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    Clinical Trial Results:
    A Phase 3 Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Doravirine (MK-1439) 100 mg Once Daily Versus Darunavir 800 mg Once Daily plus Ritonavir 100 mg Once Daily, Each in Combination with TRUVADA™ or EPZICOM™/KIVEXA™, in Treatment-Naïve HIV-1 Infected Subjects

    Summary
    EudraCT number
    		 2014-001127-69
    Trial protocol
    		 AT   GB   DE   DK   ES   RO   PT   IT  
    Global end of trial date
    06 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2024
    First version publication date
    13 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1439-018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02275780
    WHO universal trial number (UTN)
    		 -
    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)
    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
    06 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish a new treatment option for treatment-naïve participants with HIV-1, the efficacy and safety of doravirine will be determined relative to a protease inhibitor (PI). Participants will receive double-blind treatment during 96-week Base Study. Eligible participants in Base Study will continue to receive doravirine-containing regimen open-label for additional 96 weeks in Study Ext 1. Eligible participants deriving benefit will continue in Study Extensions 2 and 3 to receive doravirine-containing regimen open-label until doravirine becomes locally available or for additional 96 weeks, whichever comes first. The Primary hypothesis is that doravirine 100 mg once a day (q.d.) is non-inferior to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as assessed by proportion of participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48.
    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
    01 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Austria: 24
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Chile: 55
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 67
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Romania: 29
    Country: Number of subjects enrolled
    Russian Federation: 95
    Country: Number of subjects enrolled
    South Africa: 45
    Country: Number of subjects enrolled
    Spain: 76
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    United States: 267
    Worldwide total number of subjects
    769
    EEA total number of subjects
    230
    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)
    762
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1027 participants were screened and 769 were randomized.

    Period 1
    Period 1 title
    Base Study: 96 weeks
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doravirine 100 mg
    Arm description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doravirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Doravirine 100 mg tablet administered p.o. q.d.

    Investigational medicinal product name
    TRUVADA™ or EPZICOM™/KIVEXA™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The investigator selects either TRUVADA™, a tablet containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate p.o. q.d. or EPZICOM™/KIVEXA™, a tablet containing 600 mg abacavir sulfate and 300 mg lamivudine, p.o. q.d.

    Arm title
    		 Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Arm description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Darunavir 800 mg tablet administered p.o. q.d.

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ritonavir 100 mg tablet administered p.o. q.d.

    Investigational medicinal product name
    TRUVADA™ or EPZICOM™/KIVEXA™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The investigator selects either TRUVADA™, a tablet containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate p.o. q.d. or EPZICOM™/KIVEXA™, a tablet containing 600 mg abacavir sulfate and 300 mg lamivudine, p.o. q.d.

    Number of subjects in period 1
    		Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Started
    385
    384
    Treated
    383
    383
    Completed
    292
    273
    Not completed
    93
    111
         Adverse event, serious fatal
    3
    1
         Consent withdrawn by subject
    19
    22
         Physician decision
    2
    4
         Randomized not treated
    2
    1
         Adverse event, non-fatal
    6
    14
         Pregnancy
    2
    1
         Noncompliance with drug
    9
    6
         Lost to follow-up
    28
    24
         Lack of efficacy
    21
    32
         Protocol deviation
    1
    6
    Period 2
    Period 2 title
    Study Extension 1: Week 96 to Week 192
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doravirine 100 mg
    Arm description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Combination therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Arm description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Combination therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Started
    259
    233
    Completed
    210
    190
    Not completed
    49
    43
         Availability of study medication locally
    2
    -
         Physician decision
    3
    7
         Consent withdrawn by subject
    19
    14
         Adverse event, non-fatal
    6
    1
         Pregnancy
    2
    1
         Non-compliance with study drug
    1
    2
         Lost to follow-up
    8
    7
         Lack of efficacy
    8
    11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants enrolled in Ext 1.
    Period 3
    Period 3 title
    Study Extension 2: Week 192 to Week 288
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doravirine 100 mg
    Arm description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Combination therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Arm description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Combination therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [2]
    		Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Started
    148
    129
    Completed
    101
    91
    Not completed
    47
    38
         Availability of study medication locally
    38
    29
         Physician decision
    1
    1
         Consent withdrawn by subject
    4
    3
         Adverse event, non-fatal
    -
    1
         Non-compliance with study drug
    2
    -
         Lost to follow-up
    -
    1
         Lack of efficacy
    2
    3
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants enrolled in Ext 2.
    Period 4
    Period 4 title
    Study Extension 3: Week 288 to Week 384
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doravirine 100 mg
    Arm description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Combination therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Arm description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Arm type
    		 Combination therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4 [3]
    		Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Started
    50
    36
    Completed
    36
    23
    Not completed
    14
    13
         Availability of study medication locally
    6
    6
         Adverse event, serious fatal
    -
    1
         Physician decision
    1
    -
         Consent withdrawn by subject
    5
    2
         Non-compliance with study drug
    1
    1
         Lost to follow-up
    1
    3
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants enrolled in Ext 3.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doravirine 100 mg
    Reporting group description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group title
    Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Reporting group description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg Total
    Number of subjects
    		 385 384 769
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 34.9 ( 10.7 ) 35.7 ( 10.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 65 58 123
        Male
    		 320 326 646
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 3 6
        Asian
    		 7 7 14
        Native Hawaiian or Other Pacific Islander
    		 1 2 3
        Black or African American
    		 87 89 176
        White
    		 281 280 561
        More than one race
    		 6 2 8
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 93 86 179
        Not Hispanic or Latino
    		 286 291 577
        Unknown or Not Reported
    		 6 7 13
    Plasma HIV-1 RNA
    Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay and included all participants who had baseline data.
    Units: Copies/mL
        median (full range (min-max))
    		 27073.0 (105 to 2776658) 27357.0 (235 to 3272236) -
    Mean Cluster of Differentiation 4 (CD4+) T-cell Count
    CD4+ T-cell count was quantified by a central laboratory using a commercially available assay and included all participants who had baseline data.
    Units: Cells/mm^3
        arithmetic mean (standard deviation)
    		 432.6 ( 208.4 ) 411.9 ( 229.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Doravirine 100 mg
    Reporting group description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group title
    Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Reporting group description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Reporting group title
    Doravirine 100 mg
    Reporting group description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group title
    Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Reporting group description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Reporting group title
    Doravirine 100 mg
    Reporting group description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group title
    Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Reporting group description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.
    Reporting group title
    Doravirine 100 mg
    Reporting group description
    		 Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group title
    Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Reporting group description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the same treatment regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Subject analysis set title
    Doravirine 100 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Double-blind Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study.

    Subject analysis set title
    Daurunavir 800 mg + Ritonavir 100 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study.

    Primary: Percentage of Participants Achieving Plasma HIV-1 RNA <50 Copies/mL at Week 48

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    End point title
    		 Percentage of Participants Achieving Plasma HIV-1 RNA <50 Copies/mL at Week 48
    End point description
    The percentage of participants in each arm achieving HIV-1 RNA levels <50 copies/mL at Week 48 was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of participants
        number (not applicable)
    83.8
    79.9
    Statistical analysis title
    		 % Achieving PL HIV-1 RNA <50 Copies/mL at Week 96
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    766
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    3.913
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.59
         upper limit
    		 9.415
    Notes
    [1] - Doravirine is concluded to be non-inferior to darunavir + ritonavir if the lower bound of the 95% CI for the difference in percent response is above -10 percentage points.

    Secondary: Change from Baseline in Mean CD4+ T-cell Count at Week 48

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    End point title
    		 Change from Baseline in Mean CD4+ T-cell Count at Week 48
    End point description
    CD4+ T-cell counts were quantified by a central laboratory using a commercially available assay. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had data for the outcome measure. Baseline values were carried forward for participants who discontinued therapy due to lack of efficacy.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    363
    353
    Units: Cells/mm^3
        arithmetic mean (confidence interval 95%)
    192.7 (171.5 to 213.9)
    185.6 (167.5 to 203.6)
    Statistical analysis title
    		 Chg from BL in Mean CD4+ T-cell Count at Wk 48
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    716
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean treatment difference
    Point estimate
    7.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.8
         upper limit
    		 35

    Secondary: Percentage of Participants Achieving Plasma HIV-1 RNA <50 Copies/mL at Week 96

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    End point title
    		 Percentage of Participants Achieving Plasma HIV-1 RNA <50 Copies/mL at Week 96
    End point description
    The percentage of participants in each arm achieving HIV-1 RNA levels <50 copies/mL at Week 96 was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had data for the outcome measure. Participants with missing HIV-1 RNA due to an Abbott RealTime manufacturing agent recall were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    379
    376
    Units: Percentage of participants
        number (not applicable)
    73.1
    66.0
    Statistical analysis title
    		 % Achieving PL HIV-1 RNA <50 Copies/mL at Week 96
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    7.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.508
         upper limit
    		 13.656
    Notes
    [2] - Doravirine is concluded to be non-inferior to darunavir + ritonavir if the lower bound of the 95% CI for the difference in percent response is above -10 percentage points.

    Secondary: Mean Change from Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL-C) at Week 48

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    End point title
    		 Mean Change from Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL-C) at Week 48
    End point description
    Serum LDL-C was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The Last Observation Carry Forward (LOCF) approach was applied for missing data or data collected after modifying lipid-lowering therapy. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had a measurement at Baseline and at the time point assessed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    326
    318
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    91.10 ( 28.61 )
    91.76 ( 30.36 )
        Change from Baseline
    -4.51 ( 20.64 )
    9.92 ( 27.31 )
    Statistical analysis title
    		 Mean Change from BL in Fasting LDL-C at Week 48
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    644
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference (mg/dL)
    Point estimate
    -14.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.15
         upper limit
    		 -11.06

    Secondary: Change from Baseline in Mean CD4+ T-cell Count at Week 96

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    End point title
    		 Change from Baseline in Mean CD4+ T-cell Count at Week 96
    End point description
    CD4+ T-cell counts were quantified by a central laboratory using a commercially available assay. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had data for the outcome measure. Baseline values were carried forward for participants who discontinued therapy due to lack of efficacy.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 96
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    342
    327
    Units: Cells/mm^3
        arithmetic mean (confidence interval 95%)
    224.1 (200.8 to 247.4)
    206.7 (184.9 to 228.5)
    Statistical analysis title
    		 Chg from BL in Mean CD4+ T-cell Count at Wk 96
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    669
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean treatment difference
    Point estimate
    17.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.5
         upper limit
    		 49.3

    Secondary: Mean Change from Baseline in Fasting Non-High Density Lipoprotein Cholesterol (non-HDL-C) at Week 48

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    End point title
    		 Mean Change from Baseline in Fasting Non-High Density Lipoprotein Cholesterol (non-HDL-C) at Week 48
    End point description
    Serum non-HDL-C was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had a measurement at Baseline and at the time point assessed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    329
    325
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    113.34 ( 34.25 )
    114.44 ( 35.01 )
        Change from Baseline
    -5.30 ( 23.28 )
    13.75 ( 31.08 )
    Statistical analysis title
    		 Mean Change from BL in Fasting non-HDL-C at Wk 48
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    654
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference (mg/dL)
    Point estimate
    -19.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.33
         upper limit
    		 -15.35

    Secondary: Mean Change from Baseline in Fasting High Density Lipoprotein Cholesterol (HDL-C) at Week 48

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    End point title
    		 Mean Change from Baseline in Fasting High Density Lipoprotein Cholesterol (HDL-C) at Week 48
    End point description
    Serum HDL-C was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had a measurement at Baseline and at the time point assessed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    329
    325
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    43.58 ( 12.99 )
    43.27 ( 13.96 )
        Change from Baseline
    3.94 ( 10.66 )
    4.15 ( 11.01 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Fasting Total Cholesterol at Week 48

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    End point title
    		 Mean Change from Baseline in Fasting Total Cholesterol at Week 48
    End point description
    Serum total cholesterol was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had a measurement at Baseline and at the time point assessed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    329
    325
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    156.92 ( 35.82 )
    157.71 ( 37.34 )
        Change from Baseline
    -1.37 ( 25.47 )
    17.90 ( 33.95 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Fasting Triglyceride at Week 48

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    End point title
    		 Mean Change from Baseline in Fasting Triglyceride at Week 48
    End point description
    Serum triglyceride was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had a measurement at Baseline and at the time point assessed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    329
    325
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    111.16 ( 75.31 )
    117.02 ( 97.30 )
        Change from Baseline
    -3.14 ( 68.81 )
    21.97 ( 92.59 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Adverse Event

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    End point title
    		 Percentage of Participants with Any Adverse Event
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a study participant and which does not necessarily have to have a causal relationship to treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study treatment is also an AE. The percentage of participants with any AE was assessed. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 98 weeks
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of participants
        number (not applicable)
    84.6
    82.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Drug-related Serious Adverse Event

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    End point title
    		 Percentage of Participants with Any Drug-related Serious Adverse Event
    End point description
    The percentage of participants with any drug-related SAE was assessed. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 98 weeks
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of participants
        number (not applicable)
    0.3
    0.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Drug-related Adverse Event

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    End point title
    		 Percentage of Participants with Any Drug-related Adverse Event
    End point description
    The investigator was to determine if an AE had a reasonable possibility of a relationship to the study drug. The percentage of participants with any drug-related AE was assessed. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 98 weeks
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of participants
        number (not applicable)
    32.1
    32.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Serious Adverse Event

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    End point title
    		 Percentage of Participants with Any Serious Adverse Event
    End point description
    A serious adverse event is an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose, or is another important medical event. The percentage of participants with any SAE was assessed. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 98 weeks
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of participants
        number (not applicable)
    7.0
    8.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event

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    End point title
    		 Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
    End point description
    The percentage of participants who discontinued study treatment due to an AE was assessed. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 96 weeks
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of Participants
        number (not applicable)
    1.6
    3.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Plasma HIV-1 RNA <40 Copies/mL at Week 48

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    End point title
    		 Percentage of Participants Achieving Plasma HIV-1 RNA <40 Copies/mL at Week 48
    End point description
    The percentage of participants in each arm achieving HIV-1 RNA levels <40 copies/mL at Week 48 was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    383
    383
    Units: Percentage of participants
        number (not applicable)
    83.3
    79.1
    Statistical analysis title
    		 % Achieving PL HIV-1 RNA <40 Copies/mL at Wk 48
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    766
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    4.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.404
         upper limit
    		 9.743

    Secondary: Percentage of Participants Achieving Plasma HIV-1 RNA <40 Copies/mL at Week 96

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    End point title
    		 Percentage of Participants Achieving Plasma HIV-1 RNA <40 Copies/mL at Week 96
    End point description
    The percentage of participants in each arm achieving HIV-1 RNA levels <40 copies/mL at Week 96 was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason. The analysis population for this endpoint included all randomized participants who received at least 1 dose of study drug and had data for the outcome measure. Participants with missing HIV-1 RNA due to an Abbott RealTime manufacturing agent recall were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 Doravirine 100 mg Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects analysed
    379
    376
    Units: Percentage of participants
        number (not applicable)
    72.0
    64.4
    Statistical analysis title
    		 % Achieving PL HIV-1 RNA <40 Copies/mL at Wk 96
    Comparison groups
    Doravirine 100 mg v Daurunavir 800 mg + Ritonavir 100 mg
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    7.606
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 14.232

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 386
    Adverse event reporting additional description
    The analysis population for Deaths (all causes) included all randomized participants. The analysis population for Serious and Non Serious Adverse Events included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg
    Reporting group description
    		 Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Reporting group title
    Doravirine 100 mg
    Reporting group description
    		 Double-blind Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants continued in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator-selected TRUVADA™ or EPZICOM™/ KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants continued to receive the Doravirine regimen in Study Extension 2 for an additional 96 weeks, and in Study Extension 3 for an additional 96 weeks.

    Serious adverse events
    		 Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg Doravirine 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 383 (12.79%)
    45 / 383 (11.75%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal squamous cell carcinoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiosarcoma
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Femoral artery aneurysm
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Post abortion haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Drug abuser
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced mood disorder
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizoaffective disorder depressive type
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exposure to toxic agent
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal injury
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bell's palsy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal skin tags
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone lesion
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatitis C
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fournier's gangrene
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis C
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis shigella
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes oesophagitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratouveitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis tuberculous
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis of central nervous system
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypovolaemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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
    		 Daurunavir 800 mg + Ritonavir 100 mg → Doravirine 100 mg Doravirine 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    247 / 383 (64.49%)
    264 / 383 (68.93%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    59 / 383 (15.40%)
    63 / 383 (16.45%)
         occurrences all number
    92
    106
    Dizziness
         subjects affected / exposed
    24 / 383 (6.27%)
    25 / 383 (6.53%)
         occurrences all number
    28
    28
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 383 (2.61%)
    21 / 383 (5.48%)
         occurrences all number
    10
    21
    Fatigue
         subjects affected / exposed
    28 / 383 (7.31%)
    38 / 383 (9.92%)
         occurrences all number
    30
    40
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    54 / 383 (14.10%)
    52 / 383 (13.58%)
         occurrences all number
    64
    65
    Diarrhoea
         subjects affected / exposed
    100 / 383 (26.11%)
    72 / 383 (18.80%)
         occurrences all number
    136
    87
    Abdominal pain
         subjects affected / exposed
    20 / 383 (5.22%)
    20 / 383 (5.22%)
         occurrences all number
    25
    22
    Abdominal pain upper
         subjects affected / exposed
    15 / 383 (3.92%)
    27 / 383 (7.05%)
         occurrences all number
    18
    30
    Vomiting
         subjects affected / exposed
    12 / 383 (3.13%)
    20 / 383 (5.22%)
         occurrences all number
    14
    32
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 383 (3.66%)
    38 / 383 (9.92%)
         occurrences all number
    15
    48
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 383 (6.01%)
    27 / 383 (7.05%)
         occurrences all number
    27
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 383 (5.74%)
    26 / 383 (6.79%)
         occurrences all number
    27
    29
    Back pain
         subjects affected / exposed
    13 / 383 (3.39%)
    37 / 383 (9.66%)
         occurrences all number
    16
    45
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    23 / 383 (6.01%)
    22 / 383 (5.74%)
         occurrences all number
    28
    25
    Bronchitis
         subjects affected / exposed
    37 / 383 (9.66%)
    31 / 383 (8.09%)
         occurrences all number
    42
    43
    Influenza
         subjects affected / exposed
    16 / 383 (4.18%)
    24 / 383 (6.27%)
         occurrences all number
    20
    29
    Upper respiratory tract infection
         subjects affected / exposed
    40 / 383 (10.44%)
    64 / 383 (16.71%)
         occurrences all number
    59
    115
    Syphilis
         subjects affected / exposed
    39 / 383 (10.18%)
    29 / 383 (7.57%)
         occurrences all number
    47
    39
    Nasopharyngitis
         subjects affected / exposed
    61 / 383 (15.93%)
    61 / 383 (15.93%)
         occurrences all number
    102
    110

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2015
    Amendment 01: The primary reasons for this protocol amendment were revisions to the Objectives and Hypotheses, Efficacy Endpoints, Statistical Analysis Plan, Subject Inclusion Criteria, Subject Withdrawal/Discontinuation Criteria, and Timing of Dose Administration.
    12 Feb 2015
    Amendment 02: The primary reasons for this protocol amendment were revisions to the Objectives and Hypotheses, Efficacy Endpoints, Statistical Analysis Plan, Subject Inclusion Criteria, Subject Withdrawal/Discontinuation Criteria, and Timing of Dose.
    23 Jul 2015
    Amendment 03: The primary reasons for this protocol amendment were revisions to the Objectives and Hypotheses, Efficacy Endpoints, Statistical Analysis Plan, Subject Inclusion Criteria, Subject Exclusion Criteria, Subject Withdrawal/Discontinuation Criteria, Timing of Dose Administration, and Concomitant Medications/Vaccinations (Allowed & Prohibited).
    02 Dec 2016
    Amendment 05: The primary reasons for this protocol amendment were revisions to the Trial Summary, Trial Design, Trial Diagram, Exploratory Objectives, Rationale for Endpoints, Rationale for Study Extension, Subject Inclusion Criteria, Trial Treatments, Dose Modification/Interruption/Discontinuation, Timing of Dose Administration, Trial Blinding/Masking, Concomitant Medications, Subject Withdrawal/Discontinuation Criteria, Trial Flow Chart, Inclusion/Exclusion Criteria, Adverse Events, Laboratory Procedures/Assessments, Blinding/Unblinding, Treatment Visits in Base Study (Visit 2 to Visit 13), Treatment Visits in Study Extension (Visit 14 to Visit 20 ), Post-Trial, Statistical Analysis Plan, Responsibility for Analyses/In-House Blinding, Statistical Methods, Compliance (Medication Adherence), and Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types.
    12 Dec 2016
    Amendment 04 : The primary reasons for this protocol amendment were revisions to reflect an amended trial design, which added an open-label extension in which patients received active MK-1439 in combination with NRTI, after completion of the 96-week, double-blind period (base study).
    09 Mar 2017
    Amendment 06: The primary reasons for this protocol amendment were revisions to the Trial Summary, Trial Design, Trial Diagram, Exploratory Objectives, Rationale for Endpoints, Rationale for Study Extension, Subject Inclusion Criteria, Trial Treatments, Dose Modification/Interruption/Discontinuation, Timing of Dose Administration, Trial Blinding/Masking, Concomitant Medications, Subject Withdrawal/Discontinuation Criteria, Trial Flow Chart, Inclusion/Exclusion Criteria, Adverse Events, Laboratory Procedures/Assessments, Blinding/Unblinding, Treatment Visits in Base Study (Visit 2 to Visit 13), Treatment Visits in Study Extension (Visit 14 to Visit 20 ), Post-Trial, Statistical Analysis Plan, Responsibility for Analyses/In-House Blinding, Statistical Methods, Compliance (Medication Adherence), Approximate Blood/Tissue Volumes, Drawn/Collected by Trial Visit and by Sample Types, Rationale for the Trial and Selected Subject Population, and Subject Inclusion Criteria.
    30 Aug 2018
    Amendment 08: The primary reasons for this protocol amendment were revisions to the Trial Design, Trial Diagram, Study Extension, Efficacy Endpoints, Safety Endpoints, Rationale for Study Extensions, Trial Treatments, Dose Modification/Interruption/Discontinuation, Concomitant Medications, Subject Withdrawal/Discontinuation Criteria, Trial Flow Chart, Inclusion/Exclusion Criteria, Trial Compliance (Medication/Diet/Activity/Other), Adverse Events, Serum/Urine Pregnancy Test Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis), Virology Test, Viral Resistance Testing, CD4 Cell Counts, Blinding/Unblinding, Treatment Visits in Base Study, Treatment Visits in Study Extension 1, Post-Trial, Assessing and Recording Adverse Events, Data Monitoring Committee, Statistical Analysis Plan, Responsibility for Analyses/In-House Blinding, Analysis Endpoints, Statistical Methods, Statistical Methods for Efficacy Analysis, Compliance (Medication Adherence), Packaging and Labeling Information, and Week 100 Through Post-Study 14-Day Follow-up (Study Extension 1).
    14 Jan 2019
    Amendment 10: The primary reasons for this protocol amendment were revisions to the Trial Summary, Duration of Participation, Trial Design, Trial Flowchart, Subject Withdrawal/Discontinuation Criteria, Treatment Visits in Study Extension, and Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types in Study Extension.
    14 Feb 2019
    Amendment 07: The primary reasons for this protocol amendment were revisions to the Trial Summary, Trial Design, Trial Diagram, Study Extension, Efficacy Endpoints, Safety Endpoints, Rationale for Study Extensions, Subject Inclusion Criteria, Trial Treatments, Dose Modification/Interruption/Discontinuation, Concomitant Medications, Subject Withdrawal/Discontinuation Criteria, Trial Flow Chart, Inclusion/Exclusion Criteria, Trial Compliance, Adverse Events, Serum/Urine Pregnancy Test, Laboratory Safety Evaluations, Virology Test, Viral Resistance Testing, CD4 Cell Counts, Blinding/Unblinding, Treatment Visits in Base Study, Treatment Visits in Study Extension 1, Post-Trial, Assessing and Recording Adverse Events, Data Monitoring Committee, Statistical Analysis Plan, Responsibility for Analyses/In-House Blinding, Analysis Endpoints, Statistical Methods, Statistical Methods for Efficacy Analysis, Compliance (Medication Adherence), Packaging and Labeling Information, Week 100 Through Post-Study 14-Day Follow-up (Study Extension 1).
    21 Mar 2019
    Amendment 09: The primary reasons for this protocol amendment were revisions to the Trial Summary, Trial Design, Trial Diagram, Study Extension, Efficacy Endpoints, Safety Endpoints, Rationale for Study Extensions, Subject Inclusion Criteria, Trial Treatments, Dose Modification/Interruption/Discontinuation, Concomitant Medications, Subject Withdrawal/Discontinuation Criteria, Trial Flow Chart, Inclusion/Exclusion Criteria, Trial Compliance, Medication/Diet/Activity/Other), Adverse Events, Serum/Urine Pregnancy Test, Laboratory Safety Evaluations, Virology Test, Viral Resistance Testing, CD4 Cell Counts, Blinding/Unblinding, Treatment Visits in Base Study, Treatment Visits in Study Extension 1, Post-Trial, Assessing and Recording Adverse Events, Data Monitoring Committee, Statistical Analysis Plan, Responsibility for Analyses/In-House Blinding, Analysis Endpoints, Statistical Methods, Statistical Methods for Efficacy Analysis, Compliance (Medication Adherence), Packaging and Labeling Information, and Week 100 Through Post-Study 14-Day Follow-up (Study Extension 1).
    15 Dec 2020
    Amendment 11: The primary reasons for this protocol amendment were revisions to the Trial Summary, Trial Design, Trial Diagram, Safety Endpoints, Rationale for Study Extensions, Subject Withdrawal/Discontinuation Criteria, Trial Flow Chart, Inclusion/Exclusion Criteria, Trial Compliance (Medication/Diet/Activity/Other), Withdrawal/Discontinuation, Visit Requirements, Assessing and Recording Adverse Events, Statistical Analysis Plan, Responsibility for Analyses/In-House Blinding, and Statistical Methods.
    16 Jan 2023
    Amendment 12: The primary reasons for this protocol amendment were to update the Sponsor name and address.

    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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