Evaluation of Renal Function, Efficacy, and Safety When Switching From Tenofovir/Emtricitabine Plus a Protease Inhibitor/Ritonavir, to a Combination of Raltegravir (MK-0518) Plus Nevirapine Plus Lamivudine in HIV-1 Participants With Suppressed Viremia and Impaired Renal Function (MK-0518-284) (RANIA)
Primary Purpose
HIV Infections
Status
Terminated
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Raltegravir (MK-0518)
Nevirapine
Lamivudine
Tenofovir
Emtricitabine
Lopinavir
Ritonavir
Atazanavir
Darunavir
Sponsored by
About this trial
This is an interventional treatment trial for HIV Infections
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Raltegravir plus Nevirapine plus Lamivudine
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
Arm Description
Raltegravir 400 mg oral twice daily for 96 weeks; plus nevirapine 200 mg oral once daily for 14 days followed by nevirapine 200 mg oral twice daily, plus lamivudine 150 mg oral twice daily for 96 weeks
Tenofovir/emtricitabine 300/200 mg oral once daily plus 1) lopinavir/ritonavir 400/100 mg oral twice daily or 800/200 mg oral once daily, or 2) atazanavir/ritonavir 300/100 mg oral once daily, or 3) darunavir/ritonavir 800/100 mg oral once daily or 600/100 mg oral twice daily
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02116660
Brief Title
Evaluation of Renal Function, Efficacy, and Safety When Switching From Tenofovir/Emtricitabine Plus a Protease Inhibitor/Ritonavir, to a Combination of Raltegravir (MK-0518) Plus Nevirapine Plus Lamivudine in HIV-1 Participants With Suppressed Viremia and Impaired Renal Function (MK-0518-284)
Acronym
RANIA
Official Title
Switching From Regimens Consisting of a RTV-Boosted Protease Inhibitor Plus TDF/FTC to a Combination of Raltegravir Plus Nevirapine and Lamivudine in HIV Patients With Suppressed Viremia and Impaired Renal Function (RANIA Study) (Pilot Study) Protocol MK-0518-284-03
Study Type
Interventional
2. Study Status
Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
This study was terminated early due to poor recruitment.
Study Start Date
September 3, 2014 (Actual)
Primary Completion Date
July 10, 2017 (Actual)
Study Completion Date
July 10, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Raltegravir plus Nevirapine plus Lamivudine
Arm Type
Experimental
Arm Description
Raltegravir 400 mg oral twice daily for 96 weeks; plus nevirapine 200 mg oral once daily for 14 days followed by nevirapine 200 mg oral twice daily, plus lamivudine 150 mg oral twice daily for 96 weeks
Arm Title
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
Arm Type
Active Comparator
Arm Description
Tenofovir/emtricitabine 300/200 mg oral once daily plus 1) lopinavir/ritonavir 400/100 mg oral twice daily or 800/200 mg oral once daily, or 2) atazanavir/ritonavir 300/100 mg oral once daily, or 3) darunavir/ritonavir 800/100 mg oral once daily or 600/100 mg oral twice daily
Intervention Type
Drug
Intervention Name(s)
Raltegravir (MK-0518)
Intervention Description
Raltegravir (MK-0518) 400 mg tablets
Intervention Type
Drug
Intervention Name(s)
Nevirapine
Intervention Description
Nevirapine (NVP) 200 mg tablets
Intervention Type
Drug
Intervention Name(s)
Lamivudine
Intervention Description
Lamivudine (3TC) 150 mg tablets
Intervention Type
Drug
Intervention Name(s)
Tenofovir
Intervention Description
Tenofovir disoproxil fumarate (TDF) 300 mg tablets
Intervention Type
Drug
Intervention Name(s)
Emtricitabine
Intervention Description
Emtricitabine (FTC) 200 mg tablets
Intervention Type
Drug
Intervention Name(s)
Lopinavir
Intervention Description
Lopinavir (LPV) 200 mg tablets
Intervention Type
Drug
Intervention Name(s)
Ritonavir
Intervention Description
Ritonavir (r) 100 mg tablets
Intervention Type
Drug
Intervention Name(s)
Atazanavir
Intervention Description
Atazanavir (ATV) 300 mg tablets
Intervention Type
Drug
Intervention Name(s)
Darunavir
Intervention Description
Darunavir (DAR) 400 mg tablets
Primary Outcome Measure Information:
Title
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
Description
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
Secondary Outcome Measure Information:
Title
Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48
Description
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
Title
Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 RNA) at Week 96
Description
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
Title
Percentage of Participants With Decline in Renal Function at Week 48
Description
Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.
Time Frame
Week 48
Title
Percentage of Participants With Virologic Failure (HIV-1 RNA > 50 Copies/mL)
Description
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
Title
Change From Baseline of HIV-RNA Absolute Values
Description
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
Title
Percentage of Participants With Mutations Associated With Resistance to NRTIs, NNRTIs, INI, at Virological Failure.
Description
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
Title
Change From Baseline in Absolute CD4+ T-lymphocyte Count
Description
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
Title
Percentage of Participants With Altered Liver Enzymes and Lipid Profile
Description
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
Title
Percentage of Participants With Altered Values of Tubular Kidney Injury Markers.
Description
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
Title
Percentage of Participants Having Changes From Baseline in Metabolic Bone Markers
Description
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
Title
Area Under the Concentration Time Curve From Time 0 the Last Measurement Time t (AUC0-t) for Raltegravir and Nevirapine
Description
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
Title
Trough Concentration (Ctrough) for Raltegravir and Nevirapine
Description
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
Title
Percentage of Participants With Genotypic Resistance at Virologic Failure.
Description
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
Title
Percentage of Participants With Adherence to Study Therapy
Description
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
Title
Change From Baseline in Bone Disease Risk Assessment
Description
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
Title
Change From Baseline in the VACS Index
Description
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
Title
Percentage of Participants Experiencing a Decline of Renal Function
Description
Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.
Time Frame
Up to Week 96
Title
Change From Baseline in eGFR at Week 96
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Learn more about this trial
Evaluation of Renal Function, Efficacy, and Safety When Switching From Tenofovir/Emtricitabine Plus a Protease Inhibitor/Ritonavir, to a Combination of Raltegravir (MK-0518) Plus Nevirapine Plus Lamivudine in HIV-1 Participants With Suppressed Viremia and Impaired Renal Function (MK-0518-284)
We'll reach out to this number within 24 hrs