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

Pfizer79 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Healthy

Interventions

PF-04965842DRUG

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.

PlaceboDRUG

Subjects will receive single doses of PF-04695842 matching placebo (solution or suspension) in a dose escalation format.

PF-04965842DRUG

Subjects will receive doses of 30, 100 or 200 mg (solution or suspension) once daily for 10 days.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

Pfizer Investigational Site

New Haven, Connecticut, United States

Outcomes

Primary Outcomes

Changes from baseline vital signs (blood pressure, pulse rate, oral temperature and respiration rate) and physical examinations

Time frame: 6 weeks

Changes from baseline in 12 lead ECG parameters

Quantitative changes in ECG intervals

Time frame: 6 weeks

Incidence and severity of treatment emergent adverse events and withdrawals due to treatment emergent adverse events

Time frame: 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

Time frame: 6 weeks

Change from baseline in immunoglobulin levels

Quantitative IgG, IgA, IgM, and IgE levels

Time frame: 6 weeks

24-hour urine creatinine clearance (Single Ascending Dose Period)

Time frame: Baseline, Day 1

24-hour urine creatinine clearance (Multiple Ascending Dose Period)

Time frame: Baseline, Day 1

Secondary Outcomes

Complement Level: C3

Time frame: 6 weeks

Complement Level: C4

Time frame: 6 weeks

Complement Level: C3A

Cohorts 1-7 and Cohort 9

Data from ClinicalTrials.gov

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Subjects will receive PF-04965842 matching placebo (solution or suspension) once daily for 10 days.

PF-04965842DRUG

Subjects will receive doses of 100 or 200 mg (suspension or solution) twice daily for 10 days.

PlaceboDRUG

Subjects will receive PF-04965842 matching placebo doses (suspension or solution) twice daily for 10 days.

PF-04965842DRUG

Subjects will receive 200 mg dose (suspension or solution) twice daily for 10 days.

PlaceboDRUG

Subjects will receive PF-04965842 matching placebo dose (suspension or solution) twice daily for 10 days.

PF-04965842DRUG

Subjects will receive 400 mg dose (suspension or solution) once daily for 10 days.

PlaceboDRUG

Subjects will receive PF-04965842 matching placebo dose (suspension or solution) once daily for 10 days.

Complement Level: Bb

Cohorts 1-7 and Cohort 9

Time frame: 6 weeks

Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Infinity (AUCinf(dn))

Time frame: 8 days

Multiple Ascending Dose: Accumulation Ratio based on Cmax (Rac(Cmax))

Time frame: 6 weeks

Urinary Pharmacokinetics; for twice-a-day dosing, amount of PF-0496842 excreted unchanged in 12 hours (AE12)

Time frame: 6 weeks

Urinary Pharmacokinetics; for twice-a-day dosing, percent of PF-0496842 excreted unchanged in 12 hours (AE12%)

Time frame: 6 weeks

Multiple Ascending Dose: Apparent Volume of Distribution at Steady State (Vz/F)

Vz/F is the distribution of a drug between plasma and the rest of the body following oral adminstration.

Time frame: 6 weeks

Multiple Ascending Dose: Apparent Total Body Clearance (CL/F)

Time frame: 6 weeks

Urinary Pharmacokinetics; for once-a-day dosing, amount of PF-0496842 excreted unchanged in 24 hours (AE24)

Time frame: 6 weeks

Urinary Pharmacokinetics; for once-a-day dosing, percent of PF-0496842 excreted unchanged in 24 hours (AE24%)

Time frame: 6 weeks

Renal Clearance (CLr)

Time frame: 6 weeks

High-Sensitivity C-Reactive Protein (hsCRP)

Time frame: 6 weeks

Neutrophil counts

Time frame: 6 weeks

Reticulocyte counts

Time frame: 6 weeks

Complement Level: CH50

Time frame: 6 weeks

Single Ascending Dose: Apparent Total Body Clearance (CL/F)

Time frame: 8 days

Multiple Ascending Dose: Maximum Observed Plasma Concentration (Cmax)

Time frame: 6 weeks

Multiple Ascending Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)

Time frame: 6 weeks

Multiple Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn))

Time frame: 6 weeks

Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau(dn))

Time frame: 6 weeks

Multiple Ascending Dose: Accumulation Ratio based on AUC predicted (Rss)

Time frame: 6 weeks

Multiple Ascending Dose: Accumulation Ration based on AUC observed (Rac)

Time frame: 6 weeks

Multiple Ascending Dose: 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: 6 weeks

Multiple Ascending Dose: Peak to Trough Fluctuation (PTF)

Time frame: 6 weeks

Single Ascending Dose: Dose-normalized Area Under the Curve to the end of the dosing period (AUCtau(dn))

Time frame: 8 days

Single Ascending Dose: Area Under the Curve From Time Zero to Infinity (AUCinf)

Time frame: 8 days

Single Ascending Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)

Time frame: 8 days

Single Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn))

Time frame: 8 days

Single Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau)

Time frame: 8 days

Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn))

Dose-normalized area under the plasma concentration time-curve from zero to the last measured concentration (AUClast(dn))

Time frame: 8 days

Single Ascending Dose: 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: 8 days

Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau)

Time frame: 6 weeks

Single Ascending Dose: Apparent Volume of Distribution (Vz/F)

Time frame: 8 days

Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax)

Time frame: 8 days