First-in-Human Study to Evaluate Safety and Tolerability of Single and Multiple Ascending Doses of Janus Kinase-1 Inhibitor PF-04965842 in Healthy Western and Japanese Subjects
- Registration Number
- NCT01835197
- Lead Sponsor
- Pfizer
- Brief Summary
This single- and multiple-ascending dose study is the first evaluation of PF-04965842, a Janus kinase1 (JAK1) inhibitor, in humans. The goal is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Western and Japanese subjects.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 79
Inclusion Criteria
- Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive.
- Females must be of non-child bearing potential and either at least 1 year post menopausal (FSH ≥40 IU/L), or have documented hysterectomy (with or without bilateral oophrectomy) at least 6 months prior to study day
- Subjects willing to defer receiving prophylactic immunizations (e.g. influenza or pneumococcal vaccines) during the study.
- Absolute lymphocyte count must be greater than or equal to the lower limit of the laboratory reference range.
- Subjects enrolled in Cohort 8 must have four Japanese grandparents born in Japan.
Exclusion Criteria
- Evidence or history of clinically significant hematological, renal, , pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
- History of hepatitis or positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBc Ab) or hepatitis C antibodies (HCV).
- Clinically significant abnormality on chest X-ray performed at screening or within 3 months of screening date; or history of tuberculosis or active or latent or inadequately treated infection.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description SAD Cohorts 1-8 Placebo Arm Placebo - SAD Cohorts 1-8 Experimental Arm PF-04965842 - MAD Cohorts 3 through 5 Placebo Arm Placebo - MAD Cohorts 6 and 7 Placebo Arm Placebo - MAD Cohort 8 Placebo Arm Placebo - MAD Cohort 9 Experimental Arm PF-04965842 - MAD Cohort 9 Placebo Arm Placebo - MAD Cohorts 3 through 5 Experimental Arm PF-04965842 - MAD Cohorts 6 and 7 Experimental Arm PF-04965842 - MAD Cohort 8 Experimental Arm PF-04965842 -
- Primary Outcome Measures
Name Time Method Incidence and severity of treatment emergent adverse events and withdrawals due to treatment emergent adverse events 6 weeks Changes from baseline vital signs (blood pressure, pulse rate, oral temperature and respiration rate) and physical examinations 6 weeks Changes from baseline in 12 lead ECG parameters 6 weeks Quantitative changes in ECG intervals
Incidence and magnitude of treatment emergent clinical laboratory abnormalities including hematology (with white blood cell count differentials, platelets, PT and aPTT), chemistry, fasting glucose, urinalysis 6 weeks Change from baseline in immunoglobulin levels 6 weeks Quantitative IgG, IgA, IgM, and IgE levels
24-hour urine creatinine clearance (Single Ascending Dose Period) Baseline, Day 1 24-hour urine creatinine clearance (Multiple Ascending Dose Period) Baseline, Day 1
- Secondary Outcome Measures
Name Time Method Complement Level: C3 6 weeks Complement Level: C4 6 weeks Complement Level: C3A 6 weeks Cohorts 1-7 and Cohort 9
Complement Level: Bb 6 weeks Cohorts 1-7 and Cohort 9
Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Infinity (AUCinf(dn)) 8 days Multiple Ascending Dose: Accumulation Ratio based on Cmax (Rac(Cmax)) 6 weeks Urinary Pharmacokinetics; for twice-a-day dosing, amount of PF-0496842 excreted unchanged in 12 hours (AE12) 6 weeks Urinary Pharmacokinetics; for twice-a-day dosing, percent of PF-0496842 excreted unchanged in 12 hours (AE12%) 6 weeks Multiple Ascending Dose: Apparent Volume of Distribution at Steady State (Vz/F) 6 weeks Vz/F is the distribution of a drug between plasma and the rest of the body following oral adminstration.
Multiple Ascending Dose: Maximum Observed Plasma Concentration (Cmax) 6 weeks Multiple Ascending Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) 6 weeks Multiple Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn)) 6 weeks Complement Level: CH50 6 weeks Single Ascending Dose: Apparent Total Body Clearance (CL/F) 8 days Multiple Ascending Dose: Apparent Total Body Clearance (CL/F) 6 weeks Urinary Pharmacokinetics; for once-a-day dosing, amount of PF-0496842 excreted unchanged in 24 hours (AE24) 6 weeks Urinary Pharmacokinetics; for once-a-day dosing, percent of PF-0496842 excreted unchanged in 24 hours (AE24%) 6 weeks Renal Clearance (CLr) 6 weeks High-Sensitivity C-Reactive Protein (hsCRP) 6 weeks Neutrophil counts 6 weeks Reticulocyte counts 6 weeks Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau(dn)) 6 weeks Multiple Ascending Dose: Accumulation Ratio based on AUC predicted (Rss) 6 weeks Multiple Ascending Dose: Accumulation Ration based on AUC observed (Rac) 6 weeks Multiple Ascending Dose: Plasma Decay Half-Life (t1/2) 6 weeks Plasma decay half-life is the time measured for the plasma concentration to decrease by one-half.
Multiple Ascending Dose: Peak to Trough Fluctuation (PTF) 6 weeks Single Ascending Dose: Dose-normalized Area Under the Curve to the end of the dosing period (AUCtau(dn)) 8 days Single Ascending Dose: Area Under the Curve From Time Zero to Infinity (AUCinf) 8 days Single Ascending Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) 8 days Single Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn)) 8 days Single Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau) 8 days Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn)) 8 days Dose-normalized area under the plasma concentration time-curve from zero to the last measured concentration (AUClast(dn))
Single Ascending Dose: Plasma Decay Half-Life (t1/2) 8 days Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau) 6 weeks Single Ascending Dose: Apparent Volume of Distribution (Vz/F) 8 days Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax) 8 days
Trial Locations
- Locations (1)
Pfizer Investigational Site
🇺🇸New Haven, Connecticut, United States