Nevirapine or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir in Human Immunodeficiency Virus (HIV)-1-infected Treatment Naive Adults

HIV Infections Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00389207
• Other study ID #: 1100.1470
• Secondary ID: 2005-004330-40
• Status: Completed
• Phase: Phase 3
• First received: October 17, 2006
• Last updated: December 9, 2013
• Start date: October 2006

Study information

• Verified date: December 2013
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: A.N.M.A.T. (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica)Germany: Federal Institute for Drugs and Medical DevicesGreat Britain: MHRAItaly: Comitato Etico dell'Azienda Osp. Riuniti di Bergamo - BergamoMexico: Comision Federal para la Proteccion contra Riesgos Sanitarios (COFEPRIS)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsPortugal: National Pharmacy and Medicines InstituteRomania: National Medicines Agency, BucharestSpain: Agencia Espanola del Medicamento y Productos SanitariosSwitzerland: Swissmedic Schweizerisches Heilmittelinstitut (Swiss Agency for Therapeutic Products)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 576
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections

Intervention

Drug:
• nevirapine bid
nevirapine twice daily
• nevirapine qd
nevirapine once daily
• atazanavir
atazanavir once daily

Locations

Country	Name	City	State
Argentina	1100.1470.54004 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1100.1470.54002 Boehringer Ingelheim Investigational Site	Córdoba
Argentina	1100.1470.54003 Boehringer Ingelheim Investigational Site	Mar del Plata
Argentina	1100.1470.54001 Boehringer Ingelheim Investigational Site	Rosario
Germany	1100.1470.49001 Boehringer Ingelheim Investigational Site	Berlin
Germany	1100.1470.49002 Boehringer Ingelheim Investigational Site	Berlin
Germany	1100.1470.49003 Boehringer Ingelheim Investigational Site	Bochum
Germany	1100.1470.49018 Boehringer Ingelheim Investigational Site	Bonn
Germany	1100.1470.49014 Boehringer Ingelheim Investigational Site	Düsseldorf
Germany	1100.1470.49008 Boehringer Ingelheim Investigational Site	Erlangen
Germany	1100.1470.49035 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	1100.1470.49036 Boehringer Ingelheim Investigational Site	Frankfurt am Main
Germany	1100.1470.49033 Boehringer Ingelheim Investigational Site	Freiburg/Breisgau
Germany	1100.1470.49016 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1100.1470.49031 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1100.1470.49037 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1100.1470.49020 Boehringer Ingelheim Investigational Site	Hannover
Germany	1100.1470.49038 Boehringer Ingelheim Investigational Site	Magdeburg
Germany	1100.1470.49034 Boehringer Ingelheim Investigational Site	München
Germany	1100.1470.49000 Boehringer Ingelheim Investigational Site	Ulm
Germany	1100.1470.49032 Boehringer Ingelheim Investigational Site	Würzburg
Italy	1100.1470.39001 Boehringer Ingelheim Investigational Site	Bergamo
Italy	1100.1470.39003 Boehringer Ingelheim Investigational Site	Bologna
Italy	1100.1470.39012 Ospedale Sant'Anna	Como
Italy	1100.1470.39006 Boehringer Ingelheim Investigational Site	Ferrara
Italy	1100.1470.39010 Boehringer Ingelheim Investigational Site	Lecco
Italy	1100.1470.39004 Boehringer Ingelheim Investigational Site	Torino
Italy	1100.1470.39009 Boehringer Ingelheim Investigational Site	Torrette Di Ancona
Italy	1100.1470.39007 Boehringer Ingelheim Investigational Site	Varese
Mexico	1100.1470.55006 Boehringer Ingelheim Investigational Site	Aguascalientes
Mexico	1100.1470.55004 Boehringer Ingelheim Investigational Site	Col Obregón
Mexico	1100.1470.55008 Boehringer Ingelheim Investigational Site	Col. Los Filtros, San Luis Potosí
Mexico	1100.1470.55001 Boehringer Ingelheim Investigational Site	Col. Toriello Guerra
Mexico	1100.1470.55007 Boehringer Ingelheim Investigational Site	Guadalajara Jal.
Mexico	1100.1470.55003 Boehringer Ingelheim Investigational Site	Tlalpan-México D,F
Poland	1100.1470.48003 Boehringer Ingelheim Investigational Site	Bydgoszcz
Poland	1100.1470.48001 Boehringer Ingelheim Investigational Site	Chorzow
Poland	1100.1470.48002 Boehringer Ingelheim Investigational Site	Szczecin
Poland	1100.1470.48004 Boehringer Ingelheim Investigational Site	Warsaw
Portugal	1100.1470.35102 Boehringer Ingelheim Investigational Site	Cascais
Portugal	1100.1470.35101 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1100.1470.35103 Boehringer Ingelheim Investigational Site	Porto
Romania	1100.1470.40001 Boehringer Ingelheim Investigational Site	Bucharest
Romania	1100.1470.40002 Boehringer Ingelheim Investigational Site	Bucharest
Spain	1100.1470.34013 Boehringer Ingelheim Investigational Site	Alcalá de Henares (Madrid)
Spain	1100.1470.34008 Boehringer Ingelheim Investigational Site	Badalona
Spain	1100.1470.34002 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1100.1470.34003 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1100.1470.34009 Boehringer Ingelheim Investigational Site	L'Hospitalet de Llobregat
Spain	1100.1470.34010 Boehringer Ingelheim Investigational Site	Madrid
Spain	1100.1470.34012 Boehringer Ingelheim Investigational Site	Madrid
Spain	1100.1470.34014 Boehringer Ingelheim Investigational Site	Madrid
Spain	1100.1470.34015 Boehringer Ingelheim Investigational Site	Madrid
Spain	1100.1470.34019 Boehringer Ingelheim Investigational Site	Malaga
Spain	1100.1470.34007 Boehringer Ingelheim Investigational Site	Sabadell (Barcelona)
Spain	1100.1470.34004 Boehringer Ingelheim Investigational Site	San Sebastian
Spain	1100.1470.34006 Boehringer Ingelheim Investigational Site	Santa Cruz de Tenerife
Spain	1100.1470.34011 Boehringer Ingelheim Investigational Site	Vigo
Switzerland	1100.1470.41004 Boehringer Ingelheim Investigational Site	Bern
Switzerland	1100.1470.41001 Boehringer Ingelheim Investigational Site	Lugano
Switzerland	1100.1470.41003 Boehringer Ingelheim Investigational Site	St. Gallen
Switzerland	1100.1470.41002 Boehringer Ingelheim Investigational Site	Zürich
United Kingdom	1100.1470.44004 Boehringer Ingelheim Investigational Site	Birmingham
United Kingdom	1100.1470.44001 Boehringer Ingelheim Investigational Site	London
United Kingdom	1100.1470.44002 Boehringer Ingelheim Investigational Site	London
United Kingdom	1100.1470.44005 Boehringer Ingelheim Investigational Site	London
United Kingdom	1100.1470.44006 Boehringer Ingelheim Investigational Site	London
United Kingdom	1100.1470.44003 Boehringer Ingelheim Investigational Site	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

Argentina,  Germany,  Italy,  Mexico,  Poland,  Portugal,  Romania,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment Response at Week 48	Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 48 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 48.	From baseline to Week 48	No
Secondary	Treatment Response at Week 48 (TLOVR Algorithm)	Treatment response is defined as a VL <50 copies/mL measured at two consecutive visits up to Week 48 and without subsequent rebound or change of ARV therapy up to Week 48, based on time to loss of virologic response (TLOVR) algorithm, as a sensitivity analysis for the primary analysis.	From baseline to Week 48	No
Secondary	Proportion of Patients With VL < 50 Copies/ml	VL <50 copies/mL among observed patients on treatment at each visit, with the final visit at Week 144 or end of trial (EOT) for the patient	From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT	No
Secondary	Proportion of Patients With VL < 400 Copies/ml	VL <400 copies/mL among observed patients on treatment at each visit, with the final visit at Week 144 or end of trial (EOT)	From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT	No
Secondary	Change in CD4+ Count From Baseline	Change in CD4+ cell count from baseline among patients on treatment at each visit, with the final visit at Week 144 or EOT	From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT	No
Secondary	Change in Framingham Score From Baseline	Change in the estimated risk of cardiovascular disease using the Framingham algorithm from baseline to after 48, 96 and 144 weeks, last observation carried forward (LOCF). The score is based on age, gender, systolic blood pressure, total cholesterol, high density lipoprotein cholesterol and smoking status. Scores range from 0 to 21 with higher scores indicating a greater risk.	From baseline to Weeks 48, 96 and 144/EOT	No
Secondary	Change in Mental Health Summary (MHS) Score From Baseline	Quality of life (QoL) assessment by change in MHS score from baseline to after 48, 96 and 144 weeks (observed cases), from the Medical Outcomes Study HIV Health Survey (MOS-HIV), a 35-item self-administered questionnaire including 10 scales covering: health perceptions, pain, physical functioning, role functioning, social and cognitive functioning, mental health, energy/fatigue, health distress, and QoL. The MHS is a weighted average of the 10 scales and ranges from 0 to 100 with higher scores indicating better QoL.	From baseline to Weeks 48, 96 and 144/EOT	No
Secondary	Change in Physical Health Summary (PHS) Score From Baseline	QoL assessment by change in PHS score from baseline to after 48, 96 and 144 weeks (observed cases), from the MOS-HIV, a 35-item self-administered questionnaire including 10 scales covering: health perceptions, pain, physical functioning, role functioning, social and cognitive functioning, mental health, energy/fatigue, health distress, and QoL. The PHS is a weighted average of the 10 scales and ranges from 0 to 100 with higher scores indicating better QoL.	From baseline to Weeks 48, 96 and 144/EOT	No
Secondary	Number of Patients Hospitalized	Cost effectiveness assessment by number of patients hospitalized	From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT	No
Secondary	Non-scheduled Physician Visits	Cost effectiveness assessment by number of patients with non-scheduled physician visits	From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT	No
Secondary	Genotypic Resistance Associated With Virologic Failure	Number of treatment-emergent drug-associated substitutions in patients with virological failure up to Week 48. The total number of genotypic mutations in those patients who were virologic failures is given, not the number of patients with mutations.	From baseline to Week 48	No
Secondary	Treatment-emergent AIDS-defining Illness	Treatment-emergent AIDS-defining illness (tr.-emerg. AIDS-def.illness) including worsening during treatment	From baseline to Week 144	No
Secondary	Treatment-emergent AIDS-defining Illness Leading to Death	Patients with an AIDS-defining illness leading to death broken out by treatment. Statistical analysis shows time to death from AIDS-defining illness.	From baseline to Week 144	No
Secondary	Lipodystrophy	Number of patients with AE lipodystrophy	From baseline to Week 144	No
Secondary	Serum Lipid Abnormalities	Number of patients with AE elevated serum lipids (i.e. hypercholesterolaemia)	From baseline to Week 144	No
Secondary	Glycaemic Abnormalities	Number of patients with AE elevated serum glucose	From baseline to Week 144	No
Secondary	Treatment Response at Week 96	Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 96 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 96.	From baseline to Week 96	No
Secondary	Treatment Response at Week 144	Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 144 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 144.	From baseline to Week 144	No
Secondary	Proportion of Patients With Virological Rebound With VL >=50 Copies/mL After CVR (Confirmed Virological Response) at Week 24, 48, 96, 144	The analyses of virologic rebound were performed on the original values at each visit(ORGV) rather than calculated results within time windows (CAL)	at Week 24, 48, 96, 144	No
Secondary	Proportion of Patients With Virological Rebound With VL >=400 Copies/mL After CVR at Week 24, 48, 96, 144	The analyses of virologic rebound were performed on the original values at each visit(ORGV) rather than calculated results within time windows (CAL)	at Week 24, 48, 96, 144	No
Secondary	Proportion of Patients With Virologic Failure at Week 48, 96, 144		at Week 48, 96, 144	No
Secondary	Time to Treatment Response (First Confirmed VL<50 Copies/mL)	Time to treatment response was defined as the time from start of treatment until the first measurement of the first confirmed virological response	baseline to week 144	No
Secondary	Time to Loss of Virologic Response (Rebound)	Time to loss of virologic response (TLOVR) was defined as the time from start of treatment to the first measurement showing VL = 50 copies/mL in the first virologic rebound, after having a confirmed virological response.	Baseline to week 144	No
Secondary	Time to Treatment Failure	Treatment failure is defined as the occurrence of the first of at least one of the following events: early discontinuation of trial drug, change in ARV therapy, failure to achieve an HIV RNA count < 50 copies/mL up to Visit 10 (week 48) or loss of virologic response	baseline to week 144	No
Secondary	Change in the Calculated Glomerular Filtration Rate (GFR) at Week 48, 96 and 144	Calculations based on the MDRD algorithm.	From baseline to Week 48, 96, 144	No
Secondary	Proportion of Patients With >= DAIDS Grade 2 Laboratory Abnormalities		week 148	No
Secondary	Proportion of Patients Reporting Rash of Any Severity	Proportion of Patients reporting rash of any severity	week 148	No
Secondary	Proportion of Patients Reporting Hepatic Events of Any Severity	Proportion of Patients reporting hepatic events of any severity	week 148	No
Secondary	Proportion of Patients Reporting CNS (Central Nervous System) Side Effects of Any Severity	Proportion of Patients reporting CNS (central nervous system) side effects of any severity	week 148	No
Secondary	Change of Cholesterol Values From Baseline to Week 48, 96, 144	Changes frombaseline in total cholesterol, LDL-cholesterol(LDL-c) and HDL	baseline to week 48, 96, 144	No
Secondary	Changes of Apolipoprotein Values From Baseline to Week 48, 96, 144	Changes frombaseline apolipoprotein A1 & B	baseline to week 48, 96, 144	No
Secondary	Change of hsCRP From Baseline to Week 48, 96, 144	Change of hsCRP from baseline to week 48, 96, 144	baseline to week 48, 96, 144	No
Secondary	Change of Total Triglycerides From Baseline to Week 48, 96, 144	Change of total triglycerides from baseline to week 48, 96, 144	baseline to week 48, 96, 144	No
Secondary	Change of Total Cholesterol to HDL-cholesterol Ratio From Baseline to Week 48, 96, 144	Change of Total cholesterol to HDL-cholesterol ratio from baseline to week 48, 96, 144	baseline to week 48, 96, 144	No