Clinical trial NCT03742336: Study of PF-04965842 Effect on Dabigatran Pharmacokinetics in Healthy Participants
Official title: A PHASE 1, RANDOMIZED, 2-WAY CROSSOVER, SINGLE DOSE, OPEN LABEL STUDY TO ESTIMATE THE EFFECT OF PF-04965842 ON DABIGATRAN PHARMACOKINETICS IN HEALTHY PARTICIPANTS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2018-11-15
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, randomized, 2 way crossover, single dose, open label study of the effect of PF 04965842 on dabigatran PK in healthy participants. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 20 healthy male and/or female participants will be enrolled in the study so that 10 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods that are each 3 days in duration. The total duration of participation from the Screening Visit to Day 7 will be a maximum of 35 days and from the Screening Visit to Follow-up Contact/Visit will be a maximum of 70 days.


Eligibility criteria: Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

Age and Sex:

1. Male and female participants must be 18 to 55 years of age, inclusive, at the time of signing the informed consent document (ICD).

   Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical evaluation including a detailed medical history, complete physical examination, laboratory tests, and ECG.
3. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.

   Weight:
4. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb).

   Informed Consent:
5. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions:

1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic (including alcoholic liver disease, nonalcoholic steatohepatitis (NASH), autoimmune hepatitis, and hereditary liver diseases), psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
2. Evidence or history of clinically significant dermatological condition (eg, atopic dermatitis or psoriasis) or visible rash present during physical examination.
3. Participants, who according to the product label for dabigatran, would be at increased risk if dosed with dabigatran.
4. Risks of bleeding including prior personal or familiar history of abnormal bleeding, hereditary or acquired coagulation or platelet disorder or abnormal coagulation test (prothrombin time \[PT\]/international normalized ratio \[INR\] or partial thromboplastin time \[PTT\]/activated partial thromboplastin time \[aPTT\] greater than upper limit of normal \[ULN\]) result at screening.
5. Surgery planned within 4 weeks after the end of the study.
6. Self reported history or risk factors for QT prolongation or torsades de pointes (eg, organic heart disease, congestive heart failure, hypokalemia, hypomagnesaemia, congenital long QT syndrome, myocardial ischemia or infarction), congenital deafness, family history of sudden death, and family history of long QT syndrome.
7. Any condition possibly affecting drug absorption (eg, gastrectomy).
8. History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus infection; positive testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HepBcAb), or hepatitis C antibody (HCVAb).

   As an exception, a positive HepBsAb as a result of participant vaccination is permissible.
9. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.

   Prior/Concomitant Therapy:
10. Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of investigational product.

    Prior/Concurrent Clinical Study Experience:
11. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of investigational product used in this study (whichever is longer).

    Diagnostic Assessments:
12. A positive urine drug test.
13. Screening supine systolic blood pressure (BP) \<90 mm Hg or \>=140 mm Hg following at least 5 minutes of supine rest; OR Screening supine diastolic BP \<50 mm Hg or \>=90 mm Hg following at least 5 minutes of supine rest.

    If a participant meets any of these criteria, the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility.
14. Screening supine 12 lead ECG demonstrating:

    * QTcF \>450 msec; OR
    * QRS interval \>120 msec. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant's eligibility.
15. Participants 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 test, if deemed necessary:

    * Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) level \>=1.5 × ULN;
    * Total bilirubin level \> ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is \<=ULN;
    * PT/INR or PTT/aPTT \> ULN;
    * Estimated creatinine clearance \<90 mL/min.

    Other Exclusions:
16. History of regular alcohol consumption exceeding 14 drinks/week for female participants or 21 drinks/week for male participants (1 drink = 5 ounces \[150 mL\] of wine or 12 ounces \[360 mL\] of beer or 1.5 ounces \[45 mL\] of hard liquor) within 6 months before screening.
17. Known relevant history of elevated liver function tests (LFTs).
18. History of tuberculosis (TB) (active or latent) or inadequately treated TB infection. Positive QuantiFERON - TB Gold test.
19. Any history of chronic infections, any history of recurrent infections, any history of latent infections, or any acute infection within 2 weeks of baseline.
20. History of disseminated herpes zoster, or disseminated herpes simplex, or recurrent localized dermatomal herpes zoster.
21. History of sensitivity to heparin or heparin induced thrombocytopenia.
22. Use of tobacco or nicotine containing products in excess of the equivalent of 5 cigarettes per day.
23. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to first dose of investigational product.
24. History of hypersensitivity to dabigatran.
25. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol.
26. Have any malignancies or have a history of malignancies with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ.
27. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study.

Primary outcomes:
measure: AUCinf of dabigatran
timeFrame: 36 hours after dabigatran administration in Period 1 and 2
measure: Plasma Cmax of dabigatran
timeFrame: 36 hours after dabigatran administration in Period 1 and 2
Secondary outcomes:
measure: AUClast of dabigatran
timeFrame: 36 hours after dabigatran administration in Period 1 and 2
measure: Tmax of dabigatran
timeFrame: 36 hours after dabigatran administration in Period 1 and 2
measure: t1/2 of dabigatran
timeFrame: 36 hours after dabigatran administration in Period 1 and 2
measure: Number of subjects with adverse events (AEs).
timeFrame: Screening up to 28-35 days after the last dose of PF 04965842 in period 2
measure: Number of subjects with laboratory tests findings of potential clinical importance
timeFrame: Screening through Day 3 of period 2
measure: Number of subjects with clinically significant abnormal vital signs
timeFrame: Screening through Day 3 of period 2
measure: Number of subjects with clinically significant abnormal ECGs
timeFrame: Screening through Day 3 of period 2
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Pfizer Clinical Research Unit
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Vourvahis M, Byon W, Chang C, Le V, Diehl A, Graham D, Tripathy S, Raha N, Luo L, Mathialagan S, Dowty M, Rodrigues AD, Malhotra B. Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers. Clin Pharmacol Ther. 2022 Sep;112(3):665-675. doi: 10.1002/cpt.2594. Epub 2022 May 9.