HIV Infection, HIV, Acquired Immunodeficiency Syndrome
Conditions
Keywords
HIV, Intelence, etravirine, ETR, TMC125, Sustiva, efavirenz, EFV, Non-nucleoside Reverse Transcriptase Inhibitor, NNRTI, treatment-naive
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.
Interventions
DRUGetravirine (ETR, TMC125)
400mg once daily (4x100mg tablet) + 2 NRTI + 1 EFV placebo tablet for 48 weeks
DRUGefavirenz (EFV)
600mg once daily (1x600mg tablet) + 2 NRTIs + 4 ETR placebo tablets for 48 weeks
Sponsors
Janssen-Cilag International NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With at Least 1 Treatment-emergent Grade 1-4 Central Nervous System or Psychiatric Adverse Event | between baseline and 12 weeks | Proportion of patients with at least 1 treatment-emergent Grade 1-4 Central Nervous System or psychiatric Adverse Event, observed between Baseline through Week 12 and judged by investigator to be at least possibly related to the study drug in ETR group versus EFV group. All Adverse Events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE grading table). Grade 1-4 covers all severities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antiviral Activity of ETR vs. EFV | between baseline and week 48 | The proportion of patients with confirmed plasma viral load \<50 copies/mL at Week 48 as assessed by Time to Loss of Virologic Response (TLOVR) |
| Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score | between baseline and week 48 | The HIV Patient Symptoms Profile measures the tolerability of HIV treatment from the patient's perspective, using 14 concept scales in maximum 84 questions. The response options include a no or yes answer to Did symptom occur?. If yes, there is a problem scale which ranges from 1 = I had this symptom and it was not a problem to 5 = I had this symptom and it was a severe problem. A neuropsychiatric tolerability score is composed as the sum of 21 items and ranges from 0 (best) to 105 (worse). A total Tolerability score (ie, the sum of all items) ranges from 0 (best) to 420 (worse) |
| Neuropsychiatric Adverse Events by Week 48 | from baseline to week 48 | The percentage of patients with at least 1 treatment emergent Grade 1 -4 neurologic or psychiatric adverse event, judged by the investigator to be at least possibly related to the study drug. |
| Mean Change From Baseline in CD4+ Cell Count | at baseline and week 2, 6, 12, 24, 36 and 48 | The mean change in CD4+ cell count from baseline was calculated with a last observation carried forward method; i.e. the last observed value was carried forward, irrespective of the reason for discontinuation. |
| Resistance Determinations | at baseline and all subsequent visits until week 48 in case if virologic failure | The evolution of viral genotype and phenotype was assessed by the number of patients with resistance-associated mutations emerging at the endpoint. A mutation was considered emerging if it was present at endpoint and not present at baseline or any pre-baseline assessment. (NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; RAM = resistance-associated mutation, IAS-USA = International AIDS Society - USA) |
Countries
Austria, Denmark, France, Germany, Hungary, Israel, Romania, Russia, Spain, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Etravirine ETR 400mg once daily (4x100mg tablet) + 2 NRTIs + 1 EFV placebo tablet for 48 weeks | 79 |
| Efavirenz EFV 600mg once daily (1x600mg tablet) + 2 NRTIs + 4 ETR placebo tablets for 48 weeks | 78 |
| Total | 157 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 13 |
| Overall Study | For Resistent Profile (Excl Crit 2 Met) | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Patient Couldn't Come For The Visit Due | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Subject Non-Compliant | 1 | 0 |
| Overall Study | Subject Reached A Virologic Endpoint | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Efavirenz | Total | Etravirine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 77 Participants | 155 Participants | 78 Participants |
| Age Continuous | 37.6 years STANDARD_DEVIATION 9.82 | 37.6 years STANDARD_DEVIATION 9.64 | 37.7 years STANDARD_DEVIATION 9.52 |
| Region of Enrollment Austria | 4 participants | 7 participants | 3 participants |
| Region of Enrollment Denmark | 2 participants | 2 participants | 0 participants |
| Region of Enrollment France | 9 participants | 18 participants | 9 participants |
| Region of Enrollment Germany | 13 participants | 29 participants | 16 participants |
| Region of Enrollment Hungary | 3 participants | 8 participants | 5 participants |
| Region of Enrollment Israel | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Italy | 6 participants | 15 participants | 9 participants |
| Region of Enrollment Romania | 10 participants | 16 participants | 6 participants |
| Region of Enrollment Russia | 8 participants | 17 participants | 9 participants |
| Region of Enrollment Spain | 9 participants | 21 participants | 12 participants |
| Region of Enrollment Switzerland | 3 participants | 4 participants | 1 participants |
| Region of Enrollment UK | 6 participants | 11 participants | 5 participants |
| Sex: Female, Male Female | 18 Participants | 30 Participants | 12 Participants |
| Sex: Female, Male Male | 60 Participants | 127 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 79 | 62 / 78 |
| serious Total, serious adverse events | 11 / 79 | 6 / 78 |
Outcome results
Primary
Proportion of Patients With at Least 1 Treatment-emergent Grade 1-4 Central Nervous System or Psychiatric Adverse Event
Proportion of patients with at least 1 treatment-emergent Grade 1-4 Central Nervous System or psychiatric Adverse Event, observed between Baseline through Week 12 and judged by investigator to be at least possibly related to the study drug in ETR group versus EFV group. All Adverse Events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE grading table). Grade 1-4 covers all severities.
Time frame: between baseline and 12 weeks
Population: The intent-to-treat (ITT) population has been defined as the set of all patients who were randomized and who have taken at least one dose of trial medication, regardless of their compliance with the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etravirine | Proportion of Patients With at Least 1 Treatment-emergent Grade 1-4 Central Nervous System or Psychiatric Adverse Event | 16.5 percentage of patients |
| Efavirenz | Proportion of Patients With at Least 1 Treatment-emergent Grade 1-4 Central Nervous System or Psychiatric Adverse Event | 46.2 percentage of patients |
Comparison: The hypothesis is that the proportion of patients with at least 1 treatment-emergent Grade 1-4 neuropsychiatric adverse event, observed between Baseline through Week 12 and judged to be at least possibly drug-related, is significantly lower in the ETR arm than in the EFV arm. Assuming a significance level of 5%, a sample size of 75 subjects per arm would provide over 90% power to detect a 29% difference in treatment-emergent, drug-related Grade 1-4 neuropsychiatric adverse events.p-value: <0.001Regression, Logistic
Secondary
Antiviral Activity of ETR vs. EFV
The proportion of patients with confirmed plasma viral load \<50 copies/mL at Week 48 as assessed by Time to Loss of Virologic Response (TLOVR)
Time frame: between baseline and week 48
Population: ITT: the set of all randomized patients who have taken at least 1 dose of trial medication, regardless of their compliance with the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etravirine | Antiviral Activity of ETR vs. EFV | 60 Number of participants |
| Efavirenz | Antiviral Activity of ETR vs. EFV | 58 Number of participants |
95% CI: [-12, 15.23]
Secondary
Antiviral Activity of ETR vs. EFV
The proportion of patients with confirmed plasma viral load \<200 copies/mL at Week 48 as assessed by Time to Loss of Virologic Response (TLOVR)
Time frame: between baseline and week 48
Population: ITT: the set of all randomized patients who have taken at least 1 dose of trial medication, regardless of their compliance with the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etravirine | Antiviral Activity of ETR vs. EFV | 64 Number of participants |
| Efavirenz | Antiviral Activity of ETR vs. EFV | 62 Number of participants |
Secondary
Mean Change From Baseline in CD4+ Cell Count
The mean change in CD4+ cell count from baseline was calculated with a last observation carried forward method; i.e. the last observed value was carried forward, irrespective of the reason for discontinuation.
Time frame: at baseline and week 2, 6, 12, 24, 36 and 48
Population: ITT: the set of all randomized patients who have taken at least 1 dose of trial medication, regardless of their compliance with the protocol
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Etravirine | Mean Change From Baseline in CD4+ Cell Count | Week 12 | 143.24 number of cells/L (x10^6) | Standard Error 13.56 |
| Etravirine | Mean Change From Baseline in CD4+ Cell Count | Week 36 | 213.45 number of cells/L (x10^6) | Standard Error 19.11 |
| Etravirine | Mean Change From Baseline in CD4+ Cell Count | Week 24 | 182.01 number of cells/L (x10^6) | Standard Error 16.48 |
| Etravirine | Mean Change From Baseline in CD4+ Cell Count | Week 6 | 128.14 number of cells/L (x10^6) | Standard Error 13.19 |
| Etravirine | Mean Change From Baseline in CD4+ Cell Count | Week 48 | 205.11 number of cells/L (x10^6) | Standard Error 20.07 |
| Etravirine | Mean Change From Baseline in CD4+ Cell Count | Week 2 | 69.96 number of cells/L (x10^6) | Standard Error 9.82 |
| Efavirenz | Mean Change From Baseline in CD4+ Cell Count | Week 48 | 221.39 number of cells/L (x10^6) | Standard Error 18.31 |
| Efavirenz | Mean Change From Baseline in CD4+ Cell Count | Week 2 | 72.45 number of cells/L (x10^6) | Standard Error 11.33 |
| Efavirenz | Mean Change From Baseline in CD4+ Cell Count | Week 6 | 121.62 number of cells/L (x10^6) | Standard Error 13.96 |
| Efavirenz | Mean Change From Baseline in CD4+ Cell Count | Week 12 | 151.46 number of cells/L (x10^6) | Standard Error 16.68 |
| Efavirenz | Mean Change From Baseline in CD4+ Cell Count | Week 36 | 180.18 number of cells/L (x10^6) | Standard Error 15.12 |
| Efavirenz | Mean Change From Baseline in CD4+ Cell Count | Week 24 | 174.08 number of cells/L (x10^6) | Standard Error 14.85 |
Secondary
Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score
The HIV Patient Symptoms Profile measures the tolerability of HIV treatment from the patient's perspective, using 14 concept scales in maximum 84 questions. The response options include a no or yes answer to Did symptom occur?. If yes, there is a problem scale which ranges from 1 = I had this symptom and it was not a problem to 5 = I had this symptom and it was a severe problem. A neuropsychiatric tolerability score is composed as the sum of 21 items and ranges from 0 (best) to 105 (worse). A total Tolerability score (ie, the sum of all items) ranges from 0 (best) to 420 (worse)
Time frame: between baseline and week 48
Population: ITT: the set of all randomized patients who have taken at least 1 dose of trial medication, regardless of their compliance with the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Etravirine | Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score | Total Tolerability Score | -0.04 points on a scale | Standard Error 0.03 |
| Etravirine | Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score | Neuropsychiatric Tolerability Score | -0.04 points on a scale | Standard Error 0.06 |
| Efavirenz | Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score | Total Tolerability Score | -0.01 points on a scale | Standard Error 0.04 |
| Efavirenz | Mean Change From Baseline in Neuropsychiatric and Total Tolerabililty Score | Neuropsychiatric Tolerability Score | -0.07 points on a scale | Standard Error 0.07 |
Secondary
Neuropsychiatric Adverse Events by Week 48
The percentage of patients with at least 1 treatment emergent Grade 1 -4 neurologic or psychiatric adverse event, judged by the investigator to be at least possibly related to the study drug.
Time frame: from baseline to week 48
Population: ITT: the set of all randomized patients who have taken at least 1 dose of trial medication, regardless of their compliance with the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etravirine | Neuropsychiatric Adverse Events by Week 48 | 20.3 percentage of patients |
| Efavirenz | Neuropsychiatric Adverse Events by Week 48 | 52.6 percentage of patients |
Secondary
Resistance Determinations
The evolution of viral genotype and phenotype was assessed by the number of patients with resistance-associated mutations emerging at the endpoint. A mutation was considered emerging if it was present at endpoint and not present at baseline or any pre-baseline assessment. (NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; RAM = resistance-associated mutation, IAS-USA = International AIDS Society - USA)
Time frame: at baseline and all subsequent visits until week 48 in case if virologic failure
Population: ITT: the set of all randomized patients who have taken at least 1 dose of trial medication, regardless of their compliance with the protocol
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Etravirine | Resistance Determinations | >= 1 IAS-USA NRTI RAMs | 0 number of participants |
| Etravirine | Resistance Determinations | >= 1 NNRTI RAMs | 2 number of participants |
| Etravirine | Resistance Determinations | >= 1 NRTI Surveillance Drug Resistance Mutation | 0 number of participants |
| Etravirine | Resistance Determinations | no NRTI or NNRTI RAMs | 9 number of participants |
| Etravirine | Resistance Determinations | >= 1 successful genotype after baseline | 11 number of participants |
| Efavirenz | Resistance Determinations | no NRTI or NNRTI RAMs | 6 number of participants |
| Efavirenz | Resistance Determinations | >= 1 successful genotype after baseline | 9 number of participants |
| Efavirenz | Resistance Determinations | >= 1 IAS-USA NRTI RAMs | 2 number of participants |
| Efavirenz | Resistance Determinations | >= 1 NRTI Surveillance Drug Resistance Mutation | 2 number of participants |
| Efavirenz | Resistance Determinations | >= 1 NNRTI RAMs | 3 number of participants |