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

• ClinicalTrials.gov Identifier: NCT02341482
• Recruitment Status: Completed
• First Posted: January 19, 2015
• Results First Posted: June 30, 2016
• Last Update Posted: January 9, 2020
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Study Description

Brief Summary:

The purpose of the current study is to characterize the pharmacokinetic (PK) profile of PF 04958242 when co administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: PF-04958242; Drug: Itraconazole	Phase 1

Detailed Description:

This study was previously posted by Pfizer, Inc. Sponsorship of the trial was transferred to Biogen.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Fixed-sequence Study To Estimate The Effects Of Multiple-dose Administration Of Itraconazole On The Pharmacokinetics Of Pf 04958242 In Healthy Adult Subjects
• Actual Study Start Date: February 5, 2015
• Actual Primary Completion Date: March 31, 2015
• Actual Study Completion Date: March 31, 2015

Arms and Interventions

Arm

Intervention/treatment

Experimental: PF-04958242 and itraconazole; PF-04958242 will be provided in a capsule. Participants will receive a 0.10 mg loading dose of PF-04958242 twice daily (BID) on Day 1 then 0.025 mg BID on Day 2-Day 16, with the last dose occurring in the morning on Day 17. Itraconazole will be provided as a solution starting on Day 4. On Day 4, a 200 mg dose of itraconazole will be administered approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4-Day 17).

Drug: PF-04958242; Administered as specified in the treatment arm; Drug: Itraconazole; Administered as specified in the treatment arm

Outcome Measures

Primary Outcome Measures :

1. Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242 [ Time Frame: Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21 ]
   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.
2. Maximum Observed Plasma Concentration (Cmax) of PF-04958242 [ Time Frame: Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21 ]
   Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

Secondary Outcome Measures :

1. Time for Cmax (Tmax) of PF-04958242 [ Time Frame: Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21 ]
   Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
2. Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242 [ Time Frame: Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21 ]
3. Predose Concentration (Ctrough) of PF-04958242 [ 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) ]
4. Apparent Oral Clearance (CL/F) of PF-04958242 [ Time Frame: Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21 ]
   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.
5. Number of Participants With Abnormal Clinical Laboratory Measurements [ Time Frame: Baseline up to Day 21 ]
   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).
6. Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern [ Time Frame: Baseline up to Day 21 ]
   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.
7. Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern [ Time Frame: Baseline up to Day 21 ]
   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.
8. Number of Participants With Significant Change in Neurological Examination From Previous Examination [ Time Frame: Baseline up to Day 21 ]
   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).
9. Number of Participants With Significant Change in Physical Examination From Previous Examination [ Time Frame: Baseline up to Day 21 ]
   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.
10. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 28 days after last study drug administration ]
    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.
11. Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to Day 21 ]
    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").

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Key Inclusion Criteria:

-Healthy male subjects and female subjects of non childbearing with a Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >55 kg (121 lbs).

Key Exclusion Criteria:

• Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary:

  • Aspartate transaminase (AST)/serum glutamic oxaloacetic transminase (SGOT) or alanine transaminase (ALT)/serum glutamic pyruvic transminase (SGPT) >=1 x upper limit of normal (ULN);
  • Total bilirubin >=1.5 x ULN; subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is <= ULN.
• Subjects with epilepsy, or history of epilepsy, or conditions that lower seizure threshold, seizures of any etiology (including substance or drug withdrawal), or who have increased risk of seizures as evidenced by self reported history of electroencephalogram (EEG) with epileptiform activity. Subjects with a history of childhood seizures and history of head trauma with loss of consciousness requiring hospitalization overnight will be excluded as well.
• Subjects who had a history of allergy or intolerance to azole antifungal drugs.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

United States, Connecticut

Pfizer New Haven Clinical Research Unit

New Haven, Connecticut, United States, 06511

Sponsors and Collaborators

Biogen

Investigators

• Study Director: Medical Director; Biogen

More Information

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02341482
• Other Study ID Numbers: B1701021; DDI ( Other Identifier: Alias Study Number )
• First Posted: January 19, 2015
• Results First Posted: June 30, 2016
• Last Update Posted: January 9, 2020
• Last Verified: December 2019

Keywords provided by Biogen:

Itraconazole; Healthy Volunteers; Drug-drug interaction; PF-04958242

Additional relevant MeSH terms:

Itraconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors