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

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ClinicalTrials.gov Identifier: NCT01200394
Recruitment Status : Completed
First Posted : September 13, 2010
Results First Posted : March 12, 2019
Last Update Posted : March 12, 2019
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE September 10, 2010
First Posted Date  ICMJE September 13, 2010
Results First Submitted Date  ICMJE January 3, 2019
Results First Posted Date  ICMJE March 12, 2019
Last Update Posted Date March 12, 2019
Actual Study Start Date  ICMJE December 2010
Actual Primary Completion Date July 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 [ Time Frame: Baseline, Week 12 (Day 5, 6, 7) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 10, 2010)
Urine albumin: creatinine ratio (UACR) [ Time Frame: 12 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
  • Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 [ Time Frame: Baseline, Week 3 (Day 5, 6, 7), Week 6 (Day 5, 6, 7), Week 16 (Day 5, 6, 7) ]
    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.
  • Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 [ Time Frame: 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) ]
    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.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 [ Time Frame: Baseline, Week 3, 6, 12, 16 (follow-up) ]
    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).
  • Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 [ Time Frame: Week 0, 3, 6, 12, 16 (follow-up) ]
    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.
  • Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 [ Time Frame: Baseline, Week 3, 6, 12, 16 (follow-up) ]
    Serum creatinine concentration was used as a marker of renal function. Baseline serum creatinine concentration was determined predose at Week 0 (Day 1).
  • Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 [ Time Frame: Baseline, Week 3, 6, 12, 16 (follow-up) ]
    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).
  • Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 [ Time Frame: Baseline, Week 12, 16 (follow-up) ]
    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).
  • Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 [ Time Frame: Baseline, Week 12, 16 (follow-up) ]
    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).
  • Plasma Concentration Versus Time Summary of PF-00489791 [ Time Frame: 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2010)
  • Urine albumin: creatinine ratio at 3, 6 and 16 weeks [ Time Frame: 16 weeks ]
  • Urine protein: creatinine ratio at 3, 6, 12 and 16 weeks [ Time Frame: 16 weeks ]
  • Estimated glomerular filtration rate at 3, 6, 12 and 16 weeks [ Time Frame: 16 weeks ]
  • Systolic, diastolic and mean arterial blood pressure at 3, 6, 12 and 16 weeks [ Time Frame: 16 weeks ]
  • Serum creatinine at 3, 6, 12 and 16 weeks [ Time Frame: 16 weeks ]
  • Urinary TGFbeta1 at Weeks 3, 6, 12 and 16. [ Time Frame: 16 weeks ]
  • Serum highly sensitive C-reactive protein (hs-CRP) at Weeks 12 and 16. [ Time Frame: 16 weeks ]
  • Serum cystatin C at Weeks 12 and 16. [ Time Frame: 16 weeks ]
  • An assessment of the pharmacokinetic parameters of PF-00489791. [ Time Frame: 16 weeks ]
  • Plasma glycosylated hemoglobin (HbA1c). [ Time Frame: 16 weeks ]
  • Safety and tolerability measures (AEs, clinical laboratory assessments, physical examination including weight, worsening of edema, increased use of diuretics). [ Time Frame: 16 weeks ]
Current Other Pre-specified Outcome Measures
 (submitted: February 18, 2019)
  • Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 [ Time Frame: Baseline, Week 12, 16 (follow-up) ]
    Level of HbA1c is an indicator for the average level of blood glucose over the previous 3 months. Baseline HbA1c level was determined predose at Week 0 (Day 1).
  • Number of Participants With Vital Signs Abnormalities [ Time Frame: Baseline up to Week 16 (follow-up) ]
    Criteria for determining vital signs abnormalities: supine or standing systolic BP (SBP) (less than [<] 90 mmHg and increase or decrease of greater than or equal to [>=] 30 mmHg compared to baseline value), supine or standing diastolic BP (DBP) (<50 mmHg and increase or decrease of >=20 mmHg compared to baseline value), supine pulse rate (>120 beats per minute [bpm] or <40 bpm), standing pulse rate (>140 bpm or <40 bpm). For supine, baseline was the average of the triplicate predose readings at Week 0 (Day 1). For standing, baseline is the predose reading at Week 0 (Day 1). Only categories who had at least 1 participant are reported.
  • Number of Participants With Edema and Fluid Overload [ Time Frame: Week 0, 3, 6, 12, 16 (follow-up) ]
    Participants were assessed for signs of edema and fluid overload.
  • Number of Participants With Increased Use of Diuretics [ Time Frame: Baseline up to Week 16 (follow-up) ]
  • Number of Participants With Laboratory Test Abnormalities [ Time Frame: Baseline up to Week 16 (follow-up) ]
    Criteria for laboratory test abnormalities: Hematology (hemoglobin [<0.8*lower limit of normal{LLN}], hematocrit [<0.8*LLN], red blood cells [<0.8*LLN], platelet [<0.5*LLN/>1.75*upper limit of normal{ULN}], white blood cells [<0.6*LLN/>1.5*ULN], lymphocytes [<0.8*LLN/>1.2*ULN], neutrophils [<0.8*LLN/>1.2*ULN], basophils [>1.2*ULN], eosinophils [>1.2*ULN], monocytes [>1.2*ULN]); Liver Function (total/direct/indirect bilirubin [>1.5*ULN], aspartate aminotransferase/ alanine aminotransferase/ gamma glutamyl transpeptidase/ lactate dehydrogenase/ alkaline phosphatase [>3.0*ULN]); Renal Function (blood urea nitrogen/ creatinine [>1.3*ULN], uric acid [>1.2*ULN]); Electrolytes (sodium [<0.95*LLN/>1.05*ULN], potassium, chloride, calcium, bicarbonate [<0.9*LLN/>1.1*ULN]); Clinical Chemistry (glucose [<0.6*LLN/>1.5*ULN], glycosylated hemoglobin [>1.3*ULN], Creatine Kinase [>2.0*ULN], Amylase, Lipase[>1.5*ULN]).
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 16 (follow-up) ]
    An AE was any untoward medical occurrence in a participant who received study medication without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study medication and up to Week 16 (follow-up) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both non-serious (AEs) and serious adverse events (SAEs)
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2, Placebo-Controlled Study To Evaluate The Efficacy And Safety Of PF-00489791 In Patients With Type 2 Diabetes And Overt Nephropathy
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Nephropathies
Intervention  ICMJE
  • Drug: PF-00489791
    Tablet, 20 mg once daily for 12 weeks
  • Drug: Placebo
    Tablet, placebo once daily for 12 weeks
Study Arms  ICMJE
  • Experimental: PF-00489791
    Intervention: Drug: PF-00489791
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 19, 2014)
256
Original Estimated Enrollment  ICMJE
 (submitted: September 10, 2010)
230
Actual Study Completion Date  ICMJE August 2013
Actual Primary Completion Date July 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Denmark,   Hong Kong,   India,   Korea, Republic of,   Malaysia,   Mexico,   Poland,   Serbia,   Slovakia,   South Africa,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01200394
Other Study ID Numbers  ICMJE A7331011
2010-021358-20 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP