Diabetic Nephropathies
Conditions
Keywords
Diabetic nephropathy, chronic kidney disease, PF-00489791, phosphodiesterase, PDE5
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.
Interventions
DRUGPF-00489791
Tablet, 20 mg once daily for 12 weeks
DRUGPlacebo
Tablet, placebo once daily for 12 weeks
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | — |
| Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Edema and Fluid Overload | 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 | Baseline up to Week 16 (follow-up) | — |
| Number of Participants With Laboratory Test Abnormalities | 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) | 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) |
| Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | 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 | 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. |
Countries
Australia, Canada, Denmark, Hong Kong, India, Malaysia, Mexico, Poland, Serbia, Slovakia, South Africa, South Korea, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to PF-00489791 tablet orally once daily for 12 weeks. | 64 |
| PF-00489791 20 mg PF-00489791 20 milligram (mg) tablet orally once daily for 12 weeks. | 192 |
| Total | 256 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 14 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Did Not Meet Entrance Criteria | 1 | 4 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Placebo | PF-00489791 20 mg | Total |
|---|---|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 11 | 62.0 years STANDARD_DEVIATION 8.8 | 61.5 years STANDARD_DEVIATION 9.4 |
| Race/Ethnicity, Customized Asian | 26 participants | 83 participants | 109 participants |
| Race/Ethnicity, Customized Black | 5 participants | 13 participants | 18 participants |
| Race/Ethnicity, Customized Other | 6 participants | 17 participants | 23 participants |
| Race/Ethnicity, Customized White | 27 participants | 79 participants | 106 participants |
| Sex: Female, Male Female | 13 Participants | 48 Participants | 61 Participants |
| Sex: Female, Male Male | 51 Participants | 144 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 64 | 0 / 192 |
| other Total, other adverse events | 35 / 64 | 104 / 192 |
| serious Total, serious adverse events | 6 / 64 | 13 / 192 |
Outcome results
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.
Time frame: Baseline, Week 12 (Day 5, 6, 7)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 | Change at Week 12 | 9.072 mg/mmol | Standard Deviation 176.436 |
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 | Baseline | 195.130 mg/mmol | Standard Deviation 171.8116 |
| PF-00489791 20 mg | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 | Baseline | 182.378 mg/mmol | Standard Deviation 156.5097 |
| PF-00489791 20 mg | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 12 | Change at Week 12 | -6.539 mg/mmol | Standard Deviation 128.4866 |
Comparison: Analysis of covariance (ANCOVA) model within an outlier robust Bayesian framework on normal logarithmic scale with treatment as fixed effect, baseline UACR and baseline supine systolic blood pressure (BP) as covariate. Values were back-transformed from log scale. Model used informative prior distribution for placebo.p-value: 0.988995% CI: [0.728, 0.975]ANCOVA
Comparison: ANCOVA model within an outlier robust Bayesian framework on normal logarithmic scale with treatment as fixed effect, baseline UACR and baseline supine systolic BP as covariate. Values were back-transformed from log scale. Model used informative prior distribution for placebo.p-value: 0.2402ANCOVA
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).
Time frame: Baseline, Week 3, 6, 12, 16 (follow-up)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 3 | 0.069 mL/min/1.73 m^2 | Standard Deviation 6.2868 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 6 | -0.930 mL/min/1.73 m^2 | Standard Deviation 5.3513 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Baseline | 38.575 mL/min/1.73 m^2 | Standard Deviation 11.9122 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 12 | -1.435 mL/min/1.73 m^2 | Standard Deviation 5.3757 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 16 | -1.915 mL/min/1.73 m^2 | Standard Deviation 5.9005 |
| PF-00489791 20 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 12 | -1.463 mL/min/1.73 m^2 | Standard Deviation 5.1074 |
| PF-00489791 20 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 16 | -1.659 mL/min/1.73 m^2 | Standard Deviation 6.0659 |
| PF-00489791 20 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Baseline | 37.740 mL/min/1.73 m^2 | Standard Deviation 9.8834 |
| PF-00489791 20 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 6 | -0.755 mL/min/1.73 m^2 | Standard Deviation 5.2701 |
| PF-00489791 20 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 3, 6, 12, and 16 | Change at Week 3 | -0.156 mL/min/1.73 m^2 | Standard Deviation 4.6044 |
Comparison: Week 3: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.358595% CI: [0.9434, 1.0214]Mixed Models Analysis
Comparison: Week 6: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.747595% CI: [0.9577, 1.0315]Mixed Models Analysis
Comparison: Week 12: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.497295% CI: [0.9488, 1.0259]Mixed Models Analysis
Comparison: Week 16: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.914695% CI: [0.9588, 1.0481]Mixed Models Analysis
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).
Time frame: Baseline, Week 3, 6, 12, 16 (follow-up)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 6 | 3.158 micromole per liter (mcmol/L) | Standard Deviation 18.0835 |
| Placebo | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 12 | 6.139 micromole per liter (mcmol/L) | Standard Deviation 20.7198 |
| Placebo | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Baseline | 164.929 micromole per liter (mcmol/L) | Standard Deviation 42.0837 |
| Placebo | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 16 | 11.527 micromole per liter (mcmol/L) | Standard Deviation 28.5175 |
| Placebo | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 3 | 1.232 micromole per liter (mcmol/L) | Standard Deviation 23.9961 |
| PF-00489791 20 mg | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 16 | 9.269 micromole per liter (mcmol/L) | Standard Deviation 26.647 |
| PF-00489791 20 mg | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 3 | 2.691 micromole per liter (mcmol/L) | Standard Deviation 20.6884 |
| PF-00489791 20 mg | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 6 | 4.974 micromole per liter (mcmol/L) | Standard Deviation 21.7977 |
| PF-00489791 20 mg | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Baseline | 163.637 micromole per liter (mcmol/L) | Standard Deviation 42.9529 |
| PF-00489791 20 mg | Change From Baseline in Serum Creatinine Concentration at Week 3, 6, 12, and 16 | Change at Week 12 | 8.110 micromole per liter (mcmol/L) | Standard Deviation 22.3709 |
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).
Time frame: Baseline, Week 12, 16 (follow-up)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Change at Week 12 | 0.096 mg/L | Standard Deviation 0.1844 |
| Placebo | Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Baseline | 1.659 mg/L | Standard Deviation 0.4122 |
| Placebo | Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Change at Week 16 | 0.104 mg/L | Standard Deviation 0.3234 |
| PF-00489791 20 mg | Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Change at Week 12 | 0.070 mg/L | Standard Deviation 0.289 |
| PF-00489791 20 mg | Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Baseline | 1.695 mg/L | Standard Deviation 0.4497 |
| PF-00489791 20 mg | Change From Baseline in Serum Cystatin-C Concentration at Week 12 and 16 | Change at Week 16 | 0.075 mg/L | Standard Deviation 0.3176 |
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).
Time frame: Baseline, Week 12, 16 (follow-up)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | Baseline | 3.019 milligram per liter (mg/L) | Standard Deviation 3.4924 |
| Placebo | Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | Change at Week 12 | 1.183 milligram per liter (mg/L) | Standard Deviation 3.46 |
| Placebo | Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | Change at Week 16 | 0.317 milligram per liter (mg/L) | Standard Deviation 2.9508 |
| PF-00489791 20 mg | Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | Baseline | 4.330 milligram per liter (mg/L) | Standard Deviation 8.6809 |
| PF-00489791 20 mg | Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | Change at Week 12 | 0.106 milligram per liter (mg/L) | Standard Deviation 7.4909 |
| PF-00489791 20 mg | Change From Baseline in Serum High Sensitivity C-Reactive Protein (Hs-CRP) Concentration at Week 12 and 16 | Change at Week 16 | -0.102 milligram per liter (mg/L) | Standard Deviation 6.3317 |
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.
Time frame: Baseline, Week 3 (Day 5, 6, 7), Week 6 (Day 5, 6, 7), Week 16 (Day 5, 6, 7)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | Change at Week 3 | -11.805 mg/mmol | Standard Deviation 161.7282 |
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | Change at Week 6 | -7.772 mg/mmol | Standard Deviation 162.0838 |
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | Change at Week 16 | 16.500 mg/mmol | Standard Deviation 202.76 |
| PF-00489791 20 mg | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | Change at Week 3 | -14.268 mg/mmol | Standard Deviation 94.8469 |
| PF-00489791 20 mg | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | Change at Week 16 | 2.802 mg/mmol | Standard Deviation 107.9582 |
| PF-00489791 20 mg | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Week 3, 6 and 16 | Change at Week 6 | -2.546 mg/mmol | Standard Deviation 179.5896 |
Comparison: Week 3: Mixed model repeated measures (MMRM) on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.038295% CI: [0.7727, 0.9927]Mixed Models Analysis
Comparison: Week 6: MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.011295% CI: [0.7208, 0.9584]Mixed Models Analysis
Comparison: Week 16: MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.14995% CI: [0.7427, 1.0465]Mixed Models Analysis
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.
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)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Baseline | 282.208 mg/mmol | Standard Deviation 259.8496 |
| Placebo | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 3 | -20.302 mg/mmol | Standard Deviation 247.449 |
| Placebo | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 6 | -10.278 mg/mmol | Standard Deviation 256.7216 |
| Placebo | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 12 | 14.632 mg/mmol | Standard Deviation 283.9874 |
| Placebo | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 16 | 30.880 mg/mmol | Standard Deviation 332.0766 |
| PF-00489791 20 mg | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 12 | -5.371 mg/mmol | Standard Deviation 207.3333 |
| PF-00489791 20 mg | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 16 | 20.299 mg/mmol | Standard Deviation 190.3546 |
| PF-00489791 20 mg | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 3 | -26.883 mg/mmol | Standard Deviation 161.0038 |
| PF-00489791 20 mg | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Baseline | 261.015 mg/mmol | Standard Deviation 220.526 |
| PF-00489791 20 mg | Change From Baseline in Urinary Protein Creatinine Ratio (UPCR) at Week 3, 6, 12, and 16 | Change at Week 6 | 10.699 mg/mmol | Standard Deviation 290.5749 |
Comparison: Week 3: MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.029795% CI: [0.745, 0.9847]Mixed Models Analysis
Comparison: Week 6: MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.030595% CI: [0.7376, 0.985]Mixed Models Analysis
Comparison: Week 12: MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.006895% CI: [0.6717, 0.9378]Mixed Models Analysis
Comparison: Week 16: MMRM on normal logarithmic scale with baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.115195% CI: [0.719, 1.0368]Mixed Models Analysis
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).
Time frame: Baseline, Week 3, 6, 12, 16 (follow-up)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 6 | 23.33 picogram per milliliter (pg/mL) | Standard Deviation 345.304 |
| Placebo | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 12 | -36.20 picogram per milliliter (pg/mL) | Standard Deviation 281.523 |
| Placebo | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Baseline | 177.88 picogram per milliliter (pg/mL) | Standard Deviation 231.154 |
| Placebo | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 16 | -23.54 picogram per milliliter (pg/mL) | Standard Deviation 134.752 |
| Placebo | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 3 | -22.81 picogram per milliliter (pg/mL) | Standard Deviation 260.14 |
| PF-00489791 20 mg | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 16 | -31.32 picogram per milliliter (pg/mL) | Standard Deviation 299.546 |
| PF-00489791 20 mg | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Baseline | 213.37 picogram per milliliter (pg/mL) | Standard Deviation 274.409 |
| PF-00489791 20 mg | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 3 | -54.06 picogram per milliliter (pg/mL) | Standard Deviation 349.817 |
| PF-00489791 20 mg | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 6 | -68.59 picogram per milliliter (pg/mL) | Standard Deviation 333.378 |
| PF-00489791 20 mg | Change From Baseline in Urine Transforming Growth Factor (TGF) Beta-1 Concentration at Week 3, 6, 12, and 16 | Change at Week 12 | -11.87 picogram per milliliter (pg/mL) | Standard Deviation 328.482 |
Comparison: Week 3: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.542295% CI: [0.7297, 1.1807]Mixed Models Analysis
Comparison: Week 6: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.04995% CI: [0.6402, 0.999]Mixed Models Analysis
Comparison: Week 12: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.726495% CI: [0.8211, 1.3262]Mixed Models Analysis
Comparison: Week 16: MMRM on normal logarithmic scale with change from baseline as response variable and baseline, baseline supine systolic BP, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. Unstructured covariance matrix was used to estimate variances and covariance within participant across time points. Values were back-transformed from log scale.p-value: 0.373395% CI: [0.8761, 1.4201]Mixed Models Analysis
Secondary
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
Population: Pharmacokinetic analysis set included all randomized and treated participants with at least 1 measured PF-00489791 concentration. Here, Number analyzed signifies number of participants evaluable for specified categories. This outcome measure was planned not to be analyzed for Placebo reporting arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Concentration Versus Time Summary of PF-00489791 | Pre-dose at Day 1 of Week 6 | 0.3514 microgram per millilitre (microgram/mL) | Standard Deviation 0.40417 |
| Placebo | Plasma Concentration Versus Time Summary of PF-00489791 | 4 hours post-dose at Day 1 of Week 6 | 0.9274 microgram per millilitre (microgram/mL) | Standard Deviation 0.52405 |
| Placebo | Plasma Concentration Versus Time Summary of PF-00489791 | 4 hours post-dose at Day 1 of Week 0 | 0.6540 microgram per millilitre (microgram/mL) | Standard Deviation 0.33644 |
| Placebo | Plasma Concentration Versus Time Summary of PF-00489791 | Pre-dose at Day 1 of Week 3 | 0.4156 microgram per millilitre (microgram/mL) | Standard Deviation 0.44674 |
| Placebo | Plasma Concentration Versus Time Summary of PF-00489791 | 4 hours post-dose at Day 1 of Week 3 | 0.9772 microgram per millilitre (microgram/mL) | Standard Deviation 0.5961 |
| Placebo | Plasma Concentration Versus Time Summary of PF-00489791 | Pre-dose at Day 1 of Week 12 | 0.3930 microgram per millilitre (microgram/mL) | Standard Deviation 0.41593 |
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.
Time frame: Week 0, 3, 6, 12, 16 (follow-up)
Population: Full analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-dose efficacy measurement.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 3 | 107.06 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 6 | 137.41 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 0 | 137.20 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 6 | 76.88 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 6 | 107.37 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 0 | 76.98 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 12 | 77.32 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 3 | 76.78 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 12 | 107.41 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 16 | 138.38 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 3 | 136.68 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 16 | 77.25 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 12 | 136.89 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 16 | 108.00 millimeter of mercury (mmHg) |
| Placebo | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 0 | 107.27 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 16 | 108.47 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 3 | 106.90 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 6 | 106.70 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 12 | 107.14 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 0 | 131.81 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Mean BP, Week 0 | 102.68 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 3 | 136.15 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 3 | 77.18 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 6 | 136.94 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 6 | 76.41 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 12 | 137.70 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 12 | 76.69 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Systolic BP, Week 16 | 138.89 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 16 | 77.90 millimeter of mercury (mmHg) |
| PF-00489791 20 mg | Systolic, Diastolic and Mean Blood Pressure at Week 0, 3, 6, 12, and 16 | Supine Diastolic BP, Week 0 | 73.27 millimeter of mercury (mmHg) |
Comparison: Supine Systolic BP, Week 0: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: <0.000195% CI: [-7.94, -2.84]Mixed Models Analysis
Comparison: Supine Diastolic BP, Week 0: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: <0.000195% CI: [-5.38, -2.04]Mixed Models Analysis
Comparison: Supine Mean BP, Week 0: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: <0.000195% CI: [-6.46, -2.72]Mixed Models Analysis
Comparison: Supine Systolic BP, Week 3: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.709395% CI: [-3.29, 2.24]Mixed Models Analysis
Comparison: Supine Diastolic BP, Week 3: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.656495% CI: [-1.39, 2.2]Mixed Models Analysis
Comparison: Supine Mean BP, Week 3: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.876395% CI: [-2.2, 1.87]Mixed Models Analysis
Comparison: Supine Systolic BP, Week 6: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.749195% CI: [-3.42, 2.46]Mixed Models Analysis
Comparison: Supine Diastolic BP, Week 6: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.614195% CI: [-2.29, 1.35]Mixed Models Analysis
Comparison: Supine Mean BP, Week 6: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.528195% CI: [-2.75, 1.42]Mixed Models Analysis
Comparison: Supine Systolic BP, Week 12: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.669595% CI: [-2.9, 4.5]Mixed Models Analysis
Comparison: Supine Diastolic BP, Week 12: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.560795% CI: [-2.74, 1.49]Mixed Models Analysis
Comparison: Supine Mean BP, Week 12: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.829795% CI: [-2.78, 2.23]Mixed Models Analysis
Comparison: Supine Systolic BP, Week 16: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.764495% CI: [-2.85, 3.87]Mixed Models Analysis
Comparison: Supine Diastolic BP, Week 16: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.512395% CI: [-1.3, 2.61]Mixed Models Analysis
Comparison: Supine Mean BP, Week 16: MMRM model included baseline, visit, treatment, baseline by visit interaction and treatment by visit interaction as fixed effects. The unstructured covariance matrix was used to estimate variances and covariance within participant across time points.p-value: 0.683895% CI: [-1.77, 2.7]Mixed Models Analysis
Other Pre-specified
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).
Time frame: Baseline, Week 12, 16 (follow-up)
Population: Safety analysis set consists of all participants who received at least 1 dose of study medication. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | Baseline | 7.13 percentage of hemoglobin | Standard Deviation 1.023 |
| Placebo | Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | Change at Week 12 | 0.12 percentage of hemoglobin | Standard Deviation 0.856 |
| Placebo | Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | Change at Week 16 | 0.14 percentage of hemoglobin | Standard Deviation 1.009 |
| PF-00489791 20 mg | Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | Baseline | 7.39 percentage of hemoglobin | Standard Deviation 1.135 |
| PF-00489791 20 mg | Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | Change at Week 12 | -0.28 percentage of hemoglobin | Standard Deviation 0.975 |
| PF-00489791 20 mg | Change From Baseline in Plasma Glycosylated Hemoglobin (HbA1c) Level at Week 12 and 16 | Change at Week 16 | -0.09 percentage of hemoglobin | Standard Deviation 0.986 |
Other Pre-specified
Number of Participants With Edema and Fluid Overload
Participants were assessed for signs of edema and fluid overload.
Time frame: Week 0, 3, 6, 12, 16 (follow-up)
Population: Safety analysis set consists of all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Edema and Fluid Overload | Week 6 | 1 Participants |
| Placebo | Number of Participants With Edema and Fluid Overload | Week 16 | 5 Participants |
| Placebo | Number of Participants With Edema and Fluid Overload | Week 0 | 0 Participants |
| Placebo | Number of Participants With Edema and Fluid Overload | Week 3 | 1 Participants |
| Placebo | Number of Participants With Edema and Fluid Overload | Week 12 | 4 Participants |
| PF-00489791 20 mg | Number of Participants With Edema and Fluid Overload | Week 3 | 8 Participants |
| PF-00489791 20 mg | Number of Participants With Edema and Fluid Overload | Week 12 | 9 Participants |
| PF-00489791 20 mg | Number of Participants With Edema and Fluid Overload | Week 6 | 11 Participants |
| PF-00489791 20 mg | Number of Participants With Edema and Fluid Overload | Week 0 | 4 Participants |
| PF-00489791 20 mg | Number of Participants With Edema and Fluid Overload | Week 16 | 6 Participants |
Other Pre-specified
Number of Participants With Increased Use of Diuretics
Time frame: Baseline up to Week 16 (follow-up)
Population: Safety analysis set consists of all participants who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Increased Use of Diuretics | 3 Participants |
| PF-00489791 20 mg | Number of Participants With Increased Use of Diuretics | 10 Participants |
Other Pre-specified
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\[\>1.5\*ULN\]).
Time frame: Baseline up to Week 16 (follow-up)
Population: Safety analysis set consists of all participants who received at least 1 dose of study medication. Here 'N' (Overall Number of Participants Analyzed) signifies participants evaluable for this measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Laboratory Test Abnormalities | 62 Participants |
| PF-00489791 20 mg | Number of Participants With Laboratory Test Abnormalities | 190 Participants |
Other Pre-specified
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)
Time frame: Baseline up to Week 16 (follow-up)
Population: Safety analysis set consists of all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 36 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 6 Participants |
| PF-00489791 20 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 105 Participants |
| PF-00489791 20 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 13 Participants |
Other Pre-specified
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.
Time frame: Baseline up to Week 16 (follow-up)
Population: Safety analysis set consists of all participants who received at least 1 dose of study medication. Here, 'Number analyzed' = Participants evaluable at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Vital Signs Abnormalities | Supine DBP <50 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Supine Pulse Rate <40 bpm | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Increase in Standing SBP >=30 mmHg | 1 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Increase in Supine DBP >=20 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Supine SBP <90 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Decrease in Supine SBP >=30 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Increase in Supine SBP >=30 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Decrease in Standing SBP >=30 mmHg | 2 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Standing SBP <90 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Decrease in Supine DBP >=20 mmHg | 0 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Increase in Standing DBP >=20 mmHg | 1 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Decrease in Standing DBP >=20 mmHg | 1 Participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Standing DBP <50 mmHg | 0 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Decrease in Standing DBP >=20 mmHg | 11 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Increase in Supine SBP >=30 mmHg | 14 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Increase in Supine DBP >=20 mmHg | 7 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Supine DBP <50 mmHg | 3 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Supine SBP <90 mmHg | 1 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Standing SBP <90 mmHg | 2 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Standing DBP <50 mmHg | 3 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Increase in Standing SBP >=30 mmHg | 1 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Increase in Standing DBP >=20 mmHg | 0 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Decrease in Supine SBP >=30 mmHg | 9 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Decrease in Standing SBP >=30 mmHg | 11 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Decrease in Supine DBP >=20 mmHg | 5 Participants |
| PF-00489791 20 mg | Number of Participants With Vital Signs Abnormalities | Supine Pulse Rate <40 bpm | 1 Participants |