Clinical trial NCT01835197: 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
Official title: A Phase 1, Within Cohort, Randomized, Double Blind, Third-Party Open, Placebo-Controlled, Single- And Multiple Dose Escalation, Parallel Group Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-04965842 In Healthy Western and Japanese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Phase 1
Randomized
Double Blind
Placebo-Controlled
Single- & Multiple Dose Escalation
Safety
Tolerability
PK
PD
Pf-04965842
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2013-04-18
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Changes from baseline vital signs (blood pressure, pulse rate, oral temperature and respiration rate) and physical examinations
timeFrame: 6 weeks
measure: Changes from baseline in 12 lead ECG parameters
timeFrame: 6 weeks
measure: Incidence and severity of treatment emergent adverse events and withdrawals due to treatment emergent adverse events
timeFrame: 6 weeks
measure: 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
timeFrame: 6 weeks
measure: Change from baseline in immunoglobulin levels
timeFrame: 6 weeks
measure: 24-hour urine creatinine clearance (Single Ascending Dose Period)
timeFrame: Baseline, Day 1
measure: 24-hour urine creatinine clearance (Multiple Ascending Dose Period)
timeFrame: Baseline, Day 1
Secondary outcomes:
measure: Complement Level: C3
timeFrame: 6 weeks
measure: Complement Level: C4
timeFrame: 6 weeks
measure: Complement Level: C3A
timeFrame: 6 weeks
measure: Complement Level: Bb
timeFrame: 6 weeks
measure: Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Infinity (AUCinf(dn))
timeFrame: 8 days
measure: Multiple Ascending Dose: Accumulation Ratio based on Cmax (Rac(Cmax))
timeFrame: 6 weeks
measure: Urinary Pharmacokinetics; for twice-a-day dosing, amount of PF-0496842 excreted unchanged in 12 hours (AE12)
timeFrame: 6 weeks
measure: Urinary Pharmacokinetics; for twice-a-day dosing, percent of PF-0496842 excreted unchanged in 12 hours (AE12%)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Apparent Volume of Distribution at Steady State (Vz/F)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Apparent Total Body Clearance (CL/F)
timeFrame: 6 weeks
measure: Urinary Pharmacokinetics; for once-a-day dosing, amount of PF-0496842 excreted unchanged in 24 hours (AE24)
timeFrame: 6 weeks
measure: Urinary Pharmacokinetics; for once-a-day dosing, percent of PF-0496842 excreted unchanged in 24 hours (AE24%)
timeFrame: 6 weeks
measure: Renal Clearance (CLr)
timeFrame: 6 weeks
measure: High-Sensitivity C-Reactive Protein (hsCRP)
timeFrame: 6 weeks
measure: Neutrophil counts
timeFrame: 6 weeks
measure: Reticulocyte counts
timeFrame: 6 weeks
measure: Complement Level: CH50
timeFrame: 6 weeks
measure: Single Ascending Dose: Apparent Total Body Clearance (CL/F)
timeFrame: 8 days
measure: Multiple Ascending Dose: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn))
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau(dn))
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Accumulation Ratio based on AUC predicted (Rss)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Accumulation Ration based on AUC observed (Rac)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Plasma Decay Half-Life (t1/2)
timeFrame: 6 weeks
measure: Multiple Ascending Dose: Peak to Trough Fluctuation (PTF)
timeFrame: 6 weeks
measure: Single Ascending Dose: Dose-normalized Area Under the Curve to the end of the dosing period (AUCtau(dn))
timeFrame: 8 days
measure: Single Ascending Dose: Area Under the Curve From Time Zero to Infinity (AUCinf)
timeFrame: 8 days
measure: Single Ascending Dose: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
timeFrame: 8 days
measure: Single Ascending Dose: Dose-normalized Maximum Observed Plasma Concentration (Cmax(dn))
timeFrame: 8 days
measure: Single Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau)
timeFrame: 8 days
measure: Single Ascending Dose: Dose-normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast(dn))
timeFrame: 8 days
measure: Single Ascending Dose: Plasma Decay Half-Life (t1/2)
timeFrame: 8 days
measure: Multiple Ascending Dose: Area Under the Curve to the end of the dosing period (AUCtau)
timeFrame: 6 weeks
measure: Single Ascending Dose: Apparent Volume of Distribution (Vz/F)
timeFrame: 8 days
measure: Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 8 days
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Pfizer Investigational Site
state: Connecticut
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Wojciechowski J, Malhotra BK, Wang X, Fostvedt L, Valdez H, Nicholas T. Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis. Clin Pharmacokinet. 2022 May;61(5):709-723. doi: 10.1007/s40262-021-01104-z. Epub 2022 Jan 21.
citation: Peeva E, Hodge MR, Kieras E, Vazquez ML, Goteti K, Tarabar SG, Alvey CW, Banfield C. Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study. Br J Clin Pharmacol. 2018 Aug;84(8):1776-1788. doi: 10.1111/bcp.13612. Epub 2018 May 24.