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    Clinical Trial Results:
    Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A) in HIV-1-infected Children and Adolescents

    Summary
    EudraCT number
    		 2017-001518-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    25 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-1439-027
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03332095
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DAIDS-ES Registry Number: 34150, Other: IMPAACT 2014
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001676-PIP01-14 EMEA-001695-PIP01-14
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the pharmacokinetics, safety, and tolerability of doravirine (also called MK-1439 or DOR) and doravirine/lamivudine/tenofovir disoproxil fumarate (also called MK-1439A or DOR/3TC/TDF) in human immunodeficiency virus (HIV)-1-infected children and adolescents.
    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
    		 Participants in Cohort 1 received a combination of dolutegravir (DTG) or raltegravir (RAL) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The Antiretroviral (ARV) medications were prescribed by participants' own health care providers and were not provided by the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2018
    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
    South Africa: 9
    Country: Number of subjects enrolled
    Thailand: 35
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    55
    EEA total number of subjects
    0
    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)
    55
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled from July 2018 to February 2020. Participants were recruited from 8 medical clinics in the United States, Thailand and South Africa.

    Pre-assignment
    Screening details
    		 There was no randomization. Enrollment started with Cohort 1, then Cohort 2 was open.

    Period 1
    Period 1 title
    Enrolled
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: DOR
    Arm description
    		 Participants received a single dose of DOR at study entry (Day 0).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doravirine (DOR)
    Investigational medicinal product code
    Other name
    MK-1439
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg of DOR administered orally

    Arm title
    		 Cohort 2: DOR/3TC/TDF
    Arm description
    		 Participants received DOR/3TC/TDF from Day 0 through Week 96.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)
    Investigational medicinal product code
    Other name
    MK-1439A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily

    Number of subjects in period 1
    		Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Started
    10
    45
    Received study treatment
    9
    45
    Completed
    9
    45
    Not completed
    1
    0
         Enrolled but not treated
    1
    -
    Period 2
    Period 2 title
    Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: DOR
    Arm description
    		 Participants received a single dose of DOR at study entry (Day 0).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doravirine (DOR)
    Investigational medicinal product code
    Other name
    MK-1439
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg of DOR administered orally

    Arm title
    		 Cohort 2: DOR/3TC/TDF
    Arm description
    		 Participants received DOR/3TC/TDF from Day 0 through Week 96.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)
    Investigational medicinal product code
    Other name
    MK-1439A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The All Patients as Treated population was used as the baseline population.
    Number of subjects in period 2 [2]
    		Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Started
    9
    45
    Completed
    9
    42
    Not completed
    0
    3
         Pregnancy
    -
    2
         Non-compliance with study drug
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The All Patients as Treated population was used as the baseline population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: DOR
    Reporting group description
    		 Participants received a single dose of DOR at study entry (Day 0).

    Reporting group title
    Cohort 2: DOR/3TC/TDF
    Reporting group description
    		 Participants received DOR/3TC/TDF from Day 0 through Week 96.

    Reporting group values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF Total
    Number of subjects
    		 9 45 54
    Age Categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 9 45 54
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.3 ± 1.6 15.0 ± 1.6 -
    Gender Categorical
    Units: Participants
        Female
    		 2 26 28
        Male
    		 7 19 26
    Race
    Units: Subjects
        Black or African American
    		 7 10 17
        White
    		 2 0 2
        Asian
    		 0 35 35
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 9 44 53
    Baseline Plasma HIV-1 RNA (copies/mL)
    Units: Subjects
        0 - <40
    		 9 43 52
        40 - <500,000
    		 0 0 0
        500,000 - <1,000,000
    		 0 2 2
    Weight Band (kg)
    Units: Subjects
        35 - <45 kg
    		 1 0 1
        ≥ 45 kg
    		 8 45 53
    Region
    Units: Subjects
        Africa
    		 0 9 9
        Asia/Pacific
    		 0 35 35
        North America
    		 9 1 10
    Class of Prior ARTs
    Units: Subjects
        Nucleoside Reverse Transcriptase Inhibitors (NRTI)
        Non-Nucleoside Reverse Transcriptase Inhibitors
        Integrase Strand Transfer Inhibitors (INSTI)
        Protease Inhibitors (PI)
        Not Applicable
        Overall number of baseline subjects
    		 9 45 54
    CD4 Cell Count
    Units: Cells/mm^3
        arithmetic mean (standard deviation)
    		 788.2 ± 203.9 717.8 ± 283.1 -
    CD4 Percent
    Units: Percent
        arithmetic mean (standard deviation)
    		 36.2 ± 5.4 33.1 ± 9.1 -
    HIV-1 log10 RNA
    Units: Log10 copies/mL
        arithmetic mean (standard deviation)
    		 1.6 ± 0.0 1.8 ± 0.9 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 55.9 ± 15.8 53.8 ± 8.0 -
    Duration of Prior ARTs
    Units: Days
        arithmetic mean (standard deviation)
    		 614.2 ± 511.3 1882.3 ± 1649.6 -
    Subject analysis sets

    Subject analysis set title
    Cohort 1: DOR
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received a single dose of DOR at study entry (Day 0).

    Subject analysis set title
    Cohort 2: DOR/3TC/TDF
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received DOR/3TC/TDF from Day 0 through Week 96.

    Subject analysis sets values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects
    9
    45
    Age Categorical
    Units: Participants
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender Categorical
    Units: Participants
        Female
        Male
    Race
    Units: Subjects
        Black or African American
        White
        Asian
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
    Baseline Plasma HIV-1 RNA (copies/mL)
    Units: Subjects
        0 - <40
        40 - <500,000
        500,000 - <1,000,000
    Weight Band (kg)
    Units: Subjects
        35 - <45 kg
        ≥ 45 kg
    Region
    Units: Subjects
        Africa
        Asia/Pacific
        North America
    Class of Prior ARTs
    Units: Subjects
        Nucleoside Reverse Transcriptase Inhibitors (NRTI)
    9
    43
        Non-Nucleoside Reverse Transcriptase Inhibitors
    0
    32
        Integrase Strand Transfer Inhibitors (INSTI)
    9
    1
        Protease Inhibitors (PI)
    0
    10
        Not Applicable
    0
    2
        Overall number of baseline subjects
    9
    45
    CD4 Cell Count
    Units: Cells/mm^3
        arithmetic mean (standard deviation)
    ±
    ±
    CD4 Percent
    Units: Percent
        arithmetic mean (standard deviation)
    ±
    ±
    HIV-1 log10 RNA
    Units: Log10 copies/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    ±
    ±
    Duration of Prior ARTs
    Units: Days
        arithmetic mean (standard deviation)
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: DOR
    Reporting group description
    		 Participants received a single dose of DOR at study entry (Day 0).

    Reporting group title
    Cohort 2: DOR/3TC/TDF
    Reporting group description
    		 Participants received DOR/3TC/TDF from Day 0 through Week 96.
    Reporting group title
    Cohort 1: DOR
    Reporting group description
    		 Participants received a single dose of DOR at study entry (Day 0).

    Reporting group title
    Cohort 2: DOR/3TC/TDF
    Reporting group description
    		 Participants received DOR/3TC/TDF from Day 0 through Week 96.

    Subject analysis set title
    Cohort 1: DOR
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received a single dose of DOR at study entry (Day 0).

    Subject analysis set title
    Cohort 2: DOR/3TC/TDF
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received DOR/3TC/TDF from Day 0 through Week 96.

    Primary: Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)

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    End point title
    		 Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1) [1]
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to infinity. Steady state AUC0-24 is equivalent to single dose AUC0-∞. Cohort 1 participants who received the study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.
    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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    0 [2]
    Units: µM*hr
        geometric mean (geometric coefficient of variation)
    34.8 ± 43.2
    ±
    Notes
    [2] - Cohort 2 was not analyzed for this end point.
    No statistical analyses for this end point

    Primary: PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1)

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    End point title
    		 PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1) [3]
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cohort 1 participants who received the study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.
    Notes
    [3] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    0 [4]
    Units: µM
        geometric mean (geometric coefficient of variation)
    2.14 ± 25.9
    ±
    Notes
    [4] - Cohort 2 was not analyzed for this end point.
    No statistical analyses for this end point

    Primary: PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1)

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    End point title
    		 PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1) [5]
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cohort 1 participants who received the study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Measured during the entry (day 0) visit. Blood samples were drawn at 24 hours post-dose.
    Notes
    [5] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    0 [6]
    Units: nM
        geometric mean (geometric coefficient of variation)
    514 ± 56.5
    ±
    Notes
    [6] - Cohort 2 was not analyzed for this end point.
    No statistical analyses for this end point

    Primary: Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug

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    End point title
    		 Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug [7]
    End point description
    Percentage and Clopper-Pearson 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. Study participants who received at least one dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.
    Notes
    [7] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (0.0 to 33.6)
    0 (0.0 to 7.9)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug

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    End point title
    		 Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug [8]
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual). Study participants who received at least one dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.
    Notes
    [8] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (0.0 to 33.6)
    0 (0.0 to 7.9)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug

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    End point title
    		 Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug [9]
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug. Study participants who received at least one dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.
    Notes
    [9] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (0.0 to 33.6)
    0 (0.0 to 7.9)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug

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    End point title
    		 Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug [10]
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with Grade 5 AEs (death) regardless of relationship to study drug. Study participants who received at least one dose of study treatment were analyzed.
    End point type
    Primary
    End point timeframe
    Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.
    Notes
    [10] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    9
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (0.0 to 33.6)
    0 (0.0 to 7.9)
    No statistical analyses for this end point

    Secondary: PK Parameter: AUC0-24hr of DOR (Cohort 2)

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    End point title
    		 PK Parameter: AUC0-24hr of DOR (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [11]
    10
    Units: µM*hr
        geometric mean (geometric coefficient of variation)
    ±
    22.9 ± 47.0
    Notes
    [11] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: AUC0-24hr of 3TC (Cohort 2)

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    End point title
    		 PK Parameter: AUC0-24hr of 3TC (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [12]
    10
    Units: h.ng/mL
        geometric mean (geometric coefficient of variation)
    ±
    11300 ± 27.9
    Notes
    [12] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: AUC0-24hr of Tenofovir (Cohort 2)

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    End point title
    		 PK Parameter: AUC0-24hr of Tenofovir (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [13]
    10
    Units: h.ng/mL
        geometric mean (geometric coefficient of variation)
    ±
    2550 ± 14.3
    Notes
    [13] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: Cmax of DOR (Cohort 2)

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    End point title
    		 PK Parameter: Cmax of DOR (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [14]
    10
    Units: µM
        geometric mean (geometric coefficient of variation)
    ±
    2.13 ± 42.7
    Notes
    [14] - Cohort 1 was not analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: PK Parameter: Cmax of 3TC (Cohort 2)

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    End point title
    		 PK Parameter: Cmax of 3TC (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [15]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ±
    2100 ± 23.6
    Notes
    [15] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: Cmax of Tenofovir (Cohort 2)

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    End point title
    		 PK Parameter: Cmax of Tenofovir (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [16]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ±
    293 ± 36.6
    Notes
    [16] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: C24hr of DOR (Cohort 2)

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    End point title
    		 PK Parameter: C24hr of DOR (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [17]
    10
    Units: nM
        geometric mean (geometric coefficient of variation)
    ±
    282 ± 73.8
    Notes
    [17] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: C24hr of 3TC (Cohort 2)

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    End point title
    		 PK Parameter: C24hr of 3TC (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [18]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ±
    66.3 ± 54.7
    Notes
    [18] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: PK Parameter: C24hr of Tenofovir (Cohort 2)

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    End point title
    		 PK Parameter: C24hr of Tenofovir (Cohort 2)
    End point description
    Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. The first 10 participants enrolled in Cohort 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Week 1 visit. Blood samples were drawn at 24 hours post-dose.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [19]
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ±
    50.2 ± 9.4
    Notes
    [19] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2)
    End point description
    Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >200 copies/mL; otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 24.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [20]
    44
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    97.7 (88.0 to 99.9)
    Notes
    [20] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)
    End point description
    Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >200 copies/mL; otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 48.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [21]
    44
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    97.7 (88.0 to 99.9)
    Notes
    [21] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)
    End point description
    Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >200 copies/mL; otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [22]
    42
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    92.9 (80.5 to 98.5)
    Notes
    [22] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)
    End point description
    Virologic responses were assessed at week 24 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >50 copies/mL. Otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded. One participant whose sample was diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL was excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 24.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [23]
    43
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    97.7 (87.7 to 99.9)
    Notes
    [23] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)
    End point description
    Virologic responses were assessed at week 48 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >50 copies/mL. Otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded. Two participants whose samples were diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 48.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [24]
    42
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    97.6 (87.4 to 99.9)
    Notes
    [24] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)
    End point description
    Virologic responses were assessed at week 96 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >50 copies/mL. Otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded. Two participants whose samples were diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [25]
    40
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    92.5 (79.6 to 98.4)
    Notes
    [25] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)
    End point description
    Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >40 copies/mL; Otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded. One participant whose sample was diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL was excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 24.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [26]
    43
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    97.7 (87.7 to 99.9)
    Notes
    [26] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)
    End point description
    Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >40 copies/mL; Otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded. Two participants whose samples were diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 48.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [27]
    42
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    97.6 (87.4 to 99.9)
    Notes
    [27] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)

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    End point title
    		 Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)
    End point description
    Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >40 copies/mL; Otherwise participants with missing values were excluded. Cohort 2 participants who received at least one dose of study treatment were analyzed. Participants who discontinued study for reasons other than virologic failure were excluded. Two participants whose samples were diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.
    End point type
    Secondary
    End point timeframe
    Measured at week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [28]
    40
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    92.5 (79.6 to 98.4)
    Notes
    [28] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)

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    End point title
    		 Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
    End point description
    The differences between log10 HIV RNA at Week 24 minus at the Day 0 are summarized, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who were ART-naive were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 24.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [29]
    2
    Units: Log10 plasma HIV-1 RNA
        arithmetic mean (confidence interval 95%)
    ( to )
    -2.6 (-5.8 to 19.0)
    Notes
    [29] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)

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    End point title
    		 Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
    End point description
    The differences between log10 HIV RNA at Week 48 minus at the Day 0 are summarized, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who were ART-naive were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 48.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [30]
    2
    Units: Log10 plasma HIV-1 RNA
        arithmetic mean (confidence interval 95%)
    ( to )
    -2.1 (-5.8 to 26.1)
    Notes
    [30] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)

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    End point title
    		 Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
    End point description
    The differences between log10 HIV RNA at Week 96 minus at the Day 0 are summarized. Cohort 2 participants who were ART-naive and had Week 96 data available were analyzed. "9999" indicates dispersion could not be estimated due to low number of participants analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [31]
    1
    Units: Log10 plasma HIV-1 RNA
        arithmetic mean (confidence interval 95%)
    ( to )
    -4.3 (-9999 to 9999)
    Notes
    [31] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)

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    End point title
    		 Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)
    End point description
    The mean differences between CD4 count at Week 24 minus at the Day 0, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who had non-missing values at both Day 0 and Week 24 timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 24.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [32]
    43
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    ( to )
    84.8 (21.1 to 148.4)
    Notes
    [32] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)

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    End point title
    		 Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)
    End point description
    The mean differences between CD4 count at Week 48 minus at the Day 0, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who had non-missing values at both Day 0 and Week 48 timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 48.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [33]
    43
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    ( to )
    80.1 (14.2 to 146.0)
    Notes
    [33] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)

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    End point title
    		 Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)
    End point description
    The mean differences between CD4 count at Week 96 minus at the Day 0, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who had non-missing values at both Day 0 and Week 96 timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [34]
    38
    Units: cells/mm^3
        arithmetic mean (confidence interval 95%)
    ( to )
    42.5 (-31.1 to 116.1)
    Notes
    [34] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of Changes in CD4 Percent From Baseline to Week 24 (Cohort 2)

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    End point title
    		 Summary of Changes in CD4 Percent From Baseline to Week 24 (Cohort 2)
    End point description
    The mean differences between CD4 percent at Week 24 minus at the Day 0, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who had non-missing values at both Day 0 and Week 24 timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 24.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [35]
    43
    Units: Percent
        arithmetic mean (confidence interval 95%)
    ( to )
    -1.5 (-2.8 to -0.2)
    Notes
    [35] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of Changes in CD4 Percent From Baseline to Week 48 (Cohort 2)

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    End point title
    		 Summary of Changes in CD4 Percent From Baseline to Week 48 (Cohort 2)
    End point description
    The mean differences between CD4 percent at Week 48 minus at the Day 0, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who had non-missing values at both Day 0 and Week 48 timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 48.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [36]
    43
    Units: Percent
        arithmetic mean (confidence interval 95%)
    ( to )
    -0.4 (-1.7 to 0.9)
    Notes
    [36] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Summary of Changes in CD4 Percent From Baseline to Week 96 (Cohort 2)

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    End point title
    		 Summary of Changes in CD4 Percent From Baseline to Week 96 (Cohort 2)
    End point description
    The mean differences between CD4 percent at Week 96 minus at the Day 0, and 95% CI calculated based on t-distribution, are presented. Cohort 2 participants who had non-missing values at both Day 0 and Week 96 timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured at Day 0 and week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [37]
    38
    Units: Percent
        arithmetic mean (confidence interval 95%)
    ( to )
    -0.5 (-2.5 to 1.5)
    Notes
    [37] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study

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    End point title
    		 Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 (DAIDS) AE Grading table corrected version 2.1. Cohort 2 participants who received at least one dose of study treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured from Day 0 through Week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [38]
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    0 (0.0 to 7.9)
    Notes
    [38] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study

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    End point title
    		 Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual). Cohort 2 participants who received at least one dose of study treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured from Day 0 through Week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [39]
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    0 (0.0 to 7.9)
    Notes
    [39] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study

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    End point title
    		 Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug. Cohort 2 participants who received at least one dose of study treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured from Day 0 through Week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [40]
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    0 (0.0 to 7.9)
    Notes
    [40] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study

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    End point title
    		 Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study
    End point description
    Percentage and Clopper-Pearson 95% CI of participants with Grade 5 adverse events (death). Cohort 2 participants who received at least one dose of study treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Measured from Day 0 through Week 96.
    End point values
    		 Cohort 1: DOR Cohort 2: DOR/3TC/TDF
    Number of subjects analysed
    0 [41]
    45
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    0 (0.0 to 7.9)
    Notes
    [41] - Cohort 1 was not analyzed for this end point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment to study completion at Week 2 in Cohort 1 or at Week 96 in Cohort 2.
    Adverse event reporting additional description
    All-cause mortality was summarized for all allocated participants and AEs were summarized for participants who received at least 1 dose of study drug. AE severity grading was based on the DAIDS AE Grading Table, Corrected Version 2.1. SAEs were graded using DAIDS EAE Manual V2.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort 2: DOR/3TC/TDF
    Reporting group description
    		 Participants received DOR/3TC/TDF from Day 0 through Week 96.

    Reporting group title
    Cohort 1: DOR
    Reporting group description
    		 Participants received a single dose of DOR at study entry (Day 0).

    Serious adverse events
    		 Cohort 2: DOR/3TC/TDF Cohort 1: DOR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lip injury
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 9 (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
    		 Cohort 2: DOR/3TC/TDF Cohort 1: DOR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 45 (100.00%)
    4 / 9 (44.44%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 45 (46.67%)
    0 / 9 (0.00%)
         occurrences all number
    87
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 45 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    38
    2
    Blood albumin decreased
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    14 / 45 (31.11%)
    1 / 9 (11.11%)
         occurrences all number
    47
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    12 / 45 (26.67%)
    0 / 9 (0.00%)
         occurrences all number
    17
    0
    Blood cholesterol increased
         subjects affected / exposed
    6 / 45 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    10
    0
    Blood creatinine increased
         subjects affected / exposed
    21 / 45 (46.67%)
    0 / 9 (0.00%)
         occurrences all number
    73
    0
    Blood glucose decreased
         subjects affected / exposed
    6 / 45 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    8
    0
    Blood glucose increased
         subjects affected / exposed
    8 / 45 (17.78%)
    1 / 9 (11.11%)
         occurrences all number
    12
    1
    Blood phosphorus decreased
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 9 (0.00%)
         occurrences all number
    5
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    9 / 45 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    20
    0
    Blood pressure increased
         subjects affected / exposed
    8 / 45 (17.78%)
    0 / 9 (0.00%)
         occurrences all number
    31
    0
    Blood sodium decreased
         subjects affected / exposed
    7 / 45 (15.56%)
    0 / 9 (0.00%)
         occurrences all number
    7
    0
    Carbon dioxide decreased
         subjects affected / exposed
    11 / 45 (24.44%)
    0 / 9 (0.00%)
         occurrences all number
    59
    0
    Blood triglycerides increased
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    25 / 45 (55.56%)
    0 / 9 (0.00%)
         occurrences all number
    117
    0
    Haemoglobin decreased
         subjects affected / exposed
    7 / 45 (15.56%)
    0 / 9 (0.00%)
         occurrences all number
    13
    0
    Lipase increased
         subjects affected / exposed
    8 / 45 (17.78%)
    0 / 9 (0.00%)
         occurrences all number
    26
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    Injury, poisoning and procedural complications
    Adverse event following immunisation
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 45 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    10
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Conjunctival pallor
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 45 (13.33%)
    1 / 9 (11.11%)
         occurrences all number
    7
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 45 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    11
    0
    Nasal congestion
         subjects affected / exposed
    6 / 45 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    7
    0
    Oropharyngeal pain
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    8
    0
    Productive cough
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    5
    0
    Rhinorrhoea
         subjects affected / exposed
    8 / 45 (17.78%)
    0 / 9 (0.00%)
         occurrences all number
    8
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Papule
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Pruritus
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Proteinuria
         subjects affected / exposed
    6 / 45 (13.33%)
    0 / 9 (0.00%)
         occurrences all number
    11
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 9 (0.00%)
         occurrences all number
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2018
    Amendment 01: Primary reason for amendment was to update testing and procedures.
    10 Jun 2019
    Amendment 02: Primary reason for amendment was to update target enrollment requirements and subject inclusion criterion.
    01 Jul 2020
    Amendment 03: Primary reason for amendment was to clarify procedural specifications.
    03 Sep 2021
    Amendment 04: Primary reason for amendment was to extend the allowable follow-up period for participants.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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