Clinical trial NCT02616029: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-11-26
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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)
timeFrame: Week 12
Secondary outcomes:
measure: Percentage of Participants With Emergence of New Mutations in HIV-1 Reverse Transcriptase and Integrase
timeFrame: Day 1 up to 48 weeks
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using PVR
timeFrame: Week 24
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using PVR
timeFrame: Week 48
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis
timeFrame: Week 12
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis
timeFrame: Week 24
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis
timeFrame: Week 48
measure: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 12 Using the FDA Snapshot Analysis
timeFrame: Week 12
measure: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 24 Using the FDA Snapshot Analysis
timeFrame: Week 24
measure: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 Using the FDA Snapshot Analysis
timeFrame: Week 48
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Failure (M = F) Approach
timeFrame: Week 12
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = F Approach
timeFrame: Week 24
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = F Approach
timeFrame: Week 48
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Excluded (M = E) Approach
timeFrame: Week 12
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = E Approach
timeFrame: Week 24
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = E Approach
timeFrame: Week 48
measure: Change From Baseline in Cluster Determinant 4+ (CD4+) Cell Count at Week 12
timeFrame: Baseline (Day 1); Week 12
measure: Change From Baseline in CD4+ Cell Count at Week 24
timeFrame: Baseline (Day 1); Week 24
measure: Change From Baseline in CD4+ Cell Count at Week 48
timeFrame: Baseline (Day 1); Week 48
measure: Change From Baseline in CD4 Percentage (%) at Week 12
timeFrame: Baseline (Day 1); Week 12
measure: Change From Baseline in CD4 % at Week 24
timeFrame: Baseline (Day 1); Week 24
measure: Change From Baseline in CD4 % at Week 48
timeFrame: Baseline (Day 1); Week 48
Other outcomes:
Locations:
city: Fort Pierce
country: United States
facility: Midway Immunology & Research Center, LLC
state: Florida
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: West Palm Beach
country: United States
facility: Triple O Research Institute PA
state: Florida
city: Marseille
country: France
facility: Hopital Sainte Marguerite - Hospital
city: Nantes
country: France
facility: CHU de Nantes
city: Nice
country: France
facility: CHU de Nice-l Archet
city: Orleans
country: France
facility: CHR Orleans la Source
city: Paris Cedex 10
country: France
facility: Hopital Saint Louis
city: Paris Cedex 15
country: France
facility: Hopital Necker les Enfants Malades
city: Tours
country: France
facility: CHU Tours Service de Médecine Internes et Maladies Infectieuses
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Hamburg
country: Germany
facility: ICH Study Center- Dedicated Research
city: Mainz
country: Germany
facility: Universitat Mainz
city: Genova
country: Italy
facility: IRCCS A.O.U. San Martino
city: Milano
country: Italy
facility: Fondazione IRCCS San Raffaele del Monte Tabor
city: Milano
country: Italy
facility: ASST Fatebenefratelli Sacco - Ospedale Luigi Sacco
city: Torino
country: Italy
facility: Comprensorio Amedeo Di Savoia Birago Di Vische
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona - Hospital
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre - Hospital
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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. 2021 Apr 1;86(4):490-495. doi: 10.1097/QAI.0000000000002595.