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    Clinical Trial Results:
    Randomized multicentre pilot study of sacubitril/valsartan (formerly known as LCZ696) versus irbesartan in patients with chronic kidney disease: UK Heart and Renal Protection (HARP)-III

    Summary
    EudraCT number
    		 2013-004205-89
    Trial protocol
    		 GB  
    Global end of trial date
    02 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2018
    First version publication date
    11 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTSUHARP3
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11958993
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Block 60, Churchill Hospital, Old Road, Oxford, United Kingdom, OX3 7LE
    Public contact
    Richard Haynes, Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, 01865 743743, richard.haynes@ndph.ox.ac.uk
    Scientific contact
    Richard Haynes, Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, 01865 743743, richard.haynes@ndph.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of UK HARP-III is to compare the short-term (i.e. over 12 months) effect on kidney function of sacubitril/valsartan (formerly known as LCZ696) with that of irbesartan (a current standard treatment for chronic kidney disease).
    Protection of trial subjects
    At every study visit, participants were asked about any serious adverse events, or non-serious adverse events that they believed to be related to study treatment. If a SAE was believed to be related to study treatment it was discussed immediately with a clinician working at the coordinating centre to ensure appropriate action was taken. At every visit blood and urine samples were taken for analysis in the local laboratory to check kidney function, electrolytes and liver function. Any abnormalities were followed-up and investigated as required. Participants were also given a 24 hour freefone telephone number so they (or any doctor looking after them) could contact a clinician working at the coordinating centre.
    Background therapy
    		 None
    Evidence for comparator
    		 Sacubitril/valsartan (the experimental drug) has properties that could reduce both renal progression and cardiovascular disease. Neprilysin (also known as neutral endopeptidase) degrades natriuretic and other vasodilatory peptides and therefore neprilysin inhibition increases concentrations of these peptides and can lower blood pressure (in combination with ACEi or ARB). Omapatrilat inhibited neprilysin but caused unacceptable angioedema when combined with ACEi. However, some data suggested it was renoprotective. Sacubitril/valsartan is a first-in-class ARNI (angiotensin receptor-neprilysin inhibitor) which has been shown to safely reduce cardiovascular mortality in patients with heart failure. The anti-fibrotic and anti-inflammatory effects of sacubitril/valsartan may be beneficial both in terms of reducing renal progression and reducing CVD events. Treatment with renin-angiotensin blockade (either ACE inhibitor or angiotensin receptor blocker) is standard of care for patients with proteinuric nephropathy (with or without diabetes) and irbesartan was selected as the comparator for this reason.
    Actual start date of recruitment
    15 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 414
    Worldwide total number of subjects
    414
    EEA total number of subjects
    414
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    205
    From 65 to 84 years
    203
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 620 participants attended a screening visit after which 566 entered the run-in period and subsequently 414 were randomized between November 2014 and March 2016.

    Pre-assignment
    Screening details
    		 Prior to randomization eligible participants entered a pre-randomization run-in period. They were instructed to stop any previous ACEi or ARB therapy to allow “wash out” and were provided with placebo sacubitril/valsartan (1 tablet daily) and placebo irbesartan (1 tablet daily) to take during the run-in period.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sacubitril/valsartan
    Arm description
    		 Experimental drug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sacubitril/valsartan
    Investigational medicinal product code
    Other name
    LCZ696
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sacubitril/valsartan (initially 200 mg once daily titrated to 200 mg twice daily after 2 weeks) and placebo irbesartan (one tablet once daily, titrated to two tablets once daily after 2 weeks)

    Arm title
    		 Irbesartan
    Arm description
    		 Active comparator
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Irbesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Irbesartan (initially one 150 mg tablet once daily, titrated to two 150 mg tablets once daily after 2 weeks) and placebo sacubitril/valsartan (one tablet once daily, titrated to one tablet twice daily after 2 weeks)

    Number of subjects in period 1
    		Sacubitril/valsartan Irbesartan
    Started
    207
    207
    Completed
    197
    199
    Not completed
    10
    8
         Consent withdrawn by subject
    8
    8
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sacubitril/valsartan
    Reporting group description
    		 Experimental drug

    Reporting group title
    Irbesartan
    Reporting group description
    		 Active comparator

    Reporting group values
    		 Sacubitril/valsartan Irbesartan Total
    Number of subjects
    		 207 207 414
    Age categorical
    Age at randomisation (years)
    Units: Subjects
        <50
    		 37 36 73
        ≥50 to <70
    		 97 99 196
        ≥70
    		 73 72 145
    Age continuous
    Age at randomisation (years)
    Units: years
        arithmetic mean (standard deviation)
    		 62.0 ± 14.1 63.6 ± 13.4 -
    Gender categorical
    Units: Subjects
        Female
    		 59 57 116
        Male
    		 148 150 298
    Ethnicity
    Units: Subjects
        White
    		 186 191 377
        Black
    		 3 4 7
        South Asian
    		 11 7 18
        Other
    		 7 5 12
    Systolic blood pressure (mmHg)
    Units: Subjects
        <140
    		 76 85 161
        ≥140 to <160
    		 93 84 177
        ≥160
    		 38 38 76
    Diastolic blood pressure (mmHg)
    Units: Subjects
        <80
    		 96 105 201
        ≥80 to <90
    		 68 58 126
        ≥90
    		 43 44 87
    Body-mass index (kg/m²)
    Units: Subjects
        <25
    		 35 33 68
        ≥25 to <30
    		 74 73 147
        ≥30
    		 95 100 195
        Not available
    		 3 1 4
    CKD-EPI eGFR (mL/min/1.73m²)
    CKD-EPI estimated glomerular filtration rate at randomisation
    Units: Subjects
        <30
    		 79 77 156
        ≥30 to <45
    		 86 91 177
        ≥45
    		 41 39 80
        Not available
    		 1 0 1
    Urine albumin:creatinine ratio (mg/mmol)
    Units: Subjects
        <3
    		 30 28 58
        ≥3 to <30
    		 43 45 88
        ≥30
    		 134 134 268
    Use of RAS blockade at screening visit
    Units: Subjects
        Yes
    		 173 166 339
        No
    		 34 41 75
    Cause of kidney disease
    *Other known causes and Unknown are all considered 'Miscellaneous renal disorders' by the ERA-EDTA registry
    Units: Subjects
        Glomerular disease
    		 60 51 111
        Tubulointerstitial disease
    		 18 32 50
        Diabetic kidney disease
    		 36 47 83
        Hypertensive/renovascular disease
    		 18 24 42
        Other systemic diseases affecting the kidneys
    		 1 2 3
        Familial/hereditary nephropathies
    		 30 13 43
        Other known causes*
    		 5 4 9
        Unknown*
    		 39 34 73
    Systolic blood pressure (mmHg)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 146 ± 16 146 ± 16 -
    Diastolic blood pressure (mmHg)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 81 ± 11 80 ± 11 -
    Body mass index (kg/m²)
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 30 ± 6 31 ± 6 -
    CKD-EPI eGFR (mL/min/1.73m²)
    CKD-EPI estimated glomerular filtration rate at randomisation
    Units: mL/min/1.73m²
        arithmetic mean (standard deviation)
    		 35.4 ± 11.0 35.5 ± 11.0 -
    24 hour urinary sodium excretion during run-in (mg/24 hours)
    Units: mg/24 hours
        median (inter-quartile range (Q1-Q3))
    		 2484 (1794 to 3795) 2875 (1932 to 4232) -
    Urine albumin:creatinine ratio (mg/mmol)
    Units: mg/mmol
        median (inter-quartile range (Q1-Q3))
    		 52 (11 to 162) 56 (11 to 146) -

    End points

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    End points reporting groups
    Reporting group title
    Sacubitril/valsartan
    Reporting group description
    		 Experimental drug

    Reporting group title
    Irbesartan
    Reporting group description
    		 Active comparator

    Primary: Mean mGFR at 12-months

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    End point title
    		 Mean mGFR at 12-months
    End point description
    The primary outcome is mean measured glomerular filtration rate (mGFR; adjusted for body-surface area) at 12 months. Glomerular filtration rate (GFR) was measured using a standard Cr-EDTA technique, although if this was not available at the site, other methods (99mTc-DTPA or iohexol) could be used with the agreement of the coordinating centre.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
        arithmetic mean (standard error)
    29.8 ± 0.5
    29.9 ± 0.5
    Statistical analysis title
    		 Mean mGFR at 12-months
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.86
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by age

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    End point title
    		 Mean mGFR at 12-months by age
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤60 years
    29.9 ± 0.8
    29.5 ± 0.8
        >60 years
    29.7 ± 0.6
    30.2 ± 0.6
    Statistical analysis title
    		 Mean mGFR at 12-months by age
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12 months by gender

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    End point title
    		 Mean mGFR at 12 months by gender
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        Female
    30.3 ± 0.9
    29.5 ± 0.9
        Male
    29.6 ± 0.5
    30.1 ± 0.5
    Statistical analysis title
    		 Mean mGFR at 12 months by gender
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by history of diabetes

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    End point title
    		 Mean mGFR at 12-months by history of diabetes
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        Prior diabetes - Yes
    29.2 ± 0.8
    29.1 ± 0.7
        Prior diabetes - No
    30.2 ± 0.6
    30.5 ± 0.6
    Statistical analysis title
    		 Mean mGFR at 12-months by history of diabetes
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.76
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by history of vascular disease

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    End point title
    		 Mean mGFR at 12-months by history of vascular disease
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        Prior vascular disease - Yes
    29.0 ± 1.0
    29.6 ± 0.8
        Prior vascular disease - No
    30.1 ± 0.5
    30.1 ± 0.5
    Statistical analysis title
    		 Mean mGFR at 12-months by prior vascular disease
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.69
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by systolic blood pressure

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    End point title
    		 Mean mGFR at 12-months by systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤140 mmHg
    30.5 ± 0.8
    30.9 ± 0.7
        >140mmHg
    29.4 ± 0.6
    29.3 ± 0.6
    Statistical analysis title
    		 Mean mGFR at 12-months by systolic blood pressure
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.69
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by diastolic blood pressure

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    End point title
    		 Mean mGFR at 12-months by diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤80 mmHg
    29.1 ± 0.7
    30.0 ± 0.6
        >80 mmHg
    30.5 ± 0.6
    29.8 ± 0.7
    Statistical analysis title
    		 Mean mGFR at 12-months by diastolic blood pressure
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.26
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by body mass index

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    End point title
    		 Mean mGFR at 12-months by body mass index
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤30 kg/m²
    30.1 ± 0.6
    30.2 ± 0.6
        >30 kg/m²
    29.8 ± 0.7
    29.9 ± 0.7
    Statistical analysis title
    		 Mean mGFR at 12-months by body mass index
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.99
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by baseline mGFR

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    End point title
    		 Mean mGFR at 12-months by baseline mGFR
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤30 mL/min/1.73m²
    22.4 ± 0.7
    22.0 ± 0.7
        >30 mL/min/1.73m²
    35.1 ± 0.6
    35.5 ± 0.6
    Statistical analysis title
    		 Mean mGFR at 12-months by baseline mGFR
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.52
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by baseline uACR

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    End point title
    		 Mean mGFR at 12-months by baseline uACR
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤30 mg/mmol
    29.1 ± 0.8
    30.0 ± 0.8
        >30 mg/mmol
    30.3 ± 0.6
    29.9 ± 0.6
    Statistical analysis title
    		 Mean mGFR at 12-months by baseline uACR
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.38
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by baseline 24 hour urinary sodium excretion

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    End point title
    		 Mean mGFR at 12-months by baseline 24 hour urinary sodium excretion
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        ≤2680 mg/24 hours
    29.9 ± 0.8
    31.0 ± 1.0
        >2680 mg/24 hours
    31.8 ± 0.6
    31.5 ± 0.9
    Statistical analysis title
    		 Baseline 24 hour urinary sodium excretion
    Statistical analysis description
    Mean mGFR at 12-months by baseline 24 hour urinary sodium excretion
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.38
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by use of RAS blockade at screening

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    End point title
    		 Mean mGFR at 12-months by use of RAS blockade at screening
    End point description
    End point type
    Secondary
    End point timeframe
    12 month
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        RAS blockade - Yes
    30.0 ± 0.5
    29.7 ± 0.5
        RAS blockade - No
    28.8 ± 1.2
    30.9 ± 1.0
    Statistical analysis title
    		 Use of RAS blockade at screening
    Statistical analysis description
    Mean mGFR at 12-months by use of RAS blockade at screening
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.15
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean mGFR at 12-months by cause of kidney disease

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    End point title
    		 Mean mGFR at 12-months by cause of kidney disease
    End point description
    *Includes obstructive renal diseases **All considered 'Systemic diseases affecting the kidney' by the ERA−EDTA registry ***All considered 'Miscellaneous renal disorders' by the ERA−EDTA registry § Includes other systemic kidney diseases
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        Glomerular disease
    30.3 ± 0.9
    30.8 ± 0.9
        Tubulointerstitial disease*
    28.6 ± 1.6
    29.7 ± 1.2
        Diabetic kidney disease**
    28.1 ± 1.1
    27.6 ± 0.9
        Hypertensive/renovascular disease**
    31.0 ± 1.6
    31.5 ± 1.4
        Familial/hereditary nephropathies
    28.5 ± 1.2
    31.0 ± 1.9
        Other known causes§***
    32.6 ± 2.8
    29.8 ± 2.6
        Unknown***
    31.2 ± 1.1
    30.7 ± 1.1
    Statistical analysis title
    		 Mean mGFR at 12-months by cause of kidney disease
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Mean uACR study average

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    End point title
    		 Mean uACR study average
    End point description
    Mean urine albumin:creatinine ratio [uACR]
    End point type
    Secondary
    End point timeframe
    Study average
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mg/mmol
    arithmetic mean (standard error)
        Study average
    16.3 ± 0.6
    17.9 ± 0.7
    Statistical analysis title
    		 Urinary albumin:creatinine ratio
    Comparison groups
    Sacubitril/valsartan v Irbesartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.08
    Method
    		 Test for heterogeneity
    Confidence interval

    Secondary: Estimated GFR [eGFR] study average

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    End point title
    		 Estimated GFR [eGFR] study average
    End point description
    Estimated GFR [eGFR] study average from centrally analysed plasma samples using CKD-EPI formula.
    End point type
    Secondary
    End point timeframe
    Study average
    End point values
    		 Sacubitril/valsartan Irbesartan
    Number of subjects analysed
    207
    207
    Units: mL/min/1.73m²
    arithmetic mean (standard error)
        Study average
    32.3 ± 0.2
    32.2 ± 0.2
    Statistical analysis title
    		 Estimated GFR [eGFR] study average
    Comparison groups
    Irbesartan v Sacubitril/valsartan
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.66
    Method
    		 Test for heterogeneity
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Adverse event reporting additional description
    All serious adverse events were reported via the electronic case report form together with non-serious adverse events that were thought to be related to the randomized study treatment (nSARs).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Sacubitril/valsartan
    Reporting group description
    		 Experimental drug

    Reporting group title
    Irbesartan
    Reporting group description
    		 Active comparator

    Serious adverse events
    		 Sacubitril/valsartan Irbesartan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    61 / 207 (29.47%)
    59 / 207 (28.50%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    5 / 207 (2.42%)
    6 / 207 (2.90%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 207 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    19 / 207 (9.18%)
    16 / 207 (7.73%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy, puerperium and perinatal conditions
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    5 / 207 (2.42%)
    4 / 207 (1.93%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    6 / 207 (2.90%)
    6 / 207 (2.90%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Investigations
         subjects affected / exposed
    8 / 207 (3.86%)
    13 / 207 (6.28%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    7 / 207 (3.38%)
    5 / 207 (2.42%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    6 / 207 (2.90%)
    5 / 207 (2.42%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    3 / 207 (1.45%)
    3 / 207 (1.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    2 / 207 (0.97%)
    2 / 207 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    5 / 207 (2.42%)
    6 / 207 (2.90%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 207 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    11 / 207 (5.31%)
    5 / 207 (2.42%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    16 / 207 (7.73%)
    15 / 207 (7.25%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    10 / 207 (4.83%)
    7 / 207 (3.38%)
         occurrences causally related to treatment / all
    1 / 11
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.1%
    Non-serious adverse events
    		 Sacubitril/valsartan Irbesartan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 207 (36.71%)
    58 / 207 (28.02%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    17 / 207 (8.21%)
    7 / 207 (3.38%)
         occurrences all number
    19
    8
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    3 / 207 (1.45%)
    6 / 207 (2.90%)
         occurrences all number
    3
    6
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    2 / 207 (0.97%)
    3 / 207 (1.45%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    4 / 207 (1.93%)
    4 / 207 (1.93%)
         occurrences all number
    5
    5
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
         occurrences all number
    0
    1
    Investigations
    Investigations
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 207 (0.48%)
         occurrences all number
    3
    1
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 207 (0.97%)
         occurrences all number
    0
    2
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    20 / 207 (9.66%)
    18 / 207 (8.70%)
         occurrences all number
    23
    21
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 207 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 207 (0.97%)
         occurrences all number
    1
    2
    Eye disorders
    Eye disorders
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    18 / 207 (8.70%)
    10 / 207 (4.83%)
         occurrences all number
    21
    13
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    18 / 207 (8.70%)
    6 / 207 (2.90%)
         occurrences all number
    23
    7
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    5 / 207 (2.42%)
    7 / 207 (3.38%)
         occurrences all number
    7
    8
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    6 / 207 (2.90%)
    5 / 207 (2.42%)
         occurrences all number
    6
    7
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 207 (0.48%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    9 / 207 (4.35%)
    2 / 207 (0.97%)
         occurrences all number
    9
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2014
    Version 5.1 Amendment: First morning void urine samples will be collected at each study visit for local and central analysis. Rationale: First morning urine samples reduce intra-individual variability compared with random urine samples
    09 Mar 2015
    Version 6.0 Original text: Inclusion criteria: eGFR ≥20 <60 mL/min/1.73m2 and urine albumin:creatinine ratio >20 mg/mmol Exclusion criteria: Serum potassium > 5.2 mmol/L Systolic BP <130 mmHg at Randomization Amended text: Inclusion criteria: eGFR ≥20 <45 mL/min/1.73m2; or eGFR ≥45 <60 mL/min/1.73m2 and urine albumin:creatinine ratio >20 mg/mmol Exclusion criteria: Serum potassium > 5.5 mmol/L Systolic BP <110 mmHg (or <130 mmHg with symptoms of orthostatic hypotension) at Randomization Rationale: To facilitate recruitment and avoid unnecessary exclusion of participants
    11 May 2015
    Version 7.0 Original text: Follow-up duration 6 months Amended text: Follow-up duration 12 months Rationale: New data from heart failure population suggested that the full effects on renal function may take at least 9 months to emerge with sacubitril/valsartan
    25 Jan 2016
    Version 8.0 Original text: Original sample size 360 participants (based on assumption that 10% might discontinue study treatment) Amended text: Sample size increased to at least 400 participants Rationale: To allow for up to 15% of participants to discontinue study treatment

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27646835
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