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

Kidney Transplant Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00502242
• Other study ID #: 0468E5-4439
• Secondary ID: B1741001
• Status: Completed
• Phase: Phase 4
• First received: July 16, 2007
• Last updated: August 13, 2014
• Start date: December 2007
• Est. completion date: September 2013

Study information

• Verified date: August 2014
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 229
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Transplant

Intervention

Drug:
• ramipril
Capsule - initial treatment is 5 mg (active)- oral - once per day
• ramipril
Capsule - initial treatment is 5 mg (placebo) - oral - once per day

Locations

Country	Name	City	State
Argentina	Pfizer Investigational Site	Buenos Aires
Argentina	Pfizer Investigational Site	Capital Federal	Buenos Aires
Argentina	Pfizer Investigational Site	Cordoba
Argentina	Pfizer Investigational Site	Córdoba
Argentina	Pfizer Investigational Site	San Martin	Buenos Aires
Australia	Pfizer Investigational Site	Brisbane	Queensland
Australia	Pfizer Investigational Site	North Terrace
Australia	Pfizer Investigational Site	Woodville South
Austria	Pfizer Investigational Site	Linz
Brazil	Pfizer Investigational Site	Porto Alegre	RS
Brazil	Pfizer Investigational Site	Porto Alegre	RS
Brazil	Pfizer Investigational Site	Rio de Janeiro	RJ
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Canada	Pfizer Investigational Site	Montreal	Quebec
Germany	Pfizer Investigational Site	Erlangen
Hungary	Pfizer Investigational Site	Szeged
Israel	Pfizer Investigational Site	Petach Tikva
Mexico	Pfizer Investigational Site	Mexico City
Mexico	Pfizer Investigational Site	Veracruz
Poland	Pfizer Investigational Site	Szczecin
South Africa	Pfizer Investigational Site	Cape Town	Western Cape
South Africa	Pfizer Investigational Site	Cape Town	Western Cape
South Africa	Pfizer Investigational Site	Johannesburg	Gauteng
United States	Pfizer Investigational Site	Aurora	Colorado
United States	Pfizer Investigational Site	Boston	Massachusetts
United States	Pfizer Investigational Site	Buffalo	New York
United States	Pfizer Investigational Site	Charleston	South Carolina
United States	Pfizer Investigational Site	Chicago	Illinois
United States	Pfizer Investigational Site	Cleveland	Ohio
United States	Pfizer Investigational Site	Cleveland	Ohio
United States	Pfizer Investigational Site	Denver	Colorado
United States	Pfizer Investigational Site	Gainesville	Florida
United States	Pfizer Investigational Site	Gosse Pointe	Michigan
United States	Pfizer Investigational Site	Harrisburg	Pennsylvania
United States	Pfizer Investigational Site	Iowa City	Iowa
United States	Pfizer Investigational Site	Lexington	Kentucky
United States	Pfizer Investigational Site	Los Angeles	California
United States	Pfizer Investigational Site	Los Angeles	California
United States	Pfizer Investigational Site	Philadelphia	Pennsylvania
United States	Pfizer Investigational Site	Philadelphia	Pennsylvania
United States	Pfizer Investigational Site	Philadelphia	Pennsylvania
United States	Pfizer Investigational Site	Portland	Maine
United States	Pfizer Investigational Site	Providence	Rhode Island
United States	Pfizer Investigational Site	San Francisco	California
United States	Pfizer Investigational Site	Springfield	Massachusetts
United States	Pfizer Investigational Site	Springfield	Massachusetts
United States	Pfizer Investigational Site	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Brazil,  Canada,  Germany,  Hungary,  Israel,  Mexico,  Poland,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	From Day 1 of SRL conversion to 52 weeks after conversion	No
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.	From Day 1 of SRL conversion to 52 weeks after conversion	No
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.	24 weeks and 52 weeks after conversion	No
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.	24 weeks and 52 weeks after conversion	No
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.	24 weeks and 52 weeks after conversion	No
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.	Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion	No
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.	Baseline and 3, 4, 8, 12, 24, 30, 36, and 52 weeks after conversion	No
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).	24 weeks and 52 weeks after conversion	No
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.	12, 24, and 52 weeks following conversion	No
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 '	24 weeks and 52 weeks after conversion	No
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.	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)	Yes
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.	From Day 1 of SRL conversion to 52 weeks after conversion	No
Secondary	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)	Yes
Secondary	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)	Yes
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).	4, 12, 24, and 52 weeks after conversion	Yes
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.	From Day 1 of SRL conversion to 52 weeks after conversion	Yes
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.	24 weeks and 52 weeks after conversion	Yes
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.	From Day 1 of SRL conversion to 52 weeks after conversion	Yes
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.	24 weeks and 52 weeks after conversion	Yes
Secondary	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)	Yes
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.)	From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion	Yes
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.	From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion	Yes
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.	From Day 1 of Ramipril/Placebo to 52 weeks after SRL conversion	Yes
Secondary	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)	Yes

External Links

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