Clinical trial NCT00903682: A Clinical Trial Comparing the Tolerability of Etravirine to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Treatment-naive HIV-1 Infected Patients
Official title: A Phase IIb, Multi-centre, Randomised, Double-blind, Active-controlled Trial Comparing the Neuropsychiatric Adverse Event Profile of Etravirine 400mg qd Versus Efavirenz 600mg qd in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in ARV Therapy-naive HIV-1 Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infection
HIV
Acquired Immunodeficiency Syndrome
Keywords: HIV
Intelence
etravirine
ETR
TMC125
Sustiva
efavirenz
EFV
Non-nucleoside Reverse Transcriptase Inhibitor
NNRTI
treatment-naive
Lead sponsor: Janssen-Cilag International NV
Sponsor class: INDUSTRY
First posted: 2009-05-18
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the neuropsychiatric adverse event profiles of etravirine 400mg once daily versus efavirenz 600mg once daily, in combination with 2 N(t)RTIs, in approximately 150 treatment-naÃ-ve HIV-1 infected patients. Safety, tolerability and efficacy of both treatment arms will be assessed throughout the study.

Detailed description: This is a phase IIb, randomised (study medication is assigned by chance), double-blind (neither the patient nor the study physician will know to which treatment group the patient is assigned) trial to assess the neuropsychiatric adverse event profile of etravirine (ETR) 400mg once daily versus efavirenz (EFV) 600mg once daily, each in combination with an investigator-selected background of 2 other anti-HIV drugs of the class nucleoside/nucleotide reverse transcriptase inhibitors (N\[t\]RTIs). The combination of N\[t\]RTIs to be chosen by the study physician can be abacavir (ABC)/lamivudine (3TC), zidovudine (AZT)/lamivudine (3TC) or tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). Approximately 150 Human Immuno-deficiency Virus type 1 (HIV-1) infected patients, who have never received any antiretroviral (ARV) treatment will be randomly assigned (like tossing a coin) to either the etravirine treatment group or the control group (efavirenz). The study period includes a screening period of maximum 6 weeks, a 48 week treatment period, an additional 2-8 weeks treatment until unblinding (study physician (and patient) will receive information to which treatment group the patient is assigned), followed by a 4 weeks follow-up period. The main purpose of this study is to gather further data on how many, how often, and how severe the central nervous system and psychiatric (neuropsychiatric) events are between the two treatment groups. In addition, the study will look at overall safety, tolerability and antiviral effectiveness between the two treatment groups. During the trial, patients' health will be monitored by physical examination, checking of vital signs (blood pressure / pulse), and laboratory testing on blood and urine samples. Also blood samples will be drawn to measure the antiviral effectiveness (i.e., decrease of the plasma viral load to a level \<50 HIV-1 RNA (ribonucleic acid) copies/mL), immunology assessments (to assess the body's immune system) and pharmacokinetic (to measure the drug level in blood) analysis of etravirine. Patients will be asked to complete the "HIV Patient Symptoms Profile" (HIV PSP) Questionnaire at each visit, which contains questions relating to the impact on patients' current health and well-being. The study hypothesis is that the proportion of patients with at least one neuropsychiatric adverse event related to the study drug, observed between start of treatment (Baseline; BSL) through Week 12, is significantly lower in the etravirine group than in the efavirenz group. Patients will be taking blinded medication twice a day, administered orally (by mouth). Only one of the blinded doses will contain an active ingredient. Etravirine 400mg (or dummy-pills) - 4 tablets - should be taken once a day, following a meal, preferably breakfast. Efavirenz 600mg (or dummy-pill) - 1 tablet - should be administered once daily on an empty stomach, preferably at bedtime.The intake of the investigator-selected N\[t\]RTIs should be taken as instructed by the investigator.

Eligibility criteria: Inclusion Criteria:

* Documented HIV-1 infection
* In the judgement of the investigator, it is appropriate to initiate ARV therapy based on the patients medical condition and taking into account applicable guidelines for the treatment of HIV-1 infection
* Patient has access to an investigator-selected ARV regimen post-study in accordance with applicable guidelines for the treatment of HIV-1 infection
* HIV-1 plasma viral load at screening \>= 5000 HIV-1 RNA (copies/ml)
* Predicted phenotypic sensitivity to the currently approved NNRTIs and to the N(t)RTIs in their background regimen at screening

Exclusion Criteria:

* Any previous treatment with a therapeutic HIV vaccine or use of ARVs, including use of NVP for the prevention of vertical HIV transmission
* The presence of at least one of the mutations that are specific indicators of transmitted (or primary) drug resistance
* Known infection with HIV-2 or with HIV-1 group O
* Category C AIDS defining illness, except stable Kaposi's Sarcoma, wasting syndrome if not progressive
* Pneumocystis jiroveci/carinii Pneumonia (PCP) that is considered not cured
* Specific grade 3 or 4 laboratory abnormalities

Primary outcomes:
measure: Proportion of Patients With at Least 1 Treatment-emergent Grade 1-4 Central Nervous System or Psychiatric Adverse Event
timeFrame: between baseline and 12 weeks
Secondary outcomes:
measure: Antiviral Activity of ETR vs. EFV
timeFrame: between baseline and week 48
measure: Antiviral Activity of ETR vs. EFV
timeFrame: between baseline and week 48
measure: Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score
timeFrame: between baseline and week 48
measure: Neuropsychiatric Adverse Events by Week 48
timeFrame: from baseline to week 48
measure: Mean Change From Baseline in CD4+ Cell Count
timeFrame: at baseline and week 2, 6, 12, 24, 36 and 48
measure: Resistance Determinations
timeFrame: at baseline and all subsequent visits until week 48 in case if virologic failure
Other outcomes:
Locations:
city: Salzburg
country: Austria
city: Vienna
country: Austria
city: Wien
country: Austria
city: Aarhus
country: Denmark
city: Odense N/A
country: Denmark
city: Bordeaux Cedex
country: France
city: Lyon
country: France
city: Nice
country: France
city: Paris
country: France
city: Strasbourg Cedex
country: France
city: Berlin
country: Germany
city: Bonn
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Koln
country: Germany
city: Budapest
country: Hungary
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Ramat-Gan
country: Israel
city: Tel-Aviv
country: Israel
city: Bucuresti
country: Romania
city: Constanta
country: Romania
city: Moscow N/A
country: Russian Federation
city: Moscow
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: Barcelona N/A
country: Spain
city: Barcelona
country: Spain
city: Granada
country: Spain
city: Madrid
country: Spain
city: Vigo
country: Spain
city: Bern
country: Switzerland
city: Zurich N/A
country: Switzerland
city: Brighton
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Janssen-Cilag International NV
name: Janssen-Cilag International NV Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Nelson M, Stellbrink HJ, Podzamczer D, Banhegyi D, Gazzard B, Hill A, van Delft Y, Vingerhoets J, Stark T, Marks S. A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. AIDS. 2011 Jan 28;25(3):335-40. doi: 10.1097/QAD.0b013e3283416873.
citation: Gazzard B, Duvivier C, Zagler C, Castagna A, Hill A, van Delft Y, Marks S. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results. AIDS. 2011 Nov 28;25(18):2249-58. doi: 10.1097/QAD.0b013e32834c4c06.
citation: Fatkenheuer G, Duvivier C, Rieger A, Durant J, Rey D, Schmidt W, Hill A, van Delft Y, Marks S; SENSE Study Team. Lipid profiles for etravirine versus efavirenz in treatment-naive patients in the randomized, double-blind SENSE trial. J Antimicrob Chemother. 2012 Mar;67(3):685-90. doi: 10.1093/jac/dkr533. Epub 2011 Dec 29.