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    Clinical Trial Results:
    A Randomised, Placebo Controlled, Double-Blinded Comparative Study Evaluating the Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus

    Summary
    EudraCT number
    		 2007-001675-11
    Trial protocol
    		 FR   ES   BE   AT   DE   IT   HU   PL  
    Global end of trial date
    09 Sep 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Aug 2016
    First version publication date
    05 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    correct of data set required

    Trial information

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    Trial identification
    Sponsor protocol code
    0468E5-4439
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00502242
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias: B1741001
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021 , ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021 , ClinicalTrials.gov_Inquiries@pfizer.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
    09 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of ramipril in preventing a urinary protein to creatinine ratio (U p/c) of 0.5 or greater following conversion to sirolimus (SRL) from a calcineurin inhibitor (CNI) (either tacrolimus [TAC] or cyclosporine [CsA]) in maintenance renal transplant patients.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants.
    Background therapy
    		 In addition to SRL, all participants, at the discretion of the investigator, received background medication of corticosteroids and/or one of the following: mycophenolate mofetil (MMF), mycophenolate sodium (MPS), or azathioprine (AZA). Participants were permitted to switch between MMF, MPS, and AZA. Participants not receiving MMF, MPS, or AZA or who discontinued these agents received corticosteroids at a minimum of 2.5 milligrams (mg) per (/) day. Participants receiving corticosteroids were not permitted to undergo corticosteroid withdrawal following randomisation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Argentina: 26
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 49
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Mexico: 28
    Country: Number of subjects enrolled
    South Africa: 21
    Country: Number of subjects enrolled
    United States: 130
    Worldwide total number of subjects
    295
    EEA total number of subjects
    17
    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)
    271
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening was completed within 3 weeks before randomisation (from time informed consent form was signed to Day of Randomisation).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ramipril
    Arm description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received ramipril, 5 or 10 mg/day orally (PO). 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 nanograms per millilitre [ng/mL] less than [<]1 year post-transplant [PT], 5-15 ng/mL greater than or equal to [≥]1 year PT) for up to 52 weeks. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    After randomisation, ramipril or placebo administration was initiated. For participants enrolled prior to implementation of Amendment 3, ramipril or placebo was initiated at 10 mg/day. For participants enrolled after implementation of Amendment 3, ramipril or placebo was initiated at 5 mg/day. If ramipril or placebo needed to be temporarily withheld but was resumed within the 4-week pre-SRL conversion phase, and the participant received a minimum of 10 consecutive days of ramipril or placebo therapy prior to SRL conversion the participant was permitted to be converted. If a participant was not able to resume ramipril or placebo therapy, the participant was dropped from the study and no further data was collected. Losartan rescue therapy was initiated at 50 mg/day and may have been titrated to 100 mg/day if the Up/c ratio was not maintained at <0.5 on 50 mg/day. All study medication doses given, were adjusted throughout the study based on the maintenance of targeted Up/c levels.

    Arm title
    		 Placebo
    Arm description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 ng/mL <1 year PT, 5-15 ng/mL ≥1 year PT) for up to 52 weeks. Placebo dose was doubled if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    After randomisation, ramipril or placebo administration was initiated. For participants enrolled prior to implementation of Amendment 3, ramipril (or placebo) was initiated at 10 mg/day. For participants enrolled following implementation of Amendment 3, ramipril or placebo was initiated at 5 mg/day. If ramipril or placebo needed to be temporarily withheld but was resumed within the 4-week pre-SRL conversion phase, and the participant received a minimum of 10 consecutive days of ramipril or placebo therapy prior to SRL conversion the participant was permitted to be converted. If a participant was not able to resume ramipril or placebo therapy, the participant was dropped from the study and no further data was collected. Losartan rescue therapy was initiated at 50 mg/day and may have been titrated to 100 mg/day if the Up/c ratio was not maintained at <0.5 on 50 mg/day. All study medication doses given, were adjusted throughout the study based on the maintenance of targeted Up/c level

    Number of subjects in period 1
    		Ramipril Placebo
    Started
    155
    140
    Completed
    104
    84
    Not completed
    51
    56
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    6
    7
         Physician decision
    2
    3
         Adverse event, non-fatal
    30
    19
         Other
    8
    14
         Lack of efficacy
    1
    11
         Protocol deviation
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ramipril
    Reporting group description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received ramipril, 5 or 10 mg/day orally (PO). 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 nanograms per millilitre [ng/mL] less than [<]1 year post-transplant [PT], 5-15 ng/mL greater than or equal to [≥]1 year PT) for up to 52 weeks. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 ng/mL <1 year PT, 5-15 ng/mL ≥1 year PT) for up to 52 weeks. Placebo dose was doubled if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.

    Reporting group values
    		 Ramipril Placebo Total
    Number of subjects
    		 155 140 295
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.8 ± 12.7 47.5 ± 12.9 -
    Gender categorical
    Units: Subjects
        Female
    		 48 50 98
        Male
    		 107 90 197

    End points

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    End points reporting groups
    Reporting group title
    Ramipril
    Reporting group description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received ramipril, 5 or 10 mg/day orally (PO). 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 nanograms per millilitre [ng/mL] less than [<]1 year post-transplant [PT], 5-15 ng/mL greater than or equal to [≥]1 year PT) for up to 52 weeks. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 ng/mL <1 year PT, 5-15 ng/mL ≥1 year PT) for up to 52 weeks. Placebo dose was doubled if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.

    Subject analysis set title
    Pharmacokinetic analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Cmin,TN was determined for SRL using the area method for the intervals: 0–2 weeks, >2–4 weeks, >4–12 weeks, >12–24 weeks, >24–36 weeks and >36–52 weeks using the equation Cmin,TN = AUCi-j/timej-timei, where AUC was the area under the concentration-time curve, i was the beginning of the interval and j was the end of the interval. Cmin,TN was calculated for participants who did not dropout of studies, but were missing concentrations at the interval endpoints by carrying the last observed concentration forward to the interval endpoint.

    Primary: Percentage of Participants who had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants who had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL
    End point description
    The event for each participant was defined as the initiation of losartan while on SRL and ramipril/placebo combination therapy. Participants who started losartan prior to SRL administration were not counted as events. Percentage was estimated using Kaplan-Meier method for time to event data. Modified Intent to Treat (mITT) population: all participants in the safety population who took at least one dose of SRL.
    End point type
    Primary
    End point timeframe
    From Day 1 of SRL conversion to 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: Percentage of Participants
        number (confidence interval 95%)
    6.2 (2.7 to 11.6)
    23.2 (15.7 to 31.4)
    Statistical analysis title
    		 Statistical Analysis Ramipril, Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0002 [1]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.228
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.099
         upper limit
    		 0.528
    Notes
    [1] - 2-sided p-value; alpha equals (=) 0.05 Stratified log-rank test with region and race strata

    Secondary: Percentage of Participants who had a Dose Escalation in Randomised Test Article (Ramipril or Placebo) by 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants who had a Dose Escalation in Randomised Test Article (Ramipril or Placebo) by 52 Weeks Following Conversion to SRL
    End point description
    Defined as the time from the first dose of SRL administration to the first dose escalation of randomised test article (ramipril or placebo; in weeks), or censored on the day that a participant stopped the combination of SRL and randomised test article (ramipril or placebo) if the participants did not experience any ramipril/placebo dose escalation following conversion to SRL. Dose-escalation was defined as an increase in total daily dose of ramipril/placebo compared to Day 1 post conversion. Percentage was estimated using Kaplan-Meier method for time to event data. mITT population.
    End point type
    Secondary
    End point timeframe
    From Day 1 of SRL conversion to 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.4 (8.7 to 21.3)
    29.2 (21.2 to 37.6)
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0031
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.425
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.237
         upper limit
    		 0.763

    Secondary: Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to SRL
    End point description
    Spot urine sample of protein and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion. mITT population; includes assessments from On-Therapy and Off-Therapy Periods.
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: Percentage of Participants
    number (not applicable)
        Up to 24 weeks post-conversion
    92
    77.8
        Up to 52 weeks post-conversion
    82.6
    73
    Statistical analysis title
    		 Up to 24 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Up to 52 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.074 [3]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants With Urinary Albumin to Creatinine Ratio (U alb/c) <0.5 at 24 and 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants With Urinary Albumin to Creatinine Ratio (U alb/c) <0.5 at 24 and 52 Weeks Following Conversion to SRL
    End point description
    Spot urine sample of albumin and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion. mITT population; includes assessments from On-Therapy and Off-Therapy Periods.
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: Percentage of Participants
    number (not applicable)
        Up to 24 weeks post-conversion
    95.7
    89.7
        Up to 52 weeks post-conversion
    88.4
    82.5
    Statistical analysis title
    		 Up to 24 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.093 [4]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Up to 52 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.219 [5]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [5] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants with Both U alb/c <0.5 and U p/c <0.5 at 24 and 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants with Both U alb/c <0.5 and U p/c <0.5 at 24 and 52 Weeks Following Conversion to SRL
    End point description
    The U alb/c and U p/c must have been collected on the same day to be counted as the numerator. mITT population; includes assessments from On-Therapy and Off-Therapy Periods.
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: Percentage of Participants
    number (not applicable)
        Up to 24 weeks post-conversion
    91.3
    77
        Up to 52 weeks post-conversion
    79
    70.6
    Statistical analysis title
    		 Up to 24 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002 [6]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [6] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Up to 52 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.121 [7]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [7] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL

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    End point title
    		 U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL
    End point description
    U p/c was measured in milligrams per milligram (mg/mg). The baseline U p/c values were the last values of the pre-SRL conversion period. mITT population; n (number) = number of participants assessed for the specified parameter at a given visit; only participants with non-missing records of U p/c were included in the analysis. Includes measures collected from On-Therapy and Off-Therapy Periods. CFB = change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: mg /mg
    arithmetic mean (standard deviation)
        Baseline (n=138,126)
    0.17 ± 0.37
    0.15 ± 0.07
        Week 3 (n=130,117)
    0.18 ± 0.11
    0.23 ± 0.19
        Week 4 (n=136,124)
    0.18 ± 0.09
    0.28 ± 0.27
        Week 8 (n=130,119)
    0.23 ± 0.39
    0.31 ± 0.37
        Week 12 (n=124,121)
    0.23 ± 0.3
    0.38 ± 1.18
        Week 24 (n=121,122)
    0.26 ± 0.4
    0.31 ± 0.39
        Week 30 (n=111,108)
    0.23 ± 0.23
    0.32 ± 0.37
        Week 36 (n=109,92)
    0.22 ± 0.13
    0.29 ± 0.3
        Week 52 (n=126,111)
    0.27 ± 0.31
    0.35 ± 0.43
    Attachments
    		 Adjusted Geometric Mean Fold Change
    Statistical analysis title
    		 CFB at Week 3, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.0098 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment ratio
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 0.96
    Notes
    [8] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [9] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). Analysis of covariance (ANCOVA) model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 4, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.0003 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.89
    Notes
    [10] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [11] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 8, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.0016 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.91
    Notes
    [12] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [13] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 12, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.0165 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.96
    Notes
    [14] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [15] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 24, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0264 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.98
    Notes
    [16] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [17] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 30, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.0062 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.93
    Notes
    [18] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [19] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 36, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.0341 [21]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.99
    Notes
    [20] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [21] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 52, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.06 [23]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.01
    Notes
    [22] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [23] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic Up/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.

    Secondary: U alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL

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    End point title
    		 U alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL
    End point description
    U alb/c was measured in mg/mg. Baseline U alb/c values were the last values of the pre-SRL conversion period. mITT population; n=number of participants assessed for the specified parameter at a given visit; only participants with non-missing records of U alb/c were included in the analysis. Includes measures collected from On-Therapy and Off-Therapy Periods. CFB = change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: mg /mg
    arithmetic mean (standard deviation)
        Baseline (n=138,126)
    0.04 ± 0.26
    0.02 ± 0.02
        Week 3 (n=129,117)
    0.03 ± 0.05
    0.06 ± 0.11
        Week 4 (n=136,124)
    0.03 ± 0.04
    0.09 ± 0.16
        Week 8 (n=129,119)
    0.06 ± 0.31
    0.11 ± 0.24
        Week 12 (n=124,121)
    0.05 ± 0.09
    0.17 ± 0.84
        Week 24 (n=121,122)
    0.08 ± 0.24
    0.11 ± 0.28
        Week 30 (n=111,108)
    0.06 ± 0.13
    0.11 ± 0.21
        Week 36 (n=109,92)
    0.05 ± 0.08
    0.1 ± 0.21
        Week 52 (n=126,111)
    0.09 ± 0.21
    0.15 ± 0.31
    Attachments
    		 Adjusted Geometric Mean Fold Change
    Statistical analysis title
    		 CFB at Week 3, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.0034 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.89
    Notes
    [24] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [25] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 4, Ramipril v Placebo
    Comparison groups
    Placebo v Ramipril
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 < 0.0001 [27]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.76
    Notes
    [26] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [27] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 8, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.0002 [29]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.79
    Notes
    [28] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [29] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 12, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.0032 [31]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.87
    Notes
    [30] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [31] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 24, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.013 [33]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.92
    Notes
    [32] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [33] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 30, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.0577 [35]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.01
    Notes
    [34] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [35] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 36, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 = 0.1146 [37]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.07
    Notes
    [36] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [37] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.
    Statistical analysis title
    		 CFB at Week 52, Ramipril v Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 = 0.3496 [39]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.2
    Notes
    [38] - Treatment ratio (Ramipril/Placebo) in the geometric mean fold-change.
    [39] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA model with change in the logarithmic U alb/c as dependent variable, treatment and region/race as factors, and logarithmic baseline as covariate.

    Secondary: Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL
    End point description
    Defined as the percentage of participants who stop SRL (as test article) between the first day of SRL and either Week 24 or Week 52 following conversion to SRL. If a participant had a >14 day gap in SRL use, the stop date of SRL was the date of the last SRL use before it was re-initiated. Participants who early terminate SRL at Week 24 were defined as having SRL stop day less than or equal to (≤) Day 190 (selected as the midpoint between Weeks 24 and 30). Participants who early terminate SRL at Week 52 were defined as having SRL stop day ≤Day 337 (selected as the midpoint between Weeks 44 and 52). mITT population.
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: p e r c e nt a ge o f participants
    number (not applicable)
        Up to 24 weeks post-conversion
    15.2
    15.9
        Up to 52 weeks post-conversion
    19.6
    28.6
    Statistical analysis title
    		 Up to 24 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [40] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Up to 52 weeks post-conversion
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 = 0.1115
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [41] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL

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    End point title
    		 Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL
    End point description
    Calculated in millimetres per minute per 1.73 square meters (mL/min/1.73m^2). Age and corresponding creatinine at each visit (Weeks 12, 24, and 52) were used to calculate GFR. mITT population; n=number of participants assessed for the specified parameter at a given visit. Includes measures collected from On-Therapy and Off-Therapy Periods.
    End point type
    Secondary
    End point timeframe
    12, 24, and 52 weeks following conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: m L /m i n / 1. 7 3 m^2
    arithmetic mean (standard deviation)
        Baseline (n=138,126)
    62.06 ± 14.08
    63.3 ± 15.64
        Week 12 (n=125,122)
    64.91 ± 16.54
    66.58 ± 15.26
        Week 24 (n=123,122)
    65.18 ± 17.99
    63.85 ± 16.49
        Week 52 (n=128,115)
    64.17 ± 16.79
    63.41 ± 15.54
    Statistical analysis title
    		 Change from Baseline at Week 12
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 = 0.4933 [43]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted LS Mean Difference
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.33
         upper limit
    		 1.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.26
    Notes
    [42] - Adjusted Least Squares (LS) Mean Difference Adjusted for baseline
    [43] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) ANCOVA model with MDRD change as dependent variable, treatment and region/race as factors, and baseline as covariate.
    Statistical analysis title
    		 Change from Baseline at Week 24
    Comparison groups
    Placebo v Ramipril
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 = 0.0888 [45]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted LS Mean Difference
    Point estimate
    2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 5.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.45
    Notes
    [44] - Adjusted LS Mean Difference Adjusted for baseline
    [45] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) ANCOVA model with MDRD change as dependent variable, treatment and region/race as factors, and baseline as covariate.
    Statistical analysis title
    		 Change from Baseline at Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 = 0.1475 [47]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted LS Mean Difference
    Point estimate
    2.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 4.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.46
    Notes
    [46] - Adjusted LS Mean Difference Adjusted for baseline
    [47] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) ANCOVA model with MDRD change as dependent variable, treatment and region/race as factors, and baseline as covariate.

    Secondary: Fraction of Albumin (milligrams per decilitre [mg/dL]) to Protein (mg/dL) in Urine at 24 and 52 Weeks After Conversion to SRL

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    End point title
    		 Fraction of Albumin (milligrams per decilitre [mg/dL]) to Protein (mg/dL) in Urine at 24 and 52 Weeks After Conversion to SRL
    End point description
    Baseline fraction was the last value of the pre-SRL conversion period. Only the last value of U p/c or U alb/c was used for analysis if multiple measurements occurred in the same data analysis interval. Fraction of albumin and protein was calculated only when urine protein was 6.2 mg/dL or higher. For urine albumin, if the value was reported as '<xx.x', the numerical portion of the value was used in the calculation of fraction of albumin and protein. mITT population; n=number of participants assessed for the specified parameter at a given visit. Includes measures collected from On-Therapy and Off-Therapy Periods.
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    111
    110
    Units: (mg /dL ) /(mg / d L)
    arithmetic mean (standard deviation)
        Week 24 (n=104,110)
    0.19 ± 0.17
    0.25 ± 0.19
        Week 52 (n=111,105)
    0.22 ± 0.18
    0.25 ± 0.2
    Statistical analysis title
    		 Week 24
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 = 0.1167 [49]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.04
    Notes
    [48] - Treatment ratio (Ramipril/Placebo) in the geometric mean.
    [49] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) Log (Fraction of albumin to protein in urine) as dependent variable, treatment and region/race as factor, and Log (baseline) as covariate.
    Statistical analysis title
    		 Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 other [50]
    P-value
    		 = 0.7519 [51]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.31
    Notes
    [50] - Treatment ratio (Ramipril/Placebo) in the geometric mean.
    [51] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) Log (Fraction of albumin to protein in urine) as dependent variable, treatment and region/race as factor, and Log (baseline) as covariate.

    Secondary: Percentage of Participants with Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category

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    End point title
    		 Percentage of Participants with Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category
    End point description
    BP values of potential clinical importance were recorded and categorised as follows: diastolic BP (DBP) ≤50 millimetres of mercury (mmHg) or ≥110 mmHg and systolic BP (SBP) ≤90 mmHg and ≥180 mmHg. Data were summarised for the on-therapy period and the off-therapy period and for the pre-SRL period. Safety population.
    End point type
    Secondary
    End point timeframe
    Baseline, Pre-SRL (from first dose of ramipril/placebo up to SRL conversion), On-Therapy (up to 52 weeks after SRL conversion), and Off-Therapy Period (up to 56 weeks after SRL conversion)
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Baseline, Low DBP ≤50 mmHg (n=155,140)
    0
    0.7
        Baseline, Low SBP: ≤90 mmHg (n=155,140)
    0
    0.7
        Pre-SRL, Low DBP: ≤50 mmHg (n=152,135)
    0
    0.7
        Pre-SRL, High DBP: ≥110 mmHg (n=152,135)
    0
    1.5
        Pre-SRL, Low SBP: ≤90 mmHg (n=152,135)
    0
    0.7
        Pre-SRL, High SBP: ≥180 mmHg (n=152,135)
    0.7
    0.7
        On Therapy, Low DBP: ≤50 mmHg (n=138,126)
    3.6
    2.4
        On Therapy, High DBP: ≥110 mmHg (n=138,126)
    0
    1.6
        On Therapy, Low SBP: ≤90 mmHg (n=138,126)
    3.6
    4
        On Therapy, High SBP: ≥180 mmHg (n=138,126)
    0.7
    4
        Off Therapy, High DBP ≥110 mmHg (n=35,69)
    2.9
    1.4
        Off Therapy, Low SBP: ≤90 mmHg (n=35,69)
    2.9
    1.4
    Statistical analysis title
    		 Pre-SRL, Low DBP ≤50 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.47 [52]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [52] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL, High DBP ≥110 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.22 [53]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [53] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL, Low SBP: ≤90 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.47 [54]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [54] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL, High SBP: ≥180 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [55]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [55] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On Therapy, Low DBP ≤50 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.725 [56]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [56] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On Therapy, High DBP ≥110 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.227 [57]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [57] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On Therapy, Low SBP: ≤90 mmHg
    Comparison groups
    Placebo v Ramipril
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1 [58]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [58] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On Therapy, High SBP: ≥180 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.106 [59]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [59] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Off Therapy, High DBP ≥110 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [60]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [60] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Off Therapy, Low SBP: ≤90 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [61]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [61] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Baseline, Low DBP ≤50 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.475 [62]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [62] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Baseline, Low SBP: ≤90 mmHg
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.475 [63]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [63] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: SRL Time Normalised Trough Concentration (Cmin,TN) by Time Interval

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    End point title
    		 SRL Time Normalised Trough Concentration (Cmin,TN) by Time Interval
    End point description
    Cmin,TN was determined for SRL using the area method for the intervals: 0–2 weeks, >2–4 weeks, >4–12 weeks, >12–24 weeks, >24–36 weeks and >36–52 weeks using the equation Cmin,TN = AUCi-j/timej-timei, where AUC was the area under the concentration-time curve, i was the beginning of the interval and j was the end of the interval. Cmin,TN was calculated for participants who did not dropout of studies, but were missing concentrations at the interval endpoints by carrying the last observed concentration forward to the interval endpoint. Safety population; n=number of participants assessed for the specified parameter for the given time interval; only participants dosed throughout the interval were included.
    End point type
    Secondary
    End point timeframe
    From Day 1 of SRL conversion to 52 weeks after conversion
    End point values
    		 Pharmacokinetic analysis set
    Number of subjects analysed
    258
    Units: ng/mL
    arithmetic mean (standard deviation)
        0-2 weeks (n=258)
    9.853 ± 6.025
        >2-4 weeks (n=257)
    9.872 ± 4.1408
        >4-12 weeks (n=256)
    9.273 ± 3.1763
        >12-24 weeks (n=244)
    9.274 ± 2.8944
        >24-36 weeks (n=226)
    9.316 ± 3.1535
        >36-52 weeks (n=193)
    8.961 ± 2.9031
        0-52 weeks (n=264)
    9.3 ± 2.2678
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Haemoglobin Levels ≤100 grams per litre (g/L)

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    End point title
    		 Percentage of Participants with Haemoglobin Levels ≤100 grams per litre (g/L)
    End point description
    Safety population
    End point type
    Secondary
    End point timeframe
    Baseline, Pre-SRL (from first dose of ramipril/placebo up to SRL conversion), On-Therapy (up to 52 weeks after SRL conversion), and Off-Therapy Period (up to 56 weeks after SRL conversion)
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Baseline (n=155,140)
    1.3
    1.4
        Pre-SRL (n=148,129)
    2
    0.8
        On-Therapy (n=138,124)
    17.4
    12.1
        Off-Therapy (n=33,34)
    9.1
    2.9
    Statistical analysis title
    		 Baseline
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [64]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [64] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.626 [65]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [65] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.297 [66]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [66] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Off-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.356 [67]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [67] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs])

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    End point title
    		 Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs])
    End point description
    Safety population; n=number of participants analysed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Pre-SRL (from first dose of ramipril/placebo up to SRL conversion), On-Therapy (up to 52 weeks after SRL conversion), and Off-Therapy Period (up to 56 weeks after SRL conversion)
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Baseline (n=155,140)
    5.8
    1.4
        Pre-SRL (n=155,140)
    4.5
    0.7
        On-Therapy (n=138,126)
    4.3
    3.2
        Off-Therapy (n=136,122)
    1.5
    4.1
    Statistical analysis title
    		 Baseline
    Comparison groups
    Placebo v Ramipril
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.064 [68]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [68] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.069 [69]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [69] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.752 [70]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [70] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Off-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.261 [71]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [71] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Change from Baseline in Fasting Lipid Parameters (millimoles per litre [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL

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    End point title
    		 Change from Baseline in Fasting Lipid Parameters (millimoles per litre [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL
    End point description
    Parameters assessed included (all fasting) total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C). Safety population; n=number of participants assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    4, 12, 24, and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    128
    109
    Units: mmol/L
    arithmetic mean (standard error)
        TC, Week 4 (n=128,109)
    0.83 ± 0.06
    0.91 ± 0.09
        TC, Week 12 (n=115,108)
    0.94 ± 0.09
    0.92 ± 0.1
        TC, Week 24 (n=105,102)
    0.91 ± 0.12
    0.87 ± 0.09
        TC, Week 52 (n=94,79)
    0.84 ± 0.11
    0.69 ± 0.12
        HDL-C, Week 4 (n=125,107)
    0.06 ± 0.02
    0.09 ± 0.03
        HDL-C, Week 12 (n=114,104)
    0.03 ± 0.02
    0.03 ± 0.02
        HDL-C, Week 24 (n=102,100)
    0.07 ± 0.03
    0.04 ± 0.03
        HDL-C, Week 52 (n=92,78)
    0.12 ± 0.03
    0.06 ± 0.04
        LDL-C, Week 4 (n=123,100)
    0.59 ± 0.06
    0.56 ± 0.07
        LDL-C, Week 12 (n=109,96)
    0.66 ± 0.08
    0.53 ± 0.08
        LDL-C, Week 24 (n=96,95)
    0.66 ± 0.1
    0.56 ± 0.08
        LDL-C, Week 52 (n=90,73)
    0.56 ± 0.1
    0.27 ± 0.09
        Triglycerides, Week 4 (n=127,108)
    0.41 ± 0.07
    0.65 ± 0.1
        Triglycerides, Week 12 (n=114,107)
    0.59 ± 0.1
    0.79 ± 0.11
        Triglycerides, Week 24 (n=104,102)
    0.54 ± 0.11
    0.72 ± 0.13
        Triglycerides, Week 52 (n=93,77)
    0.44 ± 0.1
    0.58 ± 0.14
    Statistical analysis title
    		 TC, Week 4
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.381 [72]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [72] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 TC, Week 12
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.956 [73]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [73] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 TC, Week 24
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.903 [74]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [74] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 TC, Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.503 [75]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [75] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 HDL-C, Week 4
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.451 [76]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [76] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 HDL-C, Week 12
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.919 [77]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [77] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 HDL-C, Week 24
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.637 [78]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [78] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 HDL-C, Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.229 [79]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [79] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 LDL-C, Week 4
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.766 [80]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [80] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 LDL-C, Week 12
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.217 [81]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [81] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 LDL-C, Week 24
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.457 [82]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [82] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 LDL-C, Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.041 [83]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [83] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 Triglycerides, Week 4
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.044 [84]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [84] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 Triglycerides, Week 12
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.18 [85]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [85] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 Triglycerides, Week 24
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.264 [86]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.19
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [86] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).
    Statistical analysis title
    		 Triglycerides, Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.408 [87]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9999
         upper limit
    		 9999
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [87] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity). ANCOVA with treatment as a factor and baseline as a covariate. -9999/9999 = data not available (no CI generated).

    Secondary: Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants with an Event

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    End point title
    		 Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants with an Event
    End point description
    BCAR was defined according to updated Banff criteria (1997) for renal allograft rejection. The time to the first BCAR was defined as the date of first BCAR to the date of the first dose of SRL (in weeks). Participants without BCAR were censored at the time of withdrawal from the study. mITT population; includes BCAR occurring in On-Therapy and Off-Therapy Periods.
    End point type
    Secondary
    End point timeframe
    From Day 1 of SRL conversion to 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: Number of Participants with an Event
        Biopsy-Confirmed Acute Rejection (BCAR)
    13
    5
    Statistical analysis title
    		 Ramipril, Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0732 [88]
    Method
    		 Logrank
    Parameter type
    		 Log hazard ratio
    Point estimate
    2.487
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.887
         upper limit
    		 6.978
    Notes
    [88] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) Hazard ratio was based on the Cox proportional hazards model.

    Secondary: Percentage of Participants with First BCAR at 24 and 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants with First BCAR at 24 and 52 Weeks Following Conversion to SRL
    End point description
    BCAR was defined according to updated Banff criteria (1997) for renal allograft rejection. Participants without BCAR were censored at the time of withdrawal from the study. Defined as the first BCAR occurring on therapy following conversion to SRL based on the mITT population. Time to first BCAR was defined as the date of first BCAR to date of the first dose of SRL (in weeks). Percentages were estimated using the Kaplan-Meier method for time to event data. mITT population; includes BCAR occurring in the On-Therapy and Off-Therapy Periods
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: percentage of participants
    number (confidence interval 95%)
        24 weeks postconversion
    8 (4.2 to 13.3)
    0.8 (0.1 to 4)
        52 weeks postconversion
    9.5 (5.3 to 15.1)
    3.2 (1.1 to 7.5)
    No statistical analyses for this end point

    Secondary: Number of Participants with BCAR by Severity of First BCAR

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    End point title
    		 Number of Participants with BCAR by Severity of First BCAR
    End point description
    Severity was summarised by type (antibody versus T-cell) and by phase: post-SRL (where both on-therapy and off-therapy events are included) and post-SRL (on-therapy). BCAR was categorised using Banff criteria as antibody-mediated (AM) or T-cell. AM BCAR severity was graded as Grade I (mild), Grade II (moderate [mod]), and Grade III (severe). T-cell BCAR severity was graded as 'Grade Ia, Ib (mild), Grade IIa, IIb (mod), and Grade III (severe). If a participant had both T-cell BCAR and AM BCAR on the first rejection, the participant was counted in each category. For participants with T-cell BCAR (post-SRL and post-SRL On -Therapy) the p-value could not be calculated and all events were mild in severity. mITT population; only participants with BCAR were included in the analysis.
    End point type
    Secondary
    End point timeframe
    From Day 1 of SRL conversion to 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    13
    8
    Units: Number of participants
        Post-SRL, AM BCAR, Grade I (mild)
    1
    2
        Post-SRL, AM BCAR, Grade II (mod)
    0
    1
        Post-SRL, AM BCAR, Grade III (severe)
    0
    1
        Post-SRL, T-Cell BCAR, Grade I (mild)
    12
    4
        Post-SRL (On-Therapy), AM BCAR, Grade I (mild)
    1
    1
        Post-SRL (On-Therapy), AM BCAR, Grade II (mod)
    0
    1
        Post-SRL (On-Therapy), T-Cell BCAR, Grade I (mild)
    10
    3
    Statistical analysis title
    		 Post-SRL, AM BCAR
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7165 [89]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [89] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) Cochran-Mantel-Haenszel row mean test
    Statistical analysis title
    		 Post-SRL (On-Therapy), AM BCAR
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4795 [90]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [90] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity) Cochran-Mantel-Haenszel row mean test

    Secondary: Percentage of Participants with Graft Loss at 24 and 52 Weeks Following Conversion to SRL

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    End point title
    		 Percentage of Participants with Graft Loss at 24 and 52 Weeks Following Conversion to SRL
    End point description
    Graft loss was defined as physical loss (nephrectomy or re-transplantation), functional loss (requiring dialysis for ≥56 days with no return of graft function), or death. mITT population
    End point type
    Secondary
    End point timeframe
    24 weeks and 52 weeks after conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    138
    126
    Units: percentage of participants
    number (not applicable)
        Week 24
    0
    0
        Week 52
    0
    0.8
    Statistical analysis title
    		 Week 52
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4773 [91]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [91] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants using Statins

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    End point title
    		 Percentage of Participants using Statins
    End point description
    Safety population; n=number of participants analysed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Pre-SRL (from first dose of ramipril/placebo up to SRL conversion), On-Therapy (up to 52 weeks after SRL conversion), and Off-Therapy Period (up to 56 weeks after SRL conversion)
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Baseline (n=155,140)
    45.8
    36.4
        Pre-SRL (n=155,140)
    45.2
    40
        On-Therapy (n=138,126)
    67.4
    72.2
        Off-Therapy (n=136,122)
    62.5
    68.9
    Statistical analysis title
    		 Baseline
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.124 [92]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [92] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.41 [93]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [93] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.423 [94]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [94] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Off-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.297 [95]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [95] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants with an Infection

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    End point title
    		 Percentage of Participants with an Infection
    End point description
    Includes treatment-emergent adverse events based on categorisation by the investigator as 'infection', regardless of the event preferred term in Medical Dictionary for Regulatory Activities (MedDRA.) Safety population
    End point type
    Secondary
    End point timeframe
    From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Percentage of Participants with
    54.2
    56.4
    Statistical analysis title
    		 Ramipril, Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.726 [96]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [96] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants with Angioedema

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    End point title
    		 Percentage of Participants with Angioedema
    End point description
    Includes treatment-emergent adverse events based on categorisation by the investigator as angioedema, regardless of the event preferred term in MedDRA. Safety population
    End point type
    Secondary
    End point timeframe
    From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Percentage of Participants with Angioedema
    1.3
    1.4
    Statistical analysis title
    		 Ramipril, Placebo
    Comparison groups
    Placebo v Ramipril
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [97]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [97] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants with Malignancy

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    End point title
    		 Percentage of Participants with Malignancy
    End point description
    Includes treatment-emergent adverse events based on categorisation by the investigator as 'malignancy', regardless of the event preferred term in MedDRA. Safety population
    End point type
    Secondary
    End point timeframe
    From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percentage of participants
    number (not applicable)
        Percentage of Participants with
    3.9
    2.9
    Statistical analysis title
    		 Ramipril, Placebo
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.753 [98]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [98] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Secondary: Percentage of Participants with Hyperkalaemia

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    End point title
    		 Percentage of Participants with Hyperkalaemia
    End point description
    Hyperkalaemia defined as serum potassium >5.6 millimoles per litre (mmol/L) Safety population; n=number of participants assessed for the specified parameter at a given visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Pre-SRL (from first dose of ramipril/placebo up to SRL conversion), On-Therapy (up to 52 weeks after SRL conversion), and Off-Therapy Period (up to 56 weeks after SRL conversion)
    End point values
    		 Ramipril Placebo
    Number of subjects analysed
    155
    140
    Units: percent of participants
    number (not applicable)
        Baseline (n=155,140)
    0
    1.4
        Pre-SRL (n=151,135)
    4.6
    1.5
        On-Therapy (n=138,124)
    0.7
    1.6
        Off-Therapy (n=34,36)
    2.9
    0
    Statistical analysis title
    		 Baseline
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.224 [99]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [99] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Pre-SRL
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.179 [100]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [100] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 On-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.604 [101]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [101] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)
    Statistical analysis title
    		 Off-Therapy
    Comparison groups
    Ramipril v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.486 [102]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [102] - 2-sided p-value; alpha=0.05 (unadjusted for multiplicity)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation through Week 52 following conversion to SRL
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorised as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per centre’s standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 ng/mL <1 year PT, 5-15 ng/mL ≥1 year PT) for up to 52 weeks. Placebo dose was doubled if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.

    Reporting group title
    Ramipril
    Reporting group description
    		 Participants were receiving CsA or TAC and either mycophenolate mofetil (MMF), mycophenolate sodium (MPS), or azathioprine (AZA) or steroids dosed per centre’s standard of care. Participants received ramipril, 5 or 10 milligrams (mg) per (/) day orally (PO). 2-6 weeks after randomisation, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/day (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 nanograms per millilitre [ng/mL] less than [<]1 year post-transplant [PT], 5-15 ng/mL greater than or equal to [≥]1 year PT) for up to 52 weeks. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/day was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/day. If then U p/c <0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.

    Serious adverse events
    		 Placebo Ramipril
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 140 (27.86%)
    50 / 155 (32.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 140 (1.43%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioblastoma
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 140 (0.71%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 140 (1.43%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena caval stenosis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 140 (0.00%)
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    3 / 140 (2.14%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    1 / 140 (0.71%)
    11 / 155 (7.10%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed [1]
    1 / 90 (1.11%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 140 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 140 (0.71%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium test positive
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Complications of transplanted kidney
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (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
    Cerebral infarction
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 140 (0.00%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 140 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 140 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 140 (1.43%)
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 140 (0.00%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         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
    Angioedema
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Obstructive uropathy
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst ruptured
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 140 (0.71%)
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 140 (0.71%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral bacterial infection
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 140 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 140 (0.71%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 140 (0.71%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 140 (0.71%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This adverse event of benign prostatic hyperplasia is only applicable to males and therefore the total number of subjects exposed is only the male participants and not the total number of participants in the reporting group.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ramipril
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 140 (87.86%)
    133 / 155 (85.81%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 140 (10.00%)
    10 / 155 (6.45%)
         occurrences all number
    16
    10
    Hypotension
         subjects affected / exposed
    7 / 140 (5.00%)
    14 / 155 (9.03%)
         occurrences all number
    8
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 140 (5.00%)
    12 / 155 (7.74%)
         occurrences all number
    8
    12
    Local swelling
         subjects affected / exposed
    9 / 140 (6.43%)
    3 / 155 (1.94%)
         occurrences all number
    10
    3
    Oedema peripheral
         subjects affected / exposed
    30 / 140 (21.43%)
    27 / 155 (17.42%)
         occurrences all number
    35
    30
    Pyrexia
         subjects affected / exposed
    9 / 140 (6.43%)
    11 / 155 (7.10%)
         occurrences all number
    9
    16
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed [2]
    6 / 90 (6.67%)
    4 / 107 (3.74%)
         occurrences all number
    8
    4
    Menorrhagia
         subjects affected / exposed [3]
    1 / 50 (2.00%)
    4 / 48 (8.33%)
         occurrences all number
    1
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 140 (10.00%)
    24 / 155 (15.48%)
         occurrences all number
    19
    26
    Oropharyngeal pain
         subjects affected / exposed
    12 / 140 (8.57%)
    7 / 155 (4.52%)
         occurrences all number
    15
    7
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    11 / 140 (7.86%)
    24 / 155 (15.48%)
         occurrences all number
    13
    28
    Weight increased
         subjects affected / exposed
    5 / 140 (3.57%)
    8 / 155 (5.16%)
         occurrences all number
    5
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 140 (7.14%)
    12 / 155 (7.74%)
         occurrences all number
    11
    16
    Headache
         subjects affected / exposed
    16 / 140 (11.43%)
    19 / 155 (12.26%)
         occurrences all number
    22
    22
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 140 (7.14%)
    18 / 155 (11.61%)
         occurrences all number
    11
    19
    Leukopenia
         subjects affected / exposed
    6 / 140 (4.29%)
    19 / 155 (12.26%)
         occurrences all number
    6
    24
    Gastrointestinal disorders
    Aphthous stomatitis
         subjects affected / exposed
    14 / 140 (10.00%)
    12 / 155 (7.74%)
         occurrences all number
    18
    21
    Diarrhoea
         subjects affected / exposed
    37 / 140 (26.43%)
    40 / 155 (25.81%)
         occurrences all number
    44
    52
    Mouth ulceration
         subjects affected / exposed
    17 / 140 (12.14%)
    12 / 155 (7.74%)
         occurrences all number
    21
    18
    Nausea
         subjects affected / exposed
    9 / 140 (6.43%)
    8 / 155 (5.16%)
         occurrences all number
    10
    9
    Stomatitis
         subjects affected / exposed
    11 / 140 (7.86%)
    7 / 155 (4.52%)
         occurrences all number
    14
    7
    Vomiting
         subjects affected / exposed
    8 / 140 (5.71%)
    10 / 155 (6.45%)
         occurrences all number
    9
    13
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    25 / 140 (17.86%)
    18 / 155 (11.61%)
         occurrences all number
    26
    21
    Rash
         subjects affected / exposed
    13 / 140 (9.29%)
    5 / 155 (3.23%)
         occurrences all number
    15
    6
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    15 / 140 (10.71%)
    8 / 155 (5.16%)
         occurrences all number
    17
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 140 (9.29%)
    15 / 155 (9.68%)
         occurrences all number
    16
    21
    Back pain
         subjects affected / exposed
    6 / 140 (4.29%)
    10 / 155 (6.45%)
         occurrences all number
    6
    10
    Pain in extremity
         subjects affected / exposed
    12 / 140 (8.57%)
    6 / 155 (3.87%)
         occurrences all number
    14
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 140 (5.00%)
    8 / 155 (5.16%)
         occurrences all number
    7
    10
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 140 (11.43%)
    27 / 155 (17.42%)
         occurrences all number
    18
    30
    Urinary tract infection
         subjects affected / exposed
    13 / 140 (9.29%)
    12 / 155 (7.74%)
         occurrences all number
    22
    26
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    19 / 140 (13.57%)
    14 / 155 (9.03%)
         occurrences all number
    20
    15
    Hypercholesterolaemia
         subjects affected / exposed
    14 / 140 (10.00%)
    17 / 155 (10.97%)
         occurrences all number
    17
    23
    Hyperlipidaemia
         subjects affected / exposed
    9 / 140 (6.43%)
    15 / 155 (9.68%)
         occurrences all number
    9
    15
    Hypertriglyceridaemia
         subjects affected / exposed
    15 / 140 (10.71%)
    16 / 155 (10.32%)
         occurrences all number
    25
    18
    Hypokalaemia
         subjects affected / exposed
    9 / 140 (6.43%)
    3 / 155 (1.94%)
         occurrences all number
    10
    3
    Notes
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event of erectile dysfunction is only applicable to males and therefore the total number of subjects exposed is only the male participants and not the total number of participants in the reporting group.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This adverse event of menorrhagia is only applicable to females and therefore the total number of subjects exposed is only the male participants and not the total number of participants in the reporting group.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Sep 2007
    • Phase 1 (Pre-SRL conversion): 2 to 4 weeks of therapy with ramipril or placebo (2 weeks were added). • Revised the total duration of the study to be approximately 160 (from 164) weeks.
    03 Sep 2008
    • Phase 1 Pre-SRL conversion was shortened to a minimum of 2 weeks up to a maximum of 4 weeks to decrease the amount of required in-clinic visits and allow participants to convert to SRL earlier while still performing all safety assessments. • Phase 2: added in MPS and editorial changes. • Formatting was changed and dosage amount of MMF, MPS, and AZA was clarified. • Time after transplant was changed from 6 to 60 months to 3 to 60 months. • The 4-weeks post randomisation period before SRL conversion was shortened to 2 to 4 weeks. Investigators then had the option to convert participants, if eligible for SRL conversion, at 2 weeks post randomisation rather than waiting until 4 weeks. The 4-week post-randomisation visit remained as an optional visit in the protocol. • Inclusion criteria number 4 was modified to include participants as early as 3 months post-transplant. • Ualb/c ratios stated in the exclusion criteria and relating to dose changes were removed from the protocol. • Target blood pressure was clarified to state <140/90 mm Hg throughout the protocol. • Angioedema was added as a safety endpoint and was considered an AE with special circumstances and was to be reported as a SAE for the duration of the study. • Day of randomisation and Day 1 of conversion may not have been required in centre visits if approved by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) and if appropriate arrangements were made for data collection and supply of study drug to participants. • Visits at Weeks 4, 8, and 12 post-discontinuation (off-therapy) had the option to be performed locally as approved by the IEC/IRB. • Ualb/c ratios for purposes of participant eligibility as well as dosage adjustments were removed from the protocol (all eligibility and dose adjustment decisions were based on the urine protein to creatinine ratios). The Ualb/c data were collected and analysed but not reported back to the centre.
    10 Dec 2008
    • Starting dose for ramipril and matching placebo lowered from 10 mg/day to 5 mg/day. • Enrolment period extended to 104 weeks. • Clarified participants can initiate conversion to SRL as late as 6 weeks following randomisation. • Participants who discontinued from assigned therapy once conversion to SRL began were followed for 52 weeks after initiation of conversion. • Clarified only women of child bearing potential required two methods of contraception when using MMF or MPS. • Updated Exclusion Criteria regarding prohibition of renin-angiotensin-aldosterone system blockade and of participants with Grade C Child-Pugh score. • Clarified dose reduction instructions regarding elevated serum creatinine, hyperkalaemia, hypotension, and hypertension applied to all participants. Hypertension was separated in its own section for clarity. • New SRL target trough levels determined by high-performance liquid chromatography. Notation that dose changes for the participants other immunosuppressive medications were based upon the new target SRL trough levels. • Changed study drug administration for off-therapy participants. • Clarified concomitant treatment for anaemia. • Changed information on concomitant use of insulin. • Clarified the definition of hypotension. • Updated definition of "off-therapy" participants. • Evaluation of hepatic impairment at screening was added. • Clarified utilisation of urine albumin to creatinine ratios. • Clarified timing for Day 1. • Added Week 24 and Week 52 post-SRL conversion visit. • Clarified AE follow-up for off-therapy participants and dropped participants; clarification of concomitant medication collection for off-therapy participants • Updated unblinding procedures. • Updated safety reporting. • Clarification of statistical methods. • Addition of secondary endpoint for evaluation of albumin to protein. • Addition of information on interim analysis. • Correction to statement of statistical power from 90% to 84%.
    26 Oct 2009
    • Updates to duration of participant participation and duration of study. • Updated exclusion criteria: Clarification to exclude planned systemic treatments with voriconazole, cisapride, or ketoconazole; haemoglobin criterion added to align with safety endpoint. • Clarification that participants with the following condition or characteristic at the visit immediately prior to the start of SRL were excluded from SRL conversion: Less than 10 consecutive days of treatment with ramipril or placebo therapy. • Based on feedback from the Food and Drug Administration, the interim analysis was removed. • Clarification regarding planned systemic treatment with voriconazole, cisapride, or ketoconazole. If a participant was receiving any of these medications before enrolment, use of the medication must have been discontinued before randomisation. If unplanned or unexpected use was deemed necessary by the investigator, further participation of the participant was discussed with the Medical Monitor. • Clarifications to: definitions of screen failures, dropped participants, and unblinding of participants. • Change in target SRL trough levels. • Clarifications to dose adjustments made for urine protein-to-creatinine ratio >0.5; and U p/c testing between protocol required visits. • Clarification that the decreasing the dose or holding/discontinuing/withdrawing of losartan was considered a dose reduction and that there was a time limit to this dose reduction consistent with ramipril or placebo dose reductions. • Clarifications to the treatment of elevated serum creatinine, the recording and reporting of AEs and SAEs, and to medication error versus overdose.
    26 Apr 2010
    • The enrolment period was extended until the end of December 2010 (time from first participant enrolled to last participant enrolled). • Clarifications added: - If treatment with SRL continued after a participant was discontinued from study treatment, this was collected in the case report form (CRF) on the immunosuppression off-therapy CRF page. - Ramipril or placebo and losartan dose adjustments due to a urine protein-to-creatinine ratio ≥0.5. Wording added to help clarify the timing of when repeat U p/c testing was required. • Previously Performed Biopsies (Data Safety Monitoring Board [DSMB] request): - All kidney biopsies that were performed on participants prior to 22 Mar 2010, including those for suspected rejection, for other indications at the discretion of the investigator, or for site protocol biopsies, were collected upon obtaining participant consent. - These biopsies were read by a central pathologist who was blinded to treatment assignment. • Mandatory Biopsies (DSMB request): - Performed at selected centres only. - Read locally according to the updated Banff 1997 criteria. - All participants enrolled at the participating centres after the implementation of Amendment 5 were required to have biopsies. - Biopsies were required for all newly enrolled participants prior to the day of randomisation (performed prior to the first dose of ramipril or placebo). - Data from a biopsy performed within 12 weeks of randomisation was permitted to be used as the baseline except for biopsies performed at the time of implantation. - A repeat biopsy was also required at Week 8 post-SRL conversion (±4 weeks).
    18 May 2010
    • A new visit was added at Week 44 Post-Conversion based on a recommendation made by the DSMB for an additional creatinine evaluation at 44 weeks post-SRL conversion. • The total volume of blood collected was increased from approximately 183 mL, to approximately 189 mL, dependent on the amount of time the participant on study.
    28 Feb 2011
    • Updated the number of participants to be enrolled; the screen failure rate and the pre conversion withdrawal rates were underestimated. Based on the current rate, approximately 440 participants were to be screened to achieve conversion targets. • Clarification that all participants, regardless if they are receiving lipid-lowering therapy, must have had fasting lipid levels below the exclusion criteria. • Enrolment timelines extended to allow complete enrolment of the study. • Addition of Hy's Law language. Changes included additional tests. • Revisions to the AE reporting section (replaced Wyeth AE and reporting sections with Pfizer sections). • There were 3 main changes for sites and study personnel: - SAEs with a causal relationship to SRL were to be collected after participants discontinued early from assigned therapy. - Criteria were provided for assessing and reporting potential drug-induced liver toxicity (Hy's Law). - Criterion was provided for reporting exposure to SRL during pregnancy (exposure in-utero).
    29 Feb 2012
    • Randomisation process for the study changed from the Wyeth randomisation system, CORE, to the Pfizer system, IMPALA. • For Turkey only, the study was changed to a Phase 3B study in order to address the Health Authority in Turkey's request that the phase of the protocol be changed. • Added exclusion criteria: Participants who were either pregnant or lactating at the time of screening. This change was made at the request of the Health Authority in Poland. • Changed the study procedure for the protocol: Per the request of the Ethics Committee in Israel, additional blood chemistry testing (for potassium) was added for the Week 1 post randomisation visit. • Per the Pfizer template for protocols, the change in terminology of events previously described as "Adverse Events with Special Circumstance" was changed to Medically Important Adverse Events. This change did not impact the reporting requirements; these events were viewed and defined in the protocol as medically important events and hence fell within the requirements for SAE reporting. • Changed as required per Pfizer template for protocol, including the addition of required specific text regarding exposure in utero, and additional clarification pertaining to cases that met or did not meet the criteria for Hy's law. • A new section was added to the protocol for medication error reporting. All medication errors events were to be reported regardless of whether or not they were accompanied by an AE and must have been documented accordingly on the medication error CRF. • A new section was added to the protocol for the DSMB; the operation of the Data Monitoring Committee and its interaction with the sponsor in terms of recommendations was stated in the protocol. • A new section was added to the protocol for the reporting of safety issue and serious breaches of the protocol or ICH GCP. • Extended study timelines to 5 years.
    14 Feb 2013
    • To reflect Pfizer’s updated policy requirements, the following change/clarification to the protocol was provided to all participating sites: SAEs occurring to a participant after the active reporting period had ended should have been reported to the sponsor if the investigator became aware of them. At a minimum, all SAEs that the investigator believed had at least a reasonable possibility of being related to study drug were to be reported to the sponsor.

    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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