Evaluating Once Daily Etravirine in Treatment-Naive Adults With HIV Infection

Condition(s) targeted: HIV Infections

Intervention: Etravirine (Intelence) (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of North Carolina, Chapel Hill

Official(s) and/or principal investigator(s):
Michelle Floris-Moore, MD, MS, Principal Investigator, Affiliation: University of North Carolina, Chapel Hill

Overall contact:
Susan Pedersen, RN, BSN, Phone: 919-966-6713, Email: spederse@med.unc.edu

The main study is a single arm, open-label, prospective study to assess antiretroviral activity and tolerability of etravirine (TMC-125) 400 mg once daily, given with fixed-dose tenofovir/emtricitabine, in treatment-naïve HIV-1-infected men and women. There are also a genital secretions pharmacokinetic (PK) sub-study and a metabolic sub-study. The purpose of the genital secretions PK sub-study is to gain information about drug levels and HIV-1 RNA in genital secretions when subjects are taking etravirine. The purpose of the metabolic sub-study is to learn about the effects of etravirine on body composition, as well as lipid and glucose levels.

Official title: Antiretroviral Activity and Tolerability of Once Daily Etravirine in Treatment-Naïve Adults With HIV-1 Infection

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To estimate the antiretroviral activity of etravirine 400 mg given once daily, with fixed-dose Truvada once daily, among treatment-naïve HIV-1 infected adults as measured by the proportion of participants with HIV RNA < 50 copies/mL at Week 24.

Secondary outcome:

To assess the proportion of participants with HIV RNA <50 copies/mL at Week 48 and Week 96 of treatment with etravirine and fixed-dose tenofovir/emtricitabine.

To assess the proportion of participants with HIV RNA <200 copies/mL at Weeks 24, 48, and 96 of treatment with etravirine and fixed-dose tenofovir/emtricitabine.

To assess change in CD4+ cell count from baseline to Weeks 24, 48 and 96 of treatment with etravirine and fixed-dose tenofovir/emtricitabine.

To assess resistance mutations in the subset of patients with virologic failure while on etravirine and fixed-dose tenofovir/emtricitabine who have HIV RNA >500 copies/mL and genotype resistance results.

To assess population pharmacokinetics of etravirine 400 mg once daily, in combination with fixed-dose emtricitabine-tenofovir among treatment-naïve HIV-1 infected adults.

To assess pharmacokinetics of etravirine in genital secretions of up to 10 men and up to 10 women at Week 4 of treatment with etravirine and fixed-dose tenofovir/emtricitabine.

To assess tolerability of etravirine in HIV-1 infected adults initiating antiretroviral therapy.

To assess change in the lipid profile and glucose metabolism, in a subgroup of up to 40 participants, from baseline to Weeks 24, 48, and 96 of treatment with etravirine and fixed-dose tenofovir/emtricitabine.

To assess change in limb and trunk fat distribution as measured by DEXA scan, in the same subgroup of up to 40 participants (as in Aim 8), from baseline to Weeks 24 and 96 of treatment with etravirine and fixed-dose tenofovir/emtricitabine.

Detailed description: Participants: There will be approximately 80 HIV-1-infected men and women aged 18 years or older who have taken less than or equal to 10 days of prior antiretroviral therapy and have never taken etravirine, dapivirine (TMC120), or rilpivirine (TMC 278) in the main study. There will be approximately 40 subjects who enroll in the main study that will be in the metabolic sub-study and approximately 20 subjects (10 pre-menopausal women and 10 men) who enroll in the main study that will be in the genital secretions PK sub-study.

Procedures (methods): For the main study subjects will take etravirine 400 mg once daily orally with fixed-dose tenofovir/emtricitabine (Truvada) one tablet once daily. For the genital secretions PK sub-study, genital secretion samples will be self-collected throughout the study except for the week 4 study visit where women will have the cervicovaginal sample at time 0 and at 24 hours collected by study staff. For the metabolic sub-study, waist measurements and DEXA scans will be performed at entry, week 24, and week 96, and 2-3 teaspoons of blood to check lipids, insulin, and glucose will be taken at entry and weeks 12, 24, 48, and 96.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- HIV-1 infection as documented by any licensed ELISA test and confirmed by Western

Blot or other confirmatory test at any time prior to study entry. Acceptable alternative confirmatory tests are plasma HIV-1 RNA, HIV-1 culture, HIV-1 antigen, or a second antibody test by a method other than ELISA. Alternatively, if an HIV-antibody test result is not available, two HIV-1 RNA values >2000 copies/mL, drawn at least 24 hours apart, performed by any laboratory that has CLIA certification, or its equivalent, may be used to document infection.

- Age 18 years or older.

- Able to provide informed consent.

- In the opinion of the investigator, able to comply with study medication and

procedures.

- Plasma HIV-1 RNA ≥ 1000 copies/mL as measured by any FDA-approved test for

quantifying HIV-1 RNA within 90 days prior to study entry.

- Less than or equal to 10 days of cumulative exposure to antiretroviral therapy.

- For all women of reproductive potential, a negative urine or serum β-HCG pregnancy

test performed within 48 hours prior to study entry.

- All study volunteers, both male and female, must agree not to participate in a

conception process (i. e., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) while receiving study medications and for 6 weeks after stopping study medications.

- If participating in sexual activity that could lead to conception, study

volunteers must agree to use at least one method of reliable contraception which must be a barrier method (i. e., a condom without spermicide, a diaphragm, or cervical cap) throughout the study and for 6 weeks thereafter.

NOTE: Acceptable documentation of lack of reproductive potential for a woman is self-reported history of being postmenopausal for at least 24 months, or having had surgical sterilization (hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation) or of male partner's azoospermia. Acceptable documentation for a man is self-reported history of azoospermia.

- Hemoglobin ≥ 7. 5 g/dL within 45 days prior to study entry.

- Absolute neutrophil count ≥ 500/mm³ within 45 days prior to study entry.

- Platelets ≥ 50,000/mm³ within 45 days prior to study entry.

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 3X ULN or

bilirubin ≤ 2. 5 ULN within 45 days prior to study entry.

- GFR > 59 as calculated by MDRD within 45 days prior to study entry.

Exclusion Criteria:

- Prior receipt of etravirine, dapivirine (TMC120), or rilpivirine (TMC 278).

- Evidence of any of the resistance-associated mutations listed below on genotype

testing performed within 90 days of study entry. Any pending resistance testing ordered prior to study entry must be available for review by the investigator prior to enrollment. Major resistance mutations include:

1. Any of the following NNRTI mutations: V90I, A98G, L100I, K101E/H/P/Q, K103H/S/T, V106A/I/M, V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P225H, F227C/L, M230I/L, P236L, K238N/T, K103N.

2. Any of the following NRTI mutations: M184V/I, K70E/R, K65R, M41L, 69 insert, L210W, T215Y/F, K219Q/E, L74V.

- Pregnancy

- Breastfeeding

- Any condition which, in the opinion of the investigator, would be likely to interfere

with ability to take the study medications appropriately and comply with the study protocol.

- Use of any systemic antineoplastic or immunomodulatory treatment, systemic

corticosteroids, investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 30 days prior to study entry.

NOTE: Routine standard of care, including hepatitis B, influenza, pneumococcus, and tetanus vaccines are permitted.

- Current active illness requiring systemic treatment and/or hospitalization until the

individual completes therapy or, in the opinion of the investigator, is clinically stable on therapy for at least 7 days prior to study entry.

- Life expectancy of less than 6 months.

- Acute viral hepatitis.

- Known allergy/hypersensitivity to components of the study drugs or their

formulations.

- Use of any medications that are prohibited during the study period (see Section 8. 1

of the protocol - Prohibited Medications).

- Refusal by an individual who is taking anti-depressant medications to allow the

investigator or Primary HIV Care provider to communicate with his/her psychiatrist/Mental Health clinician regarding the initiation of study medications in those cases where co-administration of study drugs may alter anti-depressant drug levels.

Susan Pedersen, RN, BSN, Phone: 919-966-6713, Email: spederse@med.unc.edu

The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7215, United States; Recruiting
Donna Pittard, RN, BSN, Phone: 919-843-6512, Email: donna_pittard@med.unc.edu
David Ragan, RN, BSN, Phone: 919-966-2623, Email: davidrag@med.unc.edu
Michelle Floris-Moore, MD, MS, Principal Investigator
Joseph Eron, MD, Sub-Investigator
David Wohl, MD, Sub-Investigator
Kristine Patterson, MD, Sub-Investigator
Angela Kashuba, PharmD, Sub-Investigator

Carolinas Medical Center, Charlotte, North Carolina 28207, United States; Recruiting
Jessica Kearney-Bryan, RN, BSN, Phone: 704-355-0244, Email: jessica.kearney-bryan@carolinashealthcare.org
Marc A Johnson, MD, Principal Investigator

Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, United States; Recruiting
Melissa Trader, Phone: 336-716-8918, Email: mtrader@wfubmc.edu
Liby Mosley, Phone: 336-716-3266, Email: limosley@wfubmc.edu
Aimee M Wilkin, MD, MPH, Principal Investigator

Related publications:

Gruzdev B, Rakhmanova A, Doubovskaya E, Yakovlev A, Peeters M, Rinehart A, de Dier K, Baede-Van Dijk P, Parys W, van 't Klooster G. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS. 2003 Nov 21;17(17):2487-94.

TMC125-C223 Writing Group; Nadler JP, Berger DS, Blick G, Cimoch PJ, Cohen CJ, Greenberg RN, Hicks CB, Hoetelmans RM, Iveson KJ, Jayaweera DS, Mills AM, Peeters MP, Ruane PJ, Shalit P, Schrader SR, Smith SM, Steinhart CR, Thompson M, Vingerhoets JH, Voorspoels E, Ward D, Woodfall B. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS. 2007 Mar 30;21(6):F1-10.

Shikuma CM, Yang Y, Glesby MJ, Meyer WA 3rd, Tashima KT, Ribaudo HJ, Webb N, Bastow B, Kuritzkes DR, Gulick RM. Metabolic effects of protease inhibitor-sparing antiretroviral regimens given as initial treatment of HIV-1 Infection (AIDS Clinical Trials Group Study A5095). J Acquir Immune Defic Syndr. 2007 Apr 15;44(5):540-50.

Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, de Smedt G, Leopold L, Trefiglio R, Woodfall B; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):29-38.

Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, de Smedt G, Baeten B, Beets G, Sinha R, Woodfall B; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):39-48.

Ghosn J, Chaix ML, Peytavin G, Rey E, Bresson JL, Goujard C, Katlama C, Viard JP, Tréluyer JM, Rouzioux C. Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. AIDS. 2004 Sep 24;18(14):1958-61.

Reddy YS, Gotzkowsky SK, Eron JJ, Kim JY, Fiske WD, Fiscus SA, Petch L, Cohen MS, Kashuba AD. Pharmacokinetic and pharmacodynamic investigation of efavirenz in the semen and blood of human immunodeficiency virus type 1-infected men. J Infect Dis. 2002 Nov 1;186(9):1339-43. Epub 2002 Oct 7.

Taylor S, Reynolds H, Sabin CA, Drake SM, White DJ, Back DJ, Pillay D. Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men. AIDS. 2001 Oct 19;15(15):2051-3.

van Praag RM, Repping S, de Vries JW, Lange JM, Hoetelmans RM, Prins JM. Pharmacokinetic profiles of nevirapine and indinavir in various fractions of seminal plasma. Antimicrob Agents Chemother. 2001 Oct;45(10):2902-7. Erratum in: Antimicrob Agents Chemother 2002 Mar;46(3):941.

Scholler-Gyure M, Kakuda TN, De Smedt G, Woodfall B, Lachaert R, Beets G, Peeters M, Hoetelmans RM. Pharmacokinetics of TMC125 in once- and twice- daily regimens in HIV-1-negative volunteers. Program and Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2007 [Abstract A-1427], Chicago IL.

[No authors listed] 144-week data released on Gilead's study 934. AIDS Patient Care STDS. 2007 Aug;21(8):603-4. No abstract available.

Starting date: September 2009
Last updated: June 2, 2011