Healthy
Conditions
Keywords
Phase 1, Metformin, Atopic dermatitis
Brief summary
This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF-04965842 on metformin (a probe for MATE1/2K activity) PK in healthy adult participants. The effect of PF-04965842 on N1-methylnicotinamide (NMN; an endogenous biomarker for MATE1/2K) PK and its correlation to the effect on metformin PK will also be assessed. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 12 healthy male and/or female participants will be enrolled in the study so that 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods.
Detailed description
This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF-04965842 on metformin (a probe for MATE1/2K activity) PK in healthy adult participants. The effect of PF-04965842 on N1-methylnicotinamide (NMN; an endogenous biomarker for MATE1/2K) PK and its correlation to the effect on metformin PK will also be assessed. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 12 healthy male and/or female participants will be enrolled in the study so that 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods. Participants who discontinue from the study may be replaced at the sponsor's discretion. The replacement participant will receive the same treatment sequence as the participant who discontinued. Participants will be screened within 28 days of the first dose of investigational product. Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie Day -1) dosing in Period 1 for both treatment sequences. In both sequences, participants will remain in the CRU for a total of 8 days and 7 nights (including Period 1 and Period 2). There will be a minimum 4 day washout period between metformin dosing events. NMN and metformin PK will be assessed in plasma and urine over 24 and 48 hours, respectively.
Interventions
DRUGMetformin
Commercially available metformin (GLUCOPHAGE®) as 500 mg tablets.
DRUGPF-04965842
PF 04965842 100 mg tablets
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF 04965842 on metformin PK in healthy adult participants. The effect of PF 04965842 on N1 methylnicotinamide (NMN) PK and its correlation to the effect on metformin PK will also be assessed. A total of approximately 12 healthy male and/or female participants will be enrolled in the study so that approximately 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods. Participants who discontinue from the study may be replaced at the sponsor's discretion. The replacement participant will receive the same treatment sequence as the participant who discontinued. Participants will be screened within 28 days of the first dose of investigational product. Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie Day -1) dosing in Period 1 for both treatment sequences. In both sequences, participants will remain in the CRU for
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Male and female participants who are overtly healthy as determined by medical evaluation including a detailed medical history, complete physical examination, laboratory tests, and cardiovascular tests. * Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. * Female participants who are of child bearing potential must not be intending to become pregnant, currently pregnant, or lactating. * Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb). * Capable of giving signed informed consent.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease. * Any condition possibly affecting drug absorption (eg, gastrectomy). * History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus infection; positive testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HepBcAb), or hepatitis C virus antibody (HCVAb). * Other acute or chronic medical or psychiatric condition including recent (within the past year). * Evidence or history of clinically significant dermatological condition (eg, atopic dermatitis or psoriasis) or visible rash present during physical examination. * Clinically relevant history of lactic acidosis. * Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of investigational product. * A positive urine drug test. * Selected laboratory abnormalities. * History of regular alcohol consumption exceeding 14 drinks/week for female participants or 21 drinks/week for male participants (1 drink = 5 ounces \[150 mL\] of wine or 12 ounces \[360 mL\] of beer or 1.5 ounces \[45 mL\] of hard liquor) within 6 months before screening. * Known relevant history of elevated liver function tests (LFTs). * History of tuberculosis (TB) (active or latent) * Any history of chronic infections, any history of recurrent infections, any history of latent infections, or any acute infection within 2 weeks of baseline. * History of disseminated herpes zoster, or disseminated herpes simplex, or recurrent localized dermatomal herpes zoster.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Clearance (CLr) of Metformin | For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose | CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | Cmax is maximum observed plasma concentration. |
| Time for Cmax (Tmax) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | Tmax of metformin administrated with or without PF-04965842. |
| Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | AUClast of metformin administrated with or without PF-04965842. |
| Apparent Clearance (CL/F) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | CL/F is a quantitative measure of the rate at which drug was removed from the blood. |
| Apparent Volume of Distribution (Vz/F) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | Vz/F 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. |
| Terminal Half-life (t1/2) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | t1/2 is the time measured for the plasma concentration to decrease by one half. |
| Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2 | AUCinf is a measure of the serum concentration of the drug over time. It was used to characterize drug absorption. |
| Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin | For both Period 1 and Period 2 at intervals of 0-12 and 12-24 hours post metformin dose | Ae% is percent of dose recovered unchanged in urine from 0 to 24 hours post-dose of metformin. |
| Number of Participants With Laboratory Abnormalities | Screening (within 28 days prior to Day 1) to Day 7 | Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocytes, ery. mean corpuscular volume, ery. mean corpuscular hemoglobin, ery. mean corpuscular HGB concentration, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, prothrombin time, prothrombin intl. normalized ratio, large unstained cells/leukocytes and large unstained cells), clinical chemistry (bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, blood urea nitrogen, urea, creatinine, urate, sodium, potassium, chloride, calcium, bicarbonate, urobilinogen and glucose -FASTING), urinalysis (specific gravity, pH, urine glucose, ketones, urine protein, urine hemoglobin, urine bilirubin, nitrite and leukocytes). Clinical significance of laboratory parameters is determined at the investigator's discretion. |
| Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Screening (within 28 days prior to Day 1) to Day 7 | Criteria for change in vital signs: pulse rate value less than (\<) 40 beats per minute (bpm) or value over than (\>) 120 bpm, systolic blood pressure (SBP) value \< 90 millimeter of mercury (mmHg) or change from baseline (Chg) equal to or over than (≥) 30 mmHg increase or ≥ Chg 30 mmHg decrease, diastolic blood pressure (DBP) value \< 50 mmHg or Chg ≥ 20 mmHg increase or Chg ≥ 20 mmHg decrease. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | Day 1 up to Day 40 (35 days after the last dose of metformin) | AEs with all causalities were any untoward medical occurrences in a study subject administered a product or medical device which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | Day 1 up to Day 40 (35 days after the last dose of metformin) | AEs with all causalities were any untoward medical occurrences in a study subject administered a product or medical device which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin | For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose | Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram \[g\]/1.020), where 1.020 g/mL is the approximate specific gravity of urine. |
Countries
Belgium
Participant flow
Pre-assignment details
A total of 12 healthy participants were enrolled in the study and 6 participants were assigned in each of the 2 treatment sequences, all receiving study treatment.
Participants by arm
| Arm | Count |
|---|---|
| All Participants This reporting group refers to the total 12 participants who were enrolled in the study. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 39.0 Years STANDARD_DEVIATION 8.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 6 / 12 | 4 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Renal Clearance (CLr) of Metformin
CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau).
Time frame: For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Renal Clearance (CLr) of Metformin | 32.18 litre per hour (L/hr) | Geometric Coefficient of Variation 39 |
| Metformin | Renal Clearance (CLr) of Metformin | 33.33 litre per hour (L/hr) | Geometric Coefficient of Variation 28 |
90% CI: [82.09, 118.2]
Secondary
Apparent Clearance (CL/F) of Metformin
CL/F is a quantitative measure of the rate at which drug was removed from the blood.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Apparent Clearance (CL/F) of Metformin | 98.97 L/hr | Geometric Coefficient of Variation 16 |
| Metformin | Apparent Clearance (CL/F) of Metformin | 96.13 L/hr | Geometric Coefficient of Variation 19 |
Secondary
Apparent Volume of Distribution (Vz/F) of Metformin
Vz/F 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.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Apparent Volume of Distribution (Vz/F) of Metformin | 1087 liter (L) | Geometric Coefficient of Variation 42 |
| Metformin | Apparent Volume of Distribution (Vz/F) of Metformin | 1211 liter (L) | Geometric Coefficient of Variation 37 |
Secondary
Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin
AUCinf is a measure of the serum concentration of the drug over time. It was used to characterize drug absorption.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin | 5050 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 16 |
| Metformin | Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin | 5202 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 19 |
90% CI: [85.15, 102.65]
Secondary
Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin
AUClast of metformin administrated with or without PF-04965842.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin | 4849 ng*h/mL | Geometric Coefficient of Variation 18 |
| Metformin | Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin | 5145 ng*h/mL | Geometric Coefficient of Variation 18 |
90% CI: [88.19, 100.73]
Secondary
Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin
Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram \[g\]/1.020), where 1.020 g/mL is the approximate specific gravity of urine.
Time frame: For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin + PF-04965842 | Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin | 168.0 milligram (mg) |
| Metformin | Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin | 170.5 milligram (mg) |
Secondary
Maximum Plasma Concentration (Cmax) of Metformin
Cmax is maximum observed plasma concentration.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Maximum Plasma Concentration (Cmax) of Metformin | 634.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 14 |
| Metformin | Maximum Plasma Concentration (Cmax) of Metformin | 720.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 20 |
90% CI: [80.99, 95.76]
Secondary
Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria
Criteria for change in vital signs: pulse rate value less than (\<) 40 beats per minute (bpm) or value over than (\>) 120 bpm, systolic blood pressure (SBP) value \< 90 millimeter of mercury (mmHg) or change from baseline (Chg) equal to or over than (≥) 30 mmHg increase or ≥ Chg 30 mmHg decrease, diastolic blood pressure (DBP) value \< 50 mmHg or Chg ≥ 20 mmHg increase or Chg ≥ 20 mmHg decrease.
Time frame: Screening (within 28 days prior to Day 1) to Day 7
Population: This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine DBP Value < 50 mmHg | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine DBP Chg ≥ 20 mmHg increase | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine DBP Chg ≥ 20 mmHg decrease | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine pulse rate Value < 40 bpm | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine pulse rate Value > 120 bpm | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine SBP Value < 90 mmHg | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine SBP Chg ≥ 30 mmHg increase | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine SBP Chg ≥ 30 mmHg decrease | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine SBP Chg ≥ 30 mmHg decrease | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine DBP Value < 50 mmHg | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine pulse rate Value > 120 bpm | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine DBP Chg ≥ 20 mmHg increase | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine SBP Chg ≥ 30 mmHg increase | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine DBP Chg ≥ 20 mmHg decrease | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine SBP Value < 90 mmHg | 0 Participants |
| Metformin | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria | Supine pulse rate Value < 40 bpm | 0 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocytes, ery. mean corpuscular volume, ery. mean corpuscular hemoglobin, ery. mean corpuscular HGB concentration, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, prothrombin time, prothrombin intl. normalized ratio, large unstained cells/leukocytes and large unstained cells), clinical chemistry (bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, blood urea nitrogen, urea, creatinine, urate, sodium, potassium, chloride, calcium, bicarbonate, urobilinogen and glucose -FASTING), urinalysis (specific gravity, pH, urine glucose, ketones, urine protein, urine hemoglobin, urine bilirubin, nitrite and leukocytes). Clinical significance of laboratory parameters is determined at the investigator's discretion.
Time frame: Screening (within 28 days prior to Day 1) to Day 7
Population: This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin + PF-04965842 | Number of Participants With Laboratory Abnormalities | 0 Participants |
| Metformin | Number of Participants With Laboratory Abnormalities | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related)
AEs with all causalities were any untoward medical occurrences in a study subject administered a product or medical device which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Day 1 up to Day 40 (35 days after the last dose of metformin)
Population: This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin + PF-04965842 | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (all causalities) | 6 Participants |
| Metformin + PF-04965842 | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (treatment-related) | 5 Participants |
| Metformin + PF-04965842 | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (all causalities) | 0 Participants |
| Metformin + PF-04965842 | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (treatment-related) | 0 Participants |
| Metformin | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (treatment-related) | 0 Participants |
| Metformin | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (all causalities) | 4 Participants |
| Metformin | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | SAEs (all causalities) | 0 Participants |
| Metformin | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) | AEs (treatment-related) | 4 Participants |
Secondary
Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related)
AEs with all causalities were any untoward medical occurrences in a study subject administered a product or medical device which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Day 1 up to Day 40 (35 days after the last dose of metformin)
Population: This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin + PF-04965842 | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | AEs (all causalities) | 50.0 percentage of participants |
| Metformin + PF-04965842 | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | AEs (treatment-related) | 41.7 percentage of participants |
| Metformin + PF-04965842 | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | SAEs (all causalities) | 0.0 percentage of participants |
| Metformin + PF-04965842 | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | SAEs (treatment-related) | 0.0 percentage of participants |
| Metformin | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | SAEs (treatment-related) | 0.0 percentage of participants |
| Metformin | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | AEs (all causalities) | 33.3 percentage of participants |
| Metformin | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | SAEs (all causalities) | 0.0 percentage of participants |
| Metformin | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) | AEs (treatment-related) | 33.3 percentage of participants |
Secondary
Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin
Ae% is percent of dose recovered unchanged in urine from 0 to 24 hours post-dose of metformin.
Time frame: For both Period 1 and Period 2 at intervals of 0-12 and 12-24 hours post metformin dose
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin + PF-04965842 | Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin | 33.60 percentage of dose |
| Metformin | Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin | 34.05 percentage of dose |
Secondary
Terminal Half-life (t1/2) of Metformin
t1/2 is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin + PF-04965842 | Terminal Half-life (t1/2) of Metformin | 8.318 hrs | Standard Deviation 4.2508 |
| Metformin | Terminal Half-life (t1/2) of Metformin | 9.261 hrs | Standard Deviation 3.5165 |
Secondary
Time for Cmax (Tmax) of Metformin
Tmax of metformin administrated with or without PF-04965842.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Population: This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin + PF-04965842 | Time for Cmax (Tmax) of Metformin | 4.00 Hours (hrs) |
| Metformin | Time for Cmax (Tmax) of Metformin | 4.00 Hours (hrs) |