Healthy
Conditions
Keywords
Phase 1, Randomized, Double Blind, Placebo-Controlled, Single- & Multiple Dose Escalation, Safety, Tolerability, PK, PD, Pf-04965842
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.
Interventions
DRUGPF-04965842
Subjects will receive single doses of 3, 10, 30, 100, 200, 400, or 800 mg of PF-04695842 (solution or suspension) in a dose escalation format.
DRUGPlacebo
Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 severity of treatment emergent adverse events and withdrawals due to treatment emergent adverse events | 6 weeks | — |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 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 | — |
| Complement Level: CH50 | 6 weeks | — |
| Single Ascending Dose: Apparent Total Body Clearance (CL/F) | 8 days | — |
| 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 | — |
| 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 From Time Zero to Infinity (AUCinf(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 | — |
| Single Ascending Dose: Dose-normalized Area Under the Curve to the end of the dosing period (AUCtau(dn)) | 8 days | — |
| 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 |
| 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 | — |
Countries
United States
Outcome results
None listed