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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)

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ClinicalTrials.gov Identifier: NCT02116660
Recruitment Status : Terminated (This study was terminated early due to poor recruitment.)
First Posted : April 17, 2014
Results First Posted : April 8, 2019
Last Update Posted : April 8, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Raltegravir (MK-0518) Drug: Nevirapine Drug: Lamivudine Drug: Tenofovir Drug: Emtricitabine Drug: Lopinavir Drug: Ritonavir Drug: Atazanavir Drug: Darunavir Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 3, 2014
Actual Primary Completion Date : July 10, 2017
Actual Study Completion Date : July 10, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Raltegravir plus Nevirapine plus Lamivudine
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
Drug: Raltegravir (MK-0518)
Raltegravir (MK-0518) 400 mg tablets

Drug: Nevirapine
Nevirapine (NVP) 200 mg tablets

Drug: Lamivudine
Lamivudine (3TC) 150 mg tablets

Active Comparator: Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
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
Drug: Tenofovir
Tenofovir disoproxil fumarate (TDF) 300 mg tablets

Drug: Emtricitabine
Emtricitabine (FTC) 200 mg tablets

Drug: Lopinavir
Lopinavir (LPV) 200 mg tablets

Drug: Ritonavir
Ritonavir (r) 100 mg tablets

Drug: Atazanavir
Atazanavir (ATV) 300 mg tablets

Drug: Darunavir
Darunavir (DAR) 400 mg tablets




Primary Outcome Measures :
  1. Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 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 Outcome Measures :
  1. Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48 [ Time Frame: 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.

  2. Percentage of Participants With Suppressed Viremia (<50 Copies/mL HIV-1 RNA) at Week 96 [ Time Frame: 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.

  3. Percentage of Participants With Decline in Renal Function at Week 48 [ Time Frame: Week 48 ]
    Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.

  4. Percentage of Participants With Virologic Failure (HIV-1 RNA > 50 Copies/mL) [ Time Frame: 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.

  5. Change From Baseline of HIV-RNA Absolute Values [ Time Frame: 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.

  6. Percentage of Participants With Mutations Associated With Resistance to NRTIs, NNRTIs, INI, at Virological Failure. [ Time Frame: 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.

  7. Change From Baseline in Absolute CD4+ T-lymphocyte Count [ Time Frame: 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.

  8. Percentage of Participants With Altered Liver Enzymes and Lipid Profile [ Time Frame: 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.

  9. Percentage of Participants With Altered Values of Tubular Kidney Injury Markers. [ Time Frame: 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.

  10. Percentage of Participants Having Changes From Baseline in Metabolic Bone Markers [ Time Frame: 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.

  11. Area Under the Concentration Time Curve From Time 0 the Last Measurement Time t (AUC0-t) for Raltegravir and Nevirapine [ Time Frame: 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

  12. Trough Concentration (Ctrough) for Raltegravir and Nevirapine [ Time Frame: 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.

  13. Percentage of Participants With Genotypic Resistance at Virologic Failure. [ Time Frame: 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.

  14. Percentage of Participants With Adherence to Study Therapy [ Time Frame: Up to Week 96 ]
    An Adherence Questionnaire was to be given in order to determine the percentage of participants who adhered to study therapy.

  15. Change From Baseline in Bone Disease Risk Assessment [ Time Frame: 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.

  16. Change From Baseline in the VACS Index [ Time Frame: 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.

  17. Percentage of Participants Experiencing a Decline of Renal Function [ Time Frame: Up to Week 96 ]
    Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.

  18. Change From Baseline in eGFR at Week 96 [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02116660


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02116660    
Other Study ID Numbers: 0518-284
2013-001637-40 ( EudraCT Number )
MK-0518-284 ( Other Identifier: Merck Protocol Number )
First Posted: April 17, 2014    Key Record Dates
Results First Posted: April 8, 2019
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Viremia
Renal Insufficiency
Virus Diseases
Kidney Diseases
Urologic Diseases
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Ritonavir
Lopinavir
Atazanavir Sulfate
Darunavir
Tenofovir
Lamivudine
Emtricitabine
Raltegravir Potassium
Nevirapine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors