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A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of PF-04958242 in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT02341482
Recruitment Status : Completed
First Posted : January 19, 2015
Results First Posted : June 30, 2016
Last Update Posted : June 30, 2016
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Healthy
Interventions Drug: PF-04958242
Drug: Itraconazole
Enrollment 13
Recruitment Details  
Pre-assignment Details  
Arm/Group Title All Subjects
Hide Arm/Group Description PF-04958242 0.10 milligram (mg) loading dose was administered orally twice daily (BID) on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), once daily (QD).
Period Title: Overall Study
Started 13
Completed 12
Not Completed 1
Reason Not Completed
Adverse Event             1
Arm/Group Title All Subjects
Hide Arm/Group Description PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Baseline Participants 13
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 13 participants
42.5  (8.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
Female
0
   0.0%
Male
13
 100.0%
1.Primary Outcome
Title Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242
Hide Description AUCtau = area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau = 12 hours. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame Day 3(0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose),Day 17(0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Overall Number of Participants Analyzed 13 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: picogram*hours per milliliter pg*h/mL
4242
(30%)
4073
(25%)
2.Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of PF-04958242
Hide Description Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame Day 3(0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose),Day 17(0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Overall Number of Participants Analyzed 13 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
553.4
(27%)
541.6
(20%)
3.Secondary Outcome
Title Time for Cmax (Tmax) of PF-04958242
Hide Description Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame Day 3(0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose),Day 17(0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Overall Number of Participants Analyzed 13 12
Median (Full Range)
Unit of Measure: hours
1.50
(1.00 to 1.52)
1.50
(1.00 to 2.00)
4.Secondary Outcome
Title Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242
Hide Description [Not Specified]
Time Frame Day 1 to Day 17
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Overall Number of Participants Analyzed 13 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
256.5
(35%)
238.2
(30%)
5.Secondary Outcome
Title Predose Concentration (Ctrough) of PF-04958242
Hide Description [Not Specified]
Time Frame 0 hour at Day 1,Day 2,Day 3,Day 4,Day 7,Day 10,Day 13,Day 16,and Day 17 (pre-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Overall Number of Participants Analyzed 13 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
289.3
(37%)
255.0
(29%)
6.Secondary Outcome
Title Apparent Oral Clearance (CL/F) of PF-04958242
Hide Description 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 influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame Day 3(0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose),Day 17(0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Overall Number of Participants Analyzed 13 12
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: milliliters per minute (mL/min)
98.25
(30%)
102.3
(25%)
7.Secondary Outcome
Title Number of Participants With Abnormal Clinical Laboratory Measurements
Hide Description The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (follicle stimulating hormone [FSH], urine cotinine, and urine drug screening).
Time Frame Baseline up to Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title All Subjects
Hide Arm/Group Description:
PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: participants
1
8.Secondary Outcome
Title Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern
Hide Description Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate more than (<)40 or less than (>)120 beats per minute (bpm); systolic blood pressure (SBP) more than or equal to (>=)30 millimeters of mercury (mm Hg) change from baseline in same posture or SBP <90 mm Hg, diastolic blood pressure (DBP) >=20 mm Hg change from baseline in same posture or DBP <50 mm Hg. IFB = increase from baseline; DFB = decrease from baseline.
Time Frame Baseline up to Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title All Subjects
Hide Arm/Group Description:
PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: participants
Supine SBP >=30 mmHg IFB 2
Supine DBP >=20 mmHg IFB 1
9.Secondary Outcome
Title Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern
Hide Description Electrocardiogram (ECG) parameters included time from ECG Q wave to the end of the T wave corresponding to electrical systole (QT) interval, beginning of the P wave until the beginning of the QRS complex (PR) interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) interval, QT interval corrected for heart rate (QTc) interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval >=300 milliseconds (msec) or >=25% increase when baseline is >200 msec and >=50% increase when baseline is less than or equal to (=<)200 msec; QRS interval >=140 msec or >=50% increase from baseline; and QTcF >=450 to <480, 480 to <500 and >=500 msec or >=30 to 60 msec increase and also >=60 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Time Frame Baseline up to Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title All Subjects
Hide Arm/Group Description:
PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: participants
0
10.Secondary Outcome
Title Number of Participants With Significant Change in Neurological Examination From Previous Examination
Hide Description The extended neurological examination, performed by a board certified neurologist, included observations for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger, nose, heel, shin, Romberg, tandem walking, positional and gaze evoked nystagmus, reflexes, muscle strength, cranial nerves, sensory function of upper and lower extremities. The brief neurological examination included an assessment of motor and sensory function, cranial nerves, reflexes, non-cerebellar tremor (eg, resting or positional) and cerebellar function. The assessment of cerebellar function were complemented by the Scale for Assessment and Rating of Ataxia (SARA).
Time Frame Baseline up to Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title All Subjects
Hide Arm/Group Description:
PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: participants
0
11.Secondary Outcome
Title Number of Participants With Significant Change in Physical Examination From Previous Examination
Hide Description A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The brief physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.
Time Frame Baseline up to Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title All Subjects
Hide Arm/Group Description:
PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: participants
0
12.Secondary Outcome
Title Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug. An 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 are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.
Time Frame Baseline up to 28 days after last study drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title PF-04958242 0.025 mg PF-04958242 0.025 mg + Itraconazole 200 mg PF-04958242 0.1 mg
Hide Arm/Group Description:
All participants who received PF-04958242 0.025 mg BID orally.
All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
All participants who received PF-04958242 0.1 mg BID orally.
Overall Number of Participants Analyzed 13 13 13
Measure Type: Number
Unit of Measure: participants
AEs 2 7 1
SAEs 0 0 0
13.Secondary Outcome
Title Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS)
Hide Description The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment [C-CASA]) is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced the following: completed suicide (1), suicide attempt (2) (response of “Yes” on “actual attempt”), preparatory acts toward imminent suicidal behavior (3)(“Yes” on “preparatory acts or behavior”), suicidal ideation (4) (“Yes” on “wish to be dead”, “non-specific active suicidal thoughts”, “active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)(“Yes” on “Has participant engaged in non-suicidal self-injurious behavior”).
Time Frame Baseline up to Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of the study medication.
Arm/Group Title All Subjects
Hide Arm/Group Description:
PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: participants
0
Time Frame Baseline up to 28 days after last dose of study drug.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title PF-04958242 0.1 mg PF-04958242 0.025 mg PF-04958242 0.025 mg Combined With Itraconazole 200 mg
Hide Arm/Group Description All participants who received PF-04958242 0.1 mg BID orally. All participants who received PF-04958242 0.025 mg BID orally. All participants who received PF-04958242 0.025 mg combined with itraconazole 200 mg orally.
All-Cause Mortality
PF-04958242 0.1 mg PF-04958242 0.025 mg PF-04958242 0.025 mg Combined With Itraconazole 200 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
PF-04958242 0.1 mg PF-04958242 0.025 mg PF-04958242 0.025 mg Combined With Itraconazole 200 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/13 (0.00%)   0/13 (0.00%)   0/13 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
PF-04958242 0.1 mg PF-04958242 0.025 mg PF-04958242 0.025 mg Combined With Itraconazole 200 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/13 (7.69%)   2/13 (15.38%)   7/13 (53.85%) 
Gastrointestinal disorders       
Abdominal discomfort * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Change of bowel habit * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Diarrhoea * 1  0/13 (0.00%)  0/13 (0.00%)  2/13 (15.38%) 
Flatulence * 1  0/13 (0.00%)  1/13 (7.69%)  0/13 (0.00%) 
General disorders       
Drug intolerance * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Fat tissue increased * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Oedema peripheral * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Thirst * 1  0/13 (0.00%)  0/13 (0.00%)  2/13 (15.38%) 
Injury, poisoning and procedural complications       
Contusion * 1  0/13 (0.00%)  1/13 (7.69%)  1/13 (7.69%) 
Joint injury * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Investigations       
Urine output decreased * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Weight increased * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Musculoskeletal and connective tissue disorders       
Back pain * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Pain in extremity * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Nervous system disorders       
Dizziness * 1  1/13 (7.69%)  0/13 (0.00%)  0/13 (0.00%) 
Headache * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Paraesthesia * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Somnolence * 1  0/13 (0.00%)  0/13 (0.00%)  2/13 (15.38%) 
Reproductive system and breast disorders       
Penile swelling * 1  0/13 (0.00%)  0/13 (0.00%)  2/13 (15.38%) 
Skin and subcutaneous tissue disorders       
Pruritus * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
Rash maculo-papular * 1  0/13 (0.00%)  0/13 (0.00%)  1/13 (7.69%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 17.1
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02341482     History of Changes
Other Study ID Numbers: B1701021
DDI ( Other Identifier: Alias Study Number )
First Submitted: January 14, 2015
First Posted: January 19, 2015
Results First Submitted: February 25, 2016
Results First Posted: June 30, 2016
Last Update Posted: June 30, 2016