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

Diabetic Nephropathies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01200394
• Other study ID #: A7331011
• Secondary ID: 2010-021358-20
• Status: Completed
• Phase: Phase 2
• Start date: December 2010
• Est. completion date: August 2013

Study information

• Verified date: February 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 256
• Est. completion date: August 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Nephropathies
• Kidney Diseases

Intervention

Drug:
• PF-00489791
Tablet, 20 mg once daily for 12 weeks
• Placebo
Tablet, placebo once daily for 12 weeks

Locations

Country	Name	City	State
Australia	Renal Research Practice	Gosford	New South Wales
Australia	Department of Nephrology	New Lambton	Newcastle
Australia	Pharmacy Department	New Lambton	Newcastle
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Melbourne Renal Research Group	Reservoir	Victoria
Canada	Entralogix Clincal Research Inc.	Brampton	Ontario
Canada	Entralogix Clinical Research Inc.	Brampton	Ontario
Canada	Sheldon M Chumir Health Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Centre de sante et de services sociaux champlain-Charles-Le Moyne	Greenfield Park	Quebec
Canada	London Health Sciences Centre	London	Ontario
Canada	Centre de Dialyse de Bois de Boulogne	Montreal	Quebec
Canada	Hopital de Sacre Coeur de Montreal	Montreal	Quebec
Canada	Entralogix Clinical Research Inc.	Oakville	Ontario
Canada	Saskatoon Nephrology Group	Saskatoon	Saskatchewan
Canada	Saskatoon Nephrology Group, Nurses Redisence	Saskatoon	Saskatchewan
Canada	Saskatoon Nephrology Group, Nurses Residence	Saskatoon	Saskatchewan
Canada	N/A - formerly with Entralogix SMO	Toronto	Ontario
Canada	Sunnybrook Health Sciences Center	Toronto	Ontario
Denmark	Aarhus Universitetshospital (Aarhus Sygehus)	Aarhus
Denmark	Rigshospitalet	Copenhagen Oe
Denmark	Steno Diabetes Center	Gentofte
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Division of Nephrology	Pokfulam
Hong Kong	Division of Nephrology, Dept. of Medicine	Pokfulam
Hong Kong	ICON Clinical Research	Quarry Bay
Hong Kong	Prince of Wales Hospital	Shatin
India	Gujarat Kidney Foundation	Ahmedabad	Gujarat
India	Shrushrut Clinical Research Association	Ahmedabad	Gujarat
India	Apollo Hospitals	Hyderabad	Andhra Pradesh
India	P. D. Hinduja National Hospital and Medical Research Centre	Mumbai	Maharashtra
India	Pfizer Centre	Mumbai	Maharashtra
India	Deenanath Mangeshkar Hospital & Research Centre	Pune	Maharashtra
India	Diabetes Care and Research Centre	Pune	Maharashtra
India	Jehangir Clinical Development Centre Pvt. Ltd.	Pune	Maharashtra
India	KE.M Hospital Research Centre	Pune	Maharashtra
India	King Edward Memorial Hospital	Pune	Maharashtra
Korea, Republic of	Clinical Trial Pharmacy	Seongnam-si
Korea, Republic of	Pharmacy	Seongnam-si	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do
Korea, Republic of	Boramae Medical Center/Division of Nephrology	Seoul
Korea, Republic of	Samsung Medical Center, Department of Pharmacy	Seoul
Korea, Republic of	Samsung Medical Center,Sungkyunkwan Univ School of Medicine	Seoul
Korea, Republic of	Samsung Medical Center/Division of Nephrology	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	SMG-SNU Boramae Medical Center	Seoul
Malaysia	Clinical Research Centre, Hospital Pulau Pinang	George Town	Pulau Pinang
Malaysia	Hospital Pulau Pinang	George Town	Pulau Pinang
Malaysia	Unit Hemodialisis, Hospital Serdang	Kajang	Selangor
Malaysia	Universiti Sains Malaysia	Kota Bharu	Kelantan
Malaysia	Nephrology Clinic, Queen Elizabeth Hospital	Kota Kinabalu	Sabah
Malaysia	Unit Kajian Klinikal, Hospital Universiti Sains Malaysia	Kubang Kerian	Kelantan
Malaysia	Hospital Taiping	Taiping	Perak
Mexico	Hospital Angeles del Pedregal	Angeles Del Pedregal Cp.
Mexico	ICLE SC	Guadalajara	Jalisco
Mexico	Comite Mexicano para la Prevencion de la Osteoporosis, A.C.	Mexico	DF
Mexico	Hospital Central Dr Ignacio Morones Prieto Unidad Regional de Osteoporosis	San Luis Potosi	San Luis
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ)	Tlalpan	Mexico CITY
Poland	NZOZ "DIAGNOMED" S.C., Poradnia Nefrologiczna	Bielsko-Biala
Poland	Samodzielny Publiczny Szpital Kliniczny im Andrzeja Mieleckiego	Katowice
Poland	NZOZ PS "Medica"	Lublin
Poland	Miedzyleski Szpital Specjalistyczny w Warszawie	Warsaw
Poland	Centrum Medyczne "Osteomed"	Warszawa
Poland	Centrum Medyczne "OSTEOMED" NZOZ	Warszawa
Poland	Centrum Medyczne "Osteomed" NZOZ, Lecznica Specjalistow	Warszawa
Poland	Centrum Medyczne OSTEOMED NZOZ; Lecznica Specjalistaw	Warszawa
Poland	SPZOZ Akademicki Szpital Kliniczny im. J. Mikulicza - Radeckiego	Wroclaw
Serbia	Clinic for Nephrology, Military Medical Academy	Belgrade
Serbia	Clinical Center of Serbia	Belgrade
Serbia	Clinical Center of Serbia Institute for Endocrinology, Diabetes and Metabolic Diseases	Belgrade
Serbia	Clinical Hospital Center "Zvezdara"	Belgrade
Serbia	Clinical Hospital Center Zvezdara	Belgrade
Serbia	Clinic for Endocrinology, Clinical Center Nis	Nis
Slovakia	FNsP Bratislava, Nemocnica Stare Mesto	Bratislava
Slovakia	Nemocnice s poliklinikami n.o.	Levice
Slovakia	Fakultna nemocnica s poliklinikou J.A.Reimana Presov	Presov
Slovakia	Vseobecna nemocnica Rimavska Sobota	Rimavska Sobota
South Africa	Worthwhile Clinical Trials (WWCT), Lake View Hospital	Benoni	Gauteng
South Africa	Latros International	Bloemfontein
South Africa	Division of Nephrology and Hypertension, E13 Renal Unit	Cape Town
South Africa	Centre for Diabetes and Endocrinology	Durban
South Africa	Centre for Diabetes and Endocrinology	Durban	Kwazulu Natal
South Africa	St Augustine's Hospital	Durban
South Africa	Centre for Diabetes and Endocrinology	Houghton, Johannesburg
South Africa	Wits Clinical research	Johannesburg	Gauteng- South Africa
South Africa	Intercare Parow Medical and Dental Centre	Parow
South Africa	Dr. George Mukhari Hospital -University of Limpopo	Pretoria	Gauteng
South Africa	Medi-Clinic Heart Hospital (Pretoria Heart Hospital)	Pretoria
Sweden	Sahlgrenska University Hospital Njurmottagningen	Goteborg
Sweden	A+ Science City site	Stockholm
Sweden	Akademiska Sjukhuset	Uppsala
United Kingdom	Research Offices (5th Floor)	Coventry
United Kingdom	Doncaster Royal Infirmary	Doncaster	South Yorkshire
United Kingdom	University of Edinburgh	Edinburgh
United Kingdom	Guy's and St Thomas' Foundation Trust	London
United Kingdom	The Royal London Hospital Whitechapel	London
United Kingdom	Northern General Hospital Campus	Sheffield
United States	Mountain Kidney and Hypertension Associates, PA	Asheville	North Carolina
United States	Central Texas Kidney Associates	Austin	Texas
United States	Research Management, Inc.	Austin	Texas
United States	North America Research Institute	Azusa	California
United States	North American Research Institute / California Kidney Specialist	Azusa	California
United States	Northeast Clinical Research Center, LLC	Bethlehem	Pennsylvania
United States	Renal Remission & Hypertension Consultants, PLLC	Bremerton	Washington
United States	Jacobi Medical Center - Department of Medicine - Nephrology	Bronx	New York
United States	Chicago Clinical Research Institute, Inc.	Chicago	Illinois
United States	Columbia Nephrology Associates, PA	Columbia	South Carolina
United States	Rockdale Medical Research Associates	Conyers	Georgia
United States	Citrus Dialysis Center	Covina	California
United States	Alzohaili Medical Consultants	Dearborn	Michigan
United States	Riverside Clinical Research	Edgewater	Florida
United States	Investigative Clinical Research of Indiana, LLC	Elwood	Indiana
United States	Associates in Nephrology, SC	Evergreen Park	Illinois
United States	Research by Design, LLC	Evergreen Park	Illinois
United States	Nephrology Associates of Northern Virginia, Inc.	Fairfax	Virginia
United States	Apex Medical Research, AMR, Inc.	Flint	Michigan
United States	Apex Medical Research, MI, Inc.	Flint	Michigan
United States	AKDHC Medical Research Services, LLC*	Glendale	Arizona
United States	Carolina Nephrology, PA	Greenville	South Carolina
United States	Palm Springs Research Institute	Hialeah	Florida
United States	Diagnostic Clinic of Houston, PA	Houston	Texas
United States	Houston Nephrology Research	Houston	Texas
United States	Research Across America	Houston	Texas
United States	Saadat Ansari Internal Medicine	Huntsville	Alabama
United States	The Office of Iqbal Saeed MD, LLC	Huntsville	Alabama
United States	ASA Clinical Research, LLC	Jupiter	Florida
United States	Clinical Research Consultants, LLC	Kansas City	Missouri
United States	California Institute of Renal Research	La Mesa	California
United States	Alliance Against Diabetes	Las Vegas	Nevada
United States	Clinical Research Consortium	Las Vegas	Nevada
United States	Lincoln Nephrology and Hypertension	Lincoln	Nebraska
United States	Nebraska Nephrology Research Institute, LLC - Research Management, Inc.	Lincoln	Nebraska
United States	Renal Physicians of Georgia	Macon	Georgia
United States	Nephrology Specialists, P.C.	Mechanicsville	Virginia
United States	Boise Kidney and Hypertension Institute	Meridian	Idaho
United States	Crescent City Clinical Research Center	Metairie	Louisiana
United States	Clinical Research Associates of Tidewater	Norfolk	Virginia
United States	Palmetto Nephrology, PA	Orangeburg	South Carolina
United States	South Carolina Nephrology & Hypertension Ctr, Inc	Orangeburg	South Carolina
United States	South Carolina Nephrology and Hypertension Center	Orangeburg	South Carolina
United States	Four Rivers Clinical Research, Inc.	Paducah	Kentucky
United States	RenalCare Associates	Peoria	Illinois
United States	Sound Medical Research	Port Orchard	Washington
United States	Biolab Research, LLC	Rockville	Maryland
United States	Capital Nephrology Clinical Research	Sacramento	California
United States	Renal Associates, PA	San Antonio	Texas
United States	San Antonio Kidney Disease Center Physicians Group, P.L.L.C.	San Antonio	Texas
United States	California Kidney Specialists	San Dimas	California
United States	Northwest Louisiana Nephrology	Shreveport	Louisiana
United States	Renal Remission and Hypertension Clinic	Silverdale	Washington
United States	Lakeview Medical Research	Summerfield	Florida
United States	Southwest Clinical Research Institute, LLC	Tempe	Arizona
United States	Southwest Clinical Research Institute, LLC	Tempe	Arizona
United States	Preferred Primary Care Physicians, Inc.	Uniontown	Pennsylvania
United States	American Institute of Research	Whittier	California
United States	Whittier Internal Medicine Nephrology Medical Group	Whittier	California
United States	Kansas Nephrology Research Institute, LLC	Wichita	Kansas
United States	Lake Medical Research	Willoughby Hills	Ohio
United States	Trial Management Associates	Wilmington	North Carolina
United States	North Valley Nephrology	Yuba	California

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  Hong Kong,  India,  Korea, Republic of,  Malaysia,  Mexico,  Poland,  Serbia,  Slovakia,  South Africa,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16	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).	Baseline, Week 12, 16 (follow-up)
Other	Number of Participants With Vital Signs Abnormalities	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.	Baseline up to Week 16 (follow-up)
Other	Number of Participants With Edema and Fluid Overload	Participants were assessed for signs of edema and fluid overload.	Week 0, 3, 6, 12, 16 (follow-up)
Other	Number of Participants With Increased Use of Diuretics		Baseline up to Week 16 (follow-up)
Other	Number of Participants With Laboratory Test Abnormalities	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]).	Baseline up to Week 16 (follow-up)
Other	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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)	Baseline up to Week 16 (follow-up)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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

External Links

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