A Phase 2, Placebo-Controlled Study To Evaluate The Efficacy And Safety Of PF-00489791 In Patients With Type 2 Diabetes And Overt Nephropathy

Study Overview
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Brief Summary
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PF-00489791 is an inhibitor of phosphodiesterase type 5. Our hypothesis is that PF-00489791 will enhance the relaxation of blood vessels within the kidney and so reduce blood pressure, improving renal function.

Official Title
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A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ONCE-DAILY ADMINISTRATION OF A PHOSPHODIESTERASE 5 INHIBITOR (PF-00489791) IN ADULTS WITH TYPE 2 DIABETES AND OVERT NEPHROPATHY

Conditions
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Diabetic Nephropathies

Intervention / Treatment
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* Drug: PF-00489791
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects greater than or equal to 18 years. Female subjects must be of non-child bearing potential. Clinical diagnosis of type 2 diabetes together with stages 3a, 3b or 4 CKD, based on an eGFR of 25-59 mL/min/1.73m2. Evidence of persistent, overt albuminuria; defined as a UACR greater than or equal to 300 mg/g (greater than or equal to 33.9 mg/mmol) for greater than 3 months. Exclusion Criteria: Subjects with CKD resulting from type 1 diabetes or non-diabetic CKD. Subjects with poorly controlled diabetes mellitus, defined as HbA1C >9%. Subjects on combination ACE inhibitor/ARB therapy.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-00489791<br> | Drug: PF-00489791<br>* Tablet, 20 mg once daily for 12 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Tablet, placebo once daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 | UACR was ratio of albumin measured in urine (milligram) to creatinine measured in urine (millimole), reported in units milligram per millimole (mg/mmol). A decrease in UACR may be associated with improved renal and cardiovascular function. The mean values of the 3 consecutive first morning void urine samples (obtained 2 days prior to [Day 5, 6 of Week 12], and with last sample collected on the morning of scheduled clinic visit [Day 7 of Week 12]) were used to determine UACR at the scheduled clinic visit. The mean values of the 3 consecutive first morning void urine samples obtained at screening were used to determine baseline UACR. | Baseline, Week 12 (Day 5, 6, 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | UACR was ratio of albumin measured in urine (milligram) to creatinine measured in urine (millimole), reported in units mg/mmol. A decrease in UACR may be associated with improved renal and cardiovascular function. The mean values of the 3 consecutive first morning void urine samples (obtained 2 days prior to [Day 5, 6 of specified Week], and with last sample collected on the morning of scheduled clinic visit [Day 7 of specified Week]) were used to determine UACR at the scheduled clinic visit. The mean values of the 3 consecutive first morning void urine samples obtained at screening were used to determine baseline UACR. | Baseline, Week 3 (Day 5, 6, 7), Week 6 (Day 5, 6, 7), Week 16 (Day 5, 6, 7) | 
| Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | UPCR is a ratio between two measured substances in urine: milligram of protein per millimole (mmol) of creatinine, reported in units mg/mmol. A decrease in UPCR may be associated with improved renal and cardiovascular function. The mean values of the 3 consecutive first morning void urine samples (obtained 2 days prior to [Day 5, 6 of Week 3, 6, 12, 16], and with last sample collected on the morning of scheduled clinic visit [Day 7 of Week 3, 6, 12, 16]) were used to determine UPCR at the scheduled clinic visit. The mean values of the 3 consecutive first morning void urine samples obtained at screening were used to determine baseline UPCR. | Baseline, Week 3 (Day 5, 6, 7), Week 6 (Day 5, 6, 7), Week 12 (Day 5, 6, 7), Week 16 (Day 5, 6, 7) | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | The eGFR was calculated using 4 variable formula developed by the modification of diet in renal disease (MDRD) study group. The 4 variables needed to estimate glomerular filtration rate (GFR) using this formula were serum creatinine concentration (sCr), age, sex (for females, eGFR was multiplied by 0.742) and ethnic origin (for African-Caribbean people only, eGFR was multiplied by 1.212). Thus eGFR in milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) = 175*(sCr/88.4)^-1.154*(Age)^-0.203*(0.742 if female)*(1.212 if African-Caribbean). Baseline eGFR was determined predose at Week 0 (Day 1). | Baseline, Week 3, 6, 12, 16 (follow-up) | 
| Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Systolic blood pressure (SBP) is the blood pressure (pressure exerted by circulating blood on the walls of blood vessels) when heart is contracting; it is the maximum arterial pressure during contraction of left ventricle of heart. diastolic blood pressure (DBP) is the blood pressure (pressure exerted by circulating blood on the walls of blood vessels) when heart is relaxing; it is the minimum arterial pressure during relaxation and dilation of ventricles of heart. Mean blood pressure (MBP) = diastolic blood pressure + ([systolic blood pressure - diastolic blood pressure]/3). After a minimum of 5 minutes of rest, supine BP was measured with the participant's arm supported at the level of the heart. | Week 0, 3, 6, 12, 16 (follow-up) | 
| Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Serum creatinine concentration was used as a marker of renal function. Baseline serum creatinine concentration was determined predose at Week 0 (Day 1). | Baseline, Week 3, 6, 12, 16 (follow-up) | 
| Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | TGF Beta-1 is a major fibrogenic growth factor implicated in the pathogenesis of renal scarring. It is overexpressed in the diabetic kidney where it may promote matrix accumulation. Baseline TGF Beta-1 concentration was determined predose at Week 0 (Day 1). | Baseline, Week 3, 6, 12, 16 (follow-up) | 
| Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | The CRP is an acute phase reactant which is virtually absent from the blood serum of healthy persons but rapidly appears in blood and body fluids in response to injurious stimuli. Baseline hs-CRP was determined predose at Week 0 (Day 1). | Baseline, Week 12, 16 (follow-up) | 
| Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Cystatin C is produced by all nucleated cells at a constant rate and is freely filtered at the glomerulus. The blood concentration of cystatin C depends almost entirely on the GFR and is not substantially affected by diet, nutritional status or inflammatory disease. Serum cystatin C had been proposed as an endogenous marker of GFR in participant with chronic kidney disease (CKD) than sCr. Baseline serum cystatin C was determined predose at Week 0 (Day 1). | Baseline, Week 12, 16 (follow-up) | 
| Plasma Concentration Versus Time Summary of PF-00489791 |  | Pre-dose at Day 1 of Week 0, 3, 6 and 12; 4 hours post-dose on Day 1 of Week 0, 3 and 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic nephropathy, chronic kidney disease, PF-00489791, phosphodiesterase, PDE5