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)

Phase 2

Terminated

• Conditions: HIV Infections
• Interventions: Drug: Raltegravir (MK-0518); Drug: Tenofovir; Drug: Nevirapine; Drug: Emtricitabine; Drug: Lamivudine; Drug: Lopinavir; Drug: Ritonavir; Drug: Atazanavir; Drug: Darunavir

• Registration Number: NCT02116660
• Lead Sponsor: Merck Sharp & Dohme LLC

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-04-15
• Study First Submitted QC: 2014-04-15
• Study First Posted: 2014-04-17
• Study Start: 2014-09-03
• Primary Completion: 2017-07-10
• Study Completion: 2017-07-10
• Results First Submitted: 2018-06-12
• Status Verified: 2019-04
• Results First Submitted QC: 2019-04-05
• Last Update Submitted: 2019-04-05
• Results First Posted: 2019-04-08
• Last Update Posted: 2019-04-08

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 11

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Raltegravir plus Nevirapine plus Lamivudine	Raltegravir (MK-0518)	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
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine	Tenofovir	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
Raltegravir plus Nevirapine plus Lamivudine	Nevirapine	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
Raltegravir plus Nevirapine plus Lamivudine	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
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine	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
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine	Darunavir	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
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine	Lopinavir	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
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine	Ritonavir	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
Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine	Atazanavir	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

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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 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 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 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 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.
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 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.
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 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.
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.
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.
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.