Pharmacokinetics Of CP-690,550 In Pediatric Patients With Juvenile Idiopathic Arthritis (JIA)

An Open-label Multiple Dose Study To Evaluate The Pharmacokinetics, Safety And Tolerability Of CP-690,550 In Pediatric Patients From 2 To Less Than 18 Years Of Age With Juvenile Idiopathic Arthritis (JIA)

Phase 1 study to describe pharmacokinetics of CP-690,550 in pediatric patients 2 to less than 18 years of age with Juvenile Idiopathic Rheumatoid Arthritis (JIA).

Study Overview

• Status: Completed
• Conditions: Juvenile Idiopathic Arthritis
• Intervention / Treatment: Drug: CP-690,550; Drug: CP-690,550; Drug: CP-690,550

Detailed Description

This is an open-label, non-randomized, multi-center, oral CP-690,550, multiple-dose (twice daily for 5 days [except Day 5 when only morning dose will be given]) study in pediatric subjects with JIA aged from 2 to less than 18 years. Baseline visit will occur within 1 month of the completion of the Screening Visit. The study will consist of three cohorts based on the age of the subjects, Cohort 3: 2 to less than 6 years, Cohort 2: 6 to less than 12 years and Cohort 1: 12 to less than 18 years. In each cohort, at least 8 pediatric subjects with JIA will participate in the study ensuring a total number of at least 24 pediatric evaluable subjects completing the PK period.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bad Bramstedt, Germany, 24576
    • PRI - Pediatric Rheumatology Research Institute GmbH
  • Hamburg, Germany, 22081
    • Hamburger Zentrum fuer Kinder-und Jugendrheumatologie SchoenKlinik Hamburg Eilbek
  • St. Augustin, Germany, 53757
    • Asklepios Klinik Sankt Augustin GmbH
• Poland
  • Krakow, Poland, 31-503
    • Wojewódzki Specjalistyczny Szpital Dzieciecy im. Sw. Ludwika w Krakowie
  • Lodz, Poland, 91-738
    • Klinika Kardiologii i Reumatologii Dzieciecej
• Slovakia
  • Piestany, Slovakia, 921 12
    • Narodny Ustav Reumatickych Chorob
• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • Explorer Clinic, University of Minnesota Children's Hospital
    • Minneapolis, Minnesota, United States, 55455
      • Clinical and Translational Science Institute Masonic Clinical Research Unit (Administration Only)
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97227
      • Randall Children's Hospital at Legacy Emanuel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pediatric patients with JIA aged from 2 to less than 18 years with active JIA (extended oligoarthritis, polyarthritis rheumatoid factor positive or negative, psoriatic arthritis, enthesitis related arthritis), in 5 or more joints (using American College Rheumatology definition of active joint) at the time of the first study drug administration.
2. For subjects receiving MTX treatment, minimum duration of therapy is 4 months and dose stable for at least 6 weeks prior to first dose of study drug. MTX may be administered either orally or parenterally at doses not to exceed 20 mg/wk or 15 mg/m2/week.
3. A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months prior to screening. A negative PPD test can be substituted for the QuantiFERON-TB Gold In-Tube test only if the central laboratory is unable to perform the test or cannot determine the results to be positive or negative and the Pfizer medical monitor approves it, on a case-by-case basis.

Exclusion Criteria:

1. Systemic JIA, persistent oligoarthritis, undifferentiated arthritis.
2. Current or recent history of uncontrolled clinically significant renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, or neurological disease.
3. History of any other rheumatic autoimmune disease.

4. Infections:

   1. Latent or active TB or any history of previous TB.
   2. Chronic infections.
   3. Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by the investigator within the 6 months prior to the first dose of study drug.
   4. Any treated infections within 2 weeks of Baseline visit.
   5. A subject known to be infected with human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus.
   6. History of infected joint prosthesis with prosthesis still in situ.
5. History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
6. The biologic agents and DMARDs are disallowed at any time during this study. If a subject needs to be treated with one of these agents, the subject should be discontinued from the study.
7. Subjects who have been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study medication or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks following discontinuation of study drug.
8. Subjects with a malignancy or with a history of malignancy with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Ages 12 to less than 18	Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Oral solution will be used for children weighing <40 kg. Oral tablets will be used for children weighing ≥40 kg. Children aged 12 to less than 18 years who are unable to swallow tablets will have the option of taking oral solution. Body Weight (kg) Dose (mg) Volume (mL) 5-11 1 1; 12-18 1.5 1.5; 19-24 2 2; 25-31 2.5 2.5; 32-39 3 3; ≥40 5 5; Other Names: Tofacitinib; Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Oral solution will be used for children weighing <40 kg. Oral tablets will be used for children weighing ≥40 kg. Children less than 12 years of age with a body weight of ≥40 kg will have the option of taking oral solution or tablets. Body Weight (kg) Dose (mg) Volume (mL) 5-11 1 1; 12-18 1.5 1.5; 19-24 2 2; 25-31 2.5 2.5; 32-39 3 3; ≥40 5 5; Other Names: Tofacitinib; Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Children with a body weight ≥30 kg will have the option of taking oral solution or tablets, and children weighing <30 kg will be dosed with the oral solution. Body Weight (kg) Dose (mg) Volume (mL) 5-6 1 1; 7-9 1.5 1.5; 10-12 2 2; 21-15 2.5 2.5; 16-19 3 3; 20-22 3.5 3.5; 23-26 4 4; 27-29 4.5 4.5; ≥30 5 5; Other Names: Tofacitinib
Experimental: Cohort 2; Ages 6 to less than 12	Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Oral solution will be used for children weighing <40 kg. Oral tablets will be used for children weighing ≥40 kg. Children aged 12 to less than 18 years who are unable to swallow tablets will have the option of taking oral solution. Body Weight (kg) Dose (mg) Volume (mL) 5-11 1 1; 12-18 1.5 1.5; 19-24 2 2; 25-31 2.5 2.5; 32-39 3 3; ≥40 5 5; Other Names: Tofacitinib; Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Oral solution will be used for children weighing <40 kg. Oral tablets will be used for children weighing ≥40 kg. Children less than 12 years of age with a body weight of ≥40 kg will have the option of taking oral solution or tablets. Body Weight (kg) Dose (mg) Volume (mL) 5-11 1 1; 12-18 1.5 1.5; 19-24 2 2; 25-31 2.5 2.5; 32-39 3 3; ≥40 5 5; Other Names: Tofacitinib; Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Children with a body weight ≥30 kg will have the option of taking oral solution or tablets, and children weighing <30 kg will be dosed with the oral solution. Body Weight (kg) Dose (mg) Volume (mL) 5-6 1 1; 7-9 1.5 1.5; 10-12 2 2; 21-15 2.5 2.5; 16-19 3 3; 20-22 3.5 3.5; 23-26 4 4; 27-29 4.5 4.5; ≥30 5 5; Other Names: Tofacitinib
Experimental: Corhort 3; Ages 2 to less than 6	Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Oral solution will be used for children weighing <40 kg. Oral tablets will be used for children weighing ≥40 kg. Children aged 12 to less than 18 years who are unable to swallow tablets will have the option of taking oral solution. Body Weight (kg) Dose (mg) Volume (mL) 5-11 1 1; 12-18 1.5 1.5; 19-24 2 2; 25-31 2.5 2.5; 32-39 3 3; ≥40 5 5; Other Names: Tofacitinib; Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Oral solution will be used for children weighing <40 kg. Oral tablets will be used for children weighing ≥40 kg. Children less than 12 years of age with a body weight of ≥40 kg will have the option of taking oral solution or tablets. Body Weight (kg) Dose (mg) Volume (mL) 5-11 1 1; 12-18 1.5 1.5; 19-24 2 2; 25-31 2.5 2.5; 32-39 3 3; ≥40 5 5; Other Names: Tofacitinib; Drug: CP-690,550; CP-690,550 will be administered orally twice daily according to the dosing regimen provided below. Children with a body weight ≥30 kg will have the option of taking oral solution or tablets, and children weighing <30 kg will be dosed with the oral solution. Body Weight (kg) Dose (mg) Volume (mL) 5-6 1 1; 7-9 1.5 1.5; 10-12 2 2; 21-15 2.5 2.5; 16-19 3 3; 20-22 3.5 3.5; 23-26 4 4; 27-29 4.5 4.5; ≥30 5 5; Other Names: Tofacitinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apparent Oral Clearance (CL/F)	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is also influenced by the fraction of the dose absorbed. Clearance was estimated by non compartmental analysis (NCA) of PK data. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. It was calculated by dividing the given oral dose by AUCtau. AUCtau is the area under the plasma concentration time-curve from time zero to end of dosing interval.	Day 5: Pre-dose, 0.5, 1, 2, 4, 8 hours post dose
Number of Participants With Treatment-Emergent Adverse Events (AEs) All Causalities	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AEs included both serious and non-serious AEs.	Baseline up to 28 days after the last dose of study drug (Day 5)
Number of Participants With Laboratory Test Abnormalities	Participants with laboratory test abnormalities of potential clinical concern without regard to baseline abnormality were reported. Criteria: Hematology(hemoglobin,hematocrit,red blood cell[RBC] count:<0.8*lower limit of normal [LLN], platelets:<0.5*LLN/greater than [>]1.75*upper limit of normal[ULN], white blood cell [WBC] count:<0.6*LLN></0>1.5*ULN, lymphocytes, total neutrophils:<0.8*LLN or >1.2*ULN, basophils, eosinophil, monocytes:>1.2*ULN); Liver Function (total bilirubin: >1.5*ULN, aspartate aminotransferase,alanine aminotransferase, alkaline phosphatase:>3.0*ULN, total protein, albumin:<0.8*LLN or >1.2*ULN);Renal Function (blood urea nitrogen, creatinine:>1.3*ULN, uric acid:>1.2*ULN); Electrolytes (sodium:<0.95*LLN or >1.05*ULN,potassium,chloride,calcium,bicarbonate:<0.9*LLN or >1.1*ULN);Clinical chemistry (glucose <0.6*LLN or >1.5*ULN, creatine kinase:>3.0*ULN); Urinalysis (Urine WBC and RBC: greater than or equal to [>=] 6/High Power Field [HPF]).	Baseline up to Day 5
Number of Participants With Clinically Significant Vital Signs Abnormalities	Criteria for vital signs of potentially clinical concern included supine/sitting pulse rate of <40 beats per minute (bpm) or >120 bpm, standing pulse rate of <40 bpm or >140 bpm, systolic blood pressure of >=30 millimeters of mercury (mmHg) change from baseline and systolic blood pressure <90 mmHg, diastolic blood pressure >=20 mmHg change from baseline and diastolic blood pressure <50 mm Hg.	Baseline up to Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)		Day 5: Pre-dose, 0.5, 1, 2, 4, 8 hours post dose
Maximum Observed Plasma Concentration (Cmax)		Day 5: Pre-dose, 0.5, 1, 2, 4, 8 hours post dose
Time to Reach Maximum Observed Plasma Concentration (Tmax)		Day 5: Pre-dose, 0.5, 1, 2, 4, 8 hours post dose
Apparent Volume of Distribution (Vz/F)	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.	Day 5: Pre-dose, 0.5, 1, 2, 4, 8 hours post dose
Plasma Decay Half-Life (t1/2)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Day 5: Pre-dose, 0.5, 1, 2, 4, 8 hours post dose
Taste Assessment	Participants were evaluated for taste assessment using a 5 categories questionnaire. Participants were asked to answer one of the following to describe the taste of oral solution of tofacitinib: Dislike very much, dislike a little, not sure, like a little, or like very much. The taste assessment was only performed for participants who received the oral solution. Number of participants within each category are reported.	Day 1, Day 5

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Ruperto N, Brunner HI, Zuber Z, Tzaribachev N, Kingsbury DJ, Foeldvari I, Horneff G, Smolewska E, Vehe RK, Hazra A, Wang R, Mebus CA, Alvey C, Lamba M, Krishnaswami S, Stock TC, Wang M, Suehiro R, Martini A, Lovell DJ; Pediatric Rheumatology International Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG). Pharmacokinetic and safety profile of tofacitinib in children with polyarticular course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter study. Pediatr Rheumatol Online J. 2017 Dec 28;15(1):86. doi: 10.1186/s12969-017-0212-y.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: January 17, 2012
• First Submitted That Met QC Criteria: January 17, 2012
• First Posted (Estimate): January 20, 2012

Study Record Updates

• Last Update Posted (Estimate): July 4, 2016
• Last Update Submitted That Met QC Criteria: May 24, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Arthritis; Pediatric; JIA; Tofacitinib
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: A3921103; 2011-004914-40 (EudraCT Number)