Human Immunodeficiency Virus-type 1 Infection
Conditions
Keywords
Human immunodeficiency virus-type 1 infection, HIV-1, Infectious diseases, Ribonucleic acid, RNA, Tenofovir disoproxil fumarate, Emtricitabine, Rilpivirine, Efavirenz, Edurant, TMC278, R278474, Fixed dose combination
Brief summary
The purpose of this study is to demonstrate noninferiority (a new treatment is equivalent to standard treatment) in terms of the percentage of patients who have plasma human immunodeficiency virus-type 1 (HIV-1) ribonucleic acid (RNA) levels less than 400 copies per mL after 48 weeks of randomized treatment with tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) versus TDF/FTC/efavirenz (TDF/FTC/EFV).
Detailed description
This is a 48-week, multicenter (study conducted at multiple sites), multinational (conducted at different countries), open-label (all people know the identity of the intervention), randomized (the study medication is assigned by chance) study to assess whether tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) shows noninferior response rates of human immunodeficiency virus-type 1 (HIV-1) ribonucleic acid (RNA) suppression less than 400 copies per mL, compared with TDF/FTC/efavirenz (TDF/FTC/EFV). The study consists of 3 phases including, the screening phase (of 6 weeks), treatment phase (of 48 weeks), and follow up phase (of 30 to 35 days after the last dose of study medication). During the 48 weeks treatment phase, patients currently with HIV-1 RNA suppression less than 50 copies per mL on their first-line antiretroviral regimen, will be randomized in a 1:1 ratio, in 2 groups, ie, Group 1 (treatment group) and Group 2 (control group). Both these groups will receive a fixed dose combination (FDC) regimen (ie, FDC tablet: one tablet per day) of either TDF/FTC/RPV in Group 1 or TDF/FTC/EFV in Group 2. Patients will return for study visits at Week 4, 12, 24, 36, and 48 during the treatment period, and then every 24 weeks thereafter during the extended treatment period until the last patient has his or her Week 48 (or treatment discontinuation) visit. Safety evaluations for adverse events, clinical laboratory (central and local) tests, electrocardiogram, vital signs, and physical examination will be performed throughout the study. The treatment duration for each patient will be expected to be between 48 and 108 weeks.
Interventions
DRUGEmtricitabine
Type=exact number, unit=mg, number=200, form=tablet, route=oral. Emtricitabine will be administered in a fixed dose combination along with rilpivirine and tenofovir disoproxil fumarate in Group 1, and along with efavirenz and tenofovir disoproxil fumarate in Group 2.
DRUGRilpivirine
Type=exact number, unit=mg, number=25, form=tablet, route=oral. Rilpivirine will be administered in a fixed dose combination along with tenofovir disoproxil fumarate and emtricitabine, as a single dose tablet.
DRUGEfavirenz
Type=exact number, unit=mg, number=600, form=tablet, route=oral. Efavirenz will be administered in a fixed dose combination along with tenofovir disoproxil fumarate and emtricitabine, as a single dose tablet.
DRUGTenofovir disoproxil fumarate
Type=exact number, unit=mg, number=300, form=tablet, route=oral. Tenofovir disoproxil fumarate will be administered in a fixed dose combination along with rilpivirine and emtricitabine in Group 1, and along with efavirenz and emtricitabine in Group 2.
Sponsors
Janssen-Cilag International NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Documented human immunodeficiency virus-type 1 (HIV-1) infection Patients who have been receiving first line highly active antiretroviral therapy (HAART) for at least 1 year before the screening visit Patients who have been taking the same ARV combination for at least 8 weeks before the screening visit and are expected to continue on this regimen throughout the screening period. Patients who prefer to change the current HAART regimen for reasons of simplification and/or toxicity of nucleoside/nucleotide reverse transcriptase inhibitor (N\[t\]RTI) Plasma HIV-1 RNA less than 50 copies per mL and CD4+ cell count higher than 200 per mm3 at the screening visit Agrees to protocol-defined use of effective contraception
Exclusion criteria
History of virologic failure (2 consecutive plasma HIV-1 ribonucleic acid (RNA) more than or equal to 400 copies per mL) while on previous or current ART History of immunologic failure (2 consecutive CD4+ cell counts during HAART treatment falling below the pre-HAART level) History of any primary N\[t\]RTI or NNRTI mutations Has a previously documented HIV-2 infection Significantly decreased hepatic function or hepatic insufficiency or diagnosed with acute clinical viral hepatitis Diagnosed with Mycobacterium tuberculosis infection Severe laboratory abnormalities Creatinine clearance less than 50 mL per minute Addicted to drug, including alcohol or recreational drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Plasma Human Immunodeficiency Virus - Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 400 Copies Per Milliliter (Copies/mL) at Week 48 | Week 48 | Percentage of Participants with viral load (plasma HIV-1 RNA levels) less than 400 copies per mL at Week 48, obtained by the modified Food and Drug Administration (FDA) Snapshot method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Plasma HIV-1 RNA Levels < 50 Copies/mL at Week 48 | Week 48 | Percentage of Participants with plasma HIV-1 RNA \<50 copies/mL, obtained by the modified Food and Drug Administration (FDA) Snapshot method. |
| Percentage of Participants With Plasma HIV-1 RNA Levels More Than or Equal to (>=) 400 Copies/mL at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method. | Week 48 | Percentage of participants with plasma HIV-1 RNA levels analysed based on time to loss of virologic response (TLOVR) imputation method which is defined as confirmed plasma HIV-1 RNA \>=400 copies/mL, excluding participants who discontinued the study with HIV-1 RNA suppression \<400 copies/mL. |
| Percentage of Participants With Plasma HIV-1 RNA Levels >= 50 Copies Per Milliliter (Copies/mL) at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method. | Week 48 | Percentage of participants with plasma HIV-1 RNA levels analysed based on TLOVR imputation method which is defined as confirmed plasma HIV-1 RNA \>=50 copies/mL, excluding participants who discontinued the study with HIV-1 RNA suppression \<50 copies/mL. |
| Percentage of Participant With Treatment Adherence Based on Tablet Count | Up to 48 Weeks | In both treatment groups adherence rates assessed by tablet count, the majority of participants had an adherence of \>95% (97% and 98% in RPV and EFV treated treatment groups respectively). |
| Number of Participants With Treatment-Emergent Nucleoside Reverse Transcriptase Inhibitor (N[t]RTI) or Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NNRTI) Mutations | Up to Week 48 | To compare the loss of treatment options, the number of participants with treatment-emergent N\[t\]RTI or NNRTI mutations, as defined by IAS-USA (2014), after virologic failure were compared between the treatment groups. |
Countries
Cameroon, Kenya, Senegal, South Africa, Thailand, Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TDF/FTC/RPV Participants received Film-coated fixed dose combination (FDC) tablet containing 300 milligram (mg) Tenofovir disoproxil fumarate (TDF), 200 mg Emtricitabine (FTC) and 25 mg Rilpivirine (RPV) with a meal, until Week 48. | 213 |
| TDF/FTC/EFV Participants received Film-coated fixed dose combination (FDC) tablet containing 300 milligram (mg) Tenofovir disoproxil fumarate (TDF), 200 mg Emtricitabine (FTC) and 600 mg Efavirenz (EFV) on an empty stomach at bedtime, until Week 48. | 211 |
| Total | 424 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 |
| Overall Study | Lost to Follow-up | 4 | 7 |
| Overall Study | Not Treated | 0 | 2 |
| Overall Study | Other | 5 | 3 |
| Overall Study | Participant Reached a Virologic Endpoint | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | TDF/FTC/EFV | Total | TDF/FTC/RPV |
|---|---|---|---|
| Age, Continuous | 40.6 years STANDARD_DEVIATION 8.7 | 40.6 years STANDARD_DEVIATION 8.34 | 40.6 years STANDARD_DEVIATION 8 |
| Region of Enrollment CAMEROON | 13 participants | 29 participants | 16 participants |
| Region of Enrollment KENYA | 37 participants | 73 participants | 36 participants |
| Region of Enrollment SENEGAL | 8 participants | 25 participants | 17 participants |
| Region of Enrollment SOUTH AFRICA | 30 participants | 63 participants | 33 participants |
| Region of Enrollment THAILAND | 58 participants | 109 participants | 51 participants |
| Region of Enrollment UGANDA | 65 participants | 125 participants | 60 participants |
| Sex: Female, Male Female | 134 Participants | 271 Participants | 137 Participants |
| Sex: Female, Male Male | 77 Participants | 153 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 128 / 213 | 137 / 211 |
| serious Total, serious adverse events | 16 / 213 | 11 / 211 |
Outcome results
Primary
Percentage of Participants With Plasma Human Immunodeficiency Virus - Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 400 Copies Per Milliliter (Copies/mL) at Week 48
Percentage of Participants with viral load (plasma HIV-1 RNA levels) less than 400 copies per mL at Week 48, obtained by the modified Food and Drug Administration (FDA) Snapshot method.
Time frame: Week 48
Population: The intent-to-treat (ITT) population included all participants who were randomized and who had taken at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF/FTC/RPV | Percentage of Participants With Plasma Human Immunodeficiency Virus - Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 400 Copies Per Milliliter (Copies/mL) at Week 48 | 93.9 Percentage of Participants |
| TDF/FTC/EFV | Percentage of Participants With Plasma Human Immunodeficiency Virus - Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 400 Copies Per Milliliter (Copies/mL) at Week 48 | 96.2 Percentage of Participants |
Secondary
Number of Participants With Treatment-Emergent Nucleoside Reverse Transcriptase Inhibitor (N[t]RTI) or Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NNRTI) Mutations
To compare the loss of treatment options, the number of participants with treatment-emergent N\[t\]RTI or NNRTI mutations, as defined by IAS-USA (2014), after virologic failure were compared between the treatment groups.
Time frame: Up to Week 48
Population: The intent-to-treat (ITT) population included all participants who were randomized and who had taken at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF/FTC/RPV | Number of Participants With Treatment-Emergent Nucleoside Reverse Transcriptase Inhibitor (N[t]RTI) or Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NNRTI) Mutations | 0 Participants |
| TDF/FTC/EFV | Number of Participants With Treatment-Emergent Nucleoside Reverse Transcriptase Inhibitor (N[t]RTI) or Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NNRTI) Mutations | 0 Participants |
Secondary
Percentage of Participants With Plasma HIV-1 RNA Levels < 50 Copies/mL at Week 48
Percentage of Participants with plasma HIV-1 RNA \<50 copies/mL, obtained by the modified Food and Drug Administration (FDA) Snapshot method.
Time frame: Week 48
Population: The intent-to-treat (ITT) population included all participants who were randomized and who had taken at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF/FTC/RPV | Percentage of Participants With Plasma HIV-1 RNA Levels < 50 Copies/mL at Week 48 | 93.9 Percentage of Participants |
| TDF/FTC/EFV | Percentage of Participants With Plasma HIV-1 RNA Levels < 50 Copies/mL at Week 48 | 96.2 Percentage of Participants |
Secondary
Percentage of Participants With Plasma HIV-1 RNA Levels >= 50 Copies Per Milliliter (Copies/mL) at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method.
Percentage of participants with plasma HIV-1 RNA levels analysed based on TLOVR imputation method which is defined as confirmed plasma HIV-1 RNA \>=50 copies/mL, excluding participants who discontinued the study with HIV-1 RNA suppression \<50 copies/mL.
Time frame: Week 48
Population: The intent-to-treat (ITT) population included all participants who were randomized and who had taken at least 1 dose of study drug. Here, N (number of participants analyzed) signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF/FTC/RPV | Percentage of Participants With Plasma HIV-1 RNA Levels >= 50 Copies Per Milliliter (Copies/mL) at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method. | 1.5 Percentage of Participants |
| TDF/FTC/EFV | Percentage of Participants With Plasma HIV-1 RNA Levels >= 50 Copies Per Milliliter (Copies/mL) at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method. | 1.0 Percentage of Participants |
Secondary
Percentage of Participants With Plasma HIV-1 RNA Levels More Than or Equal to (>=) 400 Copies/mL at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method.
Percentage of participants with plasma HIV-1 RNA levels analysed based on time to loss of virologic response (TLOVR) imputation method which is defined as confirmed plasma HIV-1 RNA \>=400 copies/mL, excluding participants who discontinued the study with HIV-1 RNA suppression \<400 copies/mL.
Time frame: Week 48
Population: The intent-to-treat (ITT) population included all participants who were randomized and who had taken at least 1 dose of study drug. Here, N (number of participants analyzed) signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF/FTC/RPV | Percentage of Participants With Plasma HIV-1 RNA Levels More Than or Equal to (>=) 400 Copies/mL at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method. | 0.5 Percentage of Participants |
| TDF/FTC/EFV | Percentage of Participants With Plasma HIV-1 RNA Levels More Than or Equal to (>=) 400 Copies/mL at Week 48 Based on Time to Loss of Virologic Response (TLOVR) [Non-virologic Failure Censored] Imputation Method. | 0.5 Percentage of Participants |
Secondary
Percentage of Participant With Treatment Adherence Based on Tablet Count
In both treatment groups adherence rates assessed by tablet count, the majority of participants had an adherence of \>95% (97% and 98% in RPV and EFV treated treatment groups respectively).
Time frame: Up to 48 Weeks
Population: The intent-to-treat (ITT) population included all participants who were randomized and who had taken at least 1 dose of study drug. Here, N (number of participants analyzed) signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| TDF/FTC/RPV | Percentage of Participant With Treatment Adherence Based on Tablet Count | 97.2 Percentage of Participants | 1.981 |
| TDF/FTC/EFV | Percentage of Participant With Treatment Adherence Based on Tablet Count | 97.6 Percentage of Participants | 1.649 |