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    Clinical Trial Results:
    An extension to study protocol CVAL489K2302 to evaluate the long term safety, tolerability and efficacy of valsartan children 6 to 17 years of age with hypertension, versus enalapril treatment for 14 weeks, or combined with enalapril for 66 weeks in chronic kidney disease patients.

    Summary
    EudraCT number
    		 2006-005408-14
    Trial protocol
    		 BE   DE   GB   HU   FR   SE   CZ   IT  
    Global end of trial date
    22 Jun 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    02 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CVAL489K2302E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00446511
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jun 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2009
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the long-term safety and tolerability of valsartan and enalapril alone or in combination in children aged 6-17 years old with hypertension and stratified on the basis of underlying chronic kidney disease (CKD).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 Enalapril, an angiotensin-converting-enzyme (ACE) inhibitor, is approved in most European Union (EU) countries for the treatment of hypertension in children aged 2 months – 16 years based on its well-established pharmacokinetics, and on efficacy and safety data in 6 – 16 year old children. Enalapril was used as an active-comparator in this study as it is also dosed once daily, similar to experimental study treatment - valsartan.
    Actual start date of recruitment
    28 Jun 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 83
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 62
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    India: 25
    Country: Number of subjects enrolled
    Turkey: 12
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    250
    EEA total number of subjects
    182
    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)
    72
    Adolescents (12-17 years)
    178
    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
    		 The study was conducted at 50 centres in 9 countries.

    Pre-assignment
    Screening details
    		 A total of 250 subjects were enrolled in the study, and were stratified on basis of underlying chronic kidney disease (CKD) i.e. 38 CKD and 212 non-CKD subjects.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    The identity of the treatments was concealed by the use of study drugs that were all identical in packaging, labeling and schedule. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Valsartan+Enalapril (CKD Stratum)
    Arm description
    		 Subjects with underlying chronic kidney disease (CKD), assigned to valsartan in the core study received combination therapy of valsartan and enalapril in the extension phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valsartan+Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Weight stratified dose of combination therapy of valsartan + enalapril (80/10, 160/20, 320/40 mg) administered orally once daily (OD) at approximately the same time each day, with or without food. Subjects whose body weight was greater than (≥ ) 18 kilogram (kg) and less than (<) 35 kg received valsartan/enalapril 80/10 mg; ≥ 35 kg and < 80 kg received valsartan/enalapril 160/20 mg and ≥ 80 kg and less than or equal to (≤) 160 kg received valsartan/enalapril 320/40 mg.

    Arm title
    		 Enalapril + Placebo (CKD Stratum)
    Arm description
    		 Subjects with CKD who were assigned to enalapril in the core study received enalapril and placebo (matching to valsartan tablet) in the extension phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Weight stratified dose of enalapril (10, 20, 40 mg) was administered OD at approximately the same time each day, with or without food. Subjects whose body weight was ≥ 18 kg and < 35 kg received 10 mg; ≥ 35 kg and < 80 kg received 20 mg, and ≥ 80 kg and ≤ 160 kg received 40 mg of enalapril.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets (matching to valsartan) was administered OD at approximately the same time each day, with or without food. Subjects whose body weight was ≥ 18 kg and < 35 kg received 80 mg; ≥ 35 kg and < 80 kg received 160 mg, and ≥ 80 kg and ≤ 160 kg received 320 mg of placebo (matching to valsartan tablet).

    Arm title
    		 Valsartan + Placebo (Non-CKD Stratum)
    Arm description
    		 Subjects without CKD who were assigned to valsartan in the core study continued their valsartan monotherapy treatment along with matching placebo to enalapril tablets in the extension phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    VAL489
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Weight stratified dose of valsartan (80, 160, 320 mg) administered OD at approximately the same time each day, with or without food. Subjects whose body weight was greater than (≥ ) 18 kilogram (kg) and less than (<) 35 kg received 80 mg; ≥ 35 kg and < 80 kg received 160 mg and ≥ 80 kg and less than or equal to (≤) 160 kg received 320 mg of valsartan.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets (matching to enalapril) was administered OD at approximately the same time each day, with or without food. Subjects whose body weight was greater than (≥ ) 18 kilogram (kg) and less than (<) 35 kg received 10 mg; ≥ 35 kg and < 80 kg received 20 mg and ≥ 80 kg and less than or equal to (≤) 160 kg received 40 mg of matching placebo to enalapril tablet.

    Arm title
    		 Enalapril + Placebo (Non-CKD Stratum)
    Arm description
    		 Subjects without CKD who were assigned to enalapril in the core study continued their enalapril monotherapy treatment with matching placebo to valsartan tablets in the extension phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Weight stratified dose of enalapril (10, 20, 40 mg) administered OD at approximately the same time each day, with or without food. Subjects whose body weight was ≥ 18 kg and < 35 kg received 10 mg; ≥ 35 kg and < 80 kg received 20 mg, and ≥ 80 kg and ≤ 160 kg received 40 mg of enalapril.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets (matching to valsartan) was administered OD at approximately the same time each day, with or without food. Subjects whose body weight was ≥ 18 kg and < 35 kg received 80 mg; ≥ 35 kg and < 80 kg received 160 mg, and ≥ 80 kg and ≤ 160 kg received 320 mg of matching placebo to valsartan.

    Number of subjects in period 1
    		Valsartan+Enalapril (CKD Stratum) Enalapril + Placebo (CKD Stratum) Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum)
    Started
    21
    17
    103
    109
    Completed
    11
    15
    96
    103
    Not completed
    10
    2
    7
    6
         Consent withdrawn by subject
    -
    -
    -
    3
         Adverse event, non-fatal
    7
    2
    3
    1
         Administrative Problems
    3
    -
    4
    1
         Protocol deviation
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Valsartan+Enalapril (CKD Stratum)
    Reporting group description
    		 Subjects with underlying chronic kidney disease (CKD), assigned to valsartan in the core study received combination therapy of valsartan and enalapril in the extension phase.

    Reporting group title
    Enalapril + Placebo (CKD Stratum)
    Reporting group description
    		 Subjects with CKD who were assigned to enalapril in the core study received enalapril and placebo (matching to valsartan tablet) in the extension phase.

    Reporting group title
    Valsartan + Placebo (Non-CKD Stratum)
    Reporting group description
    		 Subjects without CKD who were assigned to valsartan in the core study continued their valsartan monotherapy treatment along with matching placebo to enalapril tablets in the extension phase.

    Reporting group title
    Enalapril + Placebo (Non-CKD Stratum)
    Reporting group description
    		 Subjects without CKD who were assigned to enalapril in the core study continued their enalapril monotherapy treatment with matching placebo to valsartan tablets in the extension phase.

    Reporting group values
    		 Valsartan+Enalapril (CKD Stratum) Enalapril + Placebo (CKD Stratum) Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum) Total
    Number of subjects
    		 21 17 103 109 250
    Age categorical
    Units: Subjects
        Children (6-12 years)
    		 12 8 42 34 96
        Adolescents (13-17 years)
    		 9 9 61 75 154
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.4 ( 3.4 ) 12.1 ( 3.07 ) 13.1 ( 2.75 ) 13.3 ( 2.81 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 41 27 81
        Male
    		 13 12 62 82 169

    End points

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    End points reporting groups
    Reporting group title
    Valsartan+Enalapril (CKD Stratum)
    Reporting group description
    		 Subjects with underlying chronic kidney disease (CKD), assigned to valsartan in the core study received combination therapy of valsartan and enalapril in the extension phase.

    Reporting group title
    Enalapril + Placebo (CKD Stratum)
    Reporting group description
    		 Subjects with CKD who were assigned to enalapril in the core study received enalapril and placebo (matching to valsartan tablet) in the extension phase.

    Reporting group title
    Valsartan + Placebo (Non-CKD Stratum)
    Reporting group description
    		 Subjects without CKD who were assigned to valsartan in the core study continued their valsartan monotherapy treatment along with matching placebo to enalapril tablets in the extension phase.

    Reporting group title
    Enalapril + Placebo (Non-CKD Stratum)
    Reporting group description
    		 Subjects without CKD who were assigned to enalapril in the core study continued their enalapril monotherapy treatment with matching placebo to valsartan tablets in the extension phase.

    Primary: Number of subjects with adverse events (AEs), serious adverse events (SAEs)

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    End point title
    		 Number of subjects with adverse events (AEs), serious adverse events (SAEs) [1]
    End point description
    An AE was defined as any undesirable sign, symptom or medical condition occurring after starting study drug (i.e. valsartan, enalapril or placebo) even if the event was not considered to be related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalisation, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the subject or require medical or surgical intervention to prevent one of the aforementioned outcomes.
    End point type
    Primary
    End point timeframe
    From Week 13 (start of extension phase) to end of extension phase (Week 26 in non-CKD subjects and Week 50 in CKD subjects)
    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: Only descriptive summary statistics was planned for this outcome measure
    End point values
    		 Valsartan+Enalapril (CKD Stratum) Enalapril + Placebo (CKD Stratum) Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum)
    Number of subjects analysed
    21
    17
    103
    109
    Units: Number of subjects
    number (not applicable)
        AEs
    16
    11
    51
    53
        SAEs
    7
    0
    1
    2
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) in non-CKD stratum at Week 26

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    End point title
    		 Change from Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) in non-CKD stratum at Week 26 [2]
    End point description
    Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sitting systolic blood pressure (SSBP) measurements were used as the average sitting office blood pressure for that visit. Analysis was performed in non-CKD stratum of extension Intent-to-Treat (ITT) population, defined as all extension subjects who had at least one post-Week 12 assessment of any efficacy variable during the extension.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    Notes
    [2] - 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: This endpoint was planned to evaluate treatment arms in non-CKD subjects only.
    End point values
    		 Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum)
    Number of subjects analysed
    103
    108
    Units: mmHg
        arithmetic mean (standard deviation)
    -11.6 ( 9.74 )
    -10.2 ( 9.7 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) in non-CKD stratum at Week 26

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    End point title
    		 Change from Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) in non-CKD stratum at Week 26 [3]
    End point description
    Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sitting diastolic blood pressure (SDBP) measurements were used as the average sitting office blood pressure for that visit. Analysis was performed in non-CKD stratum of extension ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    Notes
    [3] - 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: This endpoint was planned to evaluate treatment arms in non-CKD subjects only.
    End point values
    		 Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum)
    Number of subjects analysed
    103
    108
    Units: mmHg
        arithmetic mean (standard deviation)
    -7.5 ( 8.47 )
    -7.2 ( 8.99 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects in non-CKD stratum achieving systolic and diastolic blood pressure (BP) control

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    End point title
    		 Percentage of subjects in non-CKD stratum achieving systolic and diastolic blood pressure (BP) control [4]
    End point description
    Treatment response or BP control (systolic and diastolic) was defined as 'Yes' for subjects whose MSSBP and MSDBP decreased to <95th percentile for gender, age, and height after 12 weeks treatment with valsartan compared to enalapril. Analysis was performed in non-CKD stratum of extension ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    Notes
    [4] - 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: This endpoint was planned to evaluate treatment arms in non-CKD subjects only.
    End point values
    		 Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum)
    Number of subjects analysed
    103
    108
    Units: Percentage of subjects
    number (not applicable)
        Systolic Responders
    66
    63
        Diastolic Responders
    95.1
    91.7
    No statistical analyses for this end point

    Secondary: Change from baseline in post-dosing 24-hour mean ambulatory systolic and diastolic blood pressure (ASBP, ADBP) at Week 20

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    End point title
    		 Change from baseline in post-dosing 24-hour mean ambulatory systolic and diastolic blood pressure (ASBP, ADBP) at Week 20
    End point description
    Ambulatory Blood Pressure Monitoring (ABPM) was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. The subjects who were selected for this evaluation wore the ABPM device for 24 hours, returned to the clinic upon completion of the 24- hour monitoring period for removal of device and BP assessments. The subjects were then administered with the study medication while in the clinic. Analysis was performed in ABPM set defined as subset of extension ITT subjects from selected centres who consented to undergo ABPM at baseline and at Week 20. Here, 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 20
    End point values
    		 Valsartan+Enalapril (CKD Stratum) Enalapril + Placebo (CKD Stratum) Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum)
    Number of subjects analysed
    5
    2
    14
    23
    Units: mmHg
    arithmetic mean (standard deviation)
        Change in ASBP (n=5,2,10,21)
    -23.3 ( 11.6 )
    -0.3 ( 14.42 )
    -11.5 ( 7.81 )
    -4.1 ( 11.49 )
        Change in ADBP (n=5,2,10,21)
    -17.8 ( 3.2 )
    2.9 ( 10.81 )
    -12.2 ( 6.6 )
    -4.5 ( 7.59 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Valsartan + Enalapril (CKD patients)
    Reporting group description
    		 Subjects with underlying chronic kidney disease (CKD), assigned to valsartan in the core study received combination therapy of valsartan and enalapril in the extension phase.

    Reporting group title
    Valsartan + Placebo (Non-CKD Stratum)
    Reporting group description
    		 Subjects without CKD who were assigned to valsartan in the core study continued their valsartan monotherapy treatment along with matching placebo to enalapril tablets in the extension phase.

    Reporting group title
    Enalapril + Placebo (Non-CKD Stratum)
    Reporting group description
    		 Subjects without CKD who were assigned to enalapril in the core study continued their enalapril monotherapy treatment with matching placebo to valsartan tablets in the extension phase.

    Reporting group title
    Enalapril + Placebo (CKD patients)
    Reporting group description
    		 Subjects with CKD who were assigned to enalapril in the core study received enalapril and placebo (matching to valsartan tablet) in the extension phase.

    Serious adverse events
    		 Valsartan + Enalapril (CKD patients) Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum) Enalapril + Placebo (CKD patients)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 21 (33.33%)
    1 / 103 (0.97%)
    2 / 109 (1.83%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (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
    Congenital, familial and genetic disorders
    Adrenogenital syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 103 (0.97%)
    0 / 109 (0.00%)
    0 / 17 (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
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 103 (0.00%)
    1 / 109 (0.92%)
    0 / 17 (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
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (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
    Musculoskeletal and connective tissue disorders
    Synostosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (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
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 103 (0.00%)
    1 / 109 (0.92%)
    0 / 17 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (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
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    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
    		 Valsartan + Enalapril (CKD patients) Valsartan + Placebo (Non-CKD Stratum) Enalapril + Placebo (Non-CKD Stratum) Enalapril + Placebo (CKD patients)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 21 (66.67%)
    25 / 103 (24.27%)
    42 / 109 (38.53%)
    11 / 17 (64.71%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 103 (0.97%)
    1 / 109 (0.92%)
    0 / 17 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Epilepsy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 103 (0.00%)
    0 / 109 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    4 / 21 (19.05%)
    11 / 103 (10.68%)
    16 / 109 (14.68%)
    1 / 17 (5.88%)
         occurrences all number
    4
    12
    22
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 21 (14.29%)
    5 / 103 (4.85%)
    4 / 109 (3.67%)
    0 / 17 (0.00%)
         occurrences all number
    3
    5
    4
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 103 (1.94%)
    4 / 109 (3.67%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    4
    1
    Nausea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 103 (0.00%)
    2 / 109 (1.83%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    1
    Vomiting
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 103 (0.00%)
    3 / 109 (2.75%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 103 (1.94%)
    1 / 109 (0.92%)
    2 / 17 (11.76%)
         occurrences all number
    1
    2
    1
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 103 (0.97%)
    0 / 109 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 21 (0.00%)
    6 / 103 (5.83%)
    9 / 109 (8.26%)
    1 / 17 (5.88%)
         occurrences all number
    0
    6
    9
    1
    Pharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 103 (6.80%)
    11 / 109 (10.09%)
    2 / 17 (11.76%)
         occurrences all number
    3
    7
    14
    2
    Sinusitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 103 (0.97%)
    0 / 109 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 103 (0.97%)
    2 / 109 (1.83%)
    1 / 17 (5.88%)
         occurrences all number
    2
    2
    4
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 103 (0.00%)
    3 / 109 (2.75%)
    2 / 17 (11.76%)
         occurrences all number
    4
    0
    3
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 103 (0.97%)
    0 / 109 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2007
    • The timing of the 24-hour ABPM was moved from Week 26 (Visit 11) to Week 20 (Visit 10). • Matching placebo was added to the doses of non-CKD patients. • The dose form was corrected to state that study medication would be provided in blister packs instead of bottles. • The reasons for discontinuation were clarified. • A statement was added to inform investigators that unscheduled visits could be conducted at their discretion. • Instructions were added to contact the IVRS whenever patients were prematurely discontinued. • The visit schedule was revised, removing the requirement for patients to be fasting before laboratory evaluations, and adding that CKD patients had to have a specimen drawn for hematology tests at Week 16 (Visit 9). • Instructions regarding the collection and reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) were added. • The calculation for GFR was clarified, deleting the formula for creatinine clearance, and adding the formula for calculating GFR. • A statement was added to the laboratory evaluations section to allow for additional testing in the event of clinically significant abnormalities.
    30 Sep 2008
    The 52 weeks prolongation of study was for CKD patients only and for a total of approximately 18 months, focusing on change in GFR and proteinuria. The protocol title and relevant sections were updated for CKD subjects. An independent External Safety Monitoring Committee (ESMC) was added to enhance the monitoring of liver function, renal function and serum potassium alerts in all subjects. However, after CKD patients completed the initial 14 week extension period, only 3 of these patients were eligible to continue into the 52 week “long term” CKD extension. As no meaningful conclusions could be drawn owing to small patient numbers, the study was terminated prematurely with these 3 CKD patients progressing to a maximum of Visit 13.

    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 study intended to compare the valsartan+enalapril vs enalapril for 66 weeks in children with CKD. The 66 week assessment of CKD subjects was terminated earlier (Week 50) in agreement with EMEA due to small number of analysable subjects.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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