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    Clinical Trial Results:
    A prospective, randomized, open label blinded end point probe trial to evaluate whether, at comparable blood pressure control, combined therapy with the ACE inhibitor Benazepril and the angiotensin II receptor blocker ARB Valsartan, reduces the incidence of microalbuminuria more effectively than Benazepril or Valsartan alone in hypertensive patients with type 2 diabetes and high-normal albuminuria VARIETY Study

    Summary
    EudraCT number
    		 2006-005954-62
    Trial protocol
    		 IT  
    Global end of trial date
    14 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2021
    First version publication date
    14 Aug 2021
    Other versions
    Summary report(s)
    		 VARIETY article

    Trial information

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    Trial identification
    Sponsor protocol code
    AIFA MICRO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00503152
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    V. G. B. Camozzi, 3, Ranica / Bergamo, Italy, 24010
    Public contact
    Dip. Renal Medicine, Clinical Research Center for Rare Diseases "Aldo & Cele Daccò", 0039 03545351, piero.ruggenenti@marionegri.it
    Scientific contact
    Dip. Renal Medicine, Clinical Research Center for Rare Diseases "Aldo & Cele Daccò", 0039 03545351, piero.ruggenenti@marionegri.it
    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
    14 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether, at comparable blood pressure control, dual RAS blockade with combined therapy with halved doses of benazepril 10 mg/day and valsartan 160 mg/day reduces the incidence of microalbuminuria more effectively than single drug RAS blockade by full doses of benazepril 20 mg/day or valsartan 320 mg/day given alone in high-risk patients with type 2 diabetes, hypertension and high normal albuminuria.
    Protection of trial subjects
    This study was conducted in conformance with Declaration of Helsinki, Good Clinical Practice standards and applicable country regulations regarding ethical committee review, informed consent, protection of human subjects participating in biomedical research and privacy
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jul 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 612
    Worldwide total number of subjects
    612
    EEA total number of subjects
    612
    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)
    280
    From 65 to 84 years
    331
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy.

    Pre-assignment
    Screening details
    		 Patients were screened according to the inclusion/exclusion criteria. They referred to the Istituto di Ricerche Farmacologiche Mario Negri and to 8 diabetology or nephrology units, all in Italy. Eligibily patients who fullfilled the inclusion/exclusion criteria entered in 1 month of washout period and stratified before the randomization

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Benazepril
    Arm description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benazepril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Benazepril 10 mg/day

    Arm title
    		 Valsartan
    Arm description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Valsartan 160 mg/day

    Arm title
    		 Combination
    Arm description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benazepril and Valsartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal film, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Benazepril 5 mg/day and Valsartan 80 mg/day combination therapy. These doses correspond to half or one-fourth, respectively, of the full doses recommended by the manufacturer for BP control

    Number of subjects in period 1
    		Benazepril Valsartan Combination
    Started
    209
    201
    202
    Completed
    203
    201
    196
    Not completed
    6
    0
    6
         Protocol deviation
    6
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benazepril
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group title
    Valsartan
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group title
    Combination
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group values
    		 Benazepril Valsartan Combination Total
    Number of subjects
    		 209 201 202 612
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 94 93 94 281
        From 65-84 years
    		 114 108 108 330
        85 years and over
    		 1 0 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ± 7.7 64.3 ± 7.9 65 ± 7.1 -
    Gender categorical
    Units: Subjects
        Female
    		 63 62 56 181
        Male
    		 146 139 146 431
    Smoking status
    Units: Subjects
        Never smoked
    		 95 102 97 294
        Former smoked
    		 34 23 32 89
        Current smoker
    		 80 76 73 229
    Known duration of diabetes
    Units: year
        arithmetic mean (standard deviation)
    		 11.5 ± 7.1 11.7 ± 6.9 12.2 ± 7.1 -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 29.8 ± 4.4 30.3 ± 4.9 30.4 ± 4.9 -
    Systolic BP
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 141.9 ± 14.6 140.9 ± 15.2 141.9 ± 13.7 -
    MAP
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 99.8 ± 8.8 99.7 ± 8 99.8 ± 8.6 -
    HbA1c
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 54.3 ± 14.2 54.3 ± 14.1 54.7 ± 12.9 -
    Serum glucose
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 151.4 ± 44.8 151.1 ± 50.6 152.5 ± 41 -
    Serum potassium
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 4.13 ± 0.42 4.11 ± 0.48 4.1 ± 0.46 -
    Hemoglobin
    Units: g/dL
        arithmetic mean (standard deviation)
    		 14 ± 1.3 14 ± 1.2 14.1 ± 1.2 -
    Total Choletserol
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 177.7 ± 33 178.4 ± 32.4 179.5 ± 34.6 -
    LDL cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 108 ± 28.2 108.4 ± 30.6 111.2 ± 32.3 -
    HDL cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 46.8 ± 12.2 48 ± 13.3 47.1 ± 11.5 -
    Tryglycerides
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 128.5 ± 72.1 127.9 ± 79 132.7 ± 76.4 -
    Serum creatinine
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 0.9 ± 0.19 0.88 ± 0.19 0.93 ± 0.2 -
    eGFR
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    		 82.22 ± 15.28 84.19 ± 14.62 80.57 ± 15.99 -
    mGFR
    Units: mL/min/1.73 m2
        arithmetic mean (standard deviation)
    		 85.93 ± 14.3 84.68 ± 20.85 83.04 ± 16.76 -
    UAE
    Units: ug/min
        median (inter-quartile range (Q1-Q3))
    		 8.74 (6.52 to 12.58) 9.44 (6.72 to 12.59) 8.35 (6.1 to 11.7) -

    End points

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    End points reporting groups
    Reporting group title
    Benazepril
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group title
    Valsartan
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group title
    Combination
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Primary: Microalbuminuria

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    End point title
    		 Microalbuminuria
    End point description
    The estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. After adjustment for predefined confounders, the estimated acceleration factors were 1.330 (95% CI: 0.784 to 2.255, P = 0.290) for benazepril compared to combination therapy, 1.051 (95% CI: 0.591 to 1.866, P = 0.866) for benazepril compared to valsartan, and 1.365 (95% CI: 0.873 to 2.132, P = 0.172) for valsartan compared to combination therapy. When using the Cox regression model, the hazard for new-onset microalbuminuria was similar with the 3 treatment regimens, even after adjustment for predefined features
    End point type
    Primary
    End point timeframe
    During a median [IQR] follow-up of 66 [42 to 83] months, the primary endpoint of persistent microalbuminuria was reached by 57 (28.1%) patients on benazepril, 53 (27.0%) on combination therapy, and 64 (31.8%) on valsartan
    End point values
    		 Benazepril Valsartan Combination
    Number of subjects analysed
    203
    201
    196
    Units: Person
    57
    64
    53
    Statistical analysis title
    		 Microalbuminuria
    Comparison groups
    Benazepril v Valsartan v Combination
    Number of subjects included in analysis
    600
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.229 [1]
    Method
    		 accelerated failure time model
    Confidence interval
    Notes
    [1] - Benazepril versus combination therapy Valsartan versus combination therapy p value=0.047 Benazepril versus Valsartan p value= 0.492

    Secondary: GFR decline

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    End point title
    		 GFR decline
    End point description
    In the subgroup of patients in whom GFR was measured by iohexol plasma clearance, GFR declined by 1.78 [0.32 to 3.54] mL/min/1.73 m2 per year. The annual rate of GFR decline did not differ significantly among the benazepril (1.73 [0.44 to 4.13] mL/min/1.73 m2), combination therapy (2.61 [0.77 to 3.59] mL/min/1.73 m2), or valsartan (1.45 [−0.94 to 2.92] mL/min/1.73 m2) groups.
    End point type
    Secondary
    End point timeframe
    Annual rate of GFR decline
    End point values
    		 Benazepril Valsartan Combination
    Number of subjects analysed
    28
    25
    24
    Units: mL/min/1.73 m2
        median (inter-quartile range (Q1-Q3))
    1.73 (0.44 to 4.13)
    1.45 (-0.94 to 2.92)
    2.61 (0.77 to 3.59)
    Statistical analysis title
    		 GFR decline
    Comparison groups
    Benazepril v Valsartan v Combination
    Number of subjects included in analysis
    77
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.2579 [2]
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [2] - P value Benazepril versus valsartan: 0.2579 Benazepril versus combination: 0.7620 Valsartan versus combination: 0.1416

    Secondary: Composite cardiovascular endpoint

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    End point title
    		 Composite cardiovascular endpoint
    End point description
    During the study period, 7 (3.3%) patients on benazepril, 9 (4.5%) on combination therapy, and 9 (4.5%) on valsartan reached the composite cardiovascular endpoint of sudden cardiac death and fatal and nonfatal acute myocardial infarction or stroke. The risk of progression to the combined endpoint was similar between groups, even after adjusting for predefined confounders
    End point type
    Secondary
    End point timeframe
    During the study period
    End point values
    		 Benazepril Valsartan Combination
    Number of subjects analysed
    209
    201
    202
    Units: Person
    7
    9
    9
    Statistical analysis title
    		 Composite cardiovascular endpoint
    Comparison groups
    Benazepril v Valsartan v Combination
    Number of subjects included in analysis
    612
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.584 [3]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [3] - p-value Benazepril versus combination: 0.584 Valsartan versus combination: 0.979 Benazepril versus valsartan: 0.567

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events will be reported during whole study up to 30 days after last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Benazepril
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group title
    Valsartan
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Reporting group title
    Combination
    Reporting group description
    		 After 1 month washout from any previous RAS blocking therapy (ACE inhibitor or ARB) and stratification by center, we randomly assigned included patients to treatment with benazepril, valsartan, or a combination of both medications on a 1:1:1 basis.

    Serious adverse events
    		 Benazepril Valsartan Combination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 209 (30.14%)
    52 / 201 (25.87%)
    56 / 202 (27.72%)
         number of deaths (all causes)
    5
    7
    4
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasia events
         subjects affected / exposed
    13 / 209 (6.22%)
    13 / 201 (6.47%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 13
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
    Injury, poisoning and procedural complications
    Traffic accident event
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 201 (0.00%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Major cardiovascular events
         subjects affected / exposed
    5 / 209 (2.39%)
    8 / 201 (3.98%)
    9 / 202 (4.46%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    Minor cardiovascular events
         subjects affected / exposed
    19 / 209 (9.09%)
    20 / 201 (9.95%)
    26 / 202 (12.87%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 20
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neurological events
         subjects affected / exposed
    1 / 209 (0.48%)
    3 / 201 (1.49%)
    7 / 202 (3.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal events
         subjects affected / exposed
    6 / 209 (2.87%)
    6 / 201 (2.99%)
    11 / 202 (5.45%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Gynecological Events
         subjects affected / exposed
    2 / 209 (0.96%)
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory events
         subjects affected / exposed
    2 / 209 (0.96%)
    2 / 201 (1.00%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal events
         subjects affected / exposed
    6 / 209 (2.87%)
    0 / 201 (0.00%)
    3 / 202 (1.49%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urological events
         subjects affected / exposed
    14 / 209 (6.70%)
    7 / 201 (3.48%)
    2 / 202 (0.99%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide event
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and trauma events
         subjects affected / exposed
    11 / 209 (5.26%)
    9 / 201 (4.48%)
    21 / 202 (10.40%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection events
         subjects affected / exposed
    4 / 209 (1.91%)
    3 / 201 (1.49%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic events
         subjects affected / exposed
    5 / 209 (2.39%)
    1 / 201 (0.50%)
    6 / 202 (2.97%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Benazepril Valsartan Combination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    184 / 209 (88.04%)
    181 / 201 (90.05%)
    171 / 202 (84.65%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm benign, malignat and unspecified events
         subjects affected / exposed
    5 / 209 (2.39%)
    5 / 201 (2.49%)
    3 / 202 (1.49%)
         occurrences all number
    5
    5
    3
    Vascular disorders
    Vacular disorder events
         subjects affected / exposed
    19 / 209 (9.09%)
    31 / 201 (15.42%)
    38 / 202 (18.81%)
         occurrences all number
    19
    31
    38
    Surgical and medical procedures
    Surgical and medical procedures events
         subjects affected / exposed
    3 / 209 (1.44%)
    0 / 201 (0.00%)
    1 / 202 (0.50%)
         occurrences all number
    3
    0
    1
    General disorders and administration site conditions
    General disorders and administration site conditions events
         subjects affected / exposed
    34 / 209 (16.27%)
    35 / 201 (17.41%)
    33 / 202 (16.34%)
         occurrences all number
    34
    35
    33
    Immune system disorders
    Immune system disorders events
         subjects affected / exposed
    5 / 209 (2.39%)
    1 / 201 (0.50%)
    0 / 202 (0.00%)
         occurrences all number
    5
    1
    0
    Reproductive system and breast disorders
    Reproductive system and breast disorders events
         subjects affected / exposed
    21 / 209 (10.05%)
    21 / 201 (10.45%)
    12 / 202 (5.94%)
         occurrences all number
    21
    21
    12
    Respiratory, thoracic and mediastinal disorders
    Respiratory thoracic and mediastinal disorders events
         subjects affected / exposed
    21 / 209 (10.05%)
    13 / 201 (6.47%)
    25 / 202 (12.38%)
         occurrences all number
    21
    13
    25
    Psychiatric disorders
    Psychiatric disorders events
         subjects affected / exposed
    10 / 209 (4.78%)
    4 / 201 (1.99%)
    8 / 202 (3.96%)
         occurrences all number
    10
    4
    8
    Investigations
    Investigations events
         subjects affected / exposed
    35 / 209 (16.75%)
    27 / 201 (13.43%)
    28 / 202 (13.86%)
         occurrences all number
    35
    27
    28
    Injury, poisoning and procedural complications
    Injury poisoning and procedural complications events
         subjects affected / exposed
    14 / 209 (6.70%)
    10 / 201 (4.98%)
    18 / 202 (8.91%)
         occurrences all number
    14
    10
    18
    Congenital, familial and genetic disorders
    Congenital familial and genetic disorders events
         subjects affected / exposed
    1 / 209 (0.48%)
    3 / 201 (1.49%)
    2 / 202 (0.99%)
         occurrences all number
    1
    3
    2
    Cardiac disorders
    Cardiac disorder events
         subjects affected / exposed
    51 / 209 (24.40%)
    61 / 201 (30.35%)
    55 / 202 (27.23%)
         occurrences all number
    51
    61
    55
    Nervous system disorders
    Nervous system disorders events
         subjects affected / exposed
    36 / 209 (17.22%)
    27 / 201 (13.43%)
    34 / 202 (16.83%)
         occurrences all number
    36
    27
    34
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders events
         subjects affected / exposed
    22 / 209 (10.53%)
    22 / 201 (10.95%)
    23 / 202 (11.39%)
         occurrences all number
    22
    22
    23
    Ear and labyrinth disorders
    Ear and labyrinth disorder events
         subjects affected / exposed
    2 / 209 (0.96%)
    2 / 201 (1.00%)
    6 / 202 (2.97%)
         occurrences all number
    2
    2
    6
    Eye disorders
    Eye disorder events
         subjects affected / exposed
    28 / 209 (13.40%)
    26 / 201 (12.94%)
    28 / 202 (13.86%)
         occurrences all number
    28
    26
    28
    Gastrointestinal disorders
    Gastrointestinal disorders event
         subjects affected / exposed
    33 / 209 (15.79%)
    35 / 201 (17.41%)
    39 / 202 (19.31%)
         occurrences all number
    33
    35
    39
    Hepatobiliary disorders
    Hepatobiliary disorder events
         subjects affected / exposed
    16 / 209 (7.66%)
    9 / 201 (4.48%)
    11 / 202 (5.45%)
         occurrences all number
    16
    9
    11
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders events
         subjects affected / exposed
    14 / 209 (6.70%)
    7 / 201 (3.48%)
    10 / 202 (4.95%)
         occurrences all number
    14
    7
    10
    Renal and urinary disorders
    Renal and urinary disorders events
         subjects affected / exposed
    17 / 209 (8.13%)
    18 / 201 (8.96%)
    23 / 202 (11.39%)
         occurrences all number
    17
    18
    23
    Endocrine disorders
    Endocrine disorders events
         subjects affected / exposed
    2 / 209 (0.96%)
    2 / 201 (1.00%)
    2 / 202 (0.99%)
         occurrences all number
    2
    2
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders events
         subjects affected / exposed
    42 / 209 (20.10%)
    40 / 201 (19.90%)
    44 / 202 (21.78%)
         occurrences all number
    42
    40
    44
    Infections and infestations
    Infection and infestetion events
         subjects affected / exposed
    51 / 209 (24.40%)
    56 / 201 (27.86%)
    48 / 202 (23.76%)
         occurrences all number
    51
    56
    48
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders events
         subjects affected / exposed
    47 / 209 (22.49%)
    55 / 201 (27.36%)
    53 / 202 (26.24%)
         occurrences all number
    47
    55
    53

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2008
    The changes made aim to facilitate patient recruitment without changing the general philosophy and main objective of the project. Specifically, the selection criteria have been expanded to also include patients with albuminuria> 7μg / min and <10 μg / min. In this way, patients are eligible for the study if they have albuminuria (including extremes) between 7 and 19.99 μg / min (instead of between 10 and 19.99 μg / min). This approach results in an increase in the pool of potentially eligible patients of approximately 60%. In this amendment we have specified that all randomized patients will be kept in active follow-up until the last patient has completed the three years of treatment. Since the period initially envisaged for recruitment has been extended, it can be expected that by the time the last randomized patient has completed the three years of planned treatment, the median follow-up of patients will be at least 4.5 years. With these new assumptions, the incidence of events expected per year in each treatment group is a little lower, but the follow up is longer. Therefore, the total number of expected events increases slightly and, consequently, the estimated numbers also decrease somewhat, from 1233 to 1020 randomized patients (17% reduction in number) .
    22 May 2015
    This amendment provides for a reduction in the number of patients with an extension of the follow-up duration compared to that established in the original version of the protocol. This change will not change the power of the analyzes to test the effect of the treatment on the main efficacy parameter of the study. In May 2015, 1060 patients were included in the study, of which 613 were randomized.The preliminary analyzes presented in the periodic report sent to AIFA, had highlighted an incidence of the main endpoint (microalbuminuria) over a 4.5-year period in the control group greater than assumed in the protocol (27.0% instead of 22.5%); a lower than expected incidence of premature exits from the study (5% vs 15%), which resulted in a substantial increase in patients available for final analyzes. These results were confirmed in the interim analysis provided for in the protocol, performed on 11/05/2015. In particular, the following were observed: an incidence of the main endpoint (microalbuminuria) over a time span of 4.5 years in the control group greater than that hypothesized in the than hypothesized in the protocol (27.6% instead of 22.5%); an incidence of premature exits from the study relative to patients not included in the main analyzes lower than expected (4.2% vs 15%). As of 31/12/2015, the median follow-up expected for the 613 patients currently randomized will be 69 months. Considering that, the current drop-out referred to patients who will not contribute to the main efficacy analysis is 4.2%, it can be estimated that at the time of reaching the third year of the last randomized patient, the power of the analyzes (80%) foreseen by the protocol to test the effect of the treatment on the main efficacy parameter will have already been achieved without the need to include additional patients.

    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 lower-than-expected albuminuria in our study population at inclusion unavoidably reduced the power of the analyses to detect a treatment effect on the primary endpoint.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34260595
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