Trial Outcomes & Findings for Study Evaluating The Effect Of Ramipril On Urinary Protein Excretion In Renal Transplant Patients Converted To Sirolimus (NCT NCT00502242)

Last Updated: 2014-08-27

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

229 participants

Primary outcome timeframe

From Day 1 of SRL conversion to 52 weeks after conversion

Results posted on

2014-08-27

Participant Flow

A Randomized, Placebo Controlled, Double-Blind Comparative Study Evaluating the Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.

Eligible participants were randomly assigned in a Double-Blind fashion to the Ramipril treatment group or the Placebo control group.

Participant milestones

Participant milestones
Measure	Ramipril Participants were receiving cyclosporine (CsA) or tacrolimus (TAC) and either mycophenolate mofetil (MMF), mycophenolate sodium (MPS), or azathioprine (AZA) or steroids dosed per center's standard of care. Participants received ramipril, 5 or 10 milligrams per day (mg/d) orally (PO). 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of sirolimus \[SRL\] initiation) and received SRL, PO, 2-4 mg/d (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 nanograms per milliliter \[ng/mL\] less than \[\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 urinary protein to creatinine ratio (U p/c) was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 ng/mL \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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Overall Study STARTED	155	140
Overall Study COMPLETED	104	84
Overall Study NOT COMPLETED	51	56

Reasons for withdrawal

Reasons for withdrawal
Measure	Ramipril Participants were receiving cyclosporine (CsA) or tacrolimus (TAC) and either mycophenolate mofetil (MMF), mycophenolate sodium (MPS), or azathioprine (AZA) or steroids dosed per center's standard of care. Participants received ramipril, 5 or 10 milligrams per day (mg/d) orally (PO). 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of sirolimus \[SRL\] initiation) and received SRL, PO, 2-4 mg/d (6-12 mg on Day 1 if TAC or CsA withdrawn abruptly) to achieve target trough levels (7-15 nanograms per milliliter \[ng/mL\] 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 urinary protein to creatinine ratio (U p/c) was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Overall Study Lack of Efficacy	1	11
Overall Study Adverse Event	31	20
Overall Study Physician Decision	2	3
Overall Study Other - Unspecified	8	14
Overall Study Protocol Violation	3	1
Overall Study Withdrawal by Subject	6	7

Baseline Characteristics

Study Evaluating The Effect Of Ramipril On Urinary Protein Excretion In Renal Transplant Patients Converted To Sirolimus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Total n=295 Participants Total of all reporting groups
Age, Continuous	46.8 Years STANDARD_DEVIATION 12.7 • n=99 Participants	47.5 Years STANDARD_DEVIATION 12.9 • n=107 Participants	47.1 Years STANDARD_DEVIATION 12.8 • n=206 Participants
Sex: Female, Male Female	48 Participants n=99 Participants	50 Participants n=107 Participants	98 Participants n=206 Participants
Sex: Female, Male Male	107 Participants n=99 Participants	90 Participants n=107 Participants	197 Participants n=206 Participants

PRIMARY outcome

Timeframe: From Day 1 of SRL conversion to 52 weeks after conversion

Population: Modified Intent to Treat (mITT) population: all participants in the safety population who took at least one dose of SRL.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants Who Had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL	6.2 percentage of participants Interval 2.7 to 11.6	23.2 percentage of participants Interval 15.7 to 31.4

SECONDARY outcome

Timeframe: From Day 1 of SRL conversion to 52 weeks after conversion

Population: mITT population

Defined as the time from the first dose of SRL administration to the first dose escalation of randomized test article (ramipril or placebo; in weeks), or censored on the day that a participant stopped the combination of SRL and randomized 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.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants Who Had a Dose Escalation in Randomized Test Article (Ramipril or Placebo) by 52 Weeks Following Conversion to SRL	14.4 percentage of participants Interval 8.7 to 21.3	29.2 percentage of participants Interval 21.2 to 37.6

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: mITT population; includes assessments from On-Therapy and Off-Therapy Periods.

Spot urine sample of protein and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to Sirolimus Up to 24 weeks post-conversion	92.0 percentage of participants	77.8 percentage of participants
Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to Sirolimus Up to 52 weeks post-conversion	82.6 percentage of participants	73.0 percentage of participants

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: mITT population; includes assessments from On-Therapy and Off-Therapy Periods.

Spot urine sample of albumin and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Urinary Albumin to Creatinine Ratio (U Alb/c) <0.5 at 24 and 52 Weeks Following Conversion to SRL Up to 24 weeks post-conversion	95.7 percentage of participants	89.7 percentage of participants
Percentage of Participants With Urinary Albumin to Creatinine Ratio (U Alb/c) <0.5 at 24 and 52 Weeks Following Conversion to SRL Up to 52 weeks post-conversion	88.4 percentage of participants	82.5 percentage of participants

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: mITT population; includes assessments from On-Therapy and Off-Therapy Periods.

The U alb/c and U p/c must have been collected on the same day to be counted as the numerator.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
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 Up to 24 weeks post-conversion	91.3 percentage of participants	77.0 percentage of participants
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 Up to 52 weeks post-conversion	79.0 percentage of participants	70.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion

Population: mITT population; n (number) = number of participants assessed for the specified parameter at a given visit; only participants with nonmissing records of U p/c were included in the analysis. Includes measures collected from On-Therapy and Off-Therapy Periods.

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.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Baseline (n=138,126)	0.17 mg/mg Standard Deviation 0.37	0.15 mg/mg Standard Deviation 0.07
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 3 (n=130,117)	0.18 mg/mg Standard Deviation 0.11	0.23 mg/mg Standard Deviation 0.19
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 4 (n=136,124)	0.18 mg/mg Standard Deviation 0.09	0.28 mg/mg Standard Deviation 0.27
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 8 (n=130,119)	0.23 mg/mg Standard Deviation 0.39	0.31 mg/mg Standard Deviation 0.37
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 12 (n=124,121)	0.23 mg/mg Standard Deviation 0.30	0.38 mg/mg Standard Deviation 1.18
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 24 (n=121,122)	0.26 mg/mg Standard Deviation 0.40	0.31 mg/mg Standard Deviation 0.39
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 30 (n=111,108)	0.23 mg/mg Standard Deviation 0.23	0.32 mg/mg Standard Deviation 0.37
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 36 (n=109,92)	0.22 mg/mg Standard Deviation 0.13	0.29 mg/mg Standard Deviation 0.30
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 52 (n=126,111)	0.27 mg/mg Standard Deviation 0.31	0.35 mg/mg Standard Deviation 0.43

SECONDARY outcome

Timeframe: Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion

Population: mITT population; n=number of participants assessed for the specified parameter at a given visit; only participants with nonmissing records of U alb/c were included in the analysis. Includes measures collected from On-Therapy and Off-Therapy Periods.

U alb/c was measured in mg/mg. Baseline U alb/c values were the last values of the pre-SRL conversion period.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Baseline (n=138,126)	0.04 mg/mg Standard Deviation 0.26	0.02 mg/mg Standard Deviation 0.02
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 3 (n=129,117)	0.03 mg/mg Standard Deviation 0.05	0.06 mg/mg Standard Deviation 0.11
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 4 (n=136,124)	0.03 mg/mg Standard Deviation 0.04	0.09 mg/mg Standard Deviation 0.16
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 8 (n=129,119)	0.06 mg/mg Standard Deviation 0.31	0.11 mg/mg Standard Deviation 0.24
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 12 (n=124,121)	0.05 mg/mg Standard Deviation 0.09	0.17 mg/mg Standard Deviation 0.84
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 24 (n=121,122)	0.08 mg/mg Standard Deviation 0.24	0.11 mg/mg Standard Deviation 0.28
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 30 (n=111,108)	0.06 mg/mg Standard Deviation 0.13	0.11 mg/mg Standard Deviation 0.21
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 36 (n=109,92)	0.05 mg/mg Standard Deviation 0.08	0.10 mg/mg Standard Deviation 0.21
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL Week 52 (n=126,111)	0.09 mg/mg Standard Deviation 0.21	0.15 mg/mg Standard Deviation 0.31

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: mITT population

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).

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL Up to 24 weeks post-conversion	15.2 percentage of participants	15.9 percentage of participants
Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL Up to 52 weeks post-conversion	19.6 percentage of participants	28.6 percentage of participants

SECONDARY outcome

Timeframe: 12, 24, and 52 weeks following conversion

Population: 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.

Calculated in millimeters 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.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL Baseline (n=138,126)	62.06 mL/min/1.73 m^2 Standard Deviation 14.08	63.30 mL/min/1.73 m^2 Standard Deviation 15.64
Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL Week 12 (n=125,122)	64.91 mL/min/1.73 m^2 Standard Deviation 16.54	66.58 mL/min/1.73 m^2 Standard Deviation 15.26
Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL Week 24 (n=123,122)	65.18 mL/min/1.73 m^2 Standard Deviation 17.99	63.85 mL/min/1.73 m^2 Standard Deviation 16.49
Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL Week 52 (n=128,115)	64.17 mL/min/1.73 m^2 Standard Deviation 16.79	63.41 mL/min/1.73 m^2 Standard Deviation 15.54

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: 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.

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 anlysis 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.

Outcome measures

Outcome measures
Measure	Ramipril n=111 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=110 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Fraction of Albumin (Milligrams Per Deciliter [mg/dL]) to Protein (mg/dL) in Urine at 24 and 52 Weeks After Conversion to SRL Week 24 (n=104,110)	0.19 (mg/dL)/(mg/dL) Standard Deviation 0.17	0.25 (mg/dL)/(mg/dL) Standard Deviation 0.19
Fraction of Albumin (Milligrams Per Deciliter [mg/dL]) to Protein (mg/dL) in Urine at 24 and 52 Weeks After Conversion to SRL Week 52 (n=111,105)	0.22 (mg/dL)/(mg/dL) Standard Deviation 0.18	0.25 (mg/dL)/(mg/dL) Standard Deviation 0.20

SECONDARY outcome

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)

Population: Safety population

BP values of potential clinical importance were recorded and categorized as follows: diastolic BP (DBP) ≤50 millimeters of mercury (mmHg) or ≥110 mmHg and systolic BP (SBP) ≤90 mmHg and ≥180 mmHg. Data were summarized for the on-therapy period and the off-therapy period and for the pre-SRL period.

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Off Therapy, Low SBP: ≤90 mmHg (n=35,69)	2.9 percentage of participants	1.4 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Baseline, Low DBP ≤50 mmHg (n=155,140)	0.0 percentage of participants	0.7 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Baseline, Low SBP: ≤90 mmHg (n=155,140)	0.0 percentage of participants	0.7 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Pre-SRL, Low DBP: ≤50 mmHg (n=152,135)	0.0 percentage of participants	0.7 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Pre-SRL, High DBP: ≥110 mmHg (n=152,135)	0.0 percentage of participants	1.5 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Pre-SRL, Low SBP: ≤90 mmHg (n=152,135)	0.0 percentage of participants	0.7 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Pre-SRL, High SBP: ≥180 mmHg (n=152,135)	0.7 percentage of participants	0.7 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category On Therapy, Low DBP: ≤50 mmHg (n=138,126)	3.6 percentage of participants	2.4 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category On Therapy, High DBP: ≥110 mmHg (n=138,126)	0.0 percentage of participants	1.6 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category On Therapy, Low SBP: ≤90 mmHg (n=138,126)	3.6 percentage of participants	4.0 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category On Therapy, High SBP: ≥180 mmHg (n=138,126)	0.7 percentage of participants	4.0 percentage of participants
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category Off Therapy, High DBP ≥110 mmHg (n=35,69)	2.9 percentage of participants	1.4 percentage of participants

SECONDARY outcome

Timeframe: From Day 1 of SRL conversion to 52 weeks after conversion

Population: Safety population; n=number of participants assessed for the specified parameter for the given time interval; only participants dosed throughout the interval were included.

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-timeiwhere AUC is the area under the concentration-time curve, i is the beginning of the interval and j is 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.

Outcome measures

Outcome measures
Measure	Ramipril n=258 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval 0-2 weeks (n=258)	9.853 ng/mL Standard Deviation 6.0250	—
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval >2-4 weeks (n=257)	9.872 ng/mL Standard Deviation 4.1408	—
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval >4-12 weeks (n=256)	9.273 ng/mL Standard Deviation 3.1763	—
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval >12-24 weeks (n=244)	9.274 ng/mL Standard Deviation 2.8944	—
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval >24-36 weeks (n=226)	9.316 ng/mL Standard Deviation 3.1535	—
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval >36-52 weeks (n=193)	8.961 ng/mL Standard Deviation 2.9031	—
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval 0-52 weeks (n=264)	9.300 ng/mL Standard Deviation 2.2678	—

SECONDARY outcome

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)

Population: Safety population

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) Baseline (n=155,140)	1.3 percentage of participants	1.4 percentage of participants
Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) Pre-SRL (n=148,129)	2.0 percentage of participants	0.8 percentage of participants
Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) On-Therapy (n=138,124)	17.4 percentage of participants	12.1 percentage of participants
Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) Off-Therapy (n=33,34)	9.1 percentage of participants	2.9 percentage of participants

SECONDARY outcome

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)

Population: Safety population; n=number of participants analyzed for the specified parameter at a given visit.

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) Baseline (n=155,140)	5.8 percentage of participants	1.4 percentage of participants
Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) Pre-SRL (n=155,140)	4.5 percentage of participants	0.7 percentage of participants
Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) On-Therapy (n=138,126)	4.3 percentage of participants	3.2 percentage of participants
Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) Off-Therapy (n=136,122)	1.5 percentage of participants	4.1 percentage of participants

SECONDARY outcome

Timeframe: 4, 12, 24, and 52 weeks after conversion

Population: Safety population; n=number of participants assessed for the specified parameter at a given visit.

Parameters assessed included (all fasting) total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-densitylipoprotein cholesterol (HDL-C).

Outcome measures

Outcome measures
Measure	Ramipril n=128 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=109 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL TC, Week 4 (n=128,109)	0.83 mmol/L Standard Error 0.06	0.91 mmol/L Standard Error 0.09
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL TC, Week 12 (n=115,108)	0.94 mmol/L Standard Error 0.09	0.92 mmol/L Standard Error 0.10
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL TC, Week 24 (n=105,102)	0.91 mmol/L Standard Error 0.12	0.87 mmol/L Standard Error 0.09
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL TC, Week 52 (n=94,79)	0.84 mmol/L Standard Error 0.11	0.69 mmol/L Standard Error 0.12
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL HDL-C, Week 4 (n=125,107)	0.06 mmol/L Standard Error 0.02	0.09 mmol/L Standard Error 0.03
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL HDL-C, Week 12 (n=114,104)	0.03 mmol/L Standard Error 0.02	0.03 mmol/L Standard Error 0.02
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL HDL-C, Week 24 (n=102,100)	0.07 mmol/L Standard Error 0.03	0.04 mmol/L Standard Error 0.03
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL HDL-C, Week 52 (n=92,78)	0.12 mmol/L Standard Error 0.03	0.06 mmol/L Standard Error 0.04
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL LDL-C, Week 4 (n=123,100)	0.59 mmol/L Standard Error 0.06	0.56 mmol/L Standard Error 0.07
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL LDL-C, Week 12 (n=109,96)	0.66 mmol/L Standard Error 0.08	0.53 mmol/L Standard Error 0.08
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL LDL-C, Week 24 (n=96,95)	0.66 mmol/L Standard Error 0.10	0.56 mmol/L Standard Error 0.08
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL LDL-C, Week 52 (n=90,73)	0.56 mmol/L Standard Error 0.10	0.27 mmol/L Standard Error 0.09
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL Triglycerides, Week 4 (n=127,108)	0.41 mmol/L Standard Error 0.07	0.65 mmol/L Standard Error 0.10
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL Triglycerides, Week 12 (n=114,107)	0.59 mmol/L Standard Error 0.10	0.79 mmol/L Standard Error 0.11
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL Triglycerides, Week 24 (n=104,102)	0.54 mmol/L Standard Error 0.11	0.72 mmol/L Standard Error 0.13
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL Triglycerides, Week 52 (n=93,77)	0.44 mmol/L Standard Error 0.10	0.58 mmol/L Standard Error 0.14

SECONDARY outcome

Timeframe: From Day 1 of SRL conversion to 52 weeks after conversion

Population: mITT population; includes BCAR occurring in On-Therapy and Off-Therapy Periods.

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.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants With an Event	13 participants	5 participants

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: mITT population; includes BCAR occurring in the On-Therapy and Off-Therapy Periods

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.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL 24 weeks post-conversion	8.0 percentage of participants Interval 4.2 to 13.3	0.8 percentage of participants Interval 0.1 to 4.0
Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL 52 weeks post-conversion	9.5 percentage of participants Interval 5.3 to 15.1	3.2 percentage of participants Interval 1.1 to 7.5

SECONDARY outcome

Timeframe: From Day 1 of SRL conversion to 52 weeks after conversion

Population: mITT population; only participants with BCAR were included in the anlaysis.

Severity was summarized 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 categorized 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 antibody-mediated 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.

Outcome measures

Outcome measures
Measure	Ramipril n=13 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=8 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Number of Participants With BCAR by Severity of First BCAR Post-SRL, AM BCAR, Grade I (mild)	1 participants	2 participants
Number of Participants With BCAR by Severity of First BCAR Post-SRL, AM BCAR, Grade II (mod)	0 participants	1 participants
Number of Participants With BCAR by Severity of First BCAR Post-SRL, AM BCAR, Grade III (severe)	0 participants	1 participants
Number of Participants With BCAR by Severity of First BCAR Post-SRL, T-Cell BCAR, Grade I (mild)	12 participants	4 participants
Number of Participants With BCAR by Severity of First BCAR Post-SRL (On-Therapy), AM BCAR, Grade I (mild)	1 participants	1 participants
Number of Participants With BCAR by Severity of First BCAR Post-SRL (On-Therapy), AM BCAR, Grade II (mod)	0 participants	1 participants
Number of Participants With BCAR by Severity of First BCAR Post-SRL (On-Therapy), T-Cell BCAR, Grade I (mild)	10 participants	3 participants

SECONDARY outcome

Timeframe: 24 weeks and 52 weeks after conversion

Population: mITT population

Graft loss was defined as physical loss (nephrectomy orretransplantation), functional loss (requiring dialysis for ≥56days with no return of graft function), or death.

Outcome measures

Outcome measures
Measure	Ramipril n=138 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=126 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL Week 24	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL Week 52	0.0 percentage of participants	0.8 percentage of participants

SECONDARY outcome

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)

Population: Safety population; n=number of participants analyzed for the specified parameter at a given visit.

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants Using Statins Baseline (n=155,140)	45.8 percentage of participants	36.4 percentage of participants
Percentage of Participants Using Statins Pre-SRL (n=155,140)	45.2 percentage of participants	40.0 percentage of participants
Percentage of Participants Using Statins On-Therapy (n=138,126)	67.4 percentage of participants	72.2 percentage of participants
Percentage of Participants Using Statins Off-Therapy (n=136,122)	62.5 percentage of participants	68.9 percentage of participants

SECONDARY outcome

Timeframe: From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion

Population: Safety population

Includes treatment-emergent adverse events based on categorization by the investigator as 'infection', regardless of the event preferred term in Medical Dictionary for Regulatory Activities (MedDRA.)

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With an Infection	54.2 percentage of participants	56.4 percentage of participants

SECONDARY outcome

Timeframe: From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion

Population: Safety population

Includes treatment-emergent adverse events based on categorization by the investigator as angioedema, regardless of the event preferred term in MedDRA.

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Angioedema	1.3 percentage of participants	1.4 percentage of participants

SECONDARY outcome

Timeframe: From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion

Population: Safety population

Includes treatment-emergent adverse events based on categorization by the investigator as 'malignancy', regardless of the event preferredterm in MedDRA.

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Malignancy	3.9 percentage of participants	2.9 percentage of participants

SECONDARY outcome

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)

Population: Safety population; n=number of participants assessed for the specified parameter at a given visit.

Hyperkalemia defined as serum potassium \>5.6 millimoles per liter (mmol/L)

Outcome measures

Outcome measures
Measure	Ramipril n=155 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received ramipril 5 or 10 mg/d PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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. Ramipril was increased to 10-20 mg if U p/c was ≥0.5. If U p/c ≥0.5 persisted, losartan 50 mg/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.	Placebo n=140 Participants Participants were receiving CsA or TAC and either MMF, MPS, or AZA or steroids dosed per center's standard of care. Participants received double-blinded placebo, 1 capsule (5 or 10 mg/day), PO. 2-6 weeks after randomization, participants stopped TAC or CsA (within 21 days of SRL initiation) and received SRL, PO, 2-4 mg/d (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/d was added; if U p/c ≥0.5 still persisted, losartan was increased to 100 mg/d. If then U p/c \<0.5 was not maintained, study medication was discontinued and participant entered off-therapy phase of study.
Percentage of Participants With Hyperkalemia Baseline (n=155,140)	0.0 percentage of participants	1.4 percentage of participants
Percentage of Participants With Hyperkalemia Pre-SRL (n=151,135)	4.6 percentage of participants	1.5 percentage of participants
Percentage of Participants With Hyperkalemia On-Therapy (n=138,124)	0.7 percentage of participants	1.6 percentage of participants
Percentage of Participants With Hyperkalemia Off-Therapy (n=34,36)	2.9 percentage of participants	0.0 percentage of participants

Adverse Events

Ramipril

Serious events: 50 serious events

Other events: 134 other events

Deaths: 0 deaths

Placebo

Serious events: 39 serious events

Other events: 123 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
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