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    Clinical Trial Results:
    AN OPEN-LABEL, MULTICENTER, MULTIPLE-DOSE PHARMACOKINETIC AND 48-WEEK SAFETY AND EFFICACY TRIAL OF MARAVIROC IN COMBINATION WITH OPTIMIZED BACKGROUND THERAPY FOR THE TREATMENT OF ANTIRETROVIRAL-EXPERIENCED CCR5-TROPIC HIV-1 INFECTED CHILDREN 2-18 YEARS OF AGE

    Summary
    EudraCT number
    2008-006873-33
    Trial protocol
    ES   PT   IT   GB   FR   Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Oct 2019
    First version publication date
    14 Apr 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    A4001031
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00791700
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    ViiV Healthcare
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc, +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc, +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000020-PIP01-07
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    11 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This study aimed to: Primary objectives: • determine the PK profile(s) and dosing schedule(s) for MVC in treatment experienced HIV infected children and adolescents on different background therapies; • determine the safety and tolerability of MVC in HIV infected children and adolescents. Secondary objectives: • describe the efficacy of multiple dose administration of MVC in treatment experienced children infected with R5 HIV 1; • describe tropism changes over time
    Protection of trial subjects
    This study was designed and monitored in accordance with Pfizer standard operating procedures (SOPs), until transition to the Contract Research Organization (CRO) PAREXEL in November 2012, after which the study was monitored in accordance with CRO SOPs. Both Pfizer and CRO SOPs complied with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki as amended by legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), Guidelines for GCP (International Conference on Harmonization 1996), and the Declaration of Helsinki (World Medical Association 2008). In addition, the study was conducted in accordance with the CSP, the International Conference on Harmonization guideline on GCP, and applicable local regulatory requirements and laws.
    Background therapy
    Optimized background treatment (OBT), consisting of 3 to 5 commercially available Anti-retroviral (ARV) agents were selected by the investigator and approved by Pfizer, on the basis of resistance testing, treatment history and safety considerations. Subjects with toxicity due to drugs in the OBT regimen were able to substitute a drug of the same class during the study in consultation with the medical monitor. All concomitant medications were recorded on the CRF. Although no other forms of therapy for the treatment of HIV infection will be allowed while on study medication, IVIG for the treatment of HIV infection is allowed. ARV agents comprising the OBT regimen were taken according to the manufacturer product labeling or local guidelines. Dose adjustments to Maraviroc (MVC) were made in subjects taking concomitant medications that significantly inhibit and/or induce CYP3A4. This is because MVC is a substrate for CYP3A4. Medications such as analgesics, antiinflammatory agents, antibiotics, and nutritional supplements other than those contraindicated (list below), could be used as needed. Contraindicated medications included but not limited to were immunomodulators (except interferon or IVIG), grapefruit or grapefruit related citrus fruits (eg, Seville oranges, pomelos) and St.John's Wort or other herbal therapies. The use of rifampin for the treatment mycobacterial infection for subjects in Stage 2 was allowed on a case-by-case basis with the approval of the study team. Rifampin was not allowed for subjects in Stage 1. Co-administration of isoniazid was allowed on an individual basis upon discussion with and approval of the study team.
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Apr 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    South Africa: 62
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    103
    EEA total number of subjects
    11
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    61
    Adolescents (12-17 years)
    42
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This open-label, multicenter, multiple dose pharmacokinetic, safety and efficacy study enrolled 103 subjects at 24 sites in 8 countries. Data reported in this result summary is the 5 year safety update.

    Pre-assignment
    Screening details
    Criteria such as the following were considered: HIV-1 infected treatment-experienced children and adolescents who were failing current ARV therapy or have failed their most recent ARV regimen, defined by plasma HIV-1 RNA>=1000 copies/mL, infected with only R5 HIV-1, and have ARV experience/intolerance of 6 months with at least 2 ARV drug classes.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Open-label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    >=2 - <6 years of age, MVC liquid formulation
    Arm type
    Experimental

    Investigational medicinal product name
    Maraviroc
    Investigational medicinal product code
    UK-427,857
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    MVC liquid formulation (20 mg/ml)

    Arm title
    Cohort 2
    Arm description
    >=6 - <12 years of age, MVC tablet formulation
    Arm type
    Experimental

    Investigational medicinal product name
    Maraviroc
    Investigational medicinal product code
    UK-427,857
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MVC tablet formulation (25 mg, 75 mg, 150 mg)

    Arm title
    Cohort 3
    Arm description
    >=6 - <12 years of age, MVC liquid formulation
    Arm type
    Experimental

    Investigational medicinal product name
    Maraviroc
    Investigational medicinal product code
    UK-427,857
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    MVC liquid formulation (20 mg/ml)

    Arm title
    Cohort 4
    Arm description
    >=12 - <18 years of age, MVC tablet formulation
    Arm type
    Experimental

    Investigational medicinal product name
    Maraviroc
    Investigational medicinal product code
    UK-427,857
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MVC tablet formulation (25 mg, 75 mg, 150 mg)

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Started
    16
    31
    13
    43
    Completed
    10
    20
    7
    13
    Not completed
    6
    11
    6
    30
         Death
    -
    -
    -
    1
         Non-compliance with study treatment
    -
    2
    -
    4
         Withdrawn due to pregnancy
    -
    -
    -
    1
         Unspecified
    -
    1
    -
    1
         Insufficient clinical response
    1
    4
    1
    8
         Adverse Event
    -
    -
    1
    1
         Lost to follow-up
    4
    3
    4
    6
         No longer willing to participate in study
    1
    1
    -
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    >=2 - <6 years of age, MVC liquid formulation

    Reporting group title
    Cohort 2
    Reporting group description
    >=6 - <12 years of age, MVC tablet formulation

    Reporting group title
    Cohort 3
    Reporting group description
    >=6 - <12 years of age, MVC liquid formulation

    Reporting group title
    Cohort 4
    Reporting group description
    >=12 - <18 years of age, MVC tablet formulation

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
    Number of subjects
    16 31 13 43 103
    Age categorical
    Units: Subjects
        Children (2-11 years)
    16 31 13 1 61
        Adolescents (12-17 years)
    0 0 0 42 42
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    3.4 ± 0.9 9.1 ± 1.7 8.9 ± 2.0 14.0 ± 1.6 -
    Gender, Male/Female
    Units: participants
        Female
    5 16 6 27 54
        Male
    11 15 7 16 49
    Subject analysis sets

    Subject analysis set title
    Response
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects with plasma HIV-1 RNA <48 copies/mL at Week 48 using Missing, Switch, Discontinuation’=Failure (MSDF) algorithm.

    Subject analysis set title
    PDVF
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects with protocol-defined virologic failure

    Subject analysis set title
    Other Failure/Remainder
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who discontinued due to other reasons.

    Subject analysis set title
    Cohort 1 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=2 - <6 years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 1 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=2 - <6 years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 2 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6 - <12 years of age, MVC tablet formulation

    Subject analysis set title
    Cohort 2 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6 - <12 years of age, MVC tablet formulation

    Subject analysis set title
    Cohort 3 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6 - <12 years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 3 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6- <12years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 4 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=12 - <18 years of age, MVC tablet formulation

    Subject analysis set title
    Cohort 4 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=12 - <18 years of age, MVC tablet formulation

    Subject analysis sets values
    Response PDVF Other Failure/Remainder Cohort 1 (Grade 3) Cohort 1 (Grade 4) Cohort 2 (Grade 3) Cohort 2 (Grade 4) Cohort 3 (Grade 3) Cohort 3 (Grade 4) Cohort 4 (Grade 3) Cohort 4 (Grade 4)
    Number of subjects
    49
    23
    31
    16
    16
    31
    31
    13
    13
    43
    43
    Age categorical
    Units: Subjects
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    Gender, Male/Female
    Units: participants
        Female
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Male
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    >=2 - <6 years of age, MVC liquid formulation

    Reporting group title
    Cohort 2
    Reporting group description
    >=6 - <12 years of age, MVC tablet formulation

    Reporting group title
    Cohort 3
    Reporting group description
    >=6 - <12 years of age, MVC liquid formulation

    Reporting group title
    Cohort 4
    Reporting group description
    >=12 - <18 years of age, MVC tablet formulation

    Subject analysis set title
    Response
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects with plasma HIV-1 RNA <48 copies/mL at Week 48 using Missing, Switch, Discontinuation’=Failure (MSDF) algorithm.

    Subject analysis set title
    PDVF
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects with protocol-defined virologic failure

    Subject analysis set title
    Other Failure/Remainder
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who discontinued due to other reasons.

    Subject analysis set title
    Cohort 1 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=2 - <6 years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 1 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=2 - <6 years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 2 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6 - <12 years of age, MVC tablet formulation

    Subject analysis set title
    Cohort 2 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6 - <12 years of age, MVC tablet formulation

    Subject analysis set title
    Cohort 3 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6 - <12 years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 3 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=6- <12years of age, MVC liquid formulation

    Subject analysis set title
    Cohort 4 (Grade 3)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=12 - <18 years of age, MVC tablet formulation

    Subject analysis set title
    Cohort 4 (Grade 4)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    >=12 - <18 years of age, MVC tablet formulation

    Primary: Pharmacokinetic (PK) Parameters for subjects with data in Stage 1 enrolled in Stage 2 – Week 2 and Week 48

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    End point title
    Pharmacokinetic (PK) Parameters for subjects with data in Stage 1 enrolled in Stage 2 – Week 2 and Week 48 [1]
    End point description
    A PK analysis was performed using PK data from subjects that participated in Stage 1 (PK Populations 2 and 3) where intensive MVC PK data were available at Week 2. The primary aim of this analysis was to describe and summarize MVC PK parameters at Week 2 and Week 48 by cohort and OBT group. Geometric Coefficient of Variation is defined as the geometric standard deviation to the power of the reciprocal of the geometric mean. PK analysis was also performed for Population 2 (subset of APS 1) consisting of all Stage 1 subjects who had a Week 2 full PK profile; and for Population 3 (subset of APS 1) consisting of all Stage 1 subjects who had an approved dose for Stage 2 / met the PK target. Number of Subjects Analyzed signifies the number of subjects analyzed for PK. n= number of subjects analyzed at individual time points for this outcome measure.
    End point type
    Primary
    End point timeframe
    Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were done.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    12
    42
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cavg-Week2(n=12, 11, 10, 17)
    237.34 ± 63
    260.65 ± 43
    264.45 ± 62
    239.85 ± 67
        Cavg-Week 48(n=9, 8, 8, 12)
    163.73 ± 146
    289.69 ± 50
    168.62 ± 117
    199.12 ± 78
        Cmax-Week2 (n=12, 11, 10, 17)
    581.47 ± 69
    546.80 ± 51
    444.37 ± 61
    530.80 ± 62
        Cmax-Week 48(n=9, 8, 8, 12)
    334.68 ± 156
    593.68 ± 25
    284.96 ± 128
    423.32 ± 48
        Cmin-Week2(n=12, 11, 10, 17)
    18.97 ± 202208
    100.02 ± 39
    115.84 ± 90
    56.17 ± 145
        Cmin-Week 48(n=9, 8, 8, 12)
    48.11 ± 180
    82.21 ± 120
    60.03 ± 245
    66.51 ± 140
    No statistical analyses for this end point

    Primary: PK Parameters for Stage 1 subjects Enrolled in Stage 2 – Week 2 and Week 48 Results for Stage 2 doses - AUCtau (Area under the curve at steady state)

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    End point title
    PK Parameters for Stage 1 subjects Enrolled in Stage 2 – Week 2 and Week 48 Results for Stage 2 doses - AUCtau (Area under the curve at steady state) [2]
    End point description
    A PK analysis was performed using PK data from participants that participated in Stage 1 (PK Populations 2 and 3) where intensive MVC PK data were available at Week 2. The primary aim of this analysis was to describe and summarize MVC PK parameters (AUCtau) at Week 2 and Week 48 by cohort and OBT group. Correlations between MVC PK and efficacy as well as compliance were also assessed. PK analysis was also performed for Population 2 (subset of APS 1) consisting of all Stage 1 participants who had a Week 2 full PK profile; and for Population 3 (subset of APS 1) consisting of all Stage 1 participants who had an approved dose for Stage 2 / met the PK target. Number of Subjects Analyzed signifies the number of subjects analyzed for PK. n= number of subjects analyzed at individual time points for this outcome measure.
    End point type
    Primary
    End point timeframe
    Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were done.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    12
    42
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        AUCtau - Week 2 (n=12, 11, 10, 17)
    2848.1 ± 63
    3127.7 ± 43
    3173.4 ± 62
    2878.2 ± 67
        AUCtau - Week 48 (n=9, 8, 8, 12)
    1964.7 ± 146
    3476.3 ± 50
    2023.5 ± 117
    2389.4 ± 78
    No statistical analyses for this end point

    Primary: PK Parameters for Stage 1 subjects Enrolled in Stage 2 – Week 2 and Week 48 Results for Stage 2 doses - Tmax (Time at maximum concentration)

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    End point title
    PK Parameters for Stage 1 subjects Enrolled in Stage 2 – Week 2 and Week 48 Results for Stage 2 doses - Tmax (Time at maximum concentration) [3]
    End point description
    A PK analysis was performed using PK data from subjects that participated in Stage 1 (PK Populations 2 and 3) where intensive MVC PK data were available at Week 2. The primary aim of this analysis was to describe and summarize MVC PK parameters (Tmax) at Week 2 and Week 48 by cohort and OBT group. Correlations between MVC PK and efficacy as well as compliance were also assessed. PK analysis was also performed for Population 2 (subset of APS 1) consisting of all Stage 1 subjects who had a Week 2 full PK profile; and for Population 3 (subset of APS 1) consisting of all Stage 1 subjects who had an approved dose for Stage 2 / met the PK target. Number of Subjects Analyzed signifies the number of subjects analyzed for PK. n= number of subjects analyzed at individual time points for this outcome measure.
    End point type
    Primary
    End point timeframe
    Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were done.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    12
    42
    Units: hour
    median (full range (min-max))
        Tmax - Week 2 (n=12, 11, 10, 17)
    2.000 (0.97 to 6.00)
    4.000 (0.75 to 6.00)
    2.000 (1.00 to 4.00)
    2.000 (1.00 to 4.00)
        Tmax - Week 48 (n=9, 8, 8, 12)
    2.000 (0.00 to 6.03)
    2.000 (1.00 to 8.00)
    3.000 (0.00 to 6.00)
    2.000 (1.00 to 4.00)
    No statistical analyses for this end point

    Primary: Incidence and Severity of Grade 3 and Grade 4 Treatment-Emergent Adverse Events (All Causality)

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    End point title
    Incidence and Severity of Grade 3 and Grade 4 Treatment-Emergent Adverse Events (All Causality) [4]
    End point description
    Safety analysis was performed on all subjects who received at least 1 dose of study drug. It was assessed by spontaneous reports, physical examination and laboratory test results in all subjects who received at least 1 dose of study drug. The investigator used the Division of AIDS (DAIDS) version 4 Table for Grading the Severity of Adult and Pediatric AEs. MCT disorders= Musculoskeletal and Connective Tissue Disorder.
    End point type
    Primary
    End point timeframe
    Baseline up to 5 years
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were done.
    End point values
    Cohort 1 (Grade 3) Cohort 1 (Grade 4) Cohort 2 (Grade 3) Cohort 2 (Grade 4) Cohort 3 (Grade 3) Cohort 3 (Grade 4) Cohort 4 (Grade 3) Cohort 4 (Grade 4)
    Number of subjects analysed
    16
    16
    31
    31
    13
    13
    43
    43
    Units: Number of events
        Gastrointestinal disorders - Vomiting
    1
    0
    1
    0
    0
    0
    0
    0
        Hepat. disorders - Drug-induced liver injury
    0
    0
    0
    0
    0
    0
    0
    1
        Infections and infestations - H1N1 influenza
    0
    0
    0
    0
    0
    0
    1
    0
        Infections and infestations - Pneumonia
    0
    0
    0
    0
    1
    0
    1
    0
        Investigations - Lipase increased
    0
    1
    0
    0
    0
    0
    0
    0
        Pyschiatric disorder - Bipolar disorder
    0
    0
    1
    0
    0
    0
    0
    0
        Gastrointestinal disorders - Gastritis
    0
    0
    1
    0
    0
    0
    0
    0
        Investigations - Hepatic enzyme abnormal
    0
    0
    1
    0
    0
    0
    0
    0
        Investigations - Transaminases increased
    0
    0
    1
    0
    0
    0
    0
    0
        Pyschiatric disorder - Aggression
    0
    0
    1
    0
    0
    0
    0
    0
        Blood and lymphatic system disorders - Anaemia
    0
    0
    0
    0
    0
    0
    1
    0
        Infections and infestations - Meningitis
    0
    0
    0
    0
    0
    0
    0
    1
        Otitis media
    0
    0
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Treatment discontinuation secondary to Serious Adverse Event (SAE) related to study drug

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    End point title
    Treatment discontinuation secondary to Serious Adverse Event (SAE) related to study drug [5]
    End point description
    The primary reason for a subject discontinuing from study drug or the clinical study was recorded in the source documents as well as the case report form. A discontinuation had to be reported immediately to the study medical monitor or his/her designated representative if it was due to an SAE. Safety analysis was performed on all subjects who received at least 1 dose of study drug. In this study, there was no treatment discontinuation secondary to Serious Adverse Event (SAE) related to study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to 5 years
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were done.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: subejcts
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with HIV‑1 RNA <400 copies/mL through Week 48 (MSDF)

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    End point title
    Percentage of subjects with HIV‑1 RNA <400 copies/mL through Week 48 (MSDF)
    End point description
    The proportion of subjects who achieved HIV-1 RNA <400 copies/mL at week 24 or 48 was assessed according to Food and Drug Administration’s (FDA’s) MSDF Snapshot algorithm. The algorithm uses the plasma HIV-1 RNA in the Week 24 or 48 visit window, follows the “virology-first principle” and considers a subject who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure. The percentage of subjects is reported below.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: percentage of subjects
    number (not applicable)
        Week 24
    68.8
    90.3
    69.2
    62.8
        Week 48
    75.0
    77.4
    69.2
    51.2
    No statistical analyses for this end point

    Secondary: Percentage of subjects with HIV‑1 RNA <48 copies/mL through Week 48 (MSDF)

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    End point title
    Percentage of subjects with HIV‑1 RNA <48 copies/mL through Week 48 (MSDF)
    End point description
    The proportion of subjects who achieved HIV-1 RNA <48 copies/mL at week 24 or 48 was assessed according to Food and Drug Administration’s (FDA’s) MSDF Snapshot algorithm. The algorithm uses the plasma HIV-1 RNA in the Week 24 or 48 visit window, follows the “virology-first principle” and considers a subject who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure. The percentage of subjects is reported below. The FAS consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: percentage of subjects
    number (not applicable)
        Week 24
    25.0
    64.5
    61.5
    48.8
        Week 48
    50.0
    54.8
    53.8
    39.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with HIV-1 RNA Levels <400 copies/mL at Weeks 24 and 48 using Missing, Discontinuation = Failure (MD=F) Approach

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    End point title
    Percentage of Subjects with HIV-1 RNA Levels <400 copies/mL at Weeks 24 and 48 using Missing, Discontinuation = Failure (MD=F) Approach
    End point description
    Subjects who have been discontinued from the study, have been lost to follow-up, or have missing HIV-1 RNA data prior to the time point of interest were considered to have HIV-1 RNA levels > lower limit of quantification (LLOQ) . This will be referred to as [non-completer = failure; NC=F] or [missing, discontinuation = failure; MD=F]. The proportion of subjects (100*n/N) is reported below. The FAS consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 24 (n=10, 27, 8, 27)
    62.5 (38.8 to 86.2)
    87.10 (75.3 to 98.9)
    69.2 (44.1 to 94.3)
    62.8 (48.3 to 77.2)
        Week 48 (n=12, 23, 9, 22)
    75.0 (53.8 to 96.2)
    74.2 (58.8 to 89.6)
    69.2 (44.1 to 94.3)
    51.2 (36.2 to 66.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with HIV-1 RNA Levels < 48 copies/mL at Weeks 24 and 48 using MD=F Approach

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    End point title
    Percentage of Subjects with HIV-1 RNA Levels < 48 copies/mL at Weeks 24 and 48 using MD=F Approach
    End point description
    Subjects who have been discontinued from the study, have been lost to follow-up, or have missing HIV-1 RNA data prior to the time point of interest were considered to have HIV-1 RNA levels > lower limit of quantification (LLOQ) . This will be referred to as [non-completer = failure; NC=F] or [missing, discontinuation = failure; MD=F]. The proportion of subjects (100*n/N) is reported below. The FAS consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 24 (n=3, 20, 8, 21)
    18.8 (0.0 to 37.9)
    64.5 (47.7 to 81.4)
    61.5 (35.1 to 89.0)
    48.8 (33.9 to 63.8)
        Week 48 (n=8, 16, 8, 17)
    50.0 (25.5 to 74.5)
    51.6 (34.0 to 69.2)
    61.5 (35.1 to 89.0)
    39.5 (24.9 to 54.2)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with HIV-1 RNA < 400 copies/mL and <48 copies/mL using the time to loss of virologic response algorithm (TLOVR) at Week 48

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    End point title
    Percentage of subjects with HIV-1 RNA < 400 copies/mL and <48 copies/mL using the time to loss of virologic response algorithm (TLOVR) at Week 48
    End point description
    TLOVR is defined as the time from first dose of study medication (Day 1) until the time of virologic failure using the a TLOVR algorithm. The FAS consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: Percentage of subjects
    number (not applicable)
        <400 copies/mL; TLOVR Responder
    62.5
    74.2
    69.2
    48.8
        <48 copies/mL; TLOVR Responder
    43.8
    54.8
    46.2
    44.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with >= 1.0 log10 reduction in HIV-1RNA concentration from baseline to Week 24 and Week 48

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    End point title
    Percentage of Subjects with >= 1.0 log10 reduction in HIV-1RNA concentration from baseline to Week 24 and Week 48
    End point description
    Percentage of subjects with at least a 1.0 log10 reduction in HIV-1 RNA from baseline to Week 24 and Week 48 were tabulated and is presented below. The number of subjects with an observation at specified time points were used to calculate the percentage.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 24
    92.3 (77.8 to 106.8)
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
    93.1 (83.9 to 102.3)
        Week 48
    100.0 (100.0 to 100.0)
    96.2 (88.8 to 103.6)
    100.0 (100.0 to 100.0)
    88.0 (75.3 to 100.7)
    No statistical analyses for this end point

    Secondary: Summary of Change from Baseline in HIV-1 RNA (Original) at Week 24 and Week 48

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    End point title
    Summary of Change from Baseline in HIV-1 RNA (Original) at Week 24 and Week 48
    End point description
    Plasma HIV-1 RNA was determined using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test (lower limit of quantification [LLOQ] <48 copies/mL). Blood samples were taken at the time points indicated in the subject evaluation schedule. Screening HIV-1 RNA >1000 copies/ml was used to determine eligibility for the study. The FAS consisted of all subjects who received at least 1 dose of study drug. LOCF was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    15
    31
    12
    39
    Units: copies/mL
    arithmetic mean (standard deviation)
        Change from Baseline - Original - Week 24
    -271974.6 ± 391843.59
    -38764.0 ± 63688.93
    -58081.0 ± 79720.33
    -57325.7 ± 172108.62
        Change from Baseline - Original - Week 48
    -267834.2 ± 378896.88
    -34787.7 ± 60222.60
    -56351.7 ± 76231.03
    -55321.1 ± 173840.55
    No statistical analyses for this end point

    Secondary: Change from Baseline in cluster of differentiation 4 (CD4+) cell count at weeks 24 and 48

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    End point title
    Change from Baseline in cluster of differentiation 4 (CD4+) cell count at weeks 24 and 48
    End point description
    Change from baseline in CD4 cell count to Week 24 and Week 48 were tabulated in aggregated and broken down by age cohort using summary statistics. The FAS consisted of all subjects who received at least 1 dose of study drug. LOCF was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    15
    30
    12
    39
    Units: cells/mm^3
    arithmetic mean (standard deviation)
        Week 24
    232.7 ± 381.6
    355.8 ± 294.0
    213.9 ± 166.4
    173.6 ± 203.6
        Week 48
    275.9 ± 363.4
    362.7 ± 373.5
    167.3 ± 150.9
    168.6 ± 211.0
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ % at weeks 24 and 48

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    End point title
    Change from Baseline in CD4+ % at weeks 24 and 48
    End point description
    Change from baseline in CD4 % to Week 24 and Week 48 were tabulated in aggregated and broken down by age cohort using summary statistics. The FAS consisted of all subjects who received at least 1 dose of study drug. LOCF was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    15
    31
    12
    39
    Units: percentage of CD4+ cells
    arithmetic mean (standard deviation)
        Week 24 (n=15, 31, 12, 39)
    7.3 ± 5.0
    3.8 ± 7.4
    3.5 ± 4.0
    3.8 ± 6.1
        Week 48 (n=15, 31, 12, 39)
    7.5 ± 7.6
    6.0 ± 6.8
    2.5 ± 4.2
    4.6 ± 6.5
    No statistical analyses for this end point

    Secondary: Protocol Defined Virologic Failure

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    End point title
    Protocol Defined Virologic Failure
    End point description
    The occurrence of any one of the following criteria would constitute Virologic failure: A=Decrease from Baseline plasma HIV-1 RNA <1 log10 and plasma HIV-1 RNA >400 copies/mL starting at Week 12 and confirmed at consecutive Week 16; B=Decrease from Baseline plasma HIV-1 RNA <2.0 log10 and plasma HIV-1 RNA >400 copies/mL at Week 24 OR plasma HIV-1 RNA >10,000 copies/mL on and after Week 24, and confirmed within 14 to 21 days; C=Increase from nadir plasma HIV-1 RNA of >=1 log10 (>=1,000 copies/mL if nadir plasma HIV-1 RNA <48 copies/mL) at any time, and confirmed within 14 to 21 days. The FAS consisted of all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    16
    31
    13
    43
    Units: Number of subjects
        A (measure description above)
    0
    2
    1
    5
        B (measure description above)
    0
    0
    0
    0
        C (measure description above)
    3
    3
    2
    8
        Number of PDVF
    3
    5
    3
    13
    No statistical analyses for this end point

    Secondary: Shift Table of Viral Tropism between Screening and Confirmed PDVF Prior to Week 48

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    End point title
    Shift Table of Viral Tropism between Screening and Confirmed PDVF Prior to Week 48
    End point description
    Virus tropism was determined using the Monogram Biosciences Trofile™ viral tropism assay. A shift table of the change in detected tropism from screening to the time of failure was produced in the aggregate and also broken down by age cohort. Subjects who experienced confirmed PDVF through Week 48 with sufficient plasma HIV-1 RNA for virology analysis while receiving MVC. One subject was excluded from summary tables as classified as MSDF response; one subject was analyzed after stopping treatment.
    End point type
    Secondary
    End point timeframe
    Screening and Week 48
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    3
    4
    3
    13
    Units: Number of subjects
        With valid on-treatment results
    2
    4
    3
    11
        Tropism at Confirmed PDVF R5
    2
    3
    2
    9
        Tropism at Confirmed PDVF DM
    0
    1
    1
    2
        Tropism at Confirmed PDVF X4
    0
    0
    0
    0
        Tropism at Confirmed PDVF Not Reportable
    1
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Summary of the Emergence of reverse transcriptase inhibitor (RTI) and protease inhibitor (PI) resistance associated mutations (RAMs) Between Screening and On-Treatment Confirmed PDVF: Total and by Cohort Prior to Week 48

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    End point title
    Summary of the Emergence of reverse transcriptase inhibitor (RTI) and protease inhibitor (PI) resistance associated mutations (RAMs) Between Screening and On-Treatment Confirmed PDVF: Total and by Cohort Prior to Week 48
    End point description
    Phenotypic and genotypic susceptibility to reverse transcriptase and protease inhibitors was evaluated at screening using the Monogram Biosciences PhenoSense™ GT (PSGT) assay. Samples from a confirmatory PDVF visit or early termination of MVC were planned to be analyzed if the plasma HIV-1 RNA was ≥400 copies/mL. Subjects with more than one mutation are counted more than once. One subject was excluded from summary tables as classified as MSDF response; one participant was analyzed after stopping treatment.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    3
    4
    3
    13
    Units: Number of subjects
        With valid on-treatment results
    2
    4
    3
    11
        PI Minor (L10L/F, L89L/I/M, V77V/I and K20K/R)
    0
    0
    2
    3
        PI Major
    0
    0
    0
    0
        NNRTI (K103K/N and K103N)
    0
    1
    1
    1
        NRTI M184V
    0
    0
    1
    0
        Total with emergence
    0
    1
    3
    4
    No statistical analyses for this end point

    Secondary: Optimized Background Treatment (OBT) Susceptibility Scores (Net/Overall) by Outcome

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    End point title
    Optimized Background Treatment (OBT) Susceptibility Scores (Net/Overall) by Outcome
    End point description
    Outcome (Response, PDVF or other/remainder) was summarized by the total ARV activity of the background regimen using simple and weighted totals (TOBT and p-wTOBTss, respectively) in the aggregate, categorized as 0, 1, ≥2 (TOBT) and 0 0.5, 1 1.5 and ≥2 (p-wOBTss) respectively, as well as by screening genotype. Six subjects (Response: n=5; Other failure: n=1) failed to have successful PhenoSense GT analysis at screening, and so a net susceptibility score was not generated. One more subject was not included in the wOBTss analysis due to failed phenotype analysis. However, net susceptibility scores were imputed for simple analysis based on genotype. The FAS consisted of all subjects who received at least 1 dose of study drug. Susceptibility scores indicate the level resistance to the study medication. Scores include: 1 = susceptible and potential low-level resistance; 0.5 = low and intermediate-level resistance; 0 = high-level resistance.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Response PDVF Other Failure/Remainder
    Number of subjects analysed
    49
    23
    31
    Units: Percentage of subjects
    number (not applicable)
        Simple score 0
    0
    0
    0
        Simple score 1.0
    8.2
    4.3
    0
        Simple score ≥ 2.0
    81.6
    95.7
    96.8
        Weighted score 0-0.5
    6.1
    30.4
    29.0
        Weighted score 1.0-1.5
    53.1
    65.2
    29.0
        Weighted score ≥ 2.0
    28.6
    4.3
    38.7
    No statistical analyses for this end point

    Secondary: Summary of Change from Baseline in HIV-1 RNA (Log10 copies/mL) at Week 24 and Week 48

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    End point title
    Summary of Change from Baseline in HIV-1 RNA (Log10 copies/mL) at Week 24 and Week 48
    End point description
    Plasma HIV-1 RNA was determined using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test (lower limit of quantification [LLOQ] <48 copies/mL). Blood samples were taken at the time points indicated in the participant evaluation schedule. Screening HIV-1 RNA >1000 copies/ml was used to determine eligibility for the study.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 post-treatment
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    15
    31
    12
    39
    Units: Log10 Copies/mL
    arithmetic mean (standard deviation)
        Change from Baseline - Log10 - Week 24
    -2.4853 ± 1.1421
    -2.2324 ± 0.8668
    -2.1756 ± 1.1854
    -1.6482 ± 1.3806
        Change from Baseline - Log10 - Week 48
    -2.5831 ± 1.2148
    -1.9579 ± 1.0861
    -2.0549 ± 1.2125
    -1.4591 ± 1.4477
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 5 years
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as non-serious in another subject, or 1 subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    >=2 - <6 years of age, MVC liquid formulation

    Reporting group title
    Cohort 2
    Reporting group description
    >=6 - <12 years of age, MVC tablet formulation

    Reporting group title
    Cohort 3
    Reporting group description
    >=6 - <12 years of age, MVC liquid formulation

    Reporting group title
    Cohort 4
    Reporting group description
    >=12 - <18 years of age, MVC tablet formulation

    Serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 16 (31.25%)
    5 / 31 (16.13%)
    3 / 13 (23.08%)
    10 / 43 (23.26%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hyperventilation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric fistula
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Prurigo
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 16 (75.00%)
    25 / 31 (80.65%)
    10 / 13 (76.92%)
    34 / 43 (79.07%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    2
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 31 (3.23%)
    2 / 13 (15.38%)
    5 / 43 (11.63%)
         occurrences all number
    3
    1
    2
    7
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Depression
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Hallucination
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nightmare
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Panic disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Aggression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flat affect
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Breast mass
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Breast enlargement
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Breast pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Accidental exposure to product
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Arthropod sting
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Fall
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    1
    Muscle strain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    2
    Overdose
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    2
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    1
    0
    3
    Thermal burn
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Underdose
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Accidental overdose
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Ankle fracture
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Traumatic ulcer
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Blood HIV RNA increased
    Additional description: From informed consent to 30 days after last MVC dose and within a frequency threshold of 2%.
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood iron decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Lipase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    3
    Viral load increased
    Additional description: From informed consent to 30 days after last MVC dose and within a frequency threshold of 2%.
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Bronchospasm
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Catarrh
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 16 (6.25%)
    6 / 31 (19.35%)
    2 / 13 (15.38%)
    3 / 43 (6.98%)
         occurrences all number
    2
    15
    3
    4
    Epistaxis
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Hyperventilation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    2
    0
    1
    Pharyngeal disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    1
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    2
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    1 / 13 (7.69%)
    2 / 43 (4.65%)
         occurrences all number
    0
    5
    2
    2
    Rhonchi
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Allergic cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    1
    0
    0
    4
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lymphadenitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    1
    0
    0
    5
    Neutropenia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    1
    0
    4
    Epilepsy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    2 / 13 (15.38%)
    6 / 43 (13.95%)
         occurrences all number
    0
    4
    3
    10
    Lethargy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Tension headache
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    11
    Intellectual disability
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Conjunctival pallor
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    2
    0
    1
    Hypermetropia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Refraction disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Cerumen impaction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Ear haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    2 / 13 (15.38%)
    4 / 43 (9.30%)
         occurrences all number
    0
    1
    3
    5
    Abdominal pain lower
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Anal pruritus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    2
    1
    0
    3
    Dental caries
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    1
    1
    Diarrhoea
         subjects affected / exposed
    7 / 16 (43.75%)
    3 / 31 (9.68%)
    4 / 13 (30.77%)
    9 / 43 (20.93%)
         occurrences all number
    12
    3
    4
    10
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    2
    Flatulence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gingival swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    1
    0
    1
    1
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 31 (9.68%)
    0 / 13 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    3
    0
    5
    Odynophagia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Proctitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Salivary gland mucocoele
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Tongue disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    6 / 16 (37.50%)
    8 / 31 (25.81%)
    3 / 13 (23.08%)
    4 / 43 (9.30%)
         occurrences all number
    15
    9
    4
    5
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Acanthosis nigricans
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    2
    0
    0
    2
    Acne
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dermatitis diaper
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    2 / 13 (15.38%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    2
    1
    Ecchymosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    1
    1
    Papule
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Prurigo
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    4
    3
    1
    1
    Rash pruritic
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    2 / 13 (15.38%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria papular
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Lipodystrophy acquired
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neurodermatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    0
    2
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bone swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bursitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myofascial pain syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Osteoporosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    1
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    2
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    0
    0
    1
    Insulin resistance
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Acarodermatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Angular cheilitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Bacterial vaginosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 31 (9.68%)
    0 / 13 (0.00%)
    7 / 43 (16.28%)
         occurrences all number
    9
    12
    0
    9
    Bullous impetigo
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    3
    2
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    0
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 31 (0.00%)
    2 / 13 (15.38%)
    2 / 43 (4.65%)
         occurrences all number
    3
    0
    2
    4
    Gastroenteritis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    0
    0
    1
    Herpes virus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Impetigo
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    3
    0
    1
    Influenza
         subjects affected / exposed
    2 / 16 (12.50%)
    6 / 31 (19.35%)
    3 / 13 (23.08%)
    5 / 43 (11.63%)
         occurrences all number
    4
    9
    5
    5
    Latent tuberculosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lice infestation
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    3
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 16 (25.00%)
    4 / 31 (12.90%)
    0 / 13 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    7
    6
    0
    4
    Oral herpes
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    3
    0
    1
    Otitis externa
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    1
    0
    0
    2
    Otitis media
         subjects affected / exposed
    6 / 16 (37.50%)
    1 / 31 (3.23%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    9
    1
    1
    0
    Otitis media acute
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    9
    2
    0
    0
    Otitis media chronic
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Parotitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    1
    1
    0
    2
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 31 (9.68%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    3
    0
    2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    5
    1
    0
    5
    Sinobronchitis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    1
    1
    0
    1
    Tinea capitis
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Tinea faciei
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinea infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 31 (6.45%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    1
    2
    0
    2
    Tooth abscess
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    1 / 13 (7.69%)
    0 / 43 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 16 (43.75%)
    6 / 31 (19.35%)
    2 / 13 (15.38%)
    5 / 43 (11.63%)
         occurrences all number
    23
    9
    2
    5
    Tuberculosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Varicella
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 31 (6.45%)
    3 / 13 (23.08%)
    1 / 43 (2.33%)
         occurrences all number
    4
    2
    4
    2
    Wound infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    0
    0
    2
    Vulvovaginitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mastoiditis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 31 (3.23%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Viral rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fungal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 31 (0.00%)
    0 / 13 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    0
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2009
    Amendment 1: Cut-off value for HIV RNA was assay added. Complete abstinence was added as an acceptable form of contraception. Grapefruit-related citrus fruits such as Seville oranges and pomelos were added to the list of concomitant medications to ensure MVC PK was not affected. Instructions for stringent liver function test monitoring were added.
    16 Aug 2010
    Amendment 2: ViiV Healthcare was added as the new Sponsor. Sparse PK Sampling was removed at the Early Termination Visits. It was clarified that confirmation virologic failure visit to be conducted 14-21 Days after subject withdrawal. Visit window for Isod visits changed to 1 month. Exclusion criteria for creatinine clearance was mentioned as <90 ml/min. Reference to “Sterilization” and “Post-Menopausal” was deleted. Supply of OBT was clarified. It was clarified that Isoniazid may be allowed on an individual basis and that rifampin was only allowed during Stage 2. It was clarified that an alternate method to Trofile assay could be performed if Trofile assay was not reportable. It was added that an alternate method to PhenoSense GT if result is not reportable. It was clarified that virus susceptibility to MVC would be done at the same time points as the virus susceptibility to OBT.
    03 Dec 2010
    Amendment 3: (Country Specific: Kenya and Uganda): It was clarified that local labs may be used for safety testing for sites in Kenya and Uganda. New safety language was addded to the AE section.
    25 Feb 2011
    Amendment 4: (Country Specific: Brazil): It was clarified that the Sponsor would cover the cost of OBTs if not covered under the Brazil National Program. New safety language was addded to the AE section.
    01 Jun 2011
    Amendment 5: Information was added to the “Subject Withdrawal” section. Exposure in Utero was renames Exposure during pregnancy and more instructions were added. Additional details were added to the “Communication of Results by Sponsor” section. The Schedule of Activities section was updated to state that the Screening Period ended on Day 1 and that the follow up period window was increased up to 1 month (this was also done elsewhere it was mentioned in the protocol). It was clarified that in the subjects who had X4 or dual/mixed tropic virus at time of failure, HIV-1 RNA and tropism would be collected at the first ISOD Follow Up visit. It was clarified that the screening BSA will be utilized for initial MVC dose. The objectives of the population PK analyses were clarified.
    10 Jun 2012
    Amendment 6: (Country Specific: Brazil): It was clarified that the Sponsor would cover the cost of OBTs if not covered under the Brazil National Program.
    09 Aug 2012
    Amendment 7: Appendix 1 was modified (Liver enzyme monitoring to be the same as other ongoing MVC studies). Appendix 5 was added (Rationale for initial MVC dose change for subjects not on potent CYP3A4 inhibitors). Appendix 6 was added (Specific for sites in Brazil). Appendix 7 was added (Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events). Changes made were aligned with CT-3: a. Reported medication error as adverse events regardless of whether it is accompanied by an AE. b. AE reporting section was updated.
    30 Dec 2013
    Amendment 8: The protocol was amended to extend and ensure the continued supply of the study drug beyond 5 years to subjects benefitting from therapy. It was clarified that the Sponsor would cover the cost of OBTs if it was not covered under the Brazil National Program.
    19 May 2014
    Amendment 9: In “Schedule of Activities” section and wherever applicable, it was a.) added that at the End of Study visit and follow-up contact, unused medications had to be returned. b.) clarified that study visits in the follow-up period would be up to Week 261. Follow up Visit 9 was added in the Schedule of Activities. The rationale was that the protocol used 52 weeks to equate to a year, however IMPALA drug management system used 48 weeks to equate to a year, resulting in a 5 month gap at the end of 5 years of follow up. c.) clarified that the window in follow-up period was updated to 14days. The rationale was to be consistent with IMPALA drug management system. d.) added that “Contraception Check” would be done at all study visits, per new protocol template. e.) added that creatinine phosphokinase, lipid profile, free T4, TSH and Hepatitis C Virus RNA from Early Termination, were done to be consistent with follow-up period.

    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.
    The Disposition section, mentioning "Overall Study" has data only for subject discontinuations up to Week 48, as the study is ongoing. The planned enrollment per protocol was 125 subjects, however, 103 subjects enrolled in the study.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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