Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   35370   clinical trials with a EudraCT protocol, of which   5789   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel, Placebo or Amlodipine-Controlled Study of the Effects of Losartan on Proteinuria in Pediatric Patients With or Without Hypertension

    Summary
    EudraCT number
    2006-006415-74
    Trial protocol
    NO   LT   HU   ES   GB   DE   Outside EU/EEA  
    Global end of trial date
    31 Mar 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Apr 2016
    First version publication date
    10 Apr 2015
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    0954-326
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00568178
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000008-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
    Final
    Date of interim/final analysis
    31 Mar 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to study the safety and efficacy of losartan compared to placebo (nonhypertensives) or amlodipine (hypertensives) on reduction of proteinuria in children and adolescents up to 17 years of age with hypertension (if ≥6 years old) and without hypertension (if ≥1 year old). The study included a 12-week double-blind treatment phase and a 36-month open-label extension phase. Participants who completed or discontinued the initial 12-week phase of the study and who opted to participate in the open label extension phase were randomized to either losartan or enalapril at a dose of the investigator's choosing for the duration of the extension. The open label extension was designed to continue until the 100th participant completed 3 years of follow-up. Thus, participants were in the extension for varying durations based upon the time of their enrollment.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Lithuania: 12
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Colombia: 31
    Country: Number of subjects enrolled
    India: 25
    Country: Number of subjects enrolled
    Guatemala: 14
    Country: Number of subjects enrolled
    Chile: 13
    Country: Number of subjects enrolled
    Mexico: 47
    Country: Number of subjects enrolled
    Panama: 9
    Country: Number of subjects enrolled
    Peru: 37
    Country: Number of subjects enrolled
    Philippines: 17
    Country: Number of subjects enrolled
    Puerto Rico: 7
    Country: Number of subjects enrolled
    Romania: 11
    Worldwide total number of subjects
    306
    EEA total number of subjects
    60
    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)
    13
    Children (2-11 years)
    154
    Adolescents (12-17 years)
    139
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    As of March 2011, the study was completed. Phase III First Patient In: 21Jun07; Last Patient Last Visit (double-blind base study): 16Sep08; and (open-label extension): 31Mar11. The study included 52 centers (USA, Europe, Latin America, and Asia) and participants included children aged 6-17 (hypertensive) or 1-17 (normotensive) with proteinuria.

    Pre-assignment
    Screening details
    During a 4-week, single-blind run-in participants received losartan placebo (normotensive) or amlodipine (hypertensive) and underwent wash-out of anti-hypertensive agents. To qualify for randomization, participants had to have a mean urine Pr/Cr ratio of ≥0.3 gram/gram (gm/gm) derived from baseline urine samples.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Losartan Double Blind Normotensive
    Arm description
    Normotensive participants who were randomized to losartan. Losartan dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Losartan Potassium
    Investigational medicinal product code
    Other name
    Cozaar®
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Either tablets (25 or 50 mg) or liquid suspension (2.5 mg/mL) were administered. Liquid suspension prepared using losartan 50 mg tablets for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. Losartan Use During the Double-Blind Treatment Phase: Losartan suspension dosing at 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks; or losartan placebo. Losartan Use During the Treatment Extension Phase: Dose modifications of the drug were left up to the discretion of the Investigators based on each participant's level of tolerance.

    Arm title
    Placebo Double Blind Normotensive
    Arm description
    Normotensive participants who were randomized to losartan placebo. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Losartan Potassium Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Either placebo tablets (25 or 50 mg) or placebo liquid suspension (2.5 mg/mL) were administered orally for 12 weeks. Placebo liquid suspension prepared using losartan placebo 50 mg tablets for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. Participants randomized to losartan placebo had a sham titration at the 2 week visit.

    Arm title
    Losartan Double Blind Hypertensive
    Arm description
    Hypertensive patients who were randomized to receive losartan and amlodipine placebo for 12 weeks. Losartan dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Amlodipine placebo dispensed as suspension for duration of study. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks. Amlodipine placebo suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Losartan Potassium
    Investigational medicinal product code
    Other name
    Cozaar®
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Either tablets (25 or 50 mg) or liquid suspension (2.5 mg/mL) were administered. Liquid suspension prepared using losartan 50 mg tablets for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. Losartan Use During the Double-Blind Treatment Phase: Losartan suspension dosing at 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks; or losartan placebo. Losartan Use During the Treatment Extension Phase: Dose modifications of the drug were left up to the discretion of the Investigators based on each participant's level of tolerance.

    Investigational medicinal product name
    Amlodipine Besylate Placebo Suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Liquid suspension prepared using amlodipine besylate placebo tablets (1 mg/mL) administered orally for 12 Weeks.

    Arm title
    Amlodipine Double Blind Hypertensive
    Arm description
    Hypertensive patients who were randomized to receive amlodipine and losartan placebo for 12 weeks. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Amlodipine Besylate Suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Liquid suspension prepared using amlodipine besylate 5 mg tablets (1 mg/mL) administered orally. Starting dose 0.05 or 0.1 mg/kg/day and titrated to 0.2 mg/kg/day (5 mg maximum dose) per day for 12 Weeks.

    Investigational medicinal product name
    Losartan Potassium Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Either placebo tablets (25 or 50 mg) or placebo liquid suspension (2.5 mg/mL) were administered orally for 12 weeks. Placebo liquid suspension prepared using losartan placebo 50 mg tablets for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. Participants randomized to losartan placebo had a sham titration at the 2 week visit.

    Number of subjects in period 1
    Losartan Double Blind Normotensive Placebo Double Blind Normotensive Losartan Double Blind Hypertensive Amlodipine Double Blind Hypertensive
    Started
    122
    124
    30
    30
    Completed
    116
    118
    29
    25
    Not completed
    6
    6
    1
    5
         Progressive disease
             -
             -
             -
             1
         Protocol deviation
             3
             2
             -
             -
         Physician decision
             1
             1
             -
             1
         Adverse event, non-fatal
             -
             2
             1
             2
         Consent withdrawn by subject
             1
             1
             -
             -
         Lost to follow-up
             1
             -
             -
             1
    Period 2
    Period 2 title
    Open Label Extension
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Losartan Open Label Extension
    Arm description
    All participants who completed the 12-week DB treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomized in a 1:1 ratio to either losartan or enalapril. Dosing of study medication during the extension phase of the study was at the investigator’s discretion. Losartan 25-mg and 50-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, losartan suspension (2.5 mg/ml) was prepared.
    Arm type
    Experimental

    Investigational medicinal product name
    Losartan Potassium
    Investigational medicinal product code
    Other name
    Cozaar®
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Either tablets (25 or 50 mg) or liquid suspension (2.5 mg/mL) were administered. Liquid suspension prepared using losartan 50 mg tablets for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. Losartan Use During the Double-Blind Treatment Phase: Losartan suspension dosing at 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks; or losartan placebo. Losartan Use During the Treatment Extension Phase: Dose modifications of the drug were left up to the discretion of the Investigators based on each participant's level of tolerance.

    Arm title
    Enalapril Open Label Extension
    Arm description
    All participants who completed the 12-week DB treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomized in a 1:1 ratio to either losartan or enalapril. Dosing of study medication during the extension phase of the study was at the investigator’s discretion. Enalapril 2.5-, 5-, 10-, and 20-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, enalapril suspension (1 mg/mL) was prepared.
    Arm type
    Active comparator

    Investigational medicinal product name
    Enalapril Maleate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Enalapril 2.5-, 5-, 10-, and 20-mg tablets or enalapril suspension (1 mg/mL prepared from 20 mg tablet), oral administration, once daily for 36 months.

    Number of subjects in period 2 [1]
    Losartan Open Label Extension Enalapril Open Label Extension
    Started
    134
    134
    Completed
    55
    54
    Not completed
    79
    80
         Termination of trial
             45
             47
         Progressive disease
             3
             1
         Protocol deviation
             1
             -
         Physician decision
             9
             8
         Pregnancy
             -
             1
         Adverse event, non-fatal
             11
             8
         Consent withdrawn by subject
             4
             4
         Lost to follow-up
             6
             11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: After completing or discontinuing early from the DB study, participants could join an optional OL losartan versus enalapril extension. Of 306 participants who began the DB study, 268 participants continued in the extension.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Double Blind Base Study
    Reporting group description
    -

    Reporting group values
    Double Blind Base Study Total
    Number of subjects
    306 306
    Age categorical
    Units: Subjects
        ≤6 Years of Age
    75 75
        7-12 Years of Age
    114 114
        13-17 Years of Age
    117 117
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.1 ± 4.7 -
    Gender categorical
    Units: Subjects
        Female
    130 130
        Male
    176 176
    Ethnicity (NIH/OMB)
    National Institutes of Health (NIH)/Office of management and Budget (OMB) ethnic categories
    Units: Subjects
        Hispanic or Latino
    161 161
        Not Hispanic or Latino
    145 145
    Hypertensive
    Sitting systolic blood pressure (SiSBP) or diastolic blood pressure (SiDBP) ≥90th percentile AND participant on medication for proteinuria/hypertension OR SiSBP or SiDBP ≥95th percentile AND participant NOT on medication for proteinuria/hypertension OR documented hypertension and on anti-hypertensive medication, whether or not medicated for proteinuria.
    Units: Subjects
        Yes
    60 60
        No
    246 246
    Prior Angiotensin Converting Enzyme Inhibitor /Angiotensin II Type I Receptor Blocker (ACE-I/ARB)Use
    Units: Subjects
        Yes
    164 164
        No
    142 142
    Race
    Units: Subjects
        Asian
    52 52
        Black
    10 10
        Multi-Racial
    70 70
        White
    162 162
        Other
    12 12
    Region
    Units: Subjects
        United States
    25 25
        Outside of United States
    281 281
    Tanner Stage
    A scale of physical development. The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair. Stages range from I to V with I being the least developed.
    Units: Subjects
        Stage I
    147 147
        Stage II
    47 47
        Stage III
    40 40
        Stage IV
    47 47
        Stage V
    25 25
    Body Mass Index (BMI)
    Units: kilograms per meter squared (kg/m2)
        arithmetic mean (standard deviation)
    19.5 ± 4.9 -
    Duration of Hypertension
    Calculated for patients in hypertensive stratum.
    Units: years
        arithmetic mean (standard deviation)
    5.5 ± 4.5 -
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    133.9 ± 27.9 -
    Protein-to-Creatinine Ratio
    Units: grams/grams
        arithmetic mean (standard deviation)
    2.5 ± 3.3 -
    Diastolic Blood Pressure
    Units: millimeters of mercury (mm Hg)
        arithmetic mean (standard deviation)
    67.3 ± 11.2 -
    Sitting Systolic Blood Pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    106.6 ± 13.6 -
    Weight
    Units: Kilograms (kg)
        arithmetic mean (standard deviation)
    38 ± 20.3 -
    Subject analysis sets

    Subject analysis set title
    Losartan Double Blind
    Subject analysis set type
    Full analysis
    Subject analysis set description
    “Losartan Double Blind” group includes the following: Normotensive participants (1 to 17 years of age) who were randomized to losartan in the double-blind and Hypertensive participants (6 to 17 years of age) who were randomized to losartan & amlodipine placebo in the double-blind. Participants were assigned to a normotensive or hypertensive group based on clinical profile. Losartan therapy was administered orally, in tablet or suspension form, at an initial dose of approximately 0.7 mg/kg once daily (up to 50 or 100 mg total daily dose, weight-dependent).

    Subject analysis set title
    Amlodipine/Placebo Double Blind
    Subject analysis set type
    Full analysis
    Subject analysis set description
    "Amlodipine/Placebo Double Blind" group includes the following: Normotensive participants randomized to losartan placebo in the double-blind and Hypertensive participants randomized to amlodipine and losartan placebo in the double-blind. Participants were assigned to a normotensive or hypertensive group based on clinical profile. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine dispensed as suspension for duration of study. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks

    Subject analysis sets values
    Losartan Double Blind Amlodipine/Placebo Double Blind
    Number of subjects
    152
    154
    Age categorical
    Units: Subjects
        ≤6 Years of Age
    33
    42
        7-12 Years of Age
    57
    57
        13-17 Years of Age
    62
    55
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.4 ± 4.7
    9.7 ± 4.6
    Gender categorical
    Units: Subjects
        Female
    66
    64
        Male
    86
    90
    Ethnicity (NIH/OMB)
    National Institutes of Health (NIH)/Office of management and Budget (OMB) ethnic categories
    Units: Subjects
        Hispanic or Latino
    79
    82
        Not Hispanic or Latino
    73
    72
    Hypertensive
    Sitting systolic blood pressure (SiSBP) or diastolic blood pressure (SiDBP) ≥90th percentile AND participant on medication for proteinuria/hypertension OR SiSBP or SiDBP ≥95th percentile AND participant NOT on medication for proteinuria/hypertension OR documented hypertension and on anti-hypertensive medication, whether or not medicated for proteinuria.
    Units: Subjects
        Yes
    30
    30
        No
    122
    124
    Prior Angiotensin Converting Enzyme Inhibitor /Angiotensin II Type I Receptor Blocker (ACE-I/ARB)Use
    Units: Subjects
        Yes
    83
    81
        No
    69
    73
    Race
    Units: Subjects
        Asian
    26
    26
        Black
    5
    5
        Multi-Racial
    36
    34
        White
    77
    85
        Other
    8
    4
    Region
    Units: Subjects
        United States
    15
    10
        Outside of United States
    137
    144
    Tanner Stage
    A scale of physical development. The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair. Stages range from I to V with I being the least developed.
    Units: Subjects
        Stage I
    69
    78
        Stage II
    26
    21
        Stage III
    22
    18
        Stage IV
    23
    24
        Stage V
    12
    13
    Body Mass Index (BMI)
    Units: kilograms per meter squared (kg/m2)
        arithmetic mean (standard deviation)
    19.8 ± 5.5
    19.2 ± 4.2
    Duration of Hypertension
    Calculated for patients in hypertensive stratum.
    Units: years
        arithmetic mean (standard deviation)
    4.8 ± 4.1
    6.1 ± 4.8
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    135.8 ± 27.3
    132 ± 28.4
    Protein-to-Creatinine Ratio
    Units: grams/grams
        arithmetic mean (standard deviation)
    2.2 ± 2.6
    2.8 ± 3.8
    Diastolic Blood Pressure
    Units: millimeters of mercury (mm Hg)
        arithmetic mean (standard deviation)
    66.8 ± 10.7
    67.8 ± 11.6
    Sitting Systolic Blood Pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    106 ± 13.4
    107.2 ± 13.8
    Weight
    Units: Kilograms (kg)
        arithmetic mean (standard deviation)
    39.6 ± 21
    36.4 ± 19.5

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Losartan Double Blind Normotensive
    Reporting group description
    Normotensive participants who were randomized to losartan. Losartan dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

    Reporting group title
    Placebo Double Blind Normotensive
    Reporting group description
    Normotensive participants who were randomized to losartan placebo. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

    Reporting group title
    Losartan Double Blind Hypertensive
    Reporting group description
    Hypertensive patients who were randomized to receive losartan and amlodipine placebo for 12 weeks. Losartan dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Amlodipine placebo dispensed as suspension for duration of study. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks. Amlodipine placebo suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks.

    Reporting group title
    Amlodipine Double Blind Hypertensive
    Reporting group description
    Hypertensive patients who were randomized to receive amlodipine and losartan placebo for 12 weeks. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks.
    Reporting group title
    Losartan Open Label Extension
    Reporting group description
    All participants who completed the 12-week DB treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomized in a 1:1 ratio to either losartan or enalapril. Dosing of study medication during the extension phase of the study was at the investigator’s discretion. Losartan 25-mg and 50-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, losartan suspension (2.5 mg/ml) was prepared.

    Reporting group title
    Enalapril Open Label Extension
    Reporting group description
    All participants who completed the 12-week DB treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomized in a 1:1 ratio to either losartan or enalapril. Dosing of study medication during the extension phase of the study was at the investigator’s discretion. Enalapril 2.5-, 5-, 10-, and 20-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, enalapril suspension (1 mg/mL) was prepared.

    Subject analysis set title
    Losartan Double Blind
    Subject analysis set type
    Full analysis
    Subject analysis set description
    “Losartan Double Blind” group includes the following: Normotensive participants (1 to 17 years of age) who were randomized to losartan in the double-blind and Hypertensive participants (6 to 17 years of age) who were randomized to losartan & amlodipine placebo in the double-blind. Participants were assigned to a normotensive or hypertensive group based on clinical profile. Losartan therapy was administered orally, in tablet or suspension form, at an initial dose of approximately 0.7 mg/kg once daily (up to 50 or 100 mg total daily dose, weight-dependent).

    Subject analysis set title
    Amlodipine/Placebo Double Blind
    Subject analysis set type
    Full analysis
    Subject analysis set description
    "Amlodipine/Placebo Double Blind" group includes the following: Normotensive participants randomized to losartan placebo in the double-blind and Hypertensive participants randomized to amlodipine and losartan placebo in the double-blind. Participants were assigned to a normotensive or hypertensive group based on clinical profile. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine dispensed as suspension for duration of study. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks

    Primary: Double-Blind Treatment Phase: Percentage Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12

    Close Top of page
    End point title
    Double-Blind Treatment Phase: Percentage Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12
    End point description
    Change in urinary protein excretion, determined as urinary Pr/Cr ratio compared to baseline (BL), after approximately twelve weeks of treatment. BL was defined as values obtained at Visit 3, Week (-1) during the Single Blind Run-in period.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    Losartan Double Blind Amlodipine/Placebo Double Blind
    Number of subjects analysed
    150 [1]
    152 [2]
    Units: percentage change
        geometric mean (confidence interval 95%)
    -35.8 (-43.11 to -27.55)
    1.37 (-10.27 to 14.51)
    Notes
    [1] - Randomized participants who took ≥1 dose of study drug and had BL and post randomization measurement
    [2] - Randomized participants who took ≥1 dose of study drug and had BL and post randomization measurement
    Statistical analysis title
    DB Treatment:Percent Change From BL in Pr/Cr Ratio
    Statistical analysis description
    Analyzed using a mixed model for the change from BL in urinary protein excretion (on a logarithmic scale) with fixed effect terms for treatment, stratification factors, time, treatment by time interaction and BL urinary protein excretion (on log scale). A random effect for patient and an unstructured variance-covariance was used. This repeated measurements model for the change from BL in urinary protein excretion included measurements taken at Weeks 4, 8, and 12 (or early discontinuation).
    Comparison groups
    Amlodipine/Placebo Double Blind v Losartan Double Blind
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    ≤ 0.001
    Method
    Mixed models analysis
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.74
    Notes
    [3] - Primary hypothesis was addressed based on the ratio of geometric means (obtained after antilog transformation of the difference in LS-means) at week 12, with its 95% confidence interval and associated p-value. Geometric means (obtained after antilog transformation of the LS-means), along with the percent change and its 95% confidence interval in each treatment group were presented.

    Primary: Open Label Extension: Percentage Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36

    Close Top of page
    End point title
    Open Label Extension: Percentage Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36
    End point description
    Change in urinary protein excretion, determined as urinary Pr/Cr ratio compared to baseline, after approximately three years of treatment. Baseline for efficacy data in the extension was defined as the last value obtained in the double-blind treatment phase.
    End point type
    Primary
    End point timeframe
    Baseline and Month 36
    End point values
    Losartan Open Label Extension Enalapril Open Label Extension
    Number of subjects analysed
    130 [4]
    130 [5]
    Units: percentage change
        geometric mean (confidence interval 95%)
    -30.01 (-44.35 to -11.98)
    -40.45 (-52.45 to -25.42)
    Notes
    [4] - Randomized participants who took ≥1 dose of study drug and had BL and post randomization measurement
    [5] - Randomized participants who took ≥1 dose of study drug and had BL and post randomization measurement
    Statistical analysis title
    Extension: Percent Change From BL in Pr/Cr Ratio
    Statistical analysis description
    Change in urinary protein excretion (on logarithmic scale) analyzed using a mixed model with fixed-effect terms for treatment, time, treatment by time interaction, stratum, and BL urinary protein excretion (on logarithmic scale, with BL defined as the last value observed in double-blind study). A random effect for patient and an unstructured variance-covariance were used.
    Comparison groups
    Losartan Open Label Extension v Enalapril Open Label Extension
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    Method
    Mixed models analysis
    Parameter type
    Geometric Mean Ratio
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.6
    Notes
    [6] - Repeated measurements model for the change from BL in urinary protein excretion included measurements taken at months 6, 12, 18, 24, 30, and 36. Geometric means and the ratio of geometric means (obtained after antilog transformation of the difference in LS-means) with 95% confidence interval at all these time points were presented.

    Primary: Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36

    Close Top of page
    End point title
    Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36
    End point description
    GFR was measured at months 6, 12, 18, 24, 30 and 36. GFR was based on creatinine clearance (mL/min/1.73 m^2), as determined by the Schwartz formula: GFR = 0.55 x height (cm) / Serum creatinine (mg/dL) [Note: For male participants, ages 13 to 17 years, 0.70 was used as the multiplier in place of 0.55]. GFR values were compared to the baseline GFR measure. Baseline in regard to the extension was defined as the last value obtained in the double-blind treatment phase.
    End point type
    Primary
    End point timeframe
    Baseline and Month 36
    End point values
    Losartan Open Label Extension Enalapril Open Label Extension
    Number of subjects analysed
    127 [7]
    127 [8]
    Units: mL/min1.73m^2
        least squares mean (confidence interval 95%)
    3.3 (-5.2 to 11.7)
    7 (-1.4 to 15.4)
    Notes
    [7] - All participants with ≥1 study dose, 1 BL measurement and a post-randomization measurement.
    [8] - All participants with ≥1 study dose, 1 BL measurement and a post-randomization measurement.
    Statistical analysis title
    Extension: Change from BL in GFR at Month 36
    Statistical analysis description
    Change in GFR analyzed using a mixed model with fixed-effect terms for treatment, time, treatment by time interaction, stratum, and BL GFR. A random effect for participant and an unstructured variance-covariance were used. This repeated measurements model for the change from BL in GFR included measurements taken at months 6, 12, 18, 24, 30, and 36. LS-means and difference in LS-means with 95% confidence interval at all these timepoints were presented.
    Comparison groups
    Losartan Open Label Extension v Enalapril Open Label Extension
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Mixed models analysis
    Parameter type
    Difference in LS Means
    Point estimate
    -3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.2
         upper limit
    7.6

    Secondary: Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure (SBP) in Hypertensive Participants at Week 12

    Close Top of page
    End point title
    Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure (SBP) in Hypertensive Participants at Week 12 [9]
    End point description
    SBP was measured in hypertensive participants at week 4, week 8 and week 12 (or early discontinuation).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subgroup analysis was performed to study the effect of losartan and amlodipine on blood pressure in pediatric participants with proteinuria and hypertension. As a result, only the DB hypertensive arms were included in the analysis.
    End point values
    Losartan Double Blind Hypertensive Amlodipine Double Blind Hypertensive
    Number of subjects analysed
    30 [10]
    30 [11]
    Units: mm Hg
        least squares mean (confidence interval 95%)
    -5.5 (-8.6 to -2.4)
    -0.1 (-3.3 to 3.1)
    Notes
    [10] - Hypertensive participants randomized to losartan in DB and receiving ≥1 dose of study therapy.
    [11] - Hypertensive participants randomized to amlodipine in DB and receiving ≥1 dose of study therapy.
    Statistical analysis title
    Change from BL in SBP at Week 12
    Statistical analysis description
    The change from baseline in systolic blood pressure was analyzed using a mixed model similar to the primary endpoint, overall and for normotensive and hypertensive participants separately.
    Comparison groups
    Losartan Double Blind Hypertensive v Amlodipine Double Blind Hypertensive
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Mixed models analysis
    Parameter type
    Difference in LS Means
    Point estimate
    -5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.9
         upper limit
    -1

    Secondary: Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure (DBP) in Hypertensive Participants at Week 12

    Close Top of page
    End point title
    Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure (DBP) in Hypertensive Participants at Week 12 [12]
    End point description
    DBP was measured in hypertensive participants at week 4, week 8 and week 12 (or early discontinuation).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: A subgroup analysis was performed to study the effect of losartan and amlodipine on blood pressure in pediatric participants with proteinuria and hypertension. As a result, only the DB hypertensive arms were included in the analysis.
    End point values
    Losartan Double Blind Hypertensive Amlodipine Double Blind Hypertensive
    Number of subjects analysed
    30 [13]
    30 [14]
    Units: mm Hg
        least squares mean (confidence interval 95%)
    -3.8 (-7 to -0.7)
    0.8 (-2.5 to 4.1)
    Notes
    [13] - Hypertensive participants randomized to losartan in DB and receiving ≥1 dose of study therapy.
    [14] - Hypertensive participants randomized to amlodipine in DB and receiving ≥1 dose of study therapy.
    Statistical analysis title
    Change from BL in DBP at Week 12
    Statistical analysis description
    The change from baseline in diastolic blood pressure was analyzed using a mixed model similar to the primary endpoint, overall and for normotensive and hypertensive participants separately.
    Comparison groups
    Losartan Double Blind Hypertensive v Amlodipine Double Blind Hypertensive
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Mixed models analysis
    Parameter type
    Difference in LS Means
    Point estimate
    -4.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    -0.1

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Double-blind base study: From Day 1 through Week 14 (double-blind treatment phase plus post-study visit) Open-Label Extension: From end of DB (Week 12) up to 36 months
    Adverse event reporting additional description
    All Subjects as Treated, Base and Extension Combined
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Losartan: Double-Blind Base Study
    Reporting group description
    “Losartan Double Blind” group includes the following: Normotensive participants (1 to 17 years of age) who were randomized to losartan in the double-blind and Hypertensive participants (6 to 17 years of age) who were randomized to losartan & amlodipine placebo in the double-blind. Participants were assigned to a normotensive or hypertensive group based on clinical profile. Losartan therapy was administered orally, in tablet or suspension form, at an initial dose of approximately 0.7 mg/kg once daily (up to 50 or 100 mg total daily dose, weight-dependent).

    Reporting group title
    Amlodipine/Placebo: Double-Blind Base Study
    Reporting group description
    "Amlodipine/Placebo Double Blind" group includes the following: Normotensive participants randomized to losartan placebo in the double-blind and Hypertensive participants randomized to amlodipine and losartan placebo in the double-blind. Participants were assigned to a normotensive or hypertensive group based on clinical profile. Losartan placebo dispensed as tablets or suspension depending on participant weight and ability to swallow tablets. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine dispensed as suspension for duration of study. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks

    Reporting group title
    Losartan: Open-Label Extension
    Reporting group description
    All participants who completed the 12-week DB treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomized in a 1:1 ratio to either losartan or enalapril. Dosing of study medication during the extension phase of the study was at the investigator’s discretion. Losartan 25-mg and 50-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, losartan suspension (2.5 mg/ml) was prepared.

    Reporting group title
    Enalapril: Open-Label Extension
    Reporting group description
    All participants who completed the 12-week DB treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomized in a 1:1 ratio to either losartan or enalapril. Dosing of study medication during the extension phase of the study was at the investigator’s discretion. Enalapril 2.5-, 5-, 10-, and 20-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, enalapril suspension (1 mg/mL) was prepared.

    Serious adverse events
    Losartan: Double-Blind Base Study Amlodipine/Placebo: Double-Blind Base Study Losartan: Open-Label Extension Enalapril: Open-Label Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 152 (5.26%)
    5 / 154 (3.25%)
    27 / 134 (20.15%)
    25 / 134 (18.66%)
         number of deaths (all causes)
    0
    0
    3
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Hypovolaemic shock
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Lipoma
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    0 / 134 (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
    Lymphoma
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    0 / 134 (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
    Metastases to lung
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    0 / 134 (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
    Metastasis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Psychiatric disorders
    Somatoform disorder neurologic
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Humerus fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Lower limb fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Overdose
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Radius fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Ulna fracture
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Congenital, familial and genetic disorders
    Lipomeningocele
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Renal hypoplasia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Epistaxis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Leukopenia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    2 / 134 (1.49%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Aphasia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Convulsion
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Intracranial pressure increased
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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 / 1
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Diarrhoea
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Ileus
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Renal and urinary disorders
    Glomerulonephritis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Glomerulonephritis membranoproliferative
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Haematuria
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    2 / 134 (1.49%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    0 / 134 (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
    Lupus nephritis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Nephrotic syndrome
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Proteinuria
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 154 (0.65%)
    1 / 134 (0.75%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Renal failure acute
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    3 / 134 (2.24%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    2 / 134 (1.49%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Erythema
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Rash
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 154 (0.65%)
    0 / 134 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Pain in extremity
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Obesity
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Bronchitis
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 154 (0.65%)
    0 / 134 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Herpangina
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Nasopharyngitis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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
    Peritonitis bacterial
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    0 / 134 (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
    Pneumonia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    2 / 134 (1.49%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    3 / 134 (2.24%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Respiratory tract infection
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    1 / 134 (0.75%)
         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
    Sepsis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    0 / 134 (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 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    1 / 134 (0.75%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 152 (0.00%)
    2 / 154 (1.30%)
    2 / 134 (1.49%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    0 / 134 (0.00%)
    0 / 134 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Losartan: Double-Blind Base Study Amlodipine/Placebo: Double-Blind Base Study Losartan: Open-Label Extension Enalapril: Open-Label Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 152 (46.71%)
    66 / 154 (42.86%)
    83 / 134 (61.94%)
    78 / 134 (58.21%)
    Investigations
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    8 / 134 (5.97%)
    6 / 134 (4.48%)
         occurrences all number
    0
    0
    10
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 152 (3.29%)
    6 / 154 (3.90%)
    8 / 134 (5.97%)
    11 / 134 (8.21%)
         occurrences all number
    6
    8
    9
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 154 (0.00%)
    11 / 134 (8.21%)
    8 / 134 (5.97%)
         occurrences all number
    0
    0
    12
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 152 (3.95%)
    3 / 154 (1.95%)
    3 / 134 (2.24%)
    7 / 134 (5.22%)
         occurrences all number
    6
    3
    3
    10
    Headache
         subjects affected / exposed
    13 / 152 (8.55%)
    20 / 154 (12.99%)
    7 / 134 (5.22%)
    12 / 134 (8.96%)
         occurrences all number
    24
    31
    19
    23
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 152 (3.95%)
    2 / 154 (1.30%)
    8 / 134 (5.97%)
    7 / 134 (5.22%)
         occurrences all number
    6
    2
    10
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 152 (5.26%)
    7 / 154 (4.55%)
    12 / 134 (8.96%)
    7 / 134 (5.22%)
         occurrences all number
    10
    7
    15
    9
    Vomiting
         subjects affected / exposed
    6 / 152 (3.95%)
    4 / 154 (2.60%)
    16 / 134 (11.94%)
    4 / 134 (2.99%)
         occurrences all number
    8
    4
    22
    4
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 154 (0.65%)
    8 / 134 (5.97%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    9
    3
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 154 (0.00%)
    4 / 134 (2.99%)
    9 / 134 (6.72%)
         occurrences all number
    1
    0
    5
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 152 (5.92%)
    8 / 154 (5.19%)
    9 / 134 (6.72%)
    9 / 134 (6.72%)
         occurrences all number
    10
    8
    13
    10
    Gastroenteritis
         subjects affected / exposed
    3 / 152 (1.97%)
    3 / 154 (1.95%)
    9 / 134 (6.72%)
    6 / 134 (4.48%)
         occurrences all number
    3
    3
    15
    10
    Influenza
         subjects affected / exposed
    2 / 152 (1.32%)
    1 / 154 (0.65%)
    3 / 134 (2.24%)
    7 / 134 (5.22%)
         occurrences all number
    2
    1
    4
    9
    Nasopharyngitis
         subjects affected / exposed
    24 / 152 (15.79%)
    19 / 154 (12.34%)
    31 / 134 (23.13%)
    20 / 134 (14.93%)
         occurrences all number
    28
    22
    40
    28
    Pharyngitis
         subjects affected / exposed
    6 / 152 (3.95%)
    6 / 154 (3.90%)
    21 / 134 (15.67%)
    20 / 134 (14.93%)
         occurrences all number
    6
    7
    43
    31
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 154 (0.65%)
    8 / 134 (5.97%)
    6 / 134 (4.48%)
         occurrences all number
    0
    1
    11
    6
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 152 (4.61%)
    9 / 154 (5.84%)
    15 / 134 (11.19%)
    9 / 134 (6.72%)
         occurrences all number
    8
    13
    50
    20
    Urinary tract infection
         subjects affected / exposed
    2 / 152 (1.32%)
    3 / 154 (1.95%)
    10 / 134 (7.46%)
    10 / 134 (7.46%)
         occurrences all number
    2
    3
    14
    15

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2007
    Protocol Amendment 1 (-01) added a provision to the protocol by which an investigator could discontinue a patient early (e.g., after Week 4 or 8) from the double-blind portion of the study based on the patient’s urine protein-to-creatinine ratio and the investigator’s judgment and knowledge of the patient. The patient was then able to directly enter the 2-year, randomized, open-label, enalapril versus losartan extension.
    14 Apr 2008
    Extension Amendment 1 (-11) added a provision to the protocol that the extension (originally 2 years for all patients who entered) would continue until 100 patients completed 3 years of follow-up, resulting in patients participating in the extension for varying durations based upon the time of their enrollment.
    29 Apr 2009
    Extension Amendment 2 (-12) indicated that a new excipient (Sodium Citrate and Citric Acid Oral Solution USP) would be used in place of Bicitra™ for preparation of the enalapril suspension formulation. This change was necessary because the manufacturer of Bicitra™ discontinued production. After Bicitra™ was used or expired (whichever came first), sites began using Sodium Citrate and Citric Acid Oral Solution USP.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2019 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA