A Study of PF-05175157 in Healthy Volunteers and Type 2 Diabetic Patients

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Placebo-controlled Study To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Ascending Oral Doses Of Pf-05175157 In Healthy Volunteers And In Patients With Type 2 Diabetes Mellitus (t2dm)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: PF-05175157 or Placebo
* Drug: PF-05175157 or Placebo
* Drug: PF-05175157 or Placebo
* Drug: PF-05175157 or Placebo
* Drug: PF-05175157 or Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30 mg PF-05175157 or Placebo QD<br> | Drug: PF-05175157 or Placebo<br>* 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.<br>|
| Experimental: 100 mg PF-05175157 or Placebo QD<br>Planned dose might be modified based on emerging safety and PK data. | Drug: PF-05175157 or Placebo<br>* 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.<br>|
| Experimental: 200 mg PF-05175157 or Placebo QD<br>Planned dose might be modified based on emerging safety and PK data. | Drug: PF-05175157 or Placebo<br>* 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.<br>|
| Experimental: 100 mg PF-05175157 or Placebo BID<br>Planned dose might be modified based on emerging safety and PK data. | Drug: PF-05175157 or Placebo<br>* One oral dose of PF-05175157 or placebo is administered as a powder-in-capsule twice daily for 14 days, immediately before breakfast and dinner, in healthy volunteers.<br>|
| Experimental: xxx mg PF-05175157<br>Dose will be determined based on results obtained from Arms 1 to 4. | Drug: PF-05175157 or Placebo<br>* One oral dose of PF-05175157 or placebo is administered as a powder-in-capsule once (or twice) daily for 14 days, immediately before breakfast (and dinner), in patients with type 2 diabetes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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) | Rˇac for the AUC is defined as AUC (τ, single dose [ss]) / AUC (τ, multiple dose [sd]). | 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 | 
| Renal Clearance (CLr) | CLr is the amount of unchanged drug excreted in the participants urine from time zero to end of dosing interval. | 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) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 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 | 
| Urinary Recovery | Percentage of PF-05175157 excreted unchanged in urine over the dosing interval. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Safety, Pharmacodynamics, Healthy Volunteers, Type 2 Diabetic Patients, Phase 1, Multiple Doses