TMC125-TiDP2-C238: An Exploratory Pharmacokinetics, Safety and Anti-HIV Activity Study of Etravirine (ETR) When Given With Boosted Atazanavir (ATV/Rtv) at Two Different Doses and 1 Nucleoside Reverse Transcriptase Inhibitor (NRTI) in Treatment Experienced HIV Patients

NCT00896051 | Completed Phase 2 Results DMC

• 2 other identifiers: CR016045TMC125-TiDP2-C238
• Study Type: interventional
• Target: 50
• Locations: 5 countries
• Sites: 18

Brief Summary

The purpose of this study is to determine the pharmacokinetics (how the body absorbs, distributes, metabolizes and eliminates a drug) (PK) of ETR when given with ATV/rtv and 1 NRTI in treatment experienced HIV-1 infected patients. In addition, safety, tolerability and anti-HIV effect of this regimen will also be studied. A total of 46 patients will be enrolled.

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome

Keywords

HIV Infections; Acquired Immunodeficiency Syndrome; TMC125-TiDP2-C238; TMC125-C238; Etravirine; Intelence; HIV; HIV-1; Pharmacokinetics

Outcome Measures

Primary Outcomes (11)

• Pharmacokinetic Results of Atazanavir (ATV): Treatment A: ATV/Low-Dose Ritonavir (Rtv) 300/100 mg (Results for C0h, Cmin, and Cmax)

  The table below shows pharmacokinetic (PK) results of atazanavir (ATZ) when administered as ATV/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), and maximum plasma concentration (Cmax).

  Day -1 (Pretreatment); Week 2 (Test)

• Pharmacokinetic Results of Atazanavir (ATV): Treatment A: ATV/Low-Dose Ritonavir (Rtv) 300/100 mg (Results for AUC24hr)

  The table below shows pharmacokinetic (PK) results of atazanavir (ATZ) when administered as ATV/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr).

  Day -1 (Pretreatment); Week 2 (Test)

• Pharmacokinetic Results of Atazanavir (ATV): Treatment B: ATV/Low-Dose Ritonavir (Rtv) 400/100 mg (Results for C0h, Cmin, and Cmax)

  The table below shows pharmacokinetic (PK) results of atazanavir (ATV) when administered as ATV/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr).

  Day -1 (Reference); Week 2 (Test)

• Pharmacokinetic Results of Atazanavir (ATV): Treatment B: ATV/Low-Dose Ritonavir (Rtv) 400/100 mg (Results for AUC24hr)

  The table below shows pharmacokinetic (PK) results of atazanavir (ATV) when administered as ATV/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr).

  Day -1 (Reference); Week 2 (Test)

• Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment A: Atazanavir (ATV)/Rtv 300/100 mg (Results for C0h, Cmin, and Cmax)

  The table below shows the pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), and maximum plasma concentration (Cmax).

  Day -1 (Reference); Week 2 (Test)

• Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment A: Atazanavir (ATV)/Rtv 300/100 mg (Results for AUC24hr)

  The table below shows the pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/rtv 300/100 mg pretreatment (Reference) and at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr).

  Day -1 (Reference); Week 2 (Test)

• Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment B: Atazanavir (ATV)/Rtv 400/100 mg (Results for C0h, Cmin, and Cmax)

  The table below shows pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr).

  Day -1 (Reference); Week 2 (Test)

• Pharmacokinetic Results of Low-Dose Ritonavir (Rtv): Treatment B: Atazanavir (ATV)/Rtv 400/100 mg (Results for AUC24hr)

  The table below shows pharmacokinetic (PK) results of low-dose ritonavir (rtv) when administered as atazanavir (ATV)/ritonavir (rtv) 300/100 mg pretreatment (Reference) and when administered as ATV/rtv 400/100 mg at Week 2 after treatment (Test). Results are expressed as the area under the plasma concentration-time curve from time of intake to 24 hours after dosing (AUC24hr).

  Day -1 (Reference); Week 2 (Test)

• Pharmacokinetic Results of Etravirine (ETR) (Results for C0h, Cmin, and Cmax)

  The table below shows pharmacokinetic (PK) results of ETR in the current study expressed as the predose plasma concentration (C0h), minimum plasma concentration (Cmin) and maximum plasma concentration (Cmax).

  Week 2

• Pharmacokinetic Results of Etravirine (ETR) (Results for AUC12hr)

  The table below shows pharmacokinetic (PK) results of ETR in the current study expressed as the area under the plasma concentration-time curve from time of intake to 12 hours after dosing (AUC12hr).

  Week 2

• Percentage of Participants With Undetectable Plasma Viral Load (VL) Values (<50 Copies/mL) at Week 48

  The table below shows the percentage of participants wih undetectable plasma viral load (VL) values (\<50 copies/mL) at Week 48 using the Non-Completing = Failure (NC=F) imputation method (ie, participants who discontinued early were counted as nonresponders by having their VL values after discontinuation imputed with their baseline value, thus resulting in a 0 change).

  Week 48

Secondary Outcomes (7)

• Change From Prebaseline in CD4+ Cell Count Over Time

  Prebaseline, Baseline, Weeks 4, 12, 24, 48

• The Percentage of Participants With a Virologic Response Using the Non-Completing = Failure (NC=F) Imputation Method

  Baseline, Weeks 4, 12, 24, 48

• The Percentage of Participants With a Virologic Response Using the Time to Loss of Virologic Response (TLOVR) Imputation Method

  Baseline, Weeks 4, 12, 24, 48

• The Percentage of Participants With a Virologic Response (Plasma Viral Load < 50 Copies/mL) at Week 48 Using the Snapshot Analysis Method

  Week 48

• Change From Pre-Baseline in Log10 Viral Load Over Time

  Pre-Baseline, Baseline, Weeks 4, 12, 24, 48

Study Arms (2)

ATV/rtv 300/100 mg (Treatment A)

EXPERIMENTAL

Treatment-experienced human immunodeficiency virus - type 1 (HIV-1) infected participants will take by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for 2 weeks pre-treatment followed by ATV/rtv 300/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks. If particpating in an optional substudy to assess the effect of adding tenofovir disoproxil fumarate (TDF) for 7 days on ATV and ETR pharmacokinetics, participants will receive TDF 300 mg once daily for 7 days in addition to their antiretroviral regimen (ETR+ATV/rtv+NRTI).

Drug: Atazanavir (ATV) 300 mg; Drug: Ritonavir (rtv) 100 mg; Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs); Drug: Etravirine (ETR) 200 mg; Drug: Tenofovir disoproxil fumarate (TDF) 300 mg

ATV/rtv 400/100 mg (Treatment B)

EXPERIMENTAL

Treatment-experienced human immunodeficiency virus - type 1 (HIV-1) infected participants will take by mouth atazanavir (ATV)/low-dose ritonavir (rtv) 300/100 mg once daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs) for 2 weeks pretreatment followed by ATV/rtv 400/100 mg once daily + etravirine (ETR) 200 mg twice daily + 1 NRTI for 48 weeks. If particpating in an optional substudy to assess the effect of adding tenofovir disoproxil fumarate (TDF) for 7 days on ATV and ETR pharmacokinetics, participants will take TDF 300 mg once daily for 7 days in addition to their antiretroviral regimen (ETR+ATV/rtv+NRTI).

Drug: Atazanavir (ATV) 400 mg; Drug: Ritonavir (rtv) 100 mg; Drug: Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs); Drug: Etravirine (ETR) 200 mg; Drug: Tenofovir disoproxil fumarate (TDF) 300 mg

Interventions

Atazanavir (ATV) 300 mg DRUG

Atazanavir (ATV) 300 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take ATV 300 mg by mouth following a meal each morning on Substudy Days -1 to 7.

ATV/rtv 300/100 mg (Treatment A)

Atazanavir (ATV) 400 mg DRUG

Atazanavir (ATV) 400 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take ATV 400 mg by mouth following a meal each morning on Substudy Days -1 to 7.

ATV/rtv 400/100 mg (Treatment B)

Ritonavir (rtv) 100 mg DRUG

Ritonavir (rtv) 100 mg taken by mouth following a meal each morning for 2 weeks during the Pre-Treatment Period and for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take rtv 100 mg by mouth following a meal each morning on Substudy Days -1 to 7.

ATV/rtv 300/100 mg (Treatment A); ATV/rtv 400/100 mg (Treatment B)

Nucleo(side)/(tide) reverse transcriptase inhibitors (NRTIs) DRUG

2 investigator-selected NRTIs taken as specified in the individual product labels for 2 weeks during the Pre-Treatment Period followed by 1 investigator-selected NRTI (of the 2 NRTIs in the Pre-Treatment Phase) taken as specified in the individual product label for 48 weeks during the Treatment Period. If participating in the optional substudy, participants will take 1 investigator-selected NRTI (of the 2 NRTIs in the Pre-Treatment Phase) mg taken as specified in the individual product label during the Substudy.

ATV/rtv 300/100 mg (Treatment A); ATV/rtv 400/100 mg (Treatment B)

Etravirine (ETR) 200 mg DRUG

Etravirine (ETR) 200 mg taken twice daily as two 100-mg tablets following a meal (morning and evening) for at least the first two weeks of the 48-week Treatment Period. If participating in the optional substudy, participants will take ETR 200 mg twice daily as two 100-mg tablets following a meal each morning and evening on Substudy Days -1 to 7.

ATV/rtv 300/100 mg (Treatment A); ATV/rtv 400/100 mg (Treatment B)

Tenofovir disoproxil fumarate (TDF) 300 mg DRUG

Tenofovir disoproxil fumarate (TDF) 300 mg taken by mouth following a meal each morning on Substudy Days 1 to 7.

ATV/rtv 300/100 mg (Treatment A); ATV/rtv 400/100 mg (Treatment B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Documented HIV-1 infection
• Failing on a stable ART (anti retroviral therapy) with HIV-1 plasma viral load above 500 HIV-1 RNA copies/ml
• Presence of at least 1 documented NNRTI mutation
• Demonstrated sensitivity to ATV, ETR and at least one of the selected NRTIs based on the resistance test at screening
• General medical condition, in the investigator's opinion, does not interfere with the assessments and completion of the trial
• Substudy: patients who have been treated in C238 for more than 24 weeks and are currently suppressed (defined as patients with at least 2 most recent and consecutive viral loads less than 50 cp/mL) will be considered eligible for the substudy

You may not qualify if:

• Primary HIV-1 infection
• Previously documented HIV-2 infection
• Previously failed 2 or more HIV PI-containing regimens
• Previous diagnosis of hereditary hyperbilirubinemia (eg. Gilbert's syndrome, Crigler-Najjar syndrome).
• Grade 3 or 4 toxicities (according to DAIDS grading)
• Acute and chronic viral hepatitis
• Receipt of an investigational drug or investigational vaccine within 30 days prior to the trial drug administration
• Pregnant or breastfeeding female

Sponsors & Collaborators

• Janssen R&D Ireland: lead

Study Sites (18)

Unknown Facility

Little Rock, Arkansas, United States

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Bakersfield, California, United States

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Beverly Hills, California, United States

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Orlando, Florida, United States

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Tampa, Florida, United States

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Vero Beach, Florida, United States

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West Palm Beach, Florida, United States

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Macon, Georgia, United States

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Dallas, Texas, United States

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Houston, Texas, United States

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Buenos Aires, Argentina

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Córdoba, Argentina

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Paris, France

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Tourcoing, France

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Bloemfontein, South Africa

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Cape Town, South Africa

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George, South Africa

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Bangkok, Thailand

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MeSH Terms

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome

Interventions

Atazanavir Sulfate; Ritonavir; Reverse Transcriptase Inhibitors; etravirine; Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antiviral Agents; Anti-Infective Agents; Therapeutic Uses; Organophosphonates; Organophosphorus Compounds; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Senior Director
• Organization: Tibotec

+32 (0) 14 641 265

Study Officials

• Janssen R&D Ireland Clinical Trial

  Janssen R&D Ireland

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2009
• First Posted: May 11, 2009
• Study Start: August 1, 2009
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: September 30, 2013
• Results First Posted: September 30, 2013

Record last verified: 2013-09

Locations

AR (2); FR (2); ZA (3); TH (1); US (10)