临床试验/NCT01736696

NCT01736696已完成1 期

Phase 1, Investigator-Blind, Subject-Blind, Sponsor-Open, Placebo-Controlled, Two-Week, Multiple Dose Escalation Study In Medically Stable Subjects With Psoriasis To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of CP-690,550

Pfizer1 个研究点分布在 1 个国家目标入组 59 人开始时间: 2002年11月最近更新: 2013年2月20日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: Pfizer
入组人数: 59
试验地点: 1
主要终点: Change From Baseline in QT Interval at 1 Hour Post Morning Dose (HPD 1) on Day 1

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This study was conducted in subjects with psoriasis to evaluate drug activity in this patient population by analysis of changes in psoriatic lesion biopsy characteristics. This subject population was selected to evaluate potentially relevant biological activity of CP-690,550 as well as assessing safety and pharmacokinetics.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
主要目的: Treatment
盲法: Triple (Participant, Care Provider, Investigator)

入排标准

年龄范围: 18 Years 至 65 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Male and/or female subjects between the ages of 18 and 65 years, inclusive, with active psoriasis lesion(s).
•Subjects should be healthy with the exception of psoriasis, where healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination. Blood pressure must be < 140/
•Body Mass Index (BMI) between 18-36 kg/m2, inclusive; and a total body weight >50 kg (110 lbs)
•The following laboratory variables must be no more than 10% below the lower limit of the normal reference range: RBC, hemoglobin, hematocrit, WBC, absolute neutrophil count. The absolute lymphocyte count must be greater than or equal to the lower limit of the reference range. Values for AST, ALT, bilirubin and alkaline phosphatase must be no more than 10% above the upper limit of the normal reference range. Values for total cholesterol and LDL must be no more than 20% above the upper limit of the normal reference range except for subjects being treated for hyperlipidemia. Normal glomerular filtration rate (> 80 mL/min).

排除标准

•Subjects with evidence or history of clinically significant hematological, renal, urological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic disorder.
•Subjects with controlled essential hypertension and/or hyperlipidemia may be eligible for the study provided that any medications that are administered.
•Screening 12-lead ECG demonstrating at least one of the following: heart rate > 100 bpm, QRS >120 msec, QTc > 430 msec (males), QTc > 450 msec (females) or PR > 220 msec.
•Abnormal chest radiographs including, but not limited to, evidence of past or present tuberculosis infection. History of tuberculosis without treatment and/or positive tuberculin reaction without known vaccination with BCG.
•Subjects with a history of tumors with the exception of adequately treated basal cell carcinoma of the skin.

研究组 & 干预措施

5 mg BID

Experimental

5 mg BID for 13 days and once on Day 14

干预措施: tofacitinib (Drug)

10 mg BID

Experimental

10 mg BID for13 days and once on Day 14*

干预措施: tofacitinib (Drug)

20 mg BID

Experimental

20 mg BID for 13 days and once on Day 14

干预措施: tofacitinib (Drug)

30 mg BID

Experimental

30 mg BID for 13 days and once on Day 14

干预措施: tofacitinib (Drug)

60 mg QD

Experimental

60 mg QD for 14 days

干预措施: tofacitinib (Drug)

50 mg BID

Experimental

50 mg BID x 13 days and once on day 14

干预措施: tofacitinib (Drug)

结局指标

主要结局

Change From Baseline in QT Interval at 1 Hour Post Morning Dose (HPD 1) on Day 1

时间窗: 23 hours (hrs) prior to morning dose on Day 1 (Baseline for HPD 1), 1 hour (hr) post morning dose on Day 1

Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles. For each scheduled hour post morning dose (HPD), except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 2 Hour Post Morning Dose (HPD 2) on Day 1

时间窗: 22 hrs prior to morning dose on Day 1 (Baseline for HPD 2), 2 hrs post morning dose on Day 1

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles. For each scheduled hour post morning dose (HPD), except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 4 Hour Post Morning Dose (HPD 4) on Day 1

时间窗: 20 hrs prior to morning dose on Day 1 (Baseline for HPD 4), 4 hrs post morning dose on Day 1

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles. For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 8 Hour Post Morning Dose (HPD 8) on Day 1

时间窗: 16 hrs prior to morning dose on Day 1 (Baseline for HPD 8), 8 hrs post morning dose on Day 1

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 12 Hour Post Morning Dose (HPD 12) on Day 1

时间窗: 12 hrs prior to morning dose on Day 1 (Baseline for HPD 12), 12 hrs post morning dose on Day 1

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 16 Hour Post Morning Dose (HPD 16) on Day 1

时间窗: 8 hrs prior to morning dose on Day 1 (Baseline for HPD 16), 16 hrs post morning dose on Day 1

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.Change from baseline in QT interval at HPD 16 was planned to be analyzed for participants who received CP-690,550 60 mg and matching placebo.

Change From Baseline in QT Interval at 0 Hour Post Morning Dose (HPD 0) on Day 14

时间窗: Hour 0 (pre-dose) on Day 1 (Baseline for HPD 0), 0 hr on Day 14

Change From Baseline in QT Interval at 1 Hour Post Morning Dose (HPD 1) on Day 14

时间窗: 23 hrs prior to morning dose on Day 1 (Baseline for HPD 1), 1 hr post morning dose on Day 14

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 2 Hour Post Morning Dose (HPD 2) on Day 14

时间窗: 22 hrs prior to morning dose on Day 1 (Baseline for HPD 2), 2 hrs post morning dose on Day 14

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 4 Hour Post Morning Dose (HPD 4) on Day 14

时间窗: 20 hrs prior to morning dose on Day 1 (Baseline for HPD 4), 4 hrs post morning dose on Day 14

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 8 Hour Post Morning Dose (HPD 8) on Day 14

时间窗: 16 hrs prior to morning dose on Day 1 (Baseline for HPD 8), 8 hrs post morning dose on Day 14

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in QT Interval at 12 Hour Post Morning Dose (HPD 12) on Day 14

时间窗: 12 hrs prior to morning dose on Day 1 (Baseline for HPD 12), 12 hrs post morning dose on Day 14

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated.QT interval: The time corresponding to the beginning of depolarization to repolarization of the ventricles.For each scheduled HPD, except for HPD=0, the time-matched baseline QT was defined as the mean of the triplicates on Day 0 at the same nominal HPD.

Change From Baseline in Reticulocyte Count at Day 28

时间窗: Baseline (Within 7 days prior to Day 1), Day 28

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Change From Baseline in Reticulocyte Count at Day 15

时间窗: Baseline (Within 7 days prior to Day 1), Day 15

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval

时间窗: 1, 2, 4, 8, 12 hrs post dose, additional 16 hrs post dose for 60 mg once daily group on Day 1; 1, 2 hrs post dose on Day 4, 7, 10;1,2,4,8,12 hrs post dose on Day 14; Day 21

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Participants with maximum increase from baseline of 30 to less than (\<) 60 msec(borderline) and greater than or equal to (\>=) 60 msec (prolonged) were summarized.

Number of Participants With Corrected QT (QTc) Interval Greater Than or Equal to 500 Millisecond

时间窗: 1, 2, 4, 8, 12 hrs post dose, additional 16 hrs post dose for 60 mg once daily group on Day 1; 1, 2 hrs post dose on Day 4, 7, 10;1,2,4,8,12 hrs post dose on Day 14; Day 21

Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Day 1

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 1

AUCtau = area under the curve from time zero to end of dosing interval.

Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Day 14

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 14

AUCtau = area under the curve from time zero to end of dosing interval.

Maximum Observed Plasma Concentration (Cmax) at Day 1

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 1

Maximum Observed Plasma Concentration (Cmax) at Day 14

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 14

Time to Reach Maximum Observed Plasma Concentration (Tmax) at Day 1

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 1

Time to Reach Maximum Observed Plasma Concentration (Tmax) at Day 14

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 14

Accumulation Ratio (R0)

时间窗: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 8, 12 hrs post dose on Day 1 and Day 14

Accumulation ratio was calculated as, R0 = area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1.

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 1

时间窗: Baseline, 1 hr post-dose on Day 1

Absolute cell counts of cluster of differentiation 3 (CD3): T lymphocytes, cluster of differentiation 4 (CD4): Helper/Inducer T- Lymphocytes reactive with Major Histocompatability Complex-II (MHC-II), and cluster of differentiation 8 (CD8): Suppressor/Cytotoxic T-lymphocyte reactive with Major Histocompatability Complex-I (MHC-I), cluster of differentiation 16/56 (CD16/56): natural killer Cells, cluster of differentiation 19 (CD19): B-Lymphocytes determined using FACS.Baseline defined as mean of samples collected during screening, visit in which biopsy was taken, at Day 0 and at 0 hour Day 1.

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 2

时间窗: Baseline, hr 0 on Day 2

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 4

时间窗: Baseline, hr 0 on Day 4

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 7

时间窗: Baseline, hr 0 on Day 7

Change From Baseline in Reticulocyte Count at Day 21

时间窗: Baseline (Within 7 days prior to Day 1), Day 21

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 10

时间窗: Baseline, hr 0 on Day 10

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 14

时间窗: Baseline; hr 0, 8 hr post-dose on Day 14

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 18

时间窗: Baseline, Hour 0 on Day 18

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 21

时间窗: Baseline, hr 0 on Day 21

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 28

时间窗: Baseline, hr 0 on Day 28

Percent Change From Baseline in Fluorescence-Activated Cell Sorting (FACS) Analysis at Day 42

时间窗: Baseline, hr 0 on Day 42

Change From Baseline in Immune Cell Function at Day 14

时间窗: Baseline (Within 7 days prior to Day 1), Day 14

The degree of immunosuppression induced by the study drug administration was evaluated using a bioluminescent assay in which the concentration of Adenosine-5-Triphosphate (ATP) released by CD4 cells was measured. ATP concentrations released from stimulated and unstimulated cells were evaluated. ATP Concentration less than or equal to (\<=) 225: low immune cell response, 226 to 524: Moderate immune cell response, \>= 525: strong immune cell response. Baseline was defined as the mean of the samples collected during the pre-dose biopsy.

Change From Baseline in Reticulocyte Count at Day 2

时间窗: Baseline (Within 7 days prior to Day 1), Day 2

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Change From Baseline in Reticulocyte Count at Day 4

时间窗: Baseline (Within 7 days prior to Day 1), Day 4

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Change From Baseline in Reticulocyte Count at Day 7

时间窗: Baseline (Within 7 days prior to Day 1), Day 7

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Change From Baseline in Reticulocyte Count at Day 10

时间窗: Baseline (Within 7 days prior to Day 1), Day 10

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Change From Baseline in Reticulocyte Count at Day 42

时间窗: Baseline (Within 7 days prior to Day 1), Day 42

Reticulocyte count was assessed to detect potential of Janus kinase 2 (JAK2) mediated erythropoiesis.

Time to Reach Maximum Change From Baseline and Time to Return to Baseline Value for Fluorescence-Activated Cell Sorting (FACS), Reticulocyte Counts and Immune Cell Function

时间窗: Day 0 (pre-dose), 1, 2, 4, 7, 10, 14, 15, 18, 21, 28, 42

Half Maximal Effective Area Under the Concentration-Time Curve 50 (EAUC 50)

时间窗: Day 14

EAUC 50 was calculated from a regression analyses using area under the concentration-time curve (AUC) as the independent variable. A sigmoid maximum effect (Emax) model was used to explain the relationship between AUC and modified Psoriasis Severity Index (mPASI) score, where Emax was the maximum effect (100 percent reduction in the total mPASI score from baseline), and EAUC 50 was the AUC where 50 percent of the maximum effect was measured.

次要结局

Number of Participants With Modified Psoriasis Severity Index (mPASI) at Day 14(Baseline (Within 7 days prior to Day 1) up to Day 14)
Number of Participants With Physician's Global Assessment (PGA) of Psoriasis(Baseline (Within 7 days prior to Day 1) up to Day 14)
Gene Expression in Psoriatic Plaque Biopsies(Day 14)
Immunohistochemistry From Psoriatic Plaque Biopsies(Baseline (within 7 days prior to Day 1), Day 14)
Number of Participants With Keratin 16 (K16) Expression(Baseline (within 7 days prior to Day 1) up to Day 14)
Number of Participants With Intracellular Adhesion Molecule (ICAM-1) by Epidermal Keratinocytes Expression(Baseline (within 7 days prior to Day 1) up to Day 14)
Gene Expression in Peripheral Blood(Day 14)

研究者

发起方

Pfizer

申办方类型

Industry

责任方

Sponsor

研究点 (1)

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