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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 dual energy x-ray absorptiometry (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.

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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Etravirine (Intelence)
* Drug: Truvada


Participation Criteria
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Eligibility Criteria
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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 clinical laboratory improvement amendments (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-human chorionic gonadotropin (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 upper limit of normal (ULN) or bilirubin ≤ 2.5 ULN within 45 days prior to study entry. Glomerular filtration rate (GFR) > 59 as calculated by Modification of Diet in Renal Disease (MDRD) equation within 45 days prior to study entry. Exclusion Criteria: Prior receipt of etravirine, dapivirine, or rilpivirine (Edurant), or Complera. 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: Any of the following nonnucleoside reverse transcriptase inhibitor (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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etravirine 400 mg once daily<br>Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily | Drug: Etravirine (Intelence)<br>* Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day<br>* Other names: Intelence;Drug: Truvada<br>* Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day<br>* Other names: Tenofovir/emtricitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Percentage of Participants With HIV RNA < 50 Copies/mL at Week 24 | The primary study endpoint was the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 24 of study participation. The per-protocol primary analysis was conducted intention-to-treat, with missing evaluations counted as failures. Achievement of HIV-1 viral load below 50 copies/ml was defined as having HIV-1 RNA <50 copies/ml during the Week 24 analysis window (>18 and <30 weeks post-entry). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Participants With HIV RNA <50 Copies/mL at Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 48 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures. | 48 weeks | 
| The Proportion of Participants With HIV RNA <50 Copies/mL at Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 96 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures. | 96 weeks | 
| The Proportion of Participants With HIV RNA <200 Copies/mL at Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <200 copies/ml at Week 24 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures. | 24 weeks | 
| The Proportion of Participants With HIV RNA <200 Copies/mL at Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <200 copies/ml at Week 48 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures. | 48 weeks | 
| The Proportion of Participants With HIV RNA <200 Copies/mL at Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA 200 copies/ml at Week 96 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures. | 96 weeks | 
| Change in CD4+ Cell Count From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | The per-protocol analysis of change in CD4+ cell count from baseline to Week 24 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% confidence interval (CI). | Baseline to 24 weeks | 
| Change in CD4+ Cell Count From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | The per-protocol intention-to-treat analysis of change in CD4+ cell count from baseline to Week 48 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% CI. | Baseline to 48 weeks | 
| Change in CD4+ Cell Count From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | The per-protocol intention-to-treat analysis of change in CD4+ cell count from baseline to Week 96 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% CI. | Baseline to 96 weeks | 
| Resistance Mutations in the Subset of Patients With Confirmed Virologic Failure Who Have HIV RNA >500 Copies/mL and Genotype Resistance Results | Per-protocol, genotype testing was conducted at confirmation of virologic failure if the confirmatory HIV-1 RNA was above the laboratory-specified threshold of 500 copies/mL. HIV-1 genotype was determined using the TRUGENE® HIV-1 assay (Siemens Healthcare Diagnostics, Tarrytown, NY) | 96 weeks | 
| Tolerability of Etravirine in HIV-1 Infected Adults Initiating Antiretroviral Therapy | The safety/tolerability endpoint was defined as the first grade 3 or higher sign, symptom or laboratory abnormality that was at least one grade higher than baseline among participants ever exposed to etravirine (regardless of treatment status), or permanent discontinuation of etravirine due to any toxicity (regardless of grade). Modification of tenofovir/emtricitabine was not a safety/tolerability event. The Kaplan-Meier method was used to estimate the proportion of participants ever exposed to etravirine who remained event-free through Week 96, with a 95% CI using Greenwood's variance estimate and a log-log transformation. Time was handled as continuous (weeks from treatment start to event or censoring). | 96 weeks | 
| Probability of Remaining Free of a Safety/Tolerability Event at 96 Weeks | The Kaplan-Meier method was used to estimate the proportion of participants ever exposed to etravirine who remained event-free through Week 96, with a 95% CI using Greenwood's variance estimate and a log-log transformation. Time was handled as continuous (weeks from treatment start to event or censoring). | 96 weeks | 
| Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. | Baseline to 24 weeks | 
| Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. | Baseline to 24 weeks | 
| Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. | Baseline to 48 weeks | 
| Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. | Baseline to 48 weeks | 
| Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. | Baseline to 96 weeks | 
| Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. | Baseline to 96 weeks | 
| 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 Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Changes from baseline to follow-up in limb fat, trunk fat, total body fat, and lean mass were calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI. | Baseline to 24 weeks | 
| 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 Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Changes from baseline to follow-up in limb fat, trunk fat, total body fat, and lean mass were calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI. | Baseline to 96 weeks | 
| Change in Fat Mass Ratio as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Change from baseline to follow-up in fat mass ratio was calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Fat mass ratio was calculated as the ratio of trunk fat percentage and lower limb fat percentage (% trunk fat mass / % lower limb fat mass). Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI. | Baseline to 24 weeks | 
| 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 | This secondary outcome measure assessed the ratio of semen:plasma concentration of etravirine in paired semen and plasma samples collected from 14 male participants at Week 4 of treatment with etravirine and fixed dose tenofovir/emtricitabine. | 4 weeks | 
| Change in Fat Mass Ratio as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine | Change from baseline to follow-up in fat mass ratio was calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Fat mass ratio was calculated as the ratio of trunk fat percentage and lower limb fat percentage (% trunk fat mass / % lower limb fat mass). Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI. | Baseline to 96 weeks | 
| Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults | Population pharmacokinetics were calculated using sparse sampling. Plasma concentrations of etravirine measured in samples from participants who provided blood samples at multiple study visits, with variation in sampling times relative to dosing of etravirine used to cover the spectrum of the dosing schedule. Model simulations and fitting were performed with NONMEM ® 7.3. (ICON, plc) and model exploration was performed with Berkeley Madonna (Berkeley, CA, USA) | At or after 4 weeks | 
| Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults: Etravirine AUC-24 Hours at Steady State | Population pharmacokinetics were calculated using sparse sampling. Plasma concentrations of etravirine measured in samples from participants who provided blood samples at multiple study visits, with variation in sampling times relative to dosing of etravirine used to cover the spectrum of the dosing schedule. Model simulations and fitting were performed with NONMEM ® 7.3. (ICON, plc) and model exploration was performed with Berkeley Madonna (Berkeley, CA, USA) | At or after 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adults, HIV, Infection, Treatment Naive, Once, Daily, Etravirine, HIV-1 Infection