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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
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

    First Posted
    April 15, 2014
    Last Updated
    April 5, 2019
    Sponsor
    Merck Sharp & Dohme LLC
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    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)

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