Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2 diabetes, safety, multiple dose, intravenous
Brief summary
This is a trial in subjects with Type 2 diabetes mellitus to study the safety, tolerability and pharmacokinetics of multiple ascending doses of PF-05231023.
Interventions
DRUGPF-05231023
5 mg IV twice a week for 4 weeks
OTHERPlacebo
0.9% w/v sodium chloride injection, United States Pharmacopeia (USP), twice a week IV for 4 weeks
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male subjects and female subjects of non-childbearing potential between the ages of 30 and 70 years, inclusive, with a historical diagnosis of type 2 diabetes mellitus, diagnosed according to the American Diabetes Association guidelines. Subjects who have other conditions but are well controlled by either diet or medications may be included as well (for example, a subject with high cholesterol level on appropriate treatment is eligible). * Body Mass Index (BMI) of 25 to 35.5 kg/m2, and a total body weight \>50 kg (110 lbs).
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). * Diagnosis of Type 1 diabetes mellitus. * Evidence of diabetic complications with significant end organ damage
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Physical Examination Findings | Baseline up to Day 42 | Physical examination included assessment of height, weight, blood pressure, pulse rate and body temperature. Criteria for abnormal physical findings was based on investigator's discretion and were reported as adverse event (AE), as planned. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Baseline up to Day 77 | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was 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 drug and up to Day 77 which were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Abnormal Laboratory Values | Baseline up to Day 42 | Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (RBCs)(less than \[\<\] 0.8\*lower limit of normal\[LLN\]); leucocytes (\<0.6/greater than \[\>\]1.5\*upper limit of normal \[ULN\]); platelets (\<0.5\*LLN\>\</0\>1.75\*ULN); neutrophils, lymphocytes (\<0.8\*LLN\>\</0\>1.2\*ULN); eosinophils, basophils, monocytes (\>1.2\*ULN); total bilirubin, direct bilirubin, indirect bilirubin (\>1.5\*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\*ULN), total protein, albumin (\<0.8\*LLN\>\</0\>1.2\*ULN); creatinine, urea (\>1.3\*ULN); glucose (\<0.6\*LLN\>\</0\>1.5\*ULN); uric acid (\>1.2\*ULN); sodium, potassium, chloride, calcium, bicarbonate (\<0.9\*LLN\>\</0\>1.1\*ULN); urine RBCs, urine white blood cells (WBCs) (\> or equal\[=\]20 high-powered field), urine bacteria \>20 high-powered field. Total number of participants with any laboratory abnormalities were reported. |
| Number of Participants With Vital Signs Abnormalities | Baseline up to Day 77 | Criteria for vital signs abnormalities: supine systolic blood pressure (SBP) \<90 millimeter of mercury (mm Hg), supine diastolic BP (DBP) \<50 mm Hg, supine pulse rate \<40 beats per minute (bpm), \> 120 bpm. Maximum increase or decrease from baseline in supine SBP \>=30 mm Hg and maximum increase or decrease from baseline in supine DBP \>=20 mm Hg. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline up to Day 77 | Criteria for potential clinical concern in ECG parameters: maximum PR interval of greater than or equal to (\>=) 300 milliseconds (msec), maximum QRS interval \>=140 msec, maximum QTCF interval (Fridericia's Correction) of 450 to \<480 msec, 480 to \<500 msec and \>=500 msec, maximum increase of \>=25 percent (%) for baseline value of \>200 msec and \>=50% for baseline value of less than or equal to (\<=) 200 msec for PR interval, maximum increase from baseline of \>=50% for QRS interval, maximum increase from baseline of \>=30 msec to \<60 msec and maximum increase from baseline of \>60 msec in QTCF interval (Fridericia's Correction). |
| Number of Participants With Blood Glucose Abnormalities | Baseline up to Day 32 | Criteria for blood glucose abnormality: Blood glucose levels \<0.6\* LLN or \>1.5\* ULN. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported. |
| Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | 0 hour (pre-dose) on Day 1, 4, 25; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1, 25; Day 2, 3, 26, 29 | Rac was obtained from AUCtau at steady state (Day 25) divided by AUCtau after single dose (Day 1). AUCtau was the area under the concentration-time profile from time zero to end of dosing interval, where tau = 72 hours for Day 1 and tau = 96 hours for Day 25. Participants who received PF-05231023 with C-terminal and N-terminal Rac at steady state were reported. |
| Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | 0 hour (pre-dose) on Day 1, 4, 25; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1, 25; Day 2, 3, 26, 29 | Accumulation ratio based on maximum plasma concentration (Cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 25) divided by Cmax at first dose (Day 1). Participants who received PF-05231023 with C-terminal and N-terminal Rac,Cmax at steady state were reported. |
| Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Plasma terminal half-life is the time measured for the plasma concentration to decrease by one half at the terminal phase. Participants who received PF-05231023 with C-terminal and N-terminal t1/2 at steady state were reported. |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | 0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3 | Participants who received PF-05231023 with C-terminal and N-terminal AUCtau were reported. |
| Volume of Distribution of PF-05231023 at Steady State (Vss) | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. PF-05231023 with C-terminal and N-terminal Vss at steady state were reported. |
| Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported. |
| Average Plasma Concentration (Cav) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Participants who received PF-05231023 with C-terminal and N-terminal Cmax at steady state were reported. |
| Apparent Clearance (CL) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Participants who received PF-05231023 with C-terminal and N-terminal CL at steady state were reported. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | 0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3 | Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported. |
| Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | 0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3 | Participants who received PF 05231023 with C-terminal and N-terminal Cmax were reported. |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Participants who received PF-05231023 with C-terminal and N-terminal AUCtau at steady state were reported. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) at steady state. Participants who received PF-05231023 with C-terminal and N-terminal AUClast at steady state were reported. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29 | Participants who received PF-05231023 with C-terminal and N-terminal Tmax at steady state were reported. |
Countries
United States
Participant flow
Recruitment details
Participants with a historical diagnosis of type 2 diabetes mellitus (T2DM), diagnosed according to the American Diabetes Association (ADA) guidelines, those with well controlled diabetes and were on stable metformin therapy were recruited in the study.
Pre-assignment details
Dose of PF-05231023 was escalated based on sponsor's and investigator's discretion, depending upon safety, tolerability and pharmacokinetic profile of PF-05231023.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to PF-05231023 intravenous infusion over approximately 1 hour on Day 1, 4, 8, 11, 15, 18, 22 and 25. | 8 |
| PF-05231023 5 mg PF-05231023 5 mg intravenous infusion over approximately 1 hour on Day 1, 4, 8, 11, 15, 18, 22 and 25. | 12 |
| PF-05231023 25 mg PF-05231023 25 mg intravenous infusion over approximately 1 hour on Day 1, 4, 8 11, 15, 18, 22 and 25. | 10 |
| PF-05231023 100 mg PF-05231023 100 mg intravenous infusion over approximately 1 hour on Day 1, 4, 8, 11, 15, 18, 22 and 25. | 10 |
| PF-05231023 140 mg PF-05231023 140 mg intravenous infusion over approximately 1 hour on Day 1, 4, 8, 11, 15, 18, 22 and 25. | 10 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Other | 1 | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | PF-05231023 5 mg | PF-05231023 25 mg | PF-05231023 100 mg | PF-05231023 140 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 4.3 | 50.2 years STANDARD_DEVIATION 10 | 56.9 years STANDARD_DEVIATION 6.9 | 59.0 years STANDARD_DEVIATION 6.3 | 57.6 years STANDARD_DEVIATION 9.1 | 55.7 years STANDARD_DEVIATION 8.2 |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 11 Participants | 9 Participants | 7 Participants | 6 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 8 | 6 / 12 | 3 / 10 | 8 / 10 | 10 / 10 |
| serious Total, serious adverse events | 0 / 8 | 0 / 12 | 0 / 10 | 0 / 10 | 1 / 10 |
Outcome results
Primary
Number of Participants With Abnormal Laboratory Values
Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (RBCs)(less than \[\<\] 0.8\*lower limit of normal\[LLN\]); leucocytes (\<0.6/greater than \[\>\]1.5\*upper limit of normal \[ULN\]); platelets (\<0.5\*LLN\>\</0\>1.75\*ULN); neutrophils, lymphocytes (\<0.8\*LLN\>\</0\>1.2\*ULN); eosinophils, basophils, monocytes (\>1.2\*ULN); total bilirubin, direct bilirubin, indirect bilirubin (\>1.5\*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\*ULN), total protein, albumin (\<0.8\*LLN\>\</0\>1.2\*ULN); creatinine, urea (\>1.3\*ULN); glucose (\<0.6\*LLN\>\</0\>1.5\*ULN); uric acid (\>1.2\*ULN); sodium, potassium, chloride, calcium, bicarbonate (\<0.9\*LLN\>\</0\>1.1\*ULN); urine RBCs, urine white blood cells (WBCs) (\> or equal\[=\]20 high-powered field), urine bacteria \>20 high-powered field. Total number of participants with any laboratory abnormalities were reported.
Time frame: Baseline up to Day 42
Population: Safety population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Abnormal Laboratory Values | 8 participants |
| PF-05231023 5 mg | Number of Participants With Abnormal Laboratory Values | 10 participants |
| PF-05231023 25 mg | Number of Participants With Abnormal Laboratory Values | 9 participants |
| PF-05231023 100 mg | Number of Participants With Abnormal Laboratory Values | 9 participants |
| PF-05231023 140 mg | Number of Participants With Abnormal Laboratory Values | 10 participants |
Primary
Number of Participants With Abnormal Physical Examination Findings
Physical examination included assessment of height, weight, blood pressure, pulse rate and body temperature. Criteria for abnormal physical findings was based on investigator's discretion and were reported as adverse event (AE), as planned.
Time frame: Baseline up to Day 42
Population: Physical examination data reported in this study was for identification of adverse events and were reported as adverse event in the AE section.
Primary
Number of Participants With Blood Glucose Abnormalities
Criteria for blood glucose abnormality: Blood glucose levels \<0.6\* LLN or \>1.5\* ULN.
Time frame: Baseline up to Day 32
Population: Safety population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Blood Glucose Abnormalities | <0.6*LLN | 0 participants |
| Placebo | Number of Participants With Blood Glucose Abnormalities | >1.5*ULN | 6 participants |
| PF-05231023 5 mg | Number of Participants With Blood Glucose Abnormalities | <0.6*LLN | 0 participants |
| PF-05231023 5 mg | Number of Participants With Blood Glucose Abnormalities | >1.5*ULN | 6 participants |
| PF-05231023 25 mg | Number of Participants With Blood Glucose Abnormalities | <0.6*LLN | 0 participants |
| PF-05231023 25 mg | Number of Participants With Blood Glucose Abnormalities | >1.5*ULN | 6 participants |
| PF-05231023 100 mg | Number of Participants With Blood Glucose Abnormalities | >1.5*ULN | 5 participants |
| PF-05231023 100 mg | Number of Participants With Blood Glucose Abnormalities | <0.6*LLN | 0 participants |
| PF-05231023 140 mg | Number of Participants With Blood Glucose Abnormalities | <0.6*LLN | 0 participants |
| PF-05231023 140 mg | Number of Participants With Blood Glucose Abnormalities | >1.5*ULN | 9 participants |
Primary
Number of Participants With Electrocardiogram (ECG) Abnormalities
Criteria for potential clinical concern in ECG parameters: maximum PR interval of greater than or equal to (\>=) 300 milliseconds (msec), maximum QRS interval \>=140 msec, maximum QTCF interval (Fridericia's Correction) of 450 to \<480 msec, 480 to \<500 msec and \>=500 msec, maximum increase of \>=25 percent (%) for baseline value of \>200 msec and \>=50% for baseline value of less than or equal to (\<=) 200 msec for PR interval, maximum increase from baseline of \>=50% for QRS interval, maximum increase from baseline of \>=30 msec to \<60 msec and maximum increase from baseline of \>60 msec in QTCF interval (Fridericia's Correction).
Time frame: Baseline up to Day 77
Population: Safety population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 480 to <500 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 450 to <480 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS complex increase from baseline >=50% | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QRS Complex >=140 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline >=60 msec | 1 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline 30 to <60msec | 1 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR interval increase from baseline >=25/50% | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval >=500 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum PR interval >=300 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QRS Complex >=140 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline >=60 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 450 to <480 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline 30 to <60msec | 1 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR interval increase from baseline >=25/50% | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 480 to <500 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval >=500 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum PR interval >=300 msec | 0 participants |
| PF-05231023 5 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS complex increase from baseline >=50% | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline 30 to <60msec | 1 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 480 to <500 msec | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS complex increase from baseline >=50% | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval >=500 msec | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline >=60 msec | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR interval increase from baseline >=25/50% | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum PR interval >=300 msec | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QRS Complex >=140 msec | 0 participants |
| PF-05231023 25 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 450 to <480 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline 30 to <60msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QRS Complex >=140 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 480 to <500 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum PR interval >=300 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline >=60 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 450 to <480 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR interval increase from baseline >=25/50% | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval >=500 msec | 0 participants |
| PF-05231023 100 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS complex increase from baseline >=50% | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline >=60 msec | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum PR interval >=300 msec | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QRS Complex >=140 msec | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 450 to <480 msec | 2 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval 480 to <500 msec | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | Maximum QTCF interval >=500 msec | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR interval increase from baseline >=25/50% | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS complex increase from baseline >=50% | 0 participants |
| PF-05231023 140 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF interval increase from baseline 30 to <60msec | 1 participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was 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 drug and up to Day 77 which were absent before treatment or that worsened relative to pretreatment state.
Time frame: Baseline up to Day 77
Population: Safety population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 5 participants |
| PF-05231023 5 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 6 participants |
| PF-05231023 5 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05231023 25 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05231023 25 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 3 participants |
| PF-05231023 100 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 8 participants |
| PF-05231023 100 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05231023 140 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 1 participants |
| PF-05231023 140 mg | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 10 participants |
Primary
Number of Participants With Vital Signs Abnormalities
Criteria for vital signs abnormalities: supine systolic blood pressure (SBP) \<90 millimeter of mercury (mm Hg), supine diastolic BP (DBP) \<50 mm Hg, supine pulse rate \<40 beats per minute (bpm), \> 120 bpm. Maximum increase or decrease from baseline in supine SBP \>=30 mm Hg and maximum increase or decrease from baseline in supine DBP \>=20 mm Hg.
Time frame: Baseline up to Day 77
Population: Safety population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Vital Signs Abnormalities | SBP: Maximum decrease>=30 mm Hg | 2 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | DBP: Maximum Decrease >= 20 mm Hg | 1 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Pulse rate < 40 bpm | 0 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | Pulse rate > 120 bpm | 0 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | SBP: Maximum increase >= 30 mm Hg | 3 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | SBP < 90 mm Hg | 0 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | DBP: Maximum increase >=20 mm Hg | 1 participants |
| Placebo | Number of Participants With Vital Signs Abnormalities | DBP< 50 mm Hg | 0 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum increase >=20 mm Hg | 1 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate > 120 bpm | 0 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum decrease>=30 mm Hg | 0 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum increase >= 30 mm Hg | 1 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate < 40 bpm | 0 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | DBP< 50 mm Hg | 0 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum Decrease >= 20 mm Hg | 0 participants |
| PF-05231023 5 mg | Number of Participants With Vital Signs Abnormalities | SBP < 90 mm Hg | 0 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | DBP< 50 mm Hg | 0 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate < 40 bpm | 0 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | SBP < 90 mm Hg | 2 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate > 120 bpm | 0 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum increase >=20 mm Hg | 1 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum increase >= 30 mm Hg | 3 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum decrease>=30 mm Hg | 0 participants |
| PF-05231023 25 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum Decrease >= 20 mm Hg | 0 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum increase >= 30 mm Hg | 2 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum Decrease >= 20 mm Hg | 1 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum decrease>=30 mm Hg | 1 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum increase >=20 mm Hg | 1 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | SBP < 90 mm Hg | 0 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate < 40 bpm | 0 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate > 120 bpm | 0 participants |
| PF-05231023 100 mg | Number of Participants With Vital Signs Abnormalities | DBP< 50 mm Hg | 0 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum Decrease >= 20 mm Hg | 1 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | SBP < 90 mm Hg | 1 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | DBP< 50 mm Hg | 0 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate < 40 bpm | 0 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | Pulse rate > 120 bpm | 0 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum increase >= 30 mm Hg | 0 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | DBP: Maximum increase >=20 mm Hg | 1 participants |
| PF-05231023 140 mg | Number of Participants With Vital Signs Abnormalities | SBP: Maximum decrease>=30 mm Hg | 3 participants |
Secondary
Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac)
Rac was obtained from AUCtau at steady state (Day 25) divided by AUCtau after single dose (Day 1). AUCtau was the area under the concentration-time profile from time zero to end of dosing interval, where tau = 72 hours for Day 1 and tau = 96 hours for Day 25. Participants who received PF-05231023 with C-terminal and N-terminal Rac at steady state were reported.
Time frame: 0 hour (pre-dose) on Day 1, 4, 25; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1, 25; Day 2, 3, 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | C-terminal | 1.258 ratio | Standard Deviation 20 |
| Placebo | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | N-terminal | 2.016 ratio | Standard Deviation 18 |
| PF-05231023 5 mg | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | N-terminal | 1.702 ratio | Standard Deviation 15 |
| PF-05231023 5 mg | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | C-terminal | 1.258 ratio | Standard Deviation 24 |
| PF-05231023 25 mg | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | C-terminal | 1.413 ratio | Standard Deviation 10 |
| PF-05231023 25 mg | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | N-terminal | 1.818 ratio | Standard Deviation 24 |
| PF-05231023 100 mg | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | C-terminal | 1.173 ratio | Standard Deviation 8 |
| PF-05231023 100 mg | Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | N-terminal | 1.810 ratio | Standard Deviation 14 |
Secondary
Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023
Accumulation ratio based on maximum plasma concentration (Cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 25) divided by Cmax at first dose (Day 1). Participants who received PF-05231023 with C-terminal and N-terminal Rac,Cmax at steady state were reported.
Time frame: 0 hour (pre-dose) on Day 1, 4, 25; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1, 25; Day 2, 3, 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | N-terminal | 1.626 ratio | Standard Deviation 17 |
| Placebo | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | C-terminal | 0.9992 ratio | Standard Deviation 19 |
| PF-05231023 5 mg | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | C-terminal | 0.9392 ratio | Standard Deviation 20 |
| PF-05231023 5 mg | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | N-terminal | 1.266 ratio | Standard Deviation 23 |
| PF-05231023 25 mg | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | N-terminal | 1.326 ratio | Standard Deviation 19 |
| PF-05231023 25 mg | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | C-terminal | 1.159 ratio | Standard Deviation 13 |
| PF-05231023 100 mg | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | N-terminal | 1.642 ratio | Standard Deviation 8 |
| PF-05231023 100 mg | Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | C-terminal | 1.033 ratio | Standard Deviation 12 |
Secondary
Apparent Clearance (CL) of PF-05231023 at Steady State
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Participants who received PF-05231023 with C-terminal and N-terminal CL at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apparent Clearance (CL) of PF-05231023 at Steady State | N-terminal | 0.07642 liter per hour | Standard Deviation 14 |
| Placebo | Apparent Clearance (CL) of PF-05231023 at Steady State | C-terminal | 0.3378 liter per hour | Standard Deviation 26 |
| PF-05231023 5 mg | Apparent Clearance (CL) of PF-05231023 at Steady State | C-terminal | 0.3383 liter per hour | Standard Deviation 23 |
| PF-05231023 5 mg | Apparent Clearance (CL) of PF-05231023 at Steady State | N-terminal | 0.07871 liter per hour | Standard Deviation 12 |
| PF-05231023 25 mg | Apparent Clearance (CL) of PF-05231023 at Steady State | N-terminal | 0.06521 liter per hour | Standard Deviation 21 |
| PF-05231023 25 mg | Apparent Clearance (CL) of PF-05231023 at Steady State | C-terminal | 0.3083 liter per hour | Standard Deviation 15 |
| PF-05231023 100 mg | Apparent Clearance (CL) of PF-05231023 at Steady State | C-terminal | 0.3086 liter per hour | Standard Deviation 23 |
| PF-05231023 100 mg | Apparent Clearance (CL) of PF-05231023 at Steady State | N-terminal | 0.07043 liter per hour | Standard Deviation 26 |
Secondary
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose
Participants who received PF-05231023 with C-terminal and N-terminal AUCtau were reported.
Time frame: 0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3
Population: Pharmacokinetic (PK) parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | N- terminal | 33240 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 22 |
| Placebo | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | C-terminal | 12680 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 23 |
| PF-05231023 5 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | N- terminal | 186800 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 16 |
| PF-05231023 5 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | C-terminal | 58780 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 23 |
| PF-05231023 25 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | C-terminal | 229500 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 22 |
| PF-05231023 25 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | N- terminal | 844200 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 12 |
| PF-05231023 100 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | C-terminal | 365300 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 22 |
| PF-05231023 100 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | N- terminal | 1051000 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 19 |
Secondary
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State
Participants who received PF-05231023 with C-terminal and N-terminal AUCtau at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | C-terminal | 14810 ng*hr/mL | Standard Deviation 33 |
| Placebo | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | N-terminal | 65420 ng*hr/mL | Standard Deviation 16 |
| PF-05231023 5 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | N-terminal | 317800 ng*hr/mL | Standard Deviation 11 |
| PF-05231023 5 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | C-terminal | 73940 ng*hr/mL | Standard Deviation 27 |
| PF-05231023 25 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | C-terminal | 324300 ng*hr/mL | Standard Deviation 15 |
| PF-05231023 25 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | N-terminal | 1533000 ng*hr/mL | Standard Deviation 24 |
| PF-05231023 100 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | C-terminal | 453400 ng*hr/mL | Standard Deviation 21 |
| PF-05231023 100 mg | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | N-terminal | 1990000 ng*hr/mL | Standard Deviation 22 |
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) at steady state. Participants who received PF-05231023 with C-terminal and N-terminal AUClast at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | C-terminal | 11280 ng*hr/mL | Standard Deviation 26 |
| Placebo | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | N-terminal | 121900 ng*hr/mL | Standard Deviation 27 |
| PF-05231023 5 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | C-terminal | 52710 ng*hr/mL | Standard Deviation 23 |
| PF-05231023 5 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | N-terminal | 590400 ng*hr/mL | Standard Deviation 11 |
| PF-05231023 25 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | C-terminal | 294100 ng*hr/mL | Standard Deviation 26 |
| PF-05231023 25 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | N-terminal | 2859000 ng*hr/mL | Standard Deviation 20 |
| PF-05231023 100 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | N-terminal | 3196000 ng*hr/mL | Standard Deviation 25 |
| PF-05231023 100 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | C-terminal | 456700 ng*hr/mL | Standard Deviation 21 |
Secondary
Average Plasma Concentration (Cav) of PF-05231023 at Steady State
Participants who received PF-05231023 with C-terminal and N-terminal Cmax at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | C-terminal | 205.5 ng/mL | Standard Deviation 33 |
| Placebo | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | N-terminal | 908.6 ng/mL | Standard Deviation 16 |
| PF-05231023 5 mg | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | N-terminal | 4411 ng/mL | Standard Deviation 11 |
| PF-05231023 5 mg | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | C-terminal | 1027 ng/mL | Standard Deviation 27 |
| PF-05231023 25 mg | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | C-terminal | 4504 ng/mL | Standard Deviation 15 |
| PF-05231023 25 mg | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | N-terminal | 21290 ng/mL | Standard Deviation 24 |
| PF-05231023 100 mg | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | C-terminal | 6300 ng/mL | Standard Deviation 21 |
| PF-05231023 100 mg | Average Plasma Concentration (Cav) of PF-05231023 at Steady State | N-terminal | 27620 ng/mL | Standard Deviation 22 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose
Participants who received PF 05231023 with C-terminal and N-terminal Cmax were reported.
Time frame: 0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | C -terminal | 1270 nanogram per milliliter (ng/mL) | Standard Deviation 11 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | N -terminal | 1182 nanogram per milliliter (ng/mL) | Standard Deviation 18 |
| PF-05231023 5 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | N -terminal | 7123 nanogram per milliliter (ng/mL) | Standard Deviation 18 |
| PF-05231023 5 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | C -terminal | 5991 nanogram per milliliter (ng/mL) | Standard Deviation 17 |
| PF-05231023 25 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | C -terminal | 23500 nanogram per milliliter (ng/mL) | Standard Deviation 21 |
| PF-05231023 25 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | N -terminal | 28480 nanogram per milliliter (ng/mL) | Standard Deviation 18 |
| PF-05231023 100 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | C -terminal | 34390 nanogram per milliliter (ng/mL) | Standard Deviation 15 |
| PF-05231023 100 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | N -terminal | 35790 nanogram per milliliter (ng/mL) | Standard Deviation 17 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State
Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | C-terminal | 1239 ng/mL | Standard Deviation 23 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | N-terminal | 1839 ng/mL | Standard Deviation 21 |
| PF-05231023 5 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | N-terminal | 9016 ng/mL | Standard Deviation 17 |
| PF-05231023 5 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | C-terminal | 5629 ng/mL | Standard Deviation 21 |
| PF-05231023 25 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | N-terminal | 37770 ng/mL | Standard Deviation 18 |
| PF-05231023 25 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | C-terminal | 27240 ng/mL | Standard Deviation 16 |
| PF-05231023 100 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | N-terminal | 61160 ng/mL | Standard Deviation 16 |
| PF-05231023 100 mg | Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | C-terminal | 37160 ng/mL | Standard Deviation 13 |
Secondary
Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State
Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | C-terminal | 0.0003894 ng/mL | Standard Deviation 6.8667 |
| Placebo | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | N-terminal | 550.5 ng/mL | Standard Deviation 33 |
| PF-05231023 5 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | N-terminal | 1861 ng/mL | Standard Deviation 30 |
| PF-05231023 5 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | C-terminal | 0.1538 ng/mL | Standard Deviation 11.864 |
| PF-05231023 25 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | C-terminal | 80.51 ng/mL | Standard Deviation 102 |
| PF-05231023 25 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | N-terminal | 9987 ng/mL | Standard Deviation 21 |
| PF-05231023 100 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | C-terminal | 218.8 ng/mL | Standard Deviation 76 |
| PF-05231023 100 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | N-terminal | 12440 ng/mL | Standard Deviation 29 |
Secondary
Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State
Plasma terminal half-life is the time measured for the plasma concentration to decrease by one half at the terminal phase. Participants who received PF-05231023 with C-terminal and N-terminal t1/2 at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. n signifies those participants who were evaluated for this measure at the specified terminal for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | C-terminal (n=8, 7, 10, 8) | 6.484 hour | Standard Deviation 0.79685 |
| Placebo | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | N-terminal (n=9, 10, 9, 6) | 83.93 hour | Standard Deviation 10.922 |
| PF-05231023 5 mg | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | N-terminal (n=9, 10, 9, 6) | 84.38 hour | Standard Deviation 8.7742 |
| PF-05231023 5 mg | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | C-terminal (n=8, 7, 10, 8) | 7.879 hour | Standard Deviation 0.78138 |
| PF-05231023 25 mg | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | C-terminal (n=8, 7, 10, 8) | 9.563 hour | Standard Deviation 2.5419 |
| PF-05231023 25 mg | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | N-terminal (n=9, 10, 9, 6) | 97.47 hour | Standard Deviation 14.534 |
| PF-05231023 100 mg | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | C-terminal (n=8, 7, 10, 8) | 10.25 hour | Standard Deviation 1.5121 |
| PF-05231023 100 mg | Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | N-terminal (n=9, 10, 9, 6) | 74.62 hour | Standard Deviation 13.781 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose
Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported.
Time frame: 0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | C- terminal | 1.02 hour |
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | N-terminal | 1.50 hour |
| PF-05231023 5 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | C- terminal | 1.26 hour |
| PF-05231023 5 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | N-terminal | 1.50 hour |
| PF-05231023 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | N-terminal | 1.50 hour |
| PF-05231023 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | C- terminal | 1.25 hour |
| PF-05231023 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | N-terminal | 1.50 hour |
| PF-05231023 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | C- terminal | 1.50 hour |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State
Participants who received PF-05231023 with C-terminal and N-terminal Tmax at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | C-terminal | 1.42 hour |
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | N-terminal | 1.48 hour |
| PF-05231023 5 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | N-terminal | 1.45 hour |
| PF-05231023 5 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | C-terminal | 1.48 hour |
| PF-05231023 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | C-terminal | 1.40 hour |
| PF-05231023 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | N-terminal | 1.99 hour |
| PF-05231023 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | C-terminal | 1.01 hour |
| PF-05231023 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | N-terminal | 1.45 hour |
Secondary
Volume of Distribution of PF-05231023 at Steady State (Vss)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. PF-05231023 with C-terminal and N-terminal Vss at steady state were reported.
Time frame: 0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29
Population: PK parameter analysis set included all enrolled and treated participants who had at least 1 of the PK parameters of interest. n signifies those participants who were evaluated for this measure at the specified terminal for each arm.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Volume of Distribution of PF-05231023 at Steady State (Vss) | N-terminal (n=9, 10, 9, 6) | 7.320 liter | Standard Deviation 20 |
| Placebo | Volume of Distribution of PF-05231023 at Steady State (Vss) | C-terminal (n=8, 7, 10, 8) | 1.467 liter | Standard Deviation 19 |
| PF-05231023 5 mg | Volume of Distribution of PF-05231023 at Steady State (Vss) | C-terminal (n=8, 7, 10, 8) | 1.873 liter | Standard Deviation 16 |
| PF-05231023 5 mg | Volume of Distribution of PF-05231023 at Steady State (Vss) | N-terminal (n=9, 10, 9, 6) | 7.594 liter | Standard Deviation 15 |
| PF-05231023 25 mg | Volume of Distribution of PF-05231023 at Steady State (Vss) | N-terminal (n=9, 10, 9, 6) | 6.570 liter | Standard Deviation 33 |
| PF-05231023 25 mg | Volume of Distribution of PF-05231023 at Steady State (Vss) | C-terminal (n=8, 7, 10, 8) | 2.940 liter | Standard Deviation 48 |
| PF-05231023 100 mg | Volume of Distribution of PF-05231023 at Steady State (Vss) | N-terminal (n=9, 10, 9, 6) | 4.863 liter | Standard Deviation 18 |
| PF-05231023 100 mg | Volume of Distribution of PF-05231023 at Steady State (Vss) | C-terminal (n=8, 7, 10, 8) | 4.110 liter | Standard Deviation 12 |