Clinical trial NCT00389207: Nevirapine or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir in Human Immunodeficiency Virus (HIV)-1-infected Treatment Naive Adults
Official title: Randomized, Open Label Study Evaluating the Lipid Profile Difference and Efficacy of a Combined Therapy Including Tenofovir, Emtricitabine + Atazanavir / r or NVP in Naive HIV - 1 Infected Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2006-10-18
Enrollment: 576
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary purpose of this study is to compare the efficacy and safety of two different nevirapine (Viramune) dosing regimens (once daily (QD) and twice daily (BID) application) and of atazanavir/ritonavir (Reyataz/Norvir), all on an emtricitabine/tenofovir disoproxil fumarate (DF) (Truvada) background. Patients will receive either nevirapine (NVP) 200 mg twice daily, or NVP 400 mg once daily , or ritonavir-boosted atazanavir (ATZ/r), all in combination with emtricitabine (FTC) and tenofovir DF (TDF).

All patients receiving NVP will start at 200 mg once daily for 2 weeks, because it has been demonstrated that this lead-in dosing regimen reduces the frequency of NVP-induced rash. At Visit 3 (Week 2), patients increase the NVP dose to either 200 mg twice daily or to 400 mg once daily. Patients receiving ATZ/r will be treated with ATZ 300 mg once daily, boosted by 100 mg ritonavir (RTV) once daily. Background antiretroviral therapy for all patients consists of one tablet of Truvada. Treatment duration is 48 weeks (primary endpoint) with an extension to 144 weeks. Patients may also participate in the metabolic sub-study, comparing NVP and ATZ/r for signs and symptoms of lipodystrophy and serum lipid/glycaemic abnormalities.


Eligibility criteria: Inclusion criteria:

Inclusion Criteria:

1. Signed informed consent in accordance with Good Clinical Practice (GCP) and local regulatory requirements prior to trial participation
2. HIV-1-infected males or females \>= 18 years of age with positive serology confirmed by Western blot
3. No previous antiretroviral treatment (of more than 7 days)
4. Males with CD4+ counts of \< 400 cells/mm3 and females with CD4+ counts of \< 250 cells/mm3
5. NVP- and ATZ/r susceptibility based on HIV-1 genotypic resistance report
6. Adequate renal function defined as a calculated creatinine clearance (CLCr) \>= 50 ml/min according to the Cockcroft-Gault formula
7. Karnofsky score \>= 70
8. Acceptable medical history, as assessed by the investigator

Exclusion criteria:

Exclusion Criteria:

1. Active drug abuse or chronic alcoholism at the investigator's discretion
2. Hepatic cirrhosis stage Child-Pugh B or C
3. Female patients of child-bearing potential who:

   * have a positive serum pregnancy test at screening or during the study,
   * are breast feeding,
   * are planning to become pregnant,
   * are not willing to use a barrier method of contraception, or are not willing to use methods of contraception other than ethinyl estradiol containing oral contraceptives
4. Laboratory parameters Division of Acquired Immunodeficiency Syndrome (DAIDS) \> grade 2 (triglycerides \> DAIDS grade 3; total cholesterol no restrictions)
5. Active hepatitis B or C disease, defined as HBsAg-positive or Hepatitis C-Virus-Ribo Nucleic Acid (HCV-RNA)- positive with Aspartate Transaminase/Alanine Transaminase (AST/ALT) \> 2.5x Upper Limit of Normal (ULN) (DAIDS grade 1)
6. Hypersensitivity to any ingredients of the test products
7. Have therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamidine, tacrolimus, cyclosporine) or potential competitors of renal excretion (e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, probenecid, high-dose non-steroidal anti-inflammatory drugs (i.e., ibuprofen)) within 3 months prior to study screening or are expected to receive these during the study
8. Patients who are receiving other concomitant treatments which are not permitted
9. Use of other investigational medications within 30 days before study entry or during the trial
10. Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g., interferon, cyclosporin, hydroxyurea, interleukin 2, chronic treatment with prednisone)
11. Patients with Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any lymphoma
12. Any AIDS defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at screening visit
13. Patients who are receiving systemic treatment for malignant disease

Primary outcomes:
measure: Treatment Response at Week 48
timeFrame: From baseline to Week 48
Secondary outcomes:
measure: Treatment Response at Week 48 (TLOVR Algorithm)
timeFrame: From baseline to Week 48
measure: Proportion of Patients With VL < 50 Copies/ml
timeFrame: From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT
measure: Proportion of Patients With VL < 400 Copies/ml
timeFrame: From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT
measure: Change in CD4+ Count From Baseline
timeFrame: From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT
measure: Change in Framingham Score From Baseline
timeFrame: From baseline to Weeks 48, 96 and 144/EOT
measure: Change in Mental Health Summary (MHS) Score From Baseline
timeFrame: From baseline to Weeks 48, 96 and 144/EOT
measure: Change in Physical Health Summary (PHS) Score From Baseline
timeFrame: From baseline to Weeks 48, 96 and 144/EOT
measure: Number of Patients Hospitalized
timeFrame: From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT
measure: Non-scheduled Physician Visits
timeFrame: From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT
measure: Genotypic Resistance Associated With Virologic Failure
timeFrame: From baseline to Week 48
measure: Treatment-emergent AIDS-defining Illness
timeFrame: From baseline to Week 144
measure: Treatment-emergent AIDS-defining Illness Leading to Death
timeFrame: From baseline to Week 144
measure: Lipodystrophy
timeFrame: From baseline to Week 144
measure: Serum Lipid Abnormalities
timeFrame: From baseline to Week 144
measure: Glycaemic Abnormalities
timeFrame: From baseline to Week 144
measure: Treatment Response at Week 96
timeFrame: From baseline to Week 96
measure: Treatment Response at Week 144
timeFrame: From baseline to Week 144
measure: Proportion of Patients With Virological Rebound With VL >=50 Copies/mL After CVR (Confirmed Virological Response) at Week 24, 48, 96, 144
timeFrame: at Week 24, 48, 96, 144
measure: Proportion of Patients With Virological Rebound With VL >=400 Copies/mL After CVR at Week 24, 48, 96, 144
timeFrame: at Week 24, 48, 96, 144
measure: Proportion of Patients With Virologic Failure at Week 48, 96, 144
timeFrame: at Week 48, 96, 144
measure: Time to Treatment Response (First Confirmed VL<50 Copies/mL)
timeFrame: baseline to week 144
measure: Time to Loss of Virologic Response (Rebound)
timeFrame: Baseline to week 144
measure: Time to Treatment Failure
timeFrame: baseline to week 144
measure: Change in the Calculated Glomerular Filtration Rate (GFR) at Week 48, 96 and 144
timeFrame: From baseline to Week 48, 96, 144
measure: Proportion of Patients With >= DAIDS Grade 2 Laboratory Abnormalities
timeFrame: week 148
measure: Proportion of Patients Reporting Rash of Any Severity
timeFrame: week 148
measure: Proportion of Patients Reporting Hepatic Events of Any Severity
timeFrame: week 148
measure: Proportion of Patients Reporting CNS (Central Nervous System) Side Effects of Any Severity
timeFrame: week 148
measure: Change of Cholesterol Values From Baseline to Week 48, 96, 144
timeFrame: baseline to week 48, 96, 144
measure: Changes of Apolipoprotein Values From Baseline to Week 48, 96, 144
timeFrame: baseline to week 48, 96, 144
measure: Change of hsCRP From Baseline to Week 48, 96, 144
timeFrame: baseline to week 48, 96, 144
measure: Change of Total Triglycerides From Baseline to Week 48, 96, 144
timeFrame: baseline to week 48, 96, 144
measure: Change of Total Cholesterol to HDL-cholesterol Ratio From Baseline to Week 48, 96, 144
timeFrame: baseline to week 48, 96, 144
Other outcomes:
Locations:
city: Capital Federal
country: Argentina
facility: 1100.1470.54004 Boehringer Ingelheim Investigational Site
city: Córdoba
country: Argentina
facility: 1100.1470.54002 Boehringer Ingelheim Investigational Site
city: Mar del Plata
country: Argentina
facility: 1100.1470.54003 Boehringer Ingelheim Investigational Site
city: Rosario
country: Argentina
facility: 1100.1470.54001 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1100.1470.49001 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1100.1470.49002 Boehringer Ingelheim Investigational Site
city: Bochum
country: Germany
facility: 1100.1470.49003 Boehringer Ingelheim Investigational Site
city: Bonn
country: Germany
facility: 1100.1470.49018 Boehringer Ingelheim Investigational Site
city: Düsseldorf
country: Germany
facility: 1100.1470.49014 Boehringer Ingelheim Investigational Site
city: Erlangen
country: Germany
facility: 1100.1470.49008 Boehringer Ingelheim Investigational Site
city: Frankfurt am Main
country: Germany
facility: 1100.1470.49036 Boehringer Ingelheim Investigational Site
city: Frankfurt
country: Germany
facility: 1100.1470.49035 Boehringer Ingelheim Investigational Site
city: Freiburg/Breisgau
country: Germany
facility: 1100.1470.49033 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1100.1470.49016 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1100.1470.49031 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1100.1470.49037 Boehringer Ingelheim Investigational Site
city: Hannover
country: Germany
facility: 1100.1470.49020 Boehringer Ingelheim Investigational Site
city: Magdeburg
country: Germany
facility: 1100.1470.49038 Boehringer Ingelheim Investigational Site
city: München
country: Germany
facility: 1100.1470.49034 Boehringer Ingelheim Investigational Site
city: Ulm
country: Germany
facility: 1100.1470.49000 Boehringer Ingelheim Investigational Site
city: Würzburg
country: Germany
facility: 1100.1470.49032 Boehringer Ingelheim Investigational Site
city: Bergamo
country: Italy
facility: 1100.1470.39001 Boehringer Ingelheim Investigational Site
city: Bologna
country: Italy
facility: 1100.1470.39003 Boehringer Ingelheim Investigational Site
city: Como
country: Italy
facility: 1100.1470.39012 Ospedale Sant'Anna
city: Ferrara
country: Italy
facility: 1100.1470.39006 Boehringer Ingelheim Investigational Site
city: Lecco
country: Italy
facility: 1100.1470.39010 Boehringer Ingelheim Investigational Site
city: Torino
country: Italy
facility: 1100.1470.39004 Boehringer Ingelheim Investigational Site
city: Torrette Di Ancona
country: Italy
facility: 1100.1470.39009 Boehringer Ingelheim Investigational Site
city: Varese
country: Italy
facility: 1100.1470.39007 Boehringer Ingelheim Investigational Site
city: Aguascalientes
country: Mexico
facility: 1100.1470.55006 Boehringer Ingelheim Investigational Site
city: Col Obregón
country: Mexico
facility: 1100.1470.55004 Boehringer Ingelheim Investigational Site
city: Col. Los Filtros, San Luis Potosí
country: Mexico
facility: 1100.1470.55008 Boehringer Ingelheim Investigational Site
city: Col. Toriello Guerra
country: Mexico
facility: 1100.1470.55001 Boehringer Ingelheim Investigational Site
city: Guadalajara Jal.
country: Mexico
facility: 1100.1470.55007 Boehringer Ingelheim Investigational Site
city: Tlalpan-México D,F
country: Mexico
facility: 1100.1470.55003 Boehringer Ingelheim Investigational Site
city: Bydgoszcz
country: Poland
facility: 1100.1470.48003 Boehringer Ingelheim Investigational Site
city: Chorzow
country: Poland
facility: 1100.1470.48001 Boehringer Ingelheim Investigational Site
city: Szczecin
country: Poland
facility: 1100.1470.48002 Boehringer Ingelheim Investigational Site
city: Warsaw
country: Poland
facility: 1100.1470.48004 Boehringer Ingelheim Investigational Site
city: Cascais
country: Portugal
facility: 1100.1470.35102 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 1100.1470.35101 Boehringer Ingelheim Investigational Site
city: Porto
country: Portugal
facility: 1100.1470.35103 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 1100.1470.40001 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 1100.1470.40002 Boehringer Ingelheim Investigational Site
city: Alcalá de Henares (Madrid)
country: Spain
facility: 1100.1470.34013 Boehringer Ingelheim Investigational Site
city: Badalona
country: Spain
facility: 1100.1470.34008 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1100.1470.34002 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1100.1470.34003 Boehringer Ingelheim Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: 1100.1470.34009 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1470.34010 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1470.34012 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1470.34014 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1470.34015 Boehringer Ingelheim Investigational Site
city: Malaga
country: Spain
facility: 1100.1470.34019 Boehringer Ingelheim Investigational Site
city: Sabadell (Barcelona)
country: Spain
facility: 1100.1470.34007 Boehringer Ingelheim Investigational Site
city: San Sebastian
country: Spain
facility: 1100.1470.34004 Boehringer Ingelheim Investigational Site
city: Santa Cruz de Tenerife
country: Spain
facility: 1100.1470.34006 Boehringer Ingelheim Investigational Site
city: Vigo
country: Spain
facility: 1100.1470.34011 Boehringer Ingelheim Investigational Site
city: Bern
country: Switzerland
facility: 1100.1470.41004 Boehringer Ingelheim Investigational Site
city: Lugano
country: Switzerland
facility: 1100.1470.41001 Boehringer Ingelheim Investigational Site
city: St. Gallen
country: Switzerland
facility: 1100.1470.41003 Boehringer Ingelheim Investigational Site
city: Zürich
country: Switzerland
facility: 1100.1470.41002 Boehringer Ingelheim Investigational Site
city: Birmingham
country: United Kingdom
facility: 1100.1470.44004 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1470.44001 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1470.44002 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1470.44005 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1470.44006 Boehringer Ingelheim Investigational Site
city: Manchester
country: United Kingdom
facility: 1100.1470.44003 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Seclen E, Soriano V, Gonzalez MM, Martin-Carbonero L, Gellermann H, Distel M, Kadus W, Poveda E. Impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in HIV-infected patients receiving first-line antiretroviral therapy. J Infect Dis. 2011 Jul 1;204(1):139-44. doi: 10.1093/infdis/jir218.
citation: Soriano V, Arasteh K, Migrone H, Lutz T, Opravil M, Andrade-Villanueva J, Antunes F, Di Perri G, Podzamczer D, Taylor S, Domingo P, Gellermann H, de Rossi L; ARTEN investigators. Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN Trial. Antivir Ther. 2011;16(3):339-48. doi: 10.3851/IMP1745.