Single Dose Lipopolysaccharide (LPS) Study In Healthy Volunteers

• Cell counts, IL-6, MPO, MCP-1, MIP1b are individual endpoints which will be evaluated in sputum however they are collected as a single sample. [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
• Post-LPS systemic inflammatory indices: Neutrophil count, IL-6, IL-10, MPO, MCP-1, MIP1b, fibrinogen, CC16 and CRP. These are individual endpoints which will be evaluated in blood however they are collected as a single sample. [ Time Frame: 1, 4, 6 and 7 hours ] [ Designated as safety issue: No ]
• Number of participants with adverse events [ Time Frame: Baseline, Day 1 and Day 2 ] [ Designated as safety issue: Yes ]
• Change from baseline in ECG parameters [ Time Frame: Baseline, Day 1 and Day 2 ] [ Designated as safety issue: Yes ]
• Change from baseline in BP parameters [ Time Frame: Baseline, Day 1 and Day 2 ] [ Designated as safety issue: Yes ]
• Change from baseline in lab safety parameters [ Time Frame: Baseline, Day 1 and Day 2 ] [ Designated as safety issue: Yes ]

• Cell counts, IL-6, MPO, MCP-1, MIP1b are individual endpoints which will be evaluated in sputum however they are collected as a single sample. [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
• Post-LPS systemic inflammatory indices: Neutrophil count, IL-6, IL-10, MPO, MCP-1, MIP1b, fibrinogen, CC16 and CRP. These are individual endpoints which will be evaluated in blood however they are collected as a single sample. [ Time Frame: 1, 4, 6 and 7 hours ] [ Designated as safety issue: No ]
• Number of participants with adverse events as a measure of safety and tolerability using 12 lead ECG, BP/pulse rate, and laboratory safety tests. [ Time Frame: Baseline, Day 1 and Day 2 ] [ Designated as safety issue: Yes ]
• Measure of phospho p38in sputum. [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
• Measure of hsp27 in sputum. [ Time Frame: 6 hours ] [ Designated as safety issue: No ]

A single dose study with the inhaled anti-inflammatory agent PF-03715455 to establish if it has anti-inflammatory activity following a challenge with LPS. Inhaled LPS invokes an acute inflammatory response in the lung which can be seen in induced sputum. PH-0797804 is an internal control for the study.

Proof of Mechanism

• Drug: PF-03715455
  20mg, Inhaled, single dose
• Drug: PH-797804
  30mg, Oral, single dose
• Drug: Placebo for PF-03715455
  Single dose, inhaled, Placebo for PF-03715455
• Drug: Placebo for PH-797804
  Single Dose, Oral, Placebo for PH-797804

• Experimental: PF-03715455
  Intervention: Drug: PF-03715455
• Experimental: PH-797804
  Intervention: Drug: PH-797804
• Placebo Comparator: Placebo for PF-03715455
  Intervention: Drug: Placebo for PF-03715455
• Placebo Comparator: Placebo for PH-797804
  Intervention: Drug: Placebo for PH-797804

Inclusion Criteria:

• Male or female (of non-child bearing potential) subjects, aged 18-50 years.
• Subjects whose FEV1 and FVC at screening are both greater than or equal to 80% of their predicted value for age, race, sex and height.
• Subjects who have normoresponsive airways.
• Subjects who are able to successfully complete screening sputum inductions.

Exclusion Criteria:

• Subjects who have evidence, on review of pre-study laboratory data and full physical examination, or history of any clinically significant hematological, renal, endocrine, gastrointestinal, dermatological, hepatic, psychiatric, neurologic diseases. Specifically liver function tests and CRP must be within the reference range.
• Subjects with a medical history of asthma symptomatology (ie, wheeze and/or dyspnea at rest).
• Subjects who have experienced a respiratory tract infection within the previous 4 weeks or any other infection within 1 week of dosing