Clinical trial NCT04878731: Study to Evaluate Safety and Tolerability of a Single Dose of PF-06741086 in Chinese Adult Participants With Severe Hemophilia
Official title: A PHASE 1, SINGLE-ARM, OPEN-LABEL, NON-RANDOMIZED, NON-CONTROLLED MULTICENTER STUDY TO EVALUATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY, AND TOLERABILITY OF A SINGLE SUBCUTANEOUS DOSE OF PF-06741086 IN CHINESE ADULT PARTICIPANTS WITH SEVERE HEMOPHILIA
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Severe Hemophilia
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2021-05-07
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: This Phase 1 study will be a single-arm, open-label, non-randomized, non-controlled investigation of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06741086 in Chinese adult participants with severe hemophilia.


Eligibility criteria: Inclusion Criteria:

* Participant must be male and 18 to \<75 years of age with a minimum body weight of 30 kg at screening.
* Participants with a diagnosis of severe hemophilia A or B (FVIII or FIX activity \<1%, respectively)
* Participants without inhibitor must also meet the following criteria:

  * No detectable or documented history of inhibitors
  * Participants with on-demand treatment regimen with ≥6 acute bleeding episodes (spontaneous or traumatic) that required coagulation factor infusion during the 4 months period prior to enrollment and willing to continue to receive on demand treatment during the study.
* Participants with Inhibitor must also meet the following criteria:

  * Documentation of current high titer inhibitor (≥5 BU/mL) or current low titer inhibitor (\<5 BU/mL) refractory to FVIII or FIX replacement and with FVIII or FIX recovery \<60% of expected within previous 4 months prior to screening.
  * Participants with on-demand treatment regimen with ≥6 bleeding episodes (spontaneous and/or traumatic) necessitating treatment with bypass factor for at least 4 months prior to screening and willing to continue to receive on-demand treatment during the study.

Exclusion Criteria:

* Previous or current treatment for and/or history of coronary artery diseases, venous or arterial thrombosis or ischemic disease
* Known planned surgical procedure during the planned study period.
* Known hemostatic defect other than hemophilia A or B.
* Abnormal renal or hepatic function
* Current unstable liver or biliary disease
* Abnormal hematologic parameters
* Abnormal coagulation activity
* Other acute or chronic medical or psychiatric condition 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.
* Corrected QT interval (QTc) \>450 msec for male participants or QTc \>480 msec in participants with bundle branch block.
* Individuals with hypersensitivity or an allergic reaction to hamster protein or other components of the study intervention.
* A positive urine drug screen
* Current routine prophylaxis with bypassing agent or non coagulation factor-replacement therapy (eg, emicizumab)
* Regular, concomitant therapy with immunomodulatory drugs
* Ongoing or planned use of immune tolerance induction or prophylaxis with FVIII or FIX replacement during the study.
* Participation in other studies involving investigational drug(s) within 30 days (or as determined by local requirements) or 5 half-lives prior to study entry and/or during study participation.
* CD4 cell count ≤200/uL if human immunodeficiency virus (HIV)-positive
* Baseline ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
* 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 participants who are Pfizer employees, including their family members, directly involved in the conduct of the study

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 1 to Day 42
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Day 1 to Day 42
measure: Number of Participants With Maximum Grade 3 or 4 or 5 TEAEs
timeFrame: Day 1 to Day 42
measure: Number of Participants With TEAEs Leading to Permanent or Temporary Discontinuation From Study
timeFrame: Day 1 to Day 42
measure: Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality
timeFrame: Day 1 to Day 28
measure: Mean Absolute Value of Prothrombin Time (PT) / International Normalized Ratio (INR)
timeFrame: Day 1, Day 2, Day 7, Day 14, Day 21, Day 28
measure: Change From Baseline in PT/INR at Days 2, 7, 14, 21 and 28
timeFrame: Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28
measure: Mean Absolute Value of Activated Partial Thromboplastin Time (APTT)
timeFrame: Day 1, Day 2, Day 7, Day 14, Day 21, Day 28
measure: Change From Baseline in APTT at Days 2, 7, 14, 21 and 28
timeFrame: Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28
measure: Mean Absolute Value of Fibrinogen
timeFrame: Day 1, Day 2, Day 7, Day 14, Day 21, Day 28
measure: Change From Baseline in Fibrinogen at Days 2, 7, 14, 21 and 28
timeFrame: Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28
measure: Mean Absolute Value of Antithrombin III (ATIII)
timeFrame: Day 1, Day 2, Day 7, Day 14, Day 21, Day 28
measure: Change From Baseline in ATIII at Days 2, 7, 14, 21 and 28
timeFrame: Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28
measure: Mean Absolute Value of Cardiac Troponin I (cTnI)
timeFrame: Day 1, Day 2, Day 4
measure: Change From Baseline in cTnI at Days 2 and 4
timeFrame: Baseline (Day 1), Day 2, Day 4
measure: Number of Participants With Vital Signs Data Meeting Categorical Criteria of Potential Clinical Concern
timeFrame: Day 1 to Day 28
measure: Change From Baseline in Supine Systolic BP at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in Diastolic Systolic BP at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in Supine Pulse Rate at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in Oral Temperature at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in Respiratory Rate at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Criteria of Potential Clinical Concern
timeFrame: Day 1 to Day 28
measure: Change From Baseline in ECG Mean Heart Rate at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in PR Interval at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in QRS Interval at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in QT Interval at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in QT Interval Corrected at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Change From Baseline in Corrected QT Interval (Fridericia Method) (QTcF Interval) at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Day 1 pre-dose (baseline); 1 hour, 2 hours, 4 hours, 8 hours and 12 hours post Day 1 dosing; Day 2; Day 3; Day 4; Day 7; Day 14; Day 21; Day 28.
measure: Number of Participants With Physical Examination Findings
timeFrame: Screening (Day -35 to Day -2), Day -1, Day 1 (for general appearance, heart, lungs), Day 7 (for general appearance, heart, lungs), Day 28 (for general appearance, heart, lungs)
measure: Number of Participants With Injection Site Reactions
timeFrame: Day 1 to Day 7
Secondary outcomes:
measure: Mean Plasma Marstacimab Concentration Versus Time at Days 1, 2, 3, 4, 7, 14, 21 and 28
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Plasma Concentration (Cmax) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Time for Cmax (Tmax) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinity (AUCinf) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Terminal Half-Life (t1/2) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Apparent Volume of Distribution (Vz/F) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Apparent Clearance (CL/F) of Marstacimab
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Increase From Baseline for Tissue Factor Pathway Inhibitor (TFPI), Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: Area Under the Curve (AUC) of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TFPI
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Increase From Baseline for Prothrombin Fragments 1+2 (PF 1+2), Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for PF 1+2
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Increase From Baseline for D-Dimer, Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for D-Dimer
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Decrease From Baseline for Dilute Prothrombin Time (dPT), Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for dPT
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Decrease From Baseline for Thrombin Generation Assay (TGA) Lag Time, Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA Lag Time
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Increase From Baseline for TGA Peak, Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA Peak
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Maximum Increase From Baseline for TGA Endogenous Thrombin Potential (EGTP), Day 1 up to Day 28
timeFrame: Day 1 to Day 28
measure: AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA EGTP
timeFrame: Pre-dose, and 1 hour, 4 hours, 12 hours, 24 hours, 48 hours, 72 hours, and approximately 144 hours, 312 hours, 480 hours and 648 hours post Day 1 dosing
measure: Number of Participants With Anti-Drug Antibody (ADA) Against Marstacimab
timeFrame: Day 1 pre-dose (-2 hours to -5 min prior to dosing); Day 14; Day 21; Day 28
measure: Number of Participants With Neutralizing Antibody (NAb) Against Marstacimab
timeFrame: Day 1 pre-dose (-2 hours to -5 min prior to dosing); Day 14; Day 21; Day 28
Other outcomes:
Locations:
city: Tianjin
country: China
facility: Institute of Hematology, Chinese Academy of Medical Sciences
state: Tianjin
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: