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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Kidney Transplant

Intervention / Treatment
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* Drug: ramipril
* Drug: ramipril


Participation Criteria
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Eligibility Criteria
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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 / Exclusion Criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Capsule - initial treatment is 5 mg (active)- oral - once per day | Drug: ramipril<br>* Capsule - initial treatment is 5 mg (active)- oral - once per day<br>|
| Placebo Comparator: B<br>Capsule - initial treatment is 5 mg (placebo) - oral - once per day | Drug: ramipril<br>* Capsule - initial treatment is 5 mg (placebo) - oral - once per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Day 1 of SRL conversion to 52 weeks after conversion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Day 1 of SRL conversion to 52 weeks after conversion | 
| 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. | 24 weeks and 52 weeks 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 | Spot urine sample of albumin and creatinine concentrations were obtained during the pre-SRL conversion period and after conversion. | 24 weeks and 52 weeks 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 | The U alb/c and U p/c must have been collected on the same day to be counted as the numerator. | 24 weeks and 52 weeks after conversion | 
| 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. | Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion | 
| 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. | Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion | 
| 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). | 24 weeks and 52 weeks after conversion | 
| 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. | 12, 24, and 52 weeks following conversion | 
| 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. | 24 weeks and 52 weeks after conversion | 
| 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. | 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) | 
| 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. | From Day 1 of SRL conversion to 52 weeks after conversion | 
| 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 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) | 
| 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). | 4, 12, 24, and 52 weeks after conversion | 
| 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. | From Day 1 of SRL conversion to 52 weeks after conversion | 
| 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. | 24 weeks and 52 weeks after conversion | 
| 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. | From Day 1 of SRL conversion to 52 weeks after conversion | 
| 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. | 24 weeks and 52 weeks after conversion | 
| 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 | 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.) | From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion | 
| 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. | From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion | 
| 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. | From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion | 
| Percentage of Participants With Hyperkalemia | Hyperkalemia defined as serum potassium >5.6 millimoles per liter (mmol/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) |