Frame: Baseline (Day 1); Week 48 ]
• Change From Baseline in CD4 Percentage (%) at Week 12 [ Time Frame: Baseline (Day 1); Week 12 ]
• Change From Baseline in CD4 % at Week 24 [ Time Frame: Baseline (Day 1); Week 24 ]
• Change From Baseline in CD4 % at Week 48 [ Time Frame: Baseline (Day 1); Week 48 ]

Original Secondary Outcome Measures (submitted: November 24, 2015)

• Proportion of participants with emergence of new mutations in HIV-1 reverse transcriptase and integrase [ Time Frame: Up to 48 weeks ]
  This outcome measure will be assessed with any post Day 1 sample with HIV-1 RNA ≥ 50 copies/mL.
• Proportion of participants with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 using PVR [ Time Frame: Weeks 24 and 48 ]
• Proportion of participants with HIV-1 RNA < 50 copies/mL at Weeks 12, 24 and 48 using the FDA snapshot analysis [ Time Frame: Weeks 12, 24, and 48 ]
• Proportion of participants with CD4+ cell count change from Day 1 at Weeks 12, 24 and 48 [ Time Frame: Day 1, Weeks 12, 24, and 48 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

Brief 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV-1 Infection

Intervention

Drug: E/C/F/TAF

150/150/200/10 mg FDC tablets administered orally once daily

Other Name: Genvoya®

Study Arms

• Experimental: Part 1: E/C/F/TAF

  Participants with M184V and/or M184I mutations in reverse transcriptase and without any other NRTI resistance mutation switched from their current human immunodeficiency virus (HIV) treatment regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF (150/150/200/10 mg) FDC tablet orally once daily for 48 weeks.

  Allowed third agents include: lopinavir/ritonavir (LPV/r), atazanavir + ritonavir (ATV+RTV), atazanavir+cobicistat (ATV+COBI), darunavir + ritonavir (DRV+RTV), darunavir + cobicistat (DRV+COBI), fosamprenavir + ritonavir (FPV + RTV), saquinavir + ritonavir (SQV + RTV), atazanavir (ATV) (no booster) efavirenz (EFV), rilpivirine (RPV), nevirapine (NVP), etravirine (ETR), raltegravir (RAL) or dolutegravir (DTG).

  Intervention: Drug: E/C/F/TAF
• Experimental: Part 2: E/C/F/TAF

  Participants with M184V and/or M184I mutations in reverse transcriptase and with or without 1 or 2 TAMs switched from their current HIV treatment regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF (150/150/200/10 mg) FDC tablet orally once daily for 48 weeks.

  Allowed third agents include: LPV/r, ATV+RTV, ATV+COBI, DRV+RTV, DRV+COBI, FPV + RTV, SQV + RTV, ATV (no booster) EFV, RPV, NVP, ETR, RAL or DTG.

  Intervention: Drug: E/C/F/TAF

Publications *

• 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 24 Results [Oral abstract]. 22nd International AIDS Conference, 23-27 July 2018, Amsterdam, The Netherlands.
• 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, Castagna A, Pulido F, Molina JM, Esser S, Margot N, Shao Y, Temme L, Piontkowsky D, McNicholl IR, Haubrich R. Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in Adults With HIV and M184V/I Mutation. J Acquir Immune Defic Syndr. 2020 Dec 10. doi: 10.1097/QAI.0000000000002595. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 10, 2019): 66
• Original Estimated Enrollment (submitted: November 24, 2015): 100
• Actual Study Completion Date: July 11, 2019
• Actual Primary Completion Date: October 11, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany, Italy, Spain, United States

Administrative Information

• NCT Number: NCT02616029
• Other Study ID Numbers: GS-US-292-1824; 2015-002710-74 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy

• Responsible Party: Gilead Sciences
• Study Sponsor: Gilead Sciences
• Collaborators: Not Provided

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: July 2020