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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2013-001637-40
    Trial protocol
    		 IT  
    Global end of trial date
    10 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2018
    First version publication date
    29 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0518-284
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02116660
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective was 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.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening 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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Raltegravir plus Nevirapine plus Lamivudine
    Arm description
    		 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
    Arm type
    		 Experimental

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    MK-0518
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg tablet orally twice daily, for 96 weeks

    Investigational medicinal product name
    Nevirapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablet orally once daily, for 14 days; followed by 200 mg tablet orally twice daily for 96 weeks

    Investigational medicinal product name
    Lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablet orally twice daily, for 96 weeks

    Arm title
    		 Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Arm description
    		 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 for 96 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablet orally once daily for 96 weeks

    Investigational medicinal product name
    Emtricitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablet orally once daily for 96 weeks

    Investigational medicinal product name
    Lopinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg tablet orally twice daily or 800 mg tablet orally once daily for 96 weeks

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg tablet orally once or twice daily or 200 mg tablet orally once daily for 96 weeks

    Investigational medicinal product name
    Atazanavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablet orally once daily for 96 weeks

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg tablet orally once daily or 600 mg tablet orally twice daily for 96 weeks

    Number of subjects in period 1
    		Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Started
    6
    5
    Completed
    4
    1
    Not completed
    2
    4
         Deteriorating renal function
    -
    1
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    1
    1
         Organization reason
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Raltegravir plus Nevirapine plus Lamivudine
    Reporting group description
    		 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

    Reporting group title
    Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Reporting group description
    		 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 for 96 weeks

    Reporting group values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine Total
    Number of subjects
    		 6 5 11
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 5 11
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.83 ± 6.21 54.00 ± 5.92 -
    Gender Categorical
    Units: Subjects
        Female
    		 2 2 4
        Male
    		 4 3 7
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 6 4 10
        More than one race
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 6 5 11
        Unknown or Not Reported
    		 0 0 0
    eGFR
    Estimated Glomerular Filtration Rate
    Units: mL/min
        arithmetic mean (standard deviation)
    		 87.5 ± 7.32 87.7 ± 6.52 -

    End points

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    End points reporting groups
    Reporting group title
    Raltegravir plus Nevirapine plus Lamivudine
    Reporting group description
    		 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

    Reporting group title
    Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Reporting group description
    		 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 for 96 weeks

    Subject analysis set title
    Raltegravir
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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

    Subject analysis set title
    Nevirapine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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

    Primary: Change from Baseline in estimated Glomerular Filtration Rate (eGFR)

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    End point title
    		 Change from Baseline in estimated Glomerular Filtration Rate (eGFR) [1]
    End point 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. The population analyzed is 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.
    End point type
    Primary
    End point timeframe
    Baseline and Week 48
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses were neither planned nor performed for this primary endpoint.
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    4
    3
    Units: mL/min
        arithmetic mean (standard deviation)
    -1.1 ± 4.65
    -5.5 ± 11.78
    No statistical analyses for this end point

    Secondary: Percentage of participants with suppressed viremia (<50 copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48

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    End point title
    		 Percentage of participants with suppressed viremia (<50 copies/mL HIV-1 Ribonucleic Acid [RNA]) at Week 48
    End point 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.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [2] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [3] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with suppressed viremia (<50 copies/mL HIV-1 RNA) at Week 96

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    End point title
    		 Percentage of participants with suppressed viremia (<50 copies/mL HIV-1 RNA) at Week 96
    End point 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.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [4] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [5] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with decline in renal function at Week 48

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    End point title
    		 Percentage of participants with decline in renal function at Week 48
    End point description
    Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [6] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [7] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with virologic failure (HIV-1 RNA > 50 copies/mL)

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    End point title
    		 Percentage of participants with virologic failure (HIV-1 RNA > 50 copies/mL)
    End point 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.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [8] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [9] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Change from baseline of HIV-RNA absolute values

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    End point title
    		 Change from baseline of HIV-RNA absolute values
    End point description
    Plasma was to be collected at baseline and Week 96 in order to determine the change from baseline in HIV-1 RNA.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Copies/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [10] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [11] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with mutations associated with resistance to NRTIs, NNRTIs, INI, at virological failure.

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    End point title
    		 Percentage of participants with mutations associated with resistance to NRTIs, NNRTIs, INI, at virological failure.
    End point 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.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [12] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [13] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Change from baseline in absolute CD4+ T-lymphocyte count

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    End point title
    		 Change from baseline in absolute CD4+ T-lymphocyte count
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Cells/mm^3
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [14] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [15] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with altered liver enzymes and lipid profile

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    End point title
    		 Percentage of participants with altered liver enzymes and lipid profile
    End point 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.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [16] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [17] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with altered values of tubular kidney injury markers

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    End point title
    		 Percentage of participants with altered values of tubular kidney injury markers
    End point description
    Values of tubular kidney injury markers. were to be determined, in order to identify the percentage of participants classified with altered values.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [18] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected..
    [19] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants having changes from baseline in metabolic bone markers

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    End point title
    		 Percentage of participants having changes from baseline in metabolic bone markers
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [20] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [21] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Area under the concentration time curve from time 0 the last measurement time t (AUC0-t) for Raltegravir and Nevirapine

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    End point title
    		 Area under the concentration time curve from time 0 the last measurement time t (AUC0-t) for Raltegravir and Nevirapine
    End point 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
    End point type
    Secondary
    End point timeframe
    Week 12: Fasted state (0 hr) and 1, 2, 3, 6 and 12 hr post-dose
    End point values
    		 Raltegravir Nevirapine
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: mmol/L*hr
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [22] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [23] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Trough concentration (Ctrough) for Raltegravir and Nevirapine

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    End point title
    		 Trough concentration (Ctrough) for Raltegravir and Nevirapine
    End point 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.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 48: at the end of dosing interval at 12 hr
    End point values
    		 Raltegravir Nevirapine
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: nM
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [24] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [25] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants with genotypic resistance at virologic failure

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    End point title
    		 Percentage of participants with genotypic resistance at virologic failure
    End point 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.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [26]
    0 [27]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [26] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [27] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected..
    No statistical analyses for this end point

    Secondary: Percentage of participants with adherence to study therapy

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    End point title
    		 Percentage of participants with adherence to study therapy
    End point description
    An Adherence Questionnaire was to be given in order to determine the percentage of participants who adhered to study therapy.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [28]
    0 [29]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [28] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [29] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Change from baseline in bone disease risk assessment

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    End point title
    		 Change from baseline in bone disease risk assessment
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [30]
    0 [31]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [30] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected..
    [31] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Change from baseline in the VACS Index

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    End point title
    		 Change from baseline in the VACS Index
    End point 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [32]
    0 [33]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [32] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [33] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Percentage of participants experiencing a decline of renal function

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    End point title
    		 Percentage of participants experiencing a decline of renal function
    End point description
    Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [34]
    0 [35]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [34] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [35] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Secondary: Change from Baseline in eGFR at Week 96

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    End point title
    		 Change from Baseline in eGFR at Week 96
    End point description
    eGFR was estimated from the 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Raltegravir plus Nevirapine plus Lamivudine Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Number of subjects analysed
    0 [36]
    0 [37]
    Units: mL/min
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [36] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    [37] - Poor enrollment led to early termination of the study; so data for this endpoint was not collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 98
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine
    Reporting group description
    		 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 for 96 weeks

    Reporting group title
    Raltegravir plus Nevirapine plus Lamivudine
    Reporting group description
    		 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

    Serious adverse events
    		 Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine Raltegravir plus Nevirapine plus Lamivudine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Protease Inhibitor/Ritonavir plus tenofovir/emtricitabine Raltegravir plus Nevirapine plus Lamivudine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Lichen planus
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Gonorrhea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2014
    Amendment 2: Clarified the rationale of study: a pilot study that involves a transition from the standard therapeutic regimen to an experimental regimen with the use of an internal control comparator to evaluate the full validity of the study. Better defined the primary endpoint as change of eGFR from the baseline to week 48. Excluded participants with anamnesis of diabetes mellitus and those with any type of cancer. Added more frequent renal safety monitoring assessments for the control arm. The statistical plan was reviewed to better define the sample size.
    06 Jul 2015
    Amendment 3: Update of the list of drug-drug interactions according to the last Summary of Product Characteristics (SmPc) updated for raltegravir and nevirapirine. Updated the text for consistent wording related to the study participation/study duration. Added to protocol the definition of overdose, previously inadvertently omitted. Updated the pharmacokinetic (PK) test to further clarify sampling requirements (regarding drug food intake).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Jul 2017
    Due to poor enrollment the study was terminated early.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.
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