Diabetes Mellitus, Type 2
Conditions
Keywords
Phase 1, Multiple Doses, Safety, Pharmacokinetics, Pharmacodynamics, Healthy Volunteers, Type 2 Diabetic Patients
Brief summary
The primary purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of PF-05175157 in healthy volunteers and patients with type 2 diabetes mellitus.
Interventions
One oral dose of PF-05175157 or placebo is administered as a powder-in-capsule once daily for 14 days immediately before breakfast, in healthy volunteers.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests. * In addition, subjects must have normal pulmonary function tests and normal ocular examination. * Body Mass Index (BMI) of 25.5 - 35.5 kg/m2; and a total body weight \>50 kg (110 lbs). * Women must be of non-childbearing potential. * Subjects with type 2 diabetes: HbA1c ≥7.0% and ≤10.0% if on metformin only, and ≥6.5% and ≤9.0% if patient requires to be washed-off an SU or DPP-4i. * For subjects with type 2 diabetes, due to possible effects on disposition, CYP P450 3A4/5 and 2D6 substrates should not be co-administered with study medications.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic seasonal allergies at time of dosing). * Evidence or history of any chronic ongoing or current pulmonary disease. * History of smoking in the past 5 years and a history of smoking more than 10 pack years, or history or evidence of habitual use of other (non smoked) tobacco or nicotine containing products within 3 months of Screening, or positive cotinine test at Screening or Day -3. * Active ocular disease including infection, glaucoma, seasonal allergies, dry eye symptoms or retinal/optic nerve disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 2 weeks | Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to PF-05175157 was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | — |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | — |
| Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC) | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | Rˇac for the AUC is defined as AUC (τ, single dose \[ss\]) / AUC (τ, multiple dose \[sd\]). |
| Maximum Observed Plasma Concentration (Cmax) | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | — |
| Plasma Decay Half-Life (t1/2) | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Urinary Recovery | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | Percentage of PF-05175157 excreted unchanged in urine over the dosing interval. |
| Renal Clearance (CLr) | Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11 | CLr is the amount of unchanged drug excreted in the participants urine from time zero to end of dosing interval. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo - HOV HOV participants administered orally matched placebo capsules QD for 14 days | 12 |
| Placebo - T2DM T2DM participants administered orally matched placebo capsules QD for 14 days | 5 |
| PF-05175157 30 mg QD - HOV HOV participants administered orally 30 mg capsules of PF-05175157 QD for 14 days | 9 |
| PF-05175157 100 mg QD -HOV HOV participants administered orally 100 mg capsules of PF-05175157 QD for 14 days | 9 |
| PF-05175157 200 mg QD - HOV HOV participants administered orally 200 mg capsules PF-05175157 QD for 14 days | 9 |
| PF-05175157 100 mg BID - HOV HOV participants administered orally 100 mg capsules of PF-05175157 BID for 14 days | 9 |
| PF-05175157 200 mg QD - T2DM T2DM participants administered orally 200 mg capsules of PF-05175157 QD for 14 days | 11 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo - HOV | Placebo - T2DM | PF-05175157 30 mg QD - HOV | PF-05175157 100 mg QD -HOV | PF-05175157 200 mg QD - HOV | PF-05175157 100 mg BID - HOV | PF-05175157 200 mg QD - T2DM | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Customized 18 to 44 years | 9 participants | 2 participants | 9 participants | 7 participants | 8 participants | 7 participants | 2 participants | 44 participants |
| Age, Customized 45 to 64 years | 3 participants | 3 participants | 0 participants | 2 participants | 1 participants | 2 participants | 9 participants | 20 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 12 Participants | 4 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 61 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 2 / 5 | 1 / 9 | 1 / 9 | 2 / 9 | 5 / 9 | 3 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 5 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 11 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to PF-05175157 was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
Time frame: 2 weeks
Population: Safety Analysis Set: all participants who received at least 1 dose of study medication (PF-05175157 or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Placebo - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Placebo - T2DM | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Placebo - T2DM | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05175157 30 mg QD - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 participants |
| PF-05175157 30 mg QD - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05175157 100 mg QD - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 participants |
| PF-05175157 100 mg QD - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05175157 200 mg QD - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05175157 200 mg QD - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| PF-05175157 100 mg BID - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-05175157 100 mg BID - HOV | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 5 participants |
| PF-05175157 200 mg QD - T2DM | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 participants |
| PF-05175157 200 mg QD - T2DM | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Secondary
Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC)
Rˇac for the AUC is defined as AUC (τ, single dose \[ss\]) / AUC (τ, multiple dose \[sd\]).
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: PKP analysis population; Participants Analyzed (N): number of participants with evaluable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - HOV | Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC) | 1.39 ratio | Standard Deviation 0.11 |
| Placebo - T2DM | Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC) | 1.01 ratio | Standard Deviation 0.34 |
| PF-05175157 30 mg QD - HOV | Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC) | 1.47 ratio | Standard Deviation 0.22 |
| PF-05175157 100 mg QD - HOV | Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC) | 2.53 ratio | Standard Deviation 0.76 |
| PF-05175157 200 mg QD - HOV | Accumulation Ratio for Area Under the Concentration-Time Curve (Rˇac, AUC) | 1.54 ratio | Standard Deviation 0.22 |
Secondary
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: PKP analysis population; Participants Analyzed (N): number of participants with evaluable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - HOV | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 32.86 µg times (*)hr divided by mL (µg *hr/mL) | Standard Deviation 4.01 |
| Placebo - T2DM | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 90.50 µg times (*)hr divided by mL (µg *hr/mL) | Standard Deviation 33.4 |
| PF-05175157 30 mg QD - HOV | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 255.9 µg times (*)hr divided by mL (µg *hr/mL) | Standard Deviation 36.98 |
| PF-05175157 100 mg QD - HOV | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 125.6 µg times (*)hr divided by mL (µg *hr/mL) | Standard Deviation 16.73 |
| PF-05175157 200 mg QD - HOV | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) | 282.6 µg times (*)hr divided by mL (µg *hr/mL) | Standard Deviation 66.21 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: Pharmacokinetic Concentration (PKC) Analysis Population: all enrolled participants who received at least 1 dose of PF-05175157 and had at least 1 concentration value reported. Number of Participants Analyzed (N): number of participants with evaluable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - HOV | Maximum Observed Plasma Concentration (Cmax) | 3.07 micrograms per milliliter (µg/mL) | Standard Deviation 0.28 |
| Placebo - T2DM | Maximum Observed Plasma Concentration (Cmax) | 7.52 micrograms per milliliter (µg/mL) | Standard Deviation 2.87 |
| PF-05175157 30 mg QD - HOV | Maximum Observed Plasma Concentration (Cmax) | 21.75 micrograms per milliliter (µg/mL) | Standard Deviation 4.44 |
| PF-05175157 100 mg QD - HOV | Maximum Observed Plasma Concentration (Cmax) | 15.18 micrograms per milliliter (µg/mL) | Standard Deviation 2.11 |
| PF-05175157 200 mg QD - HOV | Maximum Observed Plasma Concentration (Cmax) | 23.26 micrograms per milliliter (µg/mL) | Standard Deviation 4.43 |
Secondary
Plasma Decay Half-Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: It was not possible to calculate data for half-life as the calculation required the slope of terminal elimination phase and the PK sampling was insufficient to characterize the terminal elimination phase, which is needed for the calculation of the half-life.
Secondary
Renal Clearance (CLr)
CLr is the amount of unchanged drug excreted in the participants urine from time zero to end of dosing interval.
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: PKP analysis population; Participants Analyzed (N): number of participants with evaluable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - HOV | Renal Clearance (CLr) | 5.48 mL/min | Standard Deviation 1.25 |
| Placebo - T2DM | Renal Clearance (CLr) | 5.30 mL/min | Standard Deviation 1.42 |
| PF-05175157 30 mg QD - HOV | Renal Clearance (CLr) | 4.57 mL/min | Standard Deviation 1.83 |
| PF-05175157 100 mg QD - HOV | Renal Clearance (CLr) | 5.93 mL/min | Standard Deviation 1.86 |
| PF-05175157 200 mg QD - HOV | Renal Clearance (CLr) | 5.42 mL/min | Standard Deviation 1.38 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: Pharmacokinetic Parameter (PKP) Analysis Population: all enrolled participante who received at least 1 dose of PF05175157 and had at least 1 PKP of interest calculated;Number of Participants Analyzed (N): number of participants with evaluable data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - HOV | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4.00 hours (hrs) |
| Placebo - T2DM | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 1.00 hours (hrs) |
| PF-05175157 30 mg QD - HOV | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4.00 hours (hrs) |
| PF-05175157 100 mg QD - HOV | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 3.00 hours (hrs) |
| PF-05175157 200 mg QD - HOV | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4.00 hours (hrs) |
Secondary
Urinary Recovery
Percentage of PF-05175157 excreted unchanged in urine over the dosing interval.
Time frame: Hour 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and 14; at Hour 0 (pre-dose), 3.5, 12 hours post-dose for Day 4, 7 and 11
Population: PKP analysis population; Participants Analyzed (N): number of participants with evaluable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - HOV | Urinary Recovery | 35.59 percentage | Standard Deviation 7.78 |
| Placebo - T2DM | Urinary Recovery | 27.30 percentage | Standard Deviation 8.14 |
| PF-05175157 30 mg QD - HOV | Urinary Recovery | 33.75 percentage | Standard Deviation 9.53 |
| PF-05175157 100 mg QD - HOV | Urinary Recovery | 43.60 percentage | Standard Deviation 10.72 |
| PF-05175157 200 mg QD - HOV | Urinary Recovery | 44.31 percentage | Standard Deviation 7.79 |