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    Clinical Trial Results:
    Multicenter parallel-group, concealed and randomized allocation and blinded-endpoint study, to evaluate the effects of Torasemide PR versus furosemide on a biochemical marker of collagen synthesis and deposition, in hypertensive patients with heart failure

    Summary
    EudraCT number
    		 2006-001446-14
    Trial protocol
    		 ES  
    Global end of trial date
    24 Feb 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2021
    First version publication date
    09 Sep 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    N/GF-TORAFIC-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NOVAG S.A., FERRER GRUPO
    Sponsor organisation address
    CALLE GRAN VIA CARLES III, 94, Barcelona, Spain,
    Public contact
    Medical Advisor, Dpto. Médico, NOVAG S.A., FERRER GRUPO, 34 93600 37 28, efernandez@ferrergrupo.com
    Scientific contact
    Medical Advisor, Dpto. Médico, NOVAG S.A., FERRER GRUPO, 34 93600 37 28, efernandez@ferrergrupo.com
    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
    16 Oct 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jul 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of Torasemide-LP over Furosemide in reducing myocardial fibrosis in patients with heart failure, in grades II, III and IV, according to the New York Heart Association (NYHA) classification.
    Protection of trial subjects
    Patients could discontinue study treatment at any time, without having to give any explanation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 8 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 155
    Worldwide total number of subjects
    155
    EEA total number of subjects
    155
    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)
    47
    From 65 to 84 years
    103
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Twenty-five centers throughout Spain participated in the present study. A total of 169 patients were included, of which 155 were randomized. The recruitment period lasted for 21 months (February 26, 2007 to November 18, 2008) and the duration of each patient in the study was 8 months.

    Pre-assignment
    Screening details
    		 169 patients were screened, 14 of them were not included for breaching any inclusion or exclusion criteria. Main inclusion criteria: adult patients with grade II-IV heart failure and with clinically stable heart failure. Main exclusion criteria: patients diagnosed with heart failure whose etiology was aortic stenosis or hypertrophic cardiomyopathy.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    At visit 0, and after obtaining the informed consent from the patient, each patient was assigned a four-digit selection number; the first two digits indicated the research center and the last two followed a sequential numbering that identified the patient during the study. If the patient was randomized, a randomization number was assigned according to the distribution of the medication by blocks, which consisted of three digits, which had been assigned sequentially to each center.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Torasemide-PR Group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Torasemide prolonged release
    Investigational medicinal product code
    Other name
    Sutril Neo®
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomized at a dosage of 10 mg/day (orally) of torasemide-prolonged release. After 4 weeks, in patients who did not respond to treatment, the dose was doubled to 20 mg/day. After 12-24 weeks, patients on torasemide at 10 mg/day who showed no response to treatment, were switched to a dose of 20 mg/day. Patients who already received a dose 20 mg/day and who did not respond to treatment, increased the dose (at investigator’s decision) to 30 mg/day or to 40 mg/day. Patients who had reached treatment doses of 40 mg/day of torasemide-prolonged release and who were not responding to treatment, dropped out of the study.

    Arm title
    		 Furosemide Group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Furosemide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Buccal use
    Dosage and administration details
    Patients were randomized at a dosage of 40 mg/day (orally) of furosemide. After 4 weeks, in patients who did not respond to treatment, the dose was doubled to 80 mg/day. After 12-24 weeks, patients on furosemide at 40 mg/day who showed no response to treatment, were switched to a dose of 80 mg/day. Patients who already received a dose 80 mg/day and who did not respond to treatment, increased the dose (at investigator’s decision) to 120 mg/day or to 160 mg/day. Patients who had reached treatment doses of 160 mg/day of furosemide and who were not responding to treatment, dropped out of the study.

    Number of subjects in period 1
    		Torasemide-PR Group Furosemide Group
    Started
    77
    78
    Completed
    63
    64
    Not completed
    14
    14
         Adverse event, serious fatal
    2
    4
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    -
    1
         Lost to follow-up
    -
    1
         Protocol deviation
    9
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Torasemide-PR Group
    Reporting group description
    		 -

    Reporting group title
    Furosemide Group
    Reporting group description
    		 -

    Reporting group values
    		 Torasemide-PR Group Furosemide Group Total
    Number of subjects
    		 77 78 155
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 28 19 47
        From 65-84 years
    		 46 57 103
        85 years and over
    		 3 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.05 ± 11.38 69.63 ± 9.84 -
    Gender categorical
    Units: Subjects
        Female
    		 35 30 65
        Male
    		 42 48 90
    Race
    Units: Subjects
        Caucasian
    		 77 77 154
        Other: Latin American
    		 0 1 1
    Heart failure
    Units: Subjects
        Yes
    		 77 78 155
        No
    		 0 0 0
    Arterial hypertension
    Units: Subjects
        Yes
    		 77 77 154
        No
    		 0 1 1
    Myocardial infarction
    Units: Subjects
        Yes
    		 13 13 26
        No
    		 64 65 129
    Coronary heart disease
    Units: Subjects
        Yes
    		 14 13 27
        No
    		 63 65 128
    Stroke
    Units: Subjects
        Yes
    		 5 8 13
        No
    		 72 70 142
    Peripheral vascular disease
    Units: Subjects
        Yes
    		 4 9 13
        No
    		 73 69 142
    Non-severe arrhythmia
    Units: Subjects
        Yes
    		 22 24 46
        No
    		 55 54 109
    Severe arrhythmia
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 77 78 155
    Valvular disease
    Units: Subjects
        Yes
    		 8 14 22
        No
    		 69 64 133
    Aortic stenosis
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 76 77 153
    Hypertrophic cardiomyopathy
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 77 78 155
    Stable angina pectoris
    Units: Subjects
        Yes
    		 7 11 18
        No
    		 70 67 137
    Unstable angina pectoris
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 77 78 155
    Metabolism and nutrition disorders
    Units: Subjects
        Yes
    		 44 51 95
        No
    		 33 27 60
    Musculoskeletal and connective tissue disorders
    Units: Subjects
        Yes
    		 19 23 42
        No
    		 58 55 113
    Psychiatric disorders
    Units: Subjects
        Yes
    		 10 18 28
        No
    		 67 60 127
    Total cholesterol
    Units: Subjects
        Clinically significant value
    		 1 0 1
        Non-clinically significant value
    		 76 78 154
    cHDL
    Units: Subjects
        Clinically significant value
    		 0 1 1
        Non-clinically significant value
    		 77 77 154
    cLDL
    Units: Subjects
        Clinically significant value
    		 4 4 8
        Non-clinically significant value
    		 73 74 147
    Triglycerides
    Units: Subjects
        Clinically significant value
    		 2 0 2
        Non-clinically significant value
    		 75 78 153
    GGT
    Units: Subjects
        Clinically significant value
    		 0 1 1
        Non-clinically significant value
    		 77 77 154
    Glucose
    Units: Subjects
        Clinically significant value
    		 1 1 2
        Non-clinically significant value
    		 76 77 153
    Uric acid
    Units: Subjects
        Clinically significant value
    		 3 2 5
        Non-clinically significant value
    		 74 76 150
    Global valuation
    Units: Subjects
        Normal
    		 23 20 43
        Abnormal not clinically relevant
    		 53 56 109
        Abnormal clinically relevant
    		 0 1 1
        Not available
    		 1 1 2
    Signs of pulmonary congestion
    Units: Subjects
        Presence of signs
    		 12 11 23
        Absence of signs
    		 59 53 112
        Not available
    		 6 14 20
    Presence of gallop S3
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 75 77 152
        Not available
    		 1 0 1
    Hepatojugular reflux
    Units: Subjects
        Yes
    		 1 3 4
        No
    		 75 75 150
        Not available
    		 1 0 1
    Jugular venous distention
    Units: Subjects
        Yes
    		 2 1 3
        No
    		 74 77 151
        Not available
    		 1 0 1
    Dyspnea at rest
    Units: Subjects
        Yes
    		 2 0 2
        No
    		 74 78 152
        Not available
    		 1 0 1
    Dyspnea on exertion
    Units: Subjects
        Yes
    		 55 61 116
        No
    		 21 17 38
        Not available
    		 1 0 1
    Type of edema
    Units: Subjects
        Absence of edema
    		 61 61 122
        Pedic edema
    		 5 5 10
        Edema of feet and ankles
    		 9 11 20
        Edema up to half legs
    		 2 1 3
        Edema to the knees
    		 0 0 0
        Edema above the knees
    		 0 0 0
    Evaluation of heart failure functional class
    Units: Subjects
        Class I
    		 0 0 0
        Class II
    		 74 70 144
        Class III
    		 3 8 11
        Class IV
    		 0 0 0
    Current medication: antithrombotic agents
    Units: Subjects
        Yes
    		 23 24 47
        No
    		 54 54 108
    Current medication: beta-blocking agents
    Units: Subjects
        Yes
    		 50 51 101
        No
    		 27 27 54
    Current medication: lipid modifying agents
    Units: Subjects
        Yes
    		 0 3 3
        No
    		 77 75 152
    Current medication: agents acting in the renin-angiotensin system
    Units: Subjects
        Yes
    		 58 57 115
        No
    		 19 21 40
    Current medication: antihypertensive
    Units: Subjects
        Yes
    		 1 4 5
        No
    		 76 74 150
    Current medication: calcium channel blockers
    Units: Subjects
        Yes
    		 12 12 24
        No
    		 65 66 131
    Current medication: diuretics
    Units: Subjects
        Yes
    		 72 71 143
        No
    		 5 7 12
    Current medication: antianemic preparations
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 77 77 154
    Current medication: mineral supplements
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 74 76 150
    Current medication: cardiac therapy
    Units: Subjects
        Yes
    		 14 14 28
        No
    		 63 64 127
    Concomitant medication: antithrombotic agents
    Units: Subjects
        Yes
    		 29 29 58
        No
    		 48 49 97
    Concomitant medication: lipid modifying agents
    Units: Subjects
        Yes
    		 38 39 77
        No
    		 39 39 78
    Concomitant medication: agents for the treatment of alterations caused by acids
    Units: Subjects
        Yes
    		 33 26 59
        No
    		 44 52 96
    Concomitant medication: atorvastatin
    Units: Subjects
        Yes
    		 19 23 42
        No
    		 58 55 113
    Concomitant medication: omeprazole
    Units: Subjects
        Yes
    		 21 19 40
        No
    		 56 59 115
    Concomitant medication: acetylsalicylic acid
    Units: Subjects
        Yes
    		 20 12 32
        No
    		 57 66 123
    Weight (kg)
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 82.30 ± 15.50 80.41 ± 15.75 -
    Size (cm)
    Units: centimeter
        arithmetic mean (standard deviation)
    		 161.25 ± 10.38 162.67 ± 9.62 -
    BMI
    Units: kilogram(s)/cubic meter
        arithmetic mean (standard deviation)
    		 31.59 ± 5.47 30.42 ± 6.32 -
    Systolic blood pressure (mmHg)
    Units: millimeter(s) of mercury
        arithmetic mean (standard deviation)
    		 133.51 ± 18.24 137.64 ± 19.08 -
    Diastolic blood pressure (mmHg)
    Units: millimeter(s) of mercury
        arithmetic mean (standard deviation)
    		 78.03 ± 11.89 78.00 ± 12.28 -
    Heart rate (bpm)
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 68.19 ± 11.48 70.85 ± 13.78 -
    Hemoglobin (g/dL)
    Units: gram(s)/decilitre
        arithmetic mean (standard deviation)
    		 13.81 ± 1.57 13.84 ± 1.58 -
    Hematocrit (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 41.24 ± 4.52 41.54 ± 4.41 -
    Total leukocytes (10*3/µL)
    Units: microlitre(s)
        arithmetic mean (standard deviation)
    		 7.05 ± 1.86 7.51 ± 2.08 -
    Platelets (10*3/µL)
    Units: microlitre(s)
        arithmetic mean (standard deviation)
    		 224.07 ± 56.90 222.85 ± 65.10 -
    Sodium (mEq/L)
    Units: milliequivalent(s)/litre
        arithmetic mean (standard deviation)
    		 141.49 ± 3.12 140.73 ± 3.23 -
    Potassium (mEq/L)
    Units: milliequivalent(s)/litre
        arithmetic mean (standard deviation)
    		 4.38 ± 0.49 4.46 ± 0.56 -
    Chlorine (mEq/L)
    Units: milliequivalent(s)/litre
        arithmetic mean (standard deviation)
    		 102.63 ± 3.40 102.75 ± 3.82 -
    Serum creatinine (mg/dL)
    Units: milligram(s)/decilitre
        arithmetic mean (standard deviation)
    		 1.03 ± 0.46 1.08 ± 0.31 -
    Ejection fraction (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 54.39 ± 15.29 50.72 ± 17.37 -
    Left ventricular mass (g)
    Units: gram(s)
        arithmetic mean (standard deviation)
    		 340.77 ± 103.88 359.36 ± 128.96 -
    Body surface (m2)
    Units: square meter
        arithmetic mean (standard deviation)
    		 1.86 ± 0.21 1.85 ± 0.19 -
    Left ventricular mass index (g/m2)
    Units: gram(s)/square meter
        arithmetic mean (standard deviation)
    		 182.30 ± 50.49 193.80 ± 65.54 -
    Diastolic septal thickness (cm)
    Units: centimeter
        arithmetic mean (standard deviation)
    		 1.25 ± 0.19 1.24 ± 0.25 -
    Diastolic posterior wall thickness (cm)
    Units: centimeter
        arithmetic mean (standard deviation)
    		 1.18 ± 0.21 1.14 ± 0.20 -
    Diastolic diameter of the left ventricle (cm)
    Units: centimeter
        arithmetic mean (standard deviation)
    		 5.34 ± 0.86 5.57 ± 1.05 -
    Relative wall thickness (cm)
    Units: centimeter
        arithmetic mean (standard deviation)
    		 1.47 ± 0.23 1.44 ± 0.29 -
    Cardiac frequency beats/min.
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 68.55 ± 12.82 69.75 ± 13.26 -
    Carboxyterminal peptide of procollagen type I (μg/l)
    Units: microgram(s)/litre
        arithmetic mean (standard deviation)
    		 102.72 ± 31.16 108.65 ± 27.54 -
    Brain natriuretic peptide (pg/ml)
    Units: picogram(s)/milliliter
        arithmetic mean (standard deviation)
    		 1638.14 ± 884.95 1875.41 ± 1043.94 -

    End points

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    End points reporting groups
    Reporting group title
    Torasemide-PR Group
    Reporting group description
    		 -

    Reporting group title
    Furosemide Group
    Reporting group description
    		 -

    Primary: Serum concentrations of the carboxy-terminal peptide of procollagen type I (ITT population)

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    End point title
    		 Serum concentrations of the carboxy-terminal peptide of procollagen type I (ITT population)
    End point description
    This variable was analyzed both in the intention to treat (ITT) population and in the per protocol (PP) population with the intention of assessing the stability of the conclusions. The ITT population (n=155) included all patients who had taken at least one dose of study medication (randomized patients). The PP population (n=122) included all the randomized patients who concluded the study in accordance with the provisions of the protocol, who met all the inclusion criteria and none of the exclusion criteria and had made the final study visit. Those subjects judged as unanalyzable due to serious deviations from the protocol do not fall into this group.
    End point type
    Primary
    End point timeframe
    Primary efficacy endpoint of the study was the evaluation of the changes in plasma levels of carboxy-terminal peptide of procollagen type I (PICP) between the baseline visit and the final visit between the two treatment groups.
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: microgram(s)/litre
    arithmetic mean (standard deviation)
        PIcP basal
    102.72 ± 29.69
    108.65 ± 26.82
        PIcP final
    97.73 ± 25.73
    98.60 ± 26.12
    Statistical analysis title
    		 ANCOVA
    Comparison groups
    Furosemide Group v Torasemide-PR Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7505 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - A statistically significant model (p <0.0001) was obtained between the baseline PIcP value and the final PIcP value in both treatment groups.

    Primary: Serum concentrations of the carboxy-terminal peptide of procollagen type I (PP population)

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    End point title
    		 Serum concentrations of the carboxy-terminal peptide of procollagen type I (PP population)
    End point description
    This variable was analyzed both in the intention to treat (ITT) population and in the per protocol (PP) population with the intention of assessing the stability of the conclusions. The ITT population (n=155) included all patients who had taken at least one dose of study medication (randomized patients). The PP population (n=122) included all the randomized patients who concluded the study in accordance with the provisions of the protocol, who met all the inclusion criteria and none of the exclusion criteria and had made the final study visit. Those subjects judged as unanalyzable due to serious deviations from the protocol do not fall into this group.
    End point type
    Primary
    End point timeframe
    Primary efficacy endpoint of the study was the evaluation of the changes in plasma levels of carboxy-terminal peptide of procollagen type I (PICP) between the baseline visit and the final visit between the two treatment groups.
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    60
    62
    Units: microgram(s)
    arithmetic mean (standard deviation)
        PIcP basal
    104.07 ± 32.79
    109.28 ± 29.34
        PIcP final
    99.07 ± 27.92
    98.74 ± 27.89
    Statistical analysis title
    		 ANCOVA
    Comparison groups
    Furosemide Group v Torasemide-PR Group
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6754 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - A statistically significant model (p <0.0001) was obtained between the baseline PIcP value and the final PIcP value in both treatment groups.

    Secondary: Signs and symptoms derived from heart failure: Weight

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    End point title
    		 Signs and symptoms derived from heart failure: Weight
    End point description
    End point type
    Secondary
    End point timeframe
    The change in weight between the baseline and the final visit was calculated as: Weight change = basal weight - final weight. Positive values indicate a decrease and negative values an increase in the final visit compared to the baseline visit.
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    65
    71
    Units: kilogram(s)
    arithmetic mean (standard deviation)
        Weight change (Kg)
    -0.86 ± 4.13
    -0.47 ± 4.71
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6834
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Edema

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    End point title
    		 Signs and symptoms derived from heart failure: Edema
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in the presence of edema between the baseline visit and the final visit.
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    8
    12
        Maintenance
    52
    55
        Deterioration
    5
    4
        Not available
    12
    7
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7341
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Gallop S3

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    End point title
    		 Signs and symptoms derived from heart failure: Gallop S3
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in the presence of gallop S3 between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    0
    0
        Maintenance
    65
    69
        Deterioration
    0
    2
        Not available
    12
    7
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4973
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Hepatojugular reflux

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    End point title
    		 Signs and symptoms derived from heart failure: Hepatojugular reflux
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in hepatojugular reflux between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    1
    2
        Maintenance
    64
    69
        Deterioration
    0
    0
        Not available
    12
    7
    No statistical analyses for this end point

    Secondary: Signs and symptoms derived from heart failure: Jugular venous distention

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    End point title
    		 Signs and symptoms derived from heart failure: Jugular venous distention
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in jugular venous distention between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    2
    1
        Maintenance
    63
    65
        Deterioration
    0
    5
        Not available
    12
    7
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0585
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Dyspnea at rest

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    End point title
    		 Signs and symptoms derived from heart failure: Dyspnea at rest
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in dyspnea at rest between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    2
    0
        Maintenance
    62
    71
        Deterioration
    1
    0
        Not available
    12
    7
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Furosemide Group v Torasemide-PR Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1065
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Dyspnea on exertion

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    End point title
    		 Signs and symptoms derived from heart failure: Dyspnea on exertion
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in dyspnea on exertion between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    10
    10
        Maintenance
    52
    53
        Deterioration
    3
    8
        Not available
    12
    7
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3639
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Heart failure functional class

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    End point title
    		 Signs and symptoms derived from heart failure: Heart failure functional class
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in New York Heart Association classification between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    14
    13
        Maintenance
    49
    56
        Deterioration
    2
    2
        Not available
    12
    7
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.875
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Electrocardiogram I

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    End point title
    		 Signs and symptoms derived from heart failure: Electrocardiogram I
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in heart rate between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    62
    70
    Units: heartbeat per minute
    arithmetic mean (standard deviation)
        Changes in heart rate
    1.87 ± 10.36
    0.34 ± 17.52
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5982
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Electrocardiogram II

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    End point title
    		 Signs and symptoms derived from heart failure: Electrocardiogram II
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in global assessment between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    7
    10
        Maintenance
    49
    53
        Deterioration
    6
    7
        Not available
    15
    8
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8696
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Echocardiogram I

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    End point title
    		 Signs and symptoms derived from heart failure: Echocardiogram I
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in ejection fraction between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    63
    69
    Units: percent
    arithmetic mean (standard deviation)
        Ejection fraction change
    -1.47 ± 8.06
    -2.93 ± 11.42
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Echocardiogram II

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    End point title
    		 Signs and symptoms derived from heart failure: Echocardiogram II
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in left ventricular mass between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    65
    70
    Units: gram(s)
    arithmetic mean (standard deviation)
        Left ventricular mass change
    9.23 ± 77.85
    24.64 ± 92.05
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Echocardiogram III

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    End point title
    		 Signs and symptoms derived from heart failure: Echocardiogram III
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in left ventricular mass index between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    65
    70
    Units: gram(s)/square meter
    arithmetic mean (standard deviation)
        LVMI change
    5.48 ± 41.60
    14.38 ± 50.02
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Brain Natriuretic Peptide

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    End point title
    		 Signs and symptoms derived from heart failure: Brain Natriuretic Peptide
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in NT-proBNP between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    63
    68
    Units: picogram(s)/milliliter
    arithmetic mean (standard deviation)
        NT-proBNP change
    -33.63 ± 844.86
    -49.33 ± 1032.57
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8592
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Signs and symptoms derived from heart failure: Urinary symptoms

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    End point title
    		 Signs and symptoms derived from heart failure: Urinary symptoms
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in the urge to urinate between baseline visit and last available questionnaire
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        Improvement
    15
    12
        Maintenance
    47
    43
        Deterioration
    11
    20
        Not available
    4
    3
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.22
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Changes in clinical parameters: Systolic Blood Pressure

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    End point title
    		 Changes in clinical parameters: Systolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in systolic blood pressure between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    65
    71
    Units: millimeter(s) of mercury
    arithmetic mean (standard deviation)
        Systolic blood pressure change
    -0.22 ± 20.86
    3.20 ± 22.82
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Changes in clinical parameters: Diastolic Blood Pressure

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    End point title
    		 Changes in clinical parameters: Diastolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in diastolic blood pressure between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    65
    71
    Units: millimeter(s) of mercury
    arithmetic mean (standard deviation)
        Diastolic blood pressure change
    1.91 ± 13.93
    1.80 ± 14.10
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Changes in clinical parameters: Cardiac Frequency

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    End point title
    		 Changes in clinical parameters: Cardiac Frequency
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in cardiac frequency between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    64
    71
    Units: beats per minute
    arithmetic mean (standard deviation)
        Cardiac frequency change
    0.97 ± 10.45
    0.83 ± 16.38
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Changes in clinical parameters: Renal function

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    End point title
    		 Changes in clinical parameters: Renal function
    End point description
    End point type
    Secondary
    End point timeframe
    Changes in serum creatinine between baseline visit and final visit
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    62
    69
    Units: milligram(s)/deciliter
    arithmetic mean (standard deviation)
        Serum creatinine change
    -0.04 ± 0.15
    -0.05 ± 0.24
    Statistical analysis title
    		 Test U de Mann-Whitney
    Comparison groups
    Torasemide-PR Group v Furosemide Group
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Incidence of cardiovascular events: Hospital admissions

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    End point title
    		 Incidence of cardiovascular events: Hospital admissions
    End point description
    End point type
    Secondary
    End point timeframe
    Patients admitted to hospital for cardiovascular causes linked to the pathology under study
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        With hospital admissions
    4
    2
        Without hospital admissions
    73
    76
    No statistical analyses for this end point

    Secondary: Incidence of cardiovascular events: Emergency care

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    End point title
    		 Incidence of cardiovascular events: Emergency care
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with care in the emergency room for cardiovascular causes linked to the pathology under study
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        With emergency care visits
    4
    4
        Without emergency care visits
    73
    74
    No statistical analyses for this end point

    Secondary: Incidence of cardiovascular events: Home care

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    End point title
    		 Incidence of cardiovascular events: Home care
    End point description
    End point type
    Secondary
    End point timeframe
    Patients with home care for cardiovascular causes linked to the pathology under study
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: subjects
        With home care
    0
    1
        Without home care
    77
    77
    No statistical analyses for this end point

    Other pre-specified: Therapeutic compliance

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    End point title
    		 Therapeutic compliance
    End point description
    As specified in the study protocol, records of the study medication used and the doses administered had to be kept. The medication record was completed by the investigator throughout the entire study. To assess compliance with treatment, the study monitor compared the amount of medication dispensed with that the patient returned.
    End point type
    Other pre-specified
    End point timeframe
    Treatment compliance (%) was calculated for each patient at the first month, at the third month, at the sixth month and at the eighth month.
    End point values
    		 Torasemide-PR Group Furosemide Group
    Number of subjects analysed
    77
    78
    Units: unit(s)
    arithmetic mean (standard error)
        Compliance (%) at 1st month
    94.37 ± 35.30
    93.97 ± 41.45
        Compliance (%) at 3rd month
    102.65 ± 26.86
    105.18 ± 36.38
        Compliance (%) at 6th month
    108.00 ± 41.18
    124.22 ± 72.92
        Compliance (%) at 8th month
    105.94 ± 52.81
    117.58 ± 72.17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded after each visit from baseline to 8 months of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Torasemide-PR Group
    Reporting group description
    		 -

    Reporting group title
    Furosemide Group
    Reporting group description
    		 -

    Serious adverse events
    		 Torasemide-PR Group Furosemide Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 77 (11.69%)
    9 / 78 (11.54%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Toxicity to various agents
    Additional description: Treatment toxicity
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Syncope
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgery
    Additional description: Surgery for obesity
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
    Additional description: Lobar pneumonia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Torasemide-PR Group Furosemide Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 77 (58.44%)
    44 / 78 (56.41%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 77 (2.60%)
    3 / 78 (3.85%)
         occurrences all number
    2
    3
    Epistaxis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 78 (1.28%)
         occurrences all number
    2
    1
    Chest pain
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Oedema
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Chest discomfort
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Atrophic vulvovaginitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 77 (2.60%)
    2 / 78 (2.56%)
         occurrences all number
    2
    2
    Bronchitis
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 78 (3.85%)
         occurrences all number
    3
    8
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 78 (0.00%)
         occurrences all number
    3
    0
    Lung neoplasm
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 77 (2.60%)
    3 / 78 (3.85%)
         occurrences all number
    2
    3
    Cognitive disorder
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Somnolence
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Mood altered
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Urine abnormality
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Vitreous detachment
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Bone fissure
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cardiac disorders
    Dizziness
         subjects affected / exposed
    1 / 77 (1.30%)
    3 / 78 (3.85%)
         occurrences all number
    1
    3
    Atrial fibrillation
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Syncope
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    2
    1
    Angina pectoris
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cardiac failure
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Palpitations
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 78 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Liver disorder
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Nodule
    Additional description: Subcutaneous nodule
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Intertrigo
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    2
    1
    Drug eruption
    Additional description: Eruption
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Fluid retention
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Micturition urgency
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Endocrine disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 77 (1.30%)
    3 / 78 (3.85%)
         occurrences all number
    1
    6
    Arthralgia
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 78 (1.28%)
         occurrences all number
    3
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    2
    Back injury
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Arthritis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Rib fracture
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Pain in extremity
    Additional description: Pain in limb
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Joint dislocation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal stiffness
    Additional description: Stiff neck
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 78 (2.56%)
         occurrences all number
    2
    3
    Pharyngitis
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 78 (2.56%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Respiratory tract infection
    Additional description: Lung infection
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Haematoma infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 78 (2.56%)
         occurrences all number
    2
    2
    Hyperuricaemia
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 78 (0.00%)
         occurrences all number
    3
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    1
    Gouty arthritis
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 78 (1.28%)
         occurrences all number
    1
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2006
    The title of the clinical trial was modified by adding the reference to the evaluation of serum levels of carboxy-terminal peptide of procollagen type I (PICP) and specifying the type of heart failure (HF) studied in the trial. The amendment also served to specify in the wording of the main objective the type of HF studied in the trial and to specify in the inclusion criterion number 2 that the patients to be included had to have grade II, III and IV heart failure. In order to establish the study population more adequately, inclusion criteria number 3 and exclusion criteria 7 and 21 were modified. The definition of non-response to treatment was improved and added as a clinical manifestation New York Heart Association (NYHA) functional grade related to congestive HF. Additionally, the fact that patients had to maintain pharmacological treatment for heart failure was clarified at the screening visit (Vs). Finally, Annex XV was added to the protocol to clarify the clinical relevance of the changes in PICP as a biomarker of myocardial deposition of collagen fibers and the value of its levels as a marker of the clinical evolution of heart failure, and the wording of point 2 of Annex VIII regarding the definition of heart failure was improved. Other corrections to the study protocol were also made.
    03 Oct 2006
    Since the request for approval of the Hospital General de Mallorca center in the sole discretion of the IEC of Reference (Hospital Clínic I Provincial de Barcelona) of September 7, 2006, was denied, this amendment 2 was proposed to expand the participating centers in order to reconsider the participation of Hospital General de Mallorca center in the clinical trial and once again request its evaluation by the Illes Balears IEC.
    15 Nov 2006
    Due to the updating of the electronic CRF system used in the trial, the text of the protocol corresponding to the Case Report Form section was modified.
    15 Feb 2007
    The exclusion criterion that established that patients receiving treatment with antiarrhythmic group 1a, 1b or 2 could not be included in the trial. However, some of the drugs included in this list (especially β-blockers) are of routine use in patients with heart failure. For this reason, it was proposed to carry out this amendment, with the aim of adapting the exclusion criteria to the reality of the pharmacological treatment of patients with this pathology and, consequently, increasing the number of eligible patients. It is also important to note that no pharmacological interactions have been described between group 1a, 1b or 2 antiarrhythmics and the drugs under study (torasemide and furosemide) and that these drugs have not been shown to interfere in the process of myocardial fibrosis. Through this amendment, the person who appears in the protocol as medical writer was changed and the members of the Scientific Committee that have supported the project since its inception were included in the study protocol. The principal investigator of one of the participating centers was also modified.
    20 Jun 2007
    The reason for this amendment was to change the validity of the echocardiogram as a diagnostic test for hypertrophy, applicable to the screening visit (Vs), from 3 months to 6 months. It was considered that this modification does not affect the diagnosis of hypertrophy because this pathology is a process with a slow evolution period, so no significant differences will be detected between the two tests. Exclusion criterion number 5 of the protocol was clarified due to confusion. This criterion establishes that patients with severe cardiac arrhythmia could not be included in the trial, so that patients with atrial fibrillation, common in most patients with heart failure, which does not show severity, could be included. Clarification is proposed in order to unify the interpretation of the criterion among all collaborators, adapting the exclusion criteria to the reality of the pharmacological treatment of patients with this pathology. The degree of severity of a cardiac arrhythmia (in this case, atrial fibrillation) is defined as poorly controlled atrial fibrillation, since it can make difficult the data acquisition and interpretation of the echocardiogram.
    03 Jul 2007
    The reason for this amendment was the expansion of the number of centers participating in the trial in order to speed up the inclusion of patients, which was being lower than expected.
    03 Sep 2007
    The reason for this amendment was the expansion of the number of centers participating in the trial in order to speed up the inclusion of patients, which was being lower than expected.
    15 Nov 2007
    The reason for this amendment was the expansion of the number of centers participating in the trial in order to speed up the inclusion of patients, which was being lower than expected. On the other hand, the Principal Investigator of the Hospital Gregorio Marañón was changed, since according to him, the typology of patients in the study is not the one usually treated in Internal Medicine. It was decided to change the department (Internal Medicine) to the Cardiology department to be in charge of the selection/inclusion of patients. The new Principal Investigator became Dr. Francisco Fernández Avilés. Through this amendment, the modification of exclusion criterion number 10 was proposed. The aforementioned criterion established the following: Patients with chronic renal failure defined by the following analytical parameters: - serum creatinine greater than 2.5 mg / dl, - glomerular filtration <30%. During the course of the study, it was found that the diagnosis of renal failure in potential patients to be included in the study was established mainly by routine clinical practice, by the clinical assessment of the investigators and by a creatinine value greater than 2.5 mg, not being a determining factor in this case the glomerular filtration value. In other words, glomerular filtration was not a determining factor by itself when it presented values close to 30. In these cases, in the opinion of the ivestigators, it was the creatinine value that determined inclusion in the study. Due to the aforementioned and at the request of the investigators, a change in the exclusion criteria was proposed in order to adapt the protocol to routine clinical practice in such a way that only the serum creatinine value was used to determine chronic renal insufficiency, since creatininemia determines the clinical decision in routine practice.

    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
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