Kidney Transplant
Conditions
Brief summary
The primary objective of the study is to determine the efficacy of ramipril in preventing a urinary protein to creatinine ratio (U p/c) greater than 0.5 following conversion to sirolimus from a calcineurin inhibitor (CNI) in maintenance kidney transplant patients.
Interventions
DRUGramipril
Capsule - initial treatment is 5 mg (active)- oral - once per day
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receiving cyclosporine (CsA) or tacrolimus (TAC) since the first month post-transplant. * In addition to a calcineurin inhibitor (CNI), subjects must be treated with either corticosteroids at a dosage range of 2.5 to 15 mg/day for prednisone or prednisolone (2 to 12mg/day for methylprednisolone or the alternate day equivalent) or a steroid-free regimen for a minimum of 12 weeks before randomization or either MMF (\>/=500mg/day), mycophenolate sodium (MPS) (\>/=360 mg/day) or AZA (\>/=50mg/day). Subjects must be taking a minimum of 2 immunosuppressive drugs if on a steroid-free regimen. * Subject is 3 to 60 months after renal transplantation. * Subject is greater than 12 weeks after treatment for any acute rejection.
Exclusion criteria
* Subjects who are currently receiving, or have received within 4 weeks before enrollment, RAAS blockade. * Subjects with a calculated GFR \< 40mL/min (per the Modification of Diet in Renal Disease \[MDRD-7\] or abbreviated MDRD formula). * Subjects with a urine protein to creatinine ratio (U p/c) of \>0.3. * Subjects with a history of uncontrolled systolic blood pressure (SBP \>140 mm Hg). * Subjects with severe hepatic impairment (Grade C Child-Pugh score). Additional Inclusion /
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL | From Day 1 of SRL conversion to 52 weeks after conversion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to Sirolimus | 24 weeks and 52 weeks after conversion | Spot urine sample of protein and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion. |
| Percentage of Participants With Urinary Albumin to Creatinine Ratio (U Alb/c) <0.5 at 24 and 52 Weeks Following Conversion to SRL | 24 weeks and 52 weeks after conversion | Spot urine sample of albumin and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion. |
| 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 | 24 weeks and 52 weeks after conversion | The U alb/c and U p/c must have been collected on the same day to be counted as the numerator. |
| U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL | Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion | 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. |
| U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL | Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion | U alb/c was measured in mg/mg. Baseline U alb/c values were the last values of the pre-SRL conversion period. |
| Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL | 24 weeks and 52 weeks after conversion | 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). |
| Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL | 12, 24, and 52 weeks following conversion | 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. |
| Fraction of Albumin (Milligrams Per Deciliter [mg/dL]) to Protein (mg/dL) in Urine at 24 and 52 Weeks After Conversion to SRL | 24 weeks and 52 weeks after conversion | 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. |
| Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category | 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) | 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. |
| SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | From Day 1 of SRL conversion to 52 weeks after conversion | 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. |
| Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | 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) | — |
| Percentage of Participants Who Had a Dose Escalation in Randomized Test Article (Ramipril or Placebo) by 52 Weeks Following Conversion to SRL | From Day 1 of SRL conversion to 52 weeks after conversion | 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. |
| Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL | 4, 12, 24, and 52 weeks after conversion | Parameters assessed included (all fasting) total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-densitylipoprotein cholesterol (HDL-C). |
| Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants With an Event | From Day 1 of SRL conversion to 52 weeks after conversion | 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. |
| Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL | 24 weeks and 52 weeks after conversion | 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. |
| Number of Participants With BCAR by Severity of First BCAR | From Day 1 of SRL conversion to 52 weeks after conversion | 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. |
| Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL | 24 weeks and 52 weeks after conversion | Graft loss was defined as physical loss (nephrectomy orretransplantation), functional loss (requiring dialysis for ≥56days with no return of graft function), or death. |
| Percentage of Participants Using Statins | 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) | — |
| Percentage of Participants With an Infection | From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion | 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.) |
| Percentage of Participants With Angioedema | From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion | Includes treatment-emergent adverse events based on categorization by the investigator as angioedema, regardless of the event preferred term in MedDRA. |
| Percentage of Participants With Malignancy | From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion | Includes treatment-emergent adverse events based on categorization by the investigator as 'malignancy', regardless of the event preferredterm in MedDRA. |
| Percentage of Participants With Hyperkalemia | 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) | Hyperkalemia defined as serum potassium \>5.6 millimoles per liter (mmol/L) |
| Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | 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) | — |
Countries
Argentina, Australia, Austria, Brazil, Canada, Germany, Hungary, Israel, Mexico, Poland, South Africa, United States
Participant flow
Recruitment details
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.
Pre-assignment details
Eligible participants were randomly assigned in a Double-Blind fashion to the Ramipril treatment group or the Placebo control group.
Participants by arm
| Arm | Count |
|---|---|
| Ramipril 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. | 155 |
| 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. | 140 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 31 | 20 |
| Overall Study | Lack of Efficacy | 1 | 11 |
| Overall Study | Other - Unspecified | 8 | 14 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Ramipril | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 46.8 Years STANDARD_DEVIATION 12.7 | 47.5 Years STANDARD_DEVIATION 12.9 | 47.1 Years STANDARD_DEVIATION 12.8 |
| Sex: Female, Male Female | 48 Participants | 50 Participants | 98 Participants |
| Sex: Female, Male Male | 107 Participants | 90 Participants | 197 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 134 / 155 | 123 / 140 |
| serious Total, serious adverse events | 50 / 155 | 39 / 140 |
Outcome results
Primary
Percentage of Participants Who Had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramipril | Percentage of Participants Who Had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL | 6.2 percentage of participants |
| Placebo | Percentage of Participants Who Had Initiated Losartan Therapy at 52 Weeks Following Conversion to SRL | 23.2 percentage of participants |
p-value: 0.000295% CI: [0.099, 0.528]Log Rank
Secondary
Abbreviated Modified Diet in Renal Disease (MDRD) Glomerular Filtration Rate (GFR) at Weeks 12, 24, and 52 Following Conversion to SRL
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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) | 63.41 mL/min/1.73 m^2 | Standard Deviation 15.54 |
| Placebo | 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) | 63.30 mL/min/1.73 m^2 | Standard Deviation 15.64 |
| Placebo | 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) | 63.85 mL/min/1.73 m^2 | Standard Deviation 16.49 |
| Placebo | 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) | 66.58 mL/min/1.73 m^2 | Standard Deviation 15.26 |
Comparison: Change from Baseline at Week 12p-value: 0.493395% CI: [-3.33, 1.61]ANCOVA
Comparison: Change from Baseline at Week 24p-value: 0.088895% CI: [-0.38, 5.33]ANCOVA
Comparison: Change from Baseline at Week 52p-value: 0.147595% CI: [-0.75, 4.99]ANCOVA
Secondary
Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants With an Event
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.
Time frame: From Day 1 of SRL conversion to 52 weeks after conversion
Population: mITT population; includes BCAR occurring in On-Therapy and Off-Therapy Periods.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramipril | Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants With an Event | 13 participants |
| Placebo | Biopsy-Confirmed Acute Rejection (BCAR) - Number of Participants With an Event | 5 participants |
p-value: 0.073295% CI: [0.887, 6.978]Log Rank
Secondary
Change From Baseline in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) at 4, 12, 24, and 52 Weeks Following Conversion to SRL
Parameters assessed included (all fasting) total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-densitylipoprotein cholesterol (HDL-C).
Time frame: 4, 12, 24, and 52 weeks after conversion
Population: Safety population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 0.1 |
| Ramipril | 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 |
| Ramipril | 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 0.1 |
| Ramipril | 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 |
| Ramipril | 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 0.1 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 0.1 |
| Ramipril | 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 |
| Placebo | 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) | 0.58 mmol/L | Standard Error 0.14 |
| Placebo | 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) | 0.69 mmol/L | Standard Error 0.12 |
| Placebo | 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) | 0.09 mmol/L | Standard Error 0.03 |
| Placebo | 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 |
| Placebo | 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) | 0.65 mmol/L | Standard Error 0.1 |
| Placebo | 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) | 0.91 mmol/L | Standard Error 0.09 |
| Placebo | 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) | 0.92 mmol/L | Standard Error 0.1 |
| Placebo | 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) | 0.04 mmol/L | Standard Error 0.03 |
| Placebo | 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) | 0.06 mmol/L | Standard Error 0.04 |
| Placebo | 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) | 0.56 mmol/L | Standard Error 0.07 |
| Placebo | 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) | 0.53 mmol/L | Standard Error 0.08 |
| Placebo | 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) | 0.56 mmol/L | Standard Error 0.08 |
| Placebo | 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) | 0.27 mmol/L | Standard Error 0.09 |
| Placebo | 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) | 0.79 mmol/L | Standard Error 0.11 |
| Placebo | 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) | 0.72 mmol/L | Standard Error 0.13 |
| Placebo | 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) | 0.87 mmol/L | Standard Error 0.09 |
Comparison: TC, Week 4p-value: 0.381ANCOVA
Comparison: TC, Week 12p-value: 0.956ANCOVA
Comparison: TC, Week 24p-value: 0.903ANCOVA
Comparison: TC, Week 52p-value: 0.503ANCOVA
Comparison: HDL-C, Week 4p-value: 0.451ANCOVA
Comparison: HDL-C, Week 12p-value: 0.919ANCOVA
Comparison: HDL-C, Week 24p-value: 0.637ANCOVA
Comparison: HDL-C, Week 52p-value: 0.229ANCOVA
Comparison: LDL-C, Week 4p-value: 0.766ANCOVA
Comparison: LDL-C, Week 12p-value: 0.217ANCOVA
Comparison: LDL-C, Week 24p-value: 0.457ANCOVA
Comparison: LDL-C, Week 52p-value: 0.041ANCOVA
Comparison: Triglycerides, Week 4p-value: 0.044ANCOVA
Comparison: Triglycerides, Week 12p-value: 0.18ANCOVA
Comparison: Triglycerides, Week 24p-value: 0.264ANCOVA
Comparison: Triglycerides, Week 52p-value: 0.408ANCOVA
Secondary
Fraction of Albumin (Milligrams Per Deciliter [mg/dL]) to Protein (mg/dL) in Urine at 24 and 52 Weeks After Conversion to SRL
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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) | 0.25 (mg/dL)/(mg/dL) | Standard Deviation 0.19 |
| Placebo | 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) | 0.25 (mg/dL)/(mg/dL) | Standard Deviation 0.2 |
Comparison: Week 24p-value: 0.116795% CI: [0.68, 1.04]ANCOVA
Comparison: Week 52p-value: 0.751995% CI: [0.82, 1.31]ANCOVA
Secondary
Number of Participants With BCAR by Severity of First BCAR
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.
Time frame: From Day 1 of SRL conversion to 52 weeks after conversion
Population: mITT population; only participants with BCAR were included in the anlaysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, T-Cell BCAR, Grade I (mild) | 12 participants |
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL (On-Therapy), AM BCAR, Grade I (mild) | 1 participants |
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, AM BCAR, Grade II (mod) | 0 participants |
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, AM BCAR, Grade III (severe) | 0 participants |
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL (On-Therapy), AM BCAR, Grade II (mod) | 0 participants |
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL (On-Therapy), T-Cell BCAR, Grade I (mild) | 10 participants |
| Ramipril | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, AM BCAR, Grade I (mild) | 1 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL (On-Therapy), T-Cell BCAR, Grade I (mild) | 3 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, AM BCAR, Grade III (severe) | 1 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL (On-Therapy), AM BCAR, Grade I (mild) | 1 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL (On-Therapy), AM BCAR, Grade II (mod) | 1 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, AM BCAR, Grade I (mild) | 2 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, AM BCAR, Grade II (mod) | 1 participants |
| Placebo | Number of Participants With BCAR by Severity of First BCAR | Post-SRL, T-Cell BCAR, Grade I (mild) | 4 participants |
Comparison: Post-SRL, AM BCARp-value: 0.7165Cochran-Mantel-Haenszel
Comparison: Post-SRL (On-Therapy), AM BCARp-value: 0.4795Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs])
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | Baseline (n=155,140) | 5.8 percentage of participants |
| Ramipril | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | Pre-SRL (n=155,140) | 4.5 percentage of participants |
| Ramipril | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | Off-Therapy (n=136,122) | 1.5 percentage of participants |
| Ramipril | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | On-Therapy (n=138,126) | 4.3 percentage of participants |
| Placebo | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | Off-Therapy (n=136,122) | 4.1 percentage of participants |
| Placebo | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | Baseline (n=155,140) | 1.4 percentage of participants |
| Placebo | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | Pre-SRL (n=155,140) | 0.7 percentage of participants |
| Placebo | Percentage of Participants Using Red Blood Cell Production Stimulants (Erythropoiesis Stimulating Agents [ESAs]) | On-Therapy (n=138,126) | 3.2 percentage of participants |
Comparison: Baselinep-value: 0.064Fisher Exact
Comparison: Pre-SRLp-value: 0.069Fisher Exact
Comparison: On-Therapyp-value: 0.752Fisher Exact
Comparison: Off-Therapyp-value: 0.261Fisher Exact
Secondary
Percentage of Participants Using Statins
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Percentage of Participants Using Statins | Off-Therapy (n=136,122) | 62.5 percentage of participants |
| Ramipril | Percentage of Participants Using Statins | On-Therapy (n=138,126) | 67.4 percentage of participants |
| Ramipril | Percentage of Participants Using Statins | Pre-SRL (n=155,140) | 45.2 percentage of participants |
| Ramipril | Percentage of Participants Using Statins | Baseline (n=155,140) | 45.8 percentage of participants |
| Placebo | Percentage of Participants Using Statins | Off-Therapy (n=136,122) | 68.9 percentage of participants |
| Placebo | Percentage of Participants Using Statins | Baseline (n=155,140) | 36.4 percentage of participants |
| Placebo | Percentage of Participants Using Statins | Pre-SRL (n=155,140) | 40.0 percentage of participants |
| Placebo | Percentage of Participants Using Statins | On-Therapy (n=138,126) | 72.2 percentage of participants |
Comparison: Baselinep-value: 0.124Fisher Exact
Comparison: Pre-SRLp-value: 0.41Fisher Exact
Comparison: On-Therapyp-value: 0.423Fisher Exact
Comparison: Off-Therapyp-value: 0.297Fisher Exact
Secondary
Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL
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).
Time frame: 24 weeks and 52 weeks after conversion
Population: mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL | Up to 24 weeks post-conversion | 15.9 percentage of participants |
| Placebo | Percentage of Participants Who Discontinued SRL Therapy at 24 and 52 Weeks Following Conversion to SRL | Up to 52 weeks post-conversion | 28.6 percentage of participants |
Comparison: Up to 24 weeks post-conversionp-value: 1Fisher Exact
Comparison: Up to 52 weeks post-conversionp-value: 0.1115Fisher Exact
Secondary
Percentage of Participants Who Had a Dose Escalation in Randomized Test Article (Ramipril or Placebo) by 52 Weeks Following Conversion to SRL
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.
Time frame: From Day 1 of SRL conversion to 52 weeks after conversion
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramipril | 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 |
| Placebo | Percentage of Participants Who Had a Dose Escalation in Randomized Test Article (Ramipril or Placebo) by 52 Weeks Following Conversion to SRL | 29.2 percentage of participants |
p-value: 0.003195% CI: [0.237, 0.763]Log Rank
Secondary
Percentage of Participants With Angioedema
Includes treatment-emergent adverse events based on categorization by the investigator as angioedema, regardless of the event preferred term in MedDRA.
Time frame: From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramipril | Percentage of Participants With Angioedema | 1.3 percentage of participants |
| Placebo | Percentage of Participants With Angioedema | 1.4 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants With an Infection
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.)
Time frame: From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramipril | Percentage of Participants With an Infection | 54.2 percentage of participants |
| Placebo | Percentage of Participants With an Infection | 56.4 percentage of participants |
p-value: 0.726Fisher Exact
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
The U alb/c and U p/c must have been collected on the same day to be counted as the numerator.
Time frame: 24 weeks and 52 weeks after conversion
Population: mITT population; includes assessments from On-Therapy and Off-Therapy Periods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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 | 77.0 percentage of participants |
| Placebo | 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 | 70.6 percentage of participants |
Comparison: Up to 24 weeks post-conversionp-value: 0.002Fisher Exact
Comparison: Up to 52 weeks post-conversionp-value: 0.121Fisher Exact
Secondary
Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL
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.
Time frame: 24 weeks and 52 weeks after conversion
Population: mITT population; includes BCAR occurring in the On-Therapy and Off-Therapy Periods
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL | 52 weeks post-conversion | 9.5 percentage of participants |
| Ramipril | Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL | 24 weeks post-conversion | 8.0 percentage of participants |
| Placebo | Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL | 24 weeks post-conversion | 0.8 percentage of participants |
| Placebo | Percentage of Participants With First BCAR at 24 and 52 Weeks Following Conversion to SRL | 52 weeks post-conversion | 3.2 percentage of participants |
Secondary
Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL
Graft loss was defined as physical loss (nephrectomy orretransplantation), functional loss (requiring dialysis for ≥56days with no return of graft function), or death.
Time frame: 24 weeks and 52 weeks after conversion
Population: mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL | Week 24 | 0.0 percentage of participants |
| Ramipril | Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL | Week 52 | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL | Week 24 | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Graft Loss at 24 and 52 Weeks Following Conversion to SRL | Week 52 | 0.8 percentage of participants |
Comparison: Week 52p-value: 0.4773Fisher Exact
Secondary
Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L)
Time frame: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | Baseline (n=155,140) | 1.3 percentage of participants |
| Ramipril | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | Pre-SRL (n=148,129) | 2.0 percentage of participants |
| Ramipril | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | On-Therapy (n=138,124) | 17.4 percentage of participants |
| Ramipril | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | Off-Therapy (n=33,34) | 9.1 percentage of participants |
| Placebo | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | Off-Therapy (n=33,34) | 2.9 percentage of participants |
| Placebo | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | Baseline (n=155,140) | 1.4 percentage of participants |
| Placebo | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | On-Therapy (n=138,124) | 12.1 percentage of participants |
| Placebo | Percentage of Participants With Hemoglobin Levels ≤100 Grams Per Liter (g/L) | Pre-SRL (n=148,129) | 0.8 percentage of participants |
Comparison: Baselinep-value: 1Fisher Exact
Comparison: Pre-SRLp-value: 0.626Fisher Exact
Comparison: On-Therapyp-value: 0.297Fisher Exact
Comparison: Off-Therapyp-value: 0.356Fisher Exact
Secondary
Percentage of Participants With Hyperkalemia
Hyperkalemia defined as serum potassium \>5.6 millimoles per liter (mmol/L)
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | Percentage of Participants With Hyperkalemia | On-Therapy (n=138,124) | 0.7 percentage of participants |
| Ramipril | Percentage of Participants With Hyperkalemia | Baseline (n=155,140) | 0.0 percentage of participants |
| Ramipril | Percentage of Participants With Hyperkalemia | Off-Therapy (n=34,36) | 2.9 percentage of participants |
| Ramipril | Percentage of Participants With Hyperkalemia | Pre-SRL (n=151,135) | 4.6 percentage of participants |
| Placebo | Percentage of Participants With Hyperkalemia | Off-Therapy (n=34,36) | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Hyperkalemia | On-Therapy (n=138,124) | 1.6 percentage of participants |
| Placebo | Percentage of Participants With Hyperkalemia | Pre-SRL (n=151,135) | 1.5 percentage of participants |
| Placebo | Percentage of Participants With Hyperkalemia | Baseline (n=155,140) | 1.4 percentage of participants |
Comparison: Baselinep-value: 0.224Fisher Exact
Comparison: Pre-SRLp-value: 0.179Fisher Exact
Comparison: On-Therapyp-value: 0.604Fisher Exact
Comparison: Off-Therapyp-value: 0.486Fisher Exact
Secondary
Percentage of Participants With Malignancy
Includes treatment-emergent adverse events based on categorization by the investigator as 'malignancy', regardless of the event preferredterm in MedDRA.
Time frame: From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramipril | Percentage of Participants With Malignancy | 3.9 percentage of participants |
| Placebo | Percentage of Participants With Malignancy | 2.9 percentage of participants |
p-value: 0.753Fisher Exact
Secondary
Percentage of Participants With Potentially Clinically Important Blood Pressure (BP) Values by Diastolic and Systolic BP Category
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.
Time frame: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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) | 1.4 percentage of participants |
| Placebo | 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) | 0.7 percentage of participants |
| Placebo | 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) | 2.4 percentage of participants |
| Placebo | 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) | 0.7 percentage of participants |
| Placebo | 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) | 4.0 percentage of participants |
| Placebo | 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) | 0.7 percentage of participants |
| Placebo | 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) | 1.6 percentage of participants |
| Placebo | 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) | 1.5 percentage of participants |
| Placebo | 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) | 1.4 percentage of participants |
| Placebo | 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) | 0.7 percentage of participants |
| Placebo | 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) | 4.0 percentage of participants |
| Placebo | 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 |
Comparison: Pre-SRL, Low DBP ≤50 mmHgp-value: 0.47Fisher Exact
Comparison: Pre-SRL, High DBP ≥110 mmHgp-value: 0.22Fisher Exact
Comparison: Pre-SRL, Low SBP: ≤90 mmHgp-value: 0.47Fisher Exact
Comparison: Pre-SRL, High SBP: ≥180 mmHgp-value: 1Fisher Exact
Comparison: On Therapy, Low DBP ≤50 mmHgp-value: 0.725Fisher Exact
Comparison: On Therapy, High DBP ≥110 mmHgp-value: 0.227Fisher Exact
Comparison: On Therapy, Low SBP: ≤90 mmHgp-value: 1Fisher Exact
Comparison: On Therapy, High SBP: ≥180 mmHgp-value: 0.106Fisher Exact
Comparison: Off Therapy, High DBP ≥110 mmHgp-value: 1Fisher Exact
Comparison: Off Therapy, Low SBP: ≤90 mmHgp-value: 1Fisher Exact
Comparison: Baseline, Low DBP ≤50 mmHgp-value: 0.475Fisher Exact
Comparison: Baseline, Low SBP: ≤90 mmHgp-value: 0.475Fisher Exact
Secondary
Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to Sirolimus
Spot urine sample of protein and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion.
Time frame: 24 weeks and 52 weeks after conversion
Population: mITT population; includes assessments from On-Therapy and Off-Therapy Periods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to Sirolimus | Up to 24 weeks post-conversion | 77.8 percentage of participants |
| Placebo | Percentage of Participants With U p/c <0.5 at 24 and 52 Weeks Following Conversion to Sirolimus | Up to 52 weeks post-conversion | 73.0 percentage of participants |
Comparison: Up to 24 weeks post-conversionp-value: 0.002Fisher Exact
Comparison: Up to 52 weeks post-conversionp-value: 0.074Fisher Exact
Secondary
Percentage of Participants With Urinary Albumin to Creatinine Ratio (U Alb/c) <0.5 at 24 and 52 Weeks Following Conversion to SRL
Spot urine sample of albumin and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion.
Time frame: 24 weeks and 52 weeks after conversion
Population: mITT population; includes assessments from On-Therapy and Off-Therapy Periods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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 | 89.7 percentage of participants |
| Placebo | 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 | 82.5 percentage of participants |
Comparison: Up to 24 weeks post-conversionp-value: 0.093Fisher Exact
Comparison: Up to 52 weeks post-conversionp-value: 0.219Fisher Exact
Secondary
SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | >2-4 weeks (n=257) | 9.872 ng/mL | Standard Deviation 4.1408 |
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | >4-12 weeks (n=256) | 9.273 ng/mL | Standard Deviation 3.1763 |
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | 0-2 weeks (n=258) | 9.853 ng/mL | Standard Deviation 6.025 |
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | >12-24 weeks (n=244) | 9.274 ng/mL | Standard Deviation 2.8944 |
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | >24-36 weeks (n=226) | 9.316 ng/mL | Standard Deviation 3.1535 |
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | >36-52 weeks (n=193) | 8.961 ng/mL | Standard Deviation 2.9031 |
| Ramipril | SRL Time-Normalized Trough Concentration (Cmin,TN) by Time Interval | 0-52 weeks (n=264) | 9.300 ng/mL | Standard Deviation 2.2678 |
Secondary
U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL
U alb/c was measured in mg/mg. Baseline U alb/c values were the last values of the pre-SRL conversion period.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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) | 0.15 mg/mg | Standard Deviation 0.31 |
| Placebo | U Alb/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL | Baseline (n=138,126) | 0.02 mg/mg | Standard Deviation 0.02 |
| Placebo | 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) | 0.06 mg/mg | Standard Deviation 0.11 |
| Placebo | 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) | 0.09 mg/mg | Standard Deviation 0.16 |
| Placebo | 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) | 0.11 mg/mg | Standard Deviation 0.24 |
| Placebo | 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) | 0.17 mg/mg | Standard Deviation 0.84 |
| Placebo | 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) | 0.11 mg/mg | Standard Deviation 0.28 |
| Placebo | 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) | 0.11 mg/mg | Standard Deviation 0.21 |
| Placebo | 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) | 0.10 mg/mg | Standard Deviation 0.21 |
Comparison: Change from Baseline at Week 30, Ramipril
Comparison: Change from Baseline at Week 3, Ramipril
Comparison: Change from Baseline at Week 3, Placebo
Comparison: Change from Baseline at Week 3, Ramipril vs. Placebop-value: 0.003495% CI: [0.57, 0.89]ANCOVA
Comparison: Change from Baseline at Week 4, Ramipril
Comparison: Change from Baseline at Week 4, Placebo
Comparison: Change from Baseline at Week 4, Ramipril vs. Placebop-value: <0.000195% CI: [0.47, 0.76]ANCOVA
Comparison: Change from Baseline at Week 8, Ramipril
Comparison: Change from Baseline at Week 8, Placebo
Comparison: Change from Baseline at Week 8, Ramipril vs. Placebop-value: 0.000295% CI: [0.47, 0.79]ANCOVA
Comparison: Change from Baseline at Week 12, Ramipril
Comparison: Change from Baseline at Week 12, Placebo
Comparison: Change from Baseline at Week 12, Ramipril vs. Placebop-value: 0.003295% CI: [0.49, 0.87]ANCOVA
Comparison: Change from Baseline at Week 24, Ramipril
Comparison: Change from Baseline at Week 24, Placebo
Comparison: Change from Baseline at Week 24, Ramipril vs. Placebop-value: 0.01395% CI: [0.51, 0.92]ANCOVA
Comparison: Change from Baseline at Week 30, Placebo
Comparison: Change from Baseline at Week 30, Ramipril vs. Placebop-value: 0.057795% CI: [0.54, 1.01]ANCOVA
Comparison: Change from Baseline at Week 36, Ramipril
Comparison: Change from Baseline at Week 36, Placebo
Comparison: Change from Baseline at Week 36, Ramipril vs. Placebop-value: 0.114695% CI: [0.56, 1.07]ANCOVA
Comparison: Change from Baseline at Week 52, Ramipril
Comparison: Change from Baseline at Week 52, Placebo
Comparison: Change from Baseline at Week 52, Ramipril vs. Placebop-value: 0.349695% CI: [0.6, 1.2]ANCOVA
Secondary
U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramipril | 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 |
| Ramipril | 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 0.4 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 |
| Ramipril | 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 0.3 |
| Ramipril | 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 |
| Ramipril | 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 |
| Placebo | 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) | 0.35 mg/mg | Standard Deviation 0.43 |
| Placebo | U p/c at Baseline and Weeks 3, 4, 8, 12, 24, 30, 36, and 52 Following Conversion to SRL | Baseline (n=138,126) | 0.15 mg/mg | Standard Deviation 0.07 |
| Placebo | 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) | 0.23 mg/mg | Standard Deviation 0.19 |
| Placebo | 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) | 0.28 mg/mg | Standard Deviation 0.27 |
| Placebo | 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) | 0.31 mg/mg | Standard Deviation 0.37 |
| Placebo | 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) | 0.38 mg/mg | Standard Deviation 1.18 |
| Placebo | 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) | 0.31 mg/mg | Standard Deviation 0.39 |
| Placebo | 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) | 0.32 mg/mg | Standard Deviation 0.37 |
| Placebo | 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) | 0.29 mg/mg | Standard Deviation 0.3 |
Comparison: Change from Baseline at Week 3, Ramipril
Comparison: Change from Baseline at Week 3, Placebo
Comparison: Change from baseline at Week 3, Ramipril versus (vs.) Placebop-value: 0.009895% CI: [0.76, 0.96]ANCOVA
Comparison: Change from baseline at Week 4, Ramipril
Comparison: Change from baseline at Week 4, Placebo
Comparison: Change from baseline at Week 4, Ramipril vs. Placebop-value: 0.000395% CI: [0.68, 0.89]ANCOVA
Comparison: Change from baseline at Week 8, Ramipirl
Comparison: Change from baseline at Week 8, Placebo
Comparison: Change from Baseline at Week 8, Ramipril vs. Placebop-value: 0.001695% CI: [0.68, 0.91]ANCOVA
Comparison: Change from Baseline at Week 12, Ramipril
Comparison: Change from Baseline at Week 12, Placebo
Comparison: Change from Baseline at Week 12, Ramipril vs. Placebop-value: 0.016595% CI: [0.7, 0.96]ANCOVA
Comparison: Change from Baseline at Week 24, Ramipril
Comparison: Change from Baseline at Week 24, Placebo
Comparison: Change from Baseline at Week 24, Ramipril vs. Placebop-value: 0.026495% CI: [0.7, 0.98]ANCOVA
Comparison: Change from Baseline at Week 30, Ramipril
Comparison: Change from Baseline at Week 30, Placebo
Comparison: Change from Baseline at Week 30, Ramipril vs. Placebop-value: 0.006295% CI: [0.66, 0.93]ANCOVA
Comparison: Change from Baseline at Week 36, Ramipril
Comparison: Change from Baseline at Week 36, Placebo
Comparison: Change from Baseline at Week 36, Ramipril vs. Placebop-value: 0.034195% CI: [0.72, 0.99]ANCOVA
Comparison: Change from Baseline at Week 52, Ramipril
Comparison: Change from Baseline at Week 52, Placebo
Comparison: Change from Baseline at Week 52, Ramipril vs. Placebop-value: 0.0695% CI: [0.7, 1.01]ANCOVA