HIV Infections
Conditions
Brief summary
To evaluate changes in renal function, efficacy, and safety when switching from a combination of tenofovir/emtricitabine (TDF/FTC) plus a protease inhibitor/ritonavir (PI/r) to a combination of raltegravir (MK-0518) plus nevirapine plus lamivudine in human immunodeficiency virus (HIV)-1 infected participants with suppressed viremia and impaired renal function.
Interventions
Raltegravir (MK-0518) 400 mg tablets
DRUGNevirapine
Nevirapine (NVP) 200 mg tablets
DRUGLamivudine
Lamivudine (3TC) 150 mg tablets
DRUGTenofovir
Tenofovir disoproxil fumarate (TDF) 300 mg tablets
DRUGEmtricitabine
Emtricitabine (FTC) 200 mg tablets
DRUGLopinavir
Lopinavir (LPV) 200 mg tablets
DRUGRitonavir
Ritonavir (r) 100 mg tablets
DRUGAtazanavir
Atazanavir (ATV) 300 mg tablets
DRUGDarunavir
Darunavir (DAR) 400 mg tablets
Sponsors
Merck Sharp & Dohme LLC
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
* Male, or non-pregnant, non-breastfeeding female * No previous history of virological failure * No previous exposure to non-nucleoside reverse transcriptase inhibitors or integrase inhibitors * No previous history of intolerance to lamivudine * At least 2 documented plasma HIV-1 RNA \<50 copies/mL and no HIV-1 \>50 copies/mL in the 12 months before screening * Receiving the same protease inhibitor/ritonavir plus tenofovir/emtricitabine combination for at least the 6 months before screening * Has no major International Antiviral Society (IAS)-USA mutations on genotype testing performed before starting antiretroviral treatment * Sexually-active participants and their partners of child-bearing potential agree to use a medically acceptable method of contraception from 2 weeks before Day 1 and for at least 6 months after the last dose of study drug (postmenopausal women are not required to use contraception; sexually-active male participants with a female partner of child-bearing potential must provide written informed consent to information regarding any pregnancy)
Exclusion criteria
* Positive for hepatitis B surface antigen (HBsAg+) or anticipated need for hepatitis C virus treatment * Liver cirrhosis * Has a history of diabetes mellitus, defined as initiation of antidiabetic treatment or verification of diabetes in a case report form * Has any cancer, excluding stable Kaposi Sarcoma * Allergy or sensitivity to the investigational product or excipients * Female participant who is nursing * Female participant who is pregnant or intends to become pregnant * Has an active Acquired Immunodeficiency Syndrome (AIDS)-defining event except stable Kaposi Sarcoma or HIV Wasting Syndrome * Received any investigational drug within 30 days before screening * Participated in any other clinical trial within 30 days before signing informed consent for the current trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Baseline and Week 48 | Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × \[serum creatinine(mg/dL)\]\^-0.858 × \[age\]-0.167 × \[0.822 if patient is female\] × \[1.178 if patient is black\] × \[serum urea nitrogen concentration (mg/dL)\]\^-0.293 × \[urine urea nitrogen excretion (g/d)\]\^0.249. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 RNA) at Week 96 | Week 96 | Plasma was to be collected at Week 96 in order to quantify HIV-1 RNA. and identify the percentage of participants with \<50 copies/mL HIV-1 RNA. |
| Percentage of Participants With Decline in Renal Function at Week 48 | Week 48 | Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate. |
| Percentage of Participants With Virologic Failure (HIV-1 RNA > 50 Copies/mL) | Up to Week 96 | Plasma was to be collected up to Week 96 in order to quantify HIV-1 RNA, and identify the percentage of participants with \>50 copies/mL HIV-1 RNA. |
| Change From Baseline of HIV-RNA Absolute Values | Baseline and Week 96 | Plasma was to be collected at baseline and Week 96 in order to determine the change from baseline in HIV-1 RNA. |
| Percentage of Participants With Mutations Associated With Resistance to NRTIs, NNRTIs, INI, at Virological Failure. | Up to Week 96 | Participants were to be identified with mutations associated with Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Inhibitor (INI). Virological failure is defined as 2 consecutive plasma HIV-1 RNA \>200 copies/mL at least two weeks apart while on previous or current ARV therapy. |
| Change From Baseline in Absolute CD4+ T-lymphocyte Count | Baseline and Week 96 | Cluster of Differentiation 4 + (CD4+) T-lymphocyte cell counts were to be determined at baseline and Week 96, in order to determine the change from baseline. |
| Percentage of Participants With Altered Liver Enzymes and Lipid Profile | Up to Week 96 | Values of liver enzymes and lipids were to be determined from laboratory tests, in order to identify the percentage of participants classified with altered values. |
| Percentage of Participants With Altered Values of Tubular Kidney Injury Markers. | Up to Week 96 | Values of tubular kidney injury markers. were to be determined, in order to identify the percentage of participants classified with altered values. |
| Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48 | Week 48 | Plasma was to be collected at Week 48 in order to quantify HIV-1 RNA. and identify the percentage of participants with \<50 copies/mL HIV-1 RNA. |
| Area Under the Concentration Time Curve From Time 0 the Last Measurement Time t (AUC0-t) for Raltegravir and Nevirapine | Week 12: Fasted state (0 h) and 1, 2, 3, 6 and 12 h post-dose | Blood samples were to be collected in Week 12 in order to use the trapezoidal method to determine the AUC0-t of Raltegravir and Nevirapine |
| Trough Concentration (Ctrough) for Raltegravir and Nevirapine | Weeks 12 and 48: at the end of dosing interval at 12 h | Blood samples were to be collected in Weeks 12 and 48 in order to use the trapezoidal method to determine the Ctrough, the lowest concentration reached by the drug before the next dose is administered, of Raltegravir and Nevirapine. |
| Percentage of Participants With Genotypic Resistance at Virologic Failure. | Up to Week 96 | Genotypic resistance measures the presence of particular HIV-1 mutations that give rise to drug resistance. Virological failure is defined as 2 consecutive plasma HIV-1 RNA \>200 copies/mL at least two weeks apart while on previous or current ARV therapy. |
| Percentage of Participants With Adherence to Study Therapy | Up to Week 96 | An Adherence Questionnaire was to be given in order to determine the percentage of participants who adhered to study therapy. |
| Change From Baseline in Bone Disease Risk Assessment | Baseline and week 96 | Bone disease risk assessment was to be based on a Fracture Risk Assessment Tool (FRAX®) score in participants \> 40 years old, and the change from baseline determined. |
| Change From Baseline in the VACS Index | Baseline and week 96 | The Veterans Aging Cohort Risk Index (VACS Index) combines various clinical biomarkers into a cumulative index weighted according to the risk of all-cause mortality. |
| Percentage of Participants Experiencing a Decline of Renal Function | Up to Week 96 | Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate. |
| Change From Baseline in eGFR at Week 96 | Baseline and Week 96 | Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × \[serum creatinine(mg/dL)\]\^-0.858 × \[age\]-0.167 × \[0.822 if patient is female\] × \[1.178 if patient is black\] × \[serum urea nitrogen concentration (mg/dL)\]\^-0.293 × \[urine urea nitrogen excretion (g/d)\]\^0.249. |
| Percentage of Participants Having Changes From Baseline in Metabolic Bone Markers | Baseline and up to Week 96 | Changes from baseline in metabolic bone markers, serum Bone Specific Alkaline Phosphatase (s-BSAP) and C-telopeptides of type 1 Collagen (s-CTx), were to be determined, in order to classify the percentage of participants with changes. |
Participant flow
Recruitment details
Human immunodeficiency virus (HIV) infected adults with stable suppressed HIV-1 ribonucleic acid (RNA) from at least 12 months prior to the screening visit, and with a current stable anti-retroviral (ARV) regimen were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir Plus Nevirapine Plus Lamivudine Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks | 6 |
| Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily | 5 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Deteriorating renal function | 0 | 1 |
| Overall Study | Organization reason | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Raltegravir Plus Nevirapine Plus Lamivudine | Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine | Total |
|---|---|---|---|
| Age, Continuous | 49.83 Years STANDARD_DEVIATION 6.21 | 54.00 Years STANDARD_DEVIATION 5.92 | 51.7 Years STANDARD_DEVIATION 6.2 |
| Estimated Glomerular Filtration Rate (eGFR) | 87.5 mL/min STANDARD_DEVIATION 7.32 | 87.7 mL/min STANDARD_DEVIATION 6.52 | 87.62 mL/min STANDARD_DEVIATION 6.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 |
| other Total, other adverse events | 3 / 6 | 2 / 5 |
| serious Total, serious adverse events | 0 / 6 | 1 / 5 |
Outcome results
Primary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × \[serum creatinine(mg/dL)\]\^-0.858 × \[age\]-0.167 × \[0.822 if patient is female\] × \[1.178 if patient is black\] × \[serum urea nitrogen concentration (mg/dL)\]\^-0.293 × \[urine urea nitrogen excretion (g/d)\]\^0.249.
Time frame: Baseline and Week 48
Population: All randomized participants who received at least one dose of study medications and who had both a baseline assessment, and at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Raltegravir Plus Nevirapine Plus Lamivudine | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -1.1 mL/min | Standard Deviation 4.65 |
| Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -5.5 mL/min | Standard Deviation 11.78 |
Secondary
Area Under the Concentration Time Curve From Time 0 the Last Measurement Time t (AUC0-t) for Raltegravir and Nevirapine
Blood samples were to be collected in Week 12 in order to use the trapezoidal method to determine the AUC0-t of Raltegravir and Nevirapine
Time frame: Week 12: Fasted state (0 h) and 1, 2, 3, 6 and 12 h post-dose
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Change From Baseline in Absolute CD4+ T-lymphocyte Count
Cluster of Differentiation 4 + (CD4+) T-lymphocyte cell counts were to be determined at baseline and Week 96, in order to determine the change from baseline.
Time frame: Baseline and Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Change From Baseline in Bone Disease Risk Assessment
Bone disease risk assessment was to be based on a Fracture Risk Assessment Tool (FRAX®) score in participants \> 40 years old, and the change from baseline determined.
Time frame: Baseline and week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Change From Baseline in eGFR at Week 96
Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × \[serum creatinine(mg/dL)\]\^-0.858 × \[age\]-0.167 × \[0.822 if patient is female\] × \[1.178 if patient is black\] × \[serum urea nitrogen concentration (mg/dL)\]\^-0.293 × \[urine urea nitrogen excretion (g/d)\]\^0.249.
Time frame: Baseline and Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Change From Baseline in the VACS Index
The Veterans Aging Cohort Risk Index (VACS Index) combines various clinical biomarkers into a cumulative index weighted according to the risk of all-cause mortality.
Time frame: Baseline and week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Change From Baseline of HIV-RNA Absolute Values
Plasma was to be collected at baseline and Week 96 in order to determine the change from baseline in HIV-1 RNA.
Time frame: Baseline and Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants Experiencing a Decline of Renal Function
Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants Having Changes From Baseline in Metabolic Bone Markers
Changes from baseline in metabolic bone markers, serum Bone Specific Alkaline Phosphatase (s-BSAP) and C-telopeptides of type 1 Collagen (s-CTx), were to be determined, in order to classify the percentage of participants with changes.
Time frame: Baseline and up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Adherence to Study Therapy
An Adherence Questionnaire was to be given in order to determine the percentage of participants who adhered to study therapy.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Altered Liver Enzymes and Lipid Profile
Values of liver enzymes and lipids were to be determined from laboratory tests, in order to identify the percentage of participants classified with altered values.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Altered Values of Tubular Kidney Injury Markers.
Values of tubular kidney injury markers. were to be determined, in order to identify the percentage of participants classified with altered values.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Decline in Renal Function at Week 48
Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.
Time frame: Week 48
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Genotypic Resistance at Virologic Failure.
Genotypic resistance measures the presence of particular HIV-1 mutations that give rise to drug resistance. Virological failure is defined as 2 consecutive plasma HIV-1 RNA \>200 copies/mL at least two weeks apart while on previous or current ARV therapy.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Mutations Associated With Resistance to NRTIs, NNRTIs, INI, at Virological Failure.
Participants were to be identified with mutations associated with Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Inhibitor (INI). Virological failure is defined as 2 consecutive plasma HIV-1 RNA \>200 copies/mL at least two weeks apart while on previous or current ARV therapy.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48
Plasma was to be collected at Week 48 in order to quantify HIV-1 RNA. and identify the percentage of participants with \<50 copies/mL HIV-1 RNA.
Time frame: Week 48
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 RNA) at Week 96
Plasma was to be collected at Week 96 in order to quantify HIV-1 RNA. and identify the percentage of participants with \<50 copies/mL HIV-1 RNA.
Time frame: Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Percentage of Participants With Virologic Failure (HIV-1 RNA > 50 Copies/mL)
Plasma was to be collected up to Week 96 in order to quantify HIV-1 RNA, and identify the percentage of participants with \>50 copies/mL HIV-1 RNA.
Time frame: Up to Week 96
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
Secondary
Trough Concentration (Ctrough) for Raltegravir and Nevirapine
Blood samples were to be collected in Weeks 12 and 48 in order to use the trapezoidal method to determine the Ctrough, the lowest concentration reached by the drug before the next dose is administered, of Raltegravir and Nevirapine.
Time frame: Weeks 12 and 48: at the end of dosing interval at 12 h
Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.