Study to Evaluate Safety and Tolerability of a Single Dose of PF-06741086 in Chinese Adult Participants With Severe Hemophilia

NCT04878731 | Completed Phase 1 Results

• 1 other identifier: B7841010
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Severe Hemophilia

Outcome Measures

Primary Outcomes (30)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

  An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs that started during the effective duration of treatment regardless of whether a similar event existed at baseline. Grades of AEs were defined by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL);Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=events with life-threatening consequences, urgent intervention indicated;Grade 5= death related to AE.Treatment-related TEAEs were determined by investigator.

  Day 1 to Day 42

• Number of Participants With Serious Adverse Events (SAEs)

  An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator.

  Day 1 to Day 42

• Number of Participants With Maximum Grade 3 or 4 or 5 TEAEs

  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs that started during the effective duration of treatment regardless of whether a similar event existed in the baseline period. Grades of AEs were defined by NCI CTCAE version 5.0. Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. Treatment-related TEAEs were determined by the investigator.

  Day 1 to Day 42

• Number of Participants With TEAEs Leading to Permanent or Temporary Discontinuation From Study

  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs that started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period. Grades of AEs were defined by NCI CTCAE version 5.0. Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. Treatment-related TEAEs were determined by the investigator.

  Day 1 to Day 42

• Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality

  Laboratory assessments included chemistry, hematology, Prothrombin Time/International Normalized Ratio (PT/INR), Activated Partial Thromboplastin Time (APTT), urinalysis, fibrinogen, Antithrombin III (ATIII) activity, and Cardiac Troponin I (cTnI). Laboratory test abnormalities reported by at least 1 participant are reported in this outcome measure. ULN = upper limit of normal.

  Day 1 to Day 28

• Mean Absolute Value of Prothrombin Time (PT) / International Normalized Ratio (INR)

  PT is one of the laboratory tests to evaluate the ability of blood clotting. The INR is derived from PT which is calculated as a ratio of a participant's PT to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the following formula: INR = Participant PT / Control PT. Blood samples were obtained to evaluate PT/INR.

  Day 1, Day 2, Day 7, Day 14, Day 21, Day 28

• Change From Baseline in PT/INR at Days 2, 7, 14, 21 and 28

  PT is one of the laboratory tests to evaluate the ability of blood clotting. The INR is derived from PT which is calculated as a ratio of a participant's PT to a control PT standardized for the potency of the thromboplastin reagent developed by the WHO using the following formula: INR = Participant PT / Control PT. Blood samples were obtained to evaluate PT/INR.

  Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28

• Mean Absolute Value of Activated Partial Thromboplastin Time (APTT)

  The APTT is a screening test that helps evaluate a person's ability to appropriately form blood clots. It measures the number of seconds it takes for a clot to form in a sample of blood after substances (reagents) are added. Blood samples were obtained to evaluate APTT.

  Day 1, Day 2, Day 7, Day 14, Day 21, Day 28

• Change From Baseline in APTT at Days 2, 7, 14, 21 and 28

  The APTT is a screening test that helps evaluate a person's ability to appropriately form blood clots. It measures the number of seconds it takes for a clot to form in a sample of blood after substances (reagents) are added. Blood samples were obtained to evaluate APTT.

  Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28

• Mean Absolute Value of Fibrinogen

  Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were obtained to evaluate the amount of fibrinogen.

  Day 1, Day 2, Day 7, Day 14, Day 21, Day 28

• Change From Baseline in Fibrinogen at Days 2, 7, 14, 21 and 28

  Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were obtained to evaluate the amount of fibrinogen.

  Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28

• Mean Absolute Value of Antithrombin III (ATIII)

  ATIII is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. The antithrombin activity test measures how well the protein inhibits thrombin, with a reference range of 75% - 125%. Blood samples were obtained to evaluate ATIII activity.

  Day 1, Day 2, Day 7, Day 14, Day 21, Day 28

• Change From Baseline in ATIII at Days 2, 7, 14, 21 and 28

  ATIII is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. The antithrombin activity test measures how well the protein inhibits thrombin, with a reference range of 75% - 125%. Blood samples were obtained to evaluate ATIII activity.

  Baseline (Day 1), Day 2, Day 7, Day 14, Day 21, Day 28

• Mean Absolute Value of Cardiac Troponin I (cTnI)

  cTnI is one of the cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin, and is considered a specific marker for cardiac damage. Blood samples were obtained to evaluate the amount of cTnI.

  Day 1, Day 2, Day 4

• Change From Baseline in cTnI at Days 2 and 4

  cTnI is one of the cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin, and is considered a specific marker for cardiac damage. Blood samples were obtained to evaluate the amount of cTnI.

  Baseline (Day 1), Day 2, Day 4

• Number of Participants With Vital Signs Data Meeting Categorical Criteria of Potential Clinical Concern

  Vital signs measurements included blood pressure (BP), pulse rate, respiratory rate and oral temperature. Categorical classes for vital signs of potential clinical concern included: (1) systolic BP - minimum (min) value \<90 mmHg, maximum (max) decrease/increase from baseline \>=30 mmHg; (2) diastolic BP - min value \<50 mmHg, max decrease/increase from baseline \>=20 mmHg; (3) supine pulse rate - min \<40 beat per minute (bpm) or max \>120 bpm; (4) standing pulse rate - min \<40 bpm or max \>140 bpm; (5) oral temperature \> 38.5 celsius degree (°C). BPs were measured in a supine position so standing BPs were not evaluated and not reported.

  Day 1 to Day 28

• Change From Baseline in Supine Systolic BP at Days 1, 2, 3, 4, 7, 14, 21 and 28

  BPs were assessed in a supine position with a completely automated device. Categorical classes for supine systolic BP of potential clinical concern included min value \<90 mmHg, max decrease/increase from baseline \>=30 mmHg.

  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.

• Change From Baseline in Diastolic Systolic BP at Days 1, 2, 3, 4, 7, 14, 21 and 28

  BPs were assessed in a supine position with a completely automated device. Categorical classes for supine diastolic BP of potential clinical concern included min value \<50 mmHg, max decrease/increase from baseline \>=20 mmHg.

  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.

• Change From Baseline in Supine Pulse Rate at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Pulse rates were assessed in a supine position with a completely automated device. Categorical classes for supine pulse rate of potential clinical concern included min value \<40 bpm or max value \>120 bpm.

  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.

• Change From Baseline in Oral Temperature at Days 1, 2, 3, 4, 7, 14, 21 and 28

  No eating, drinking, or smoking was allowed for 15 minutes prior to the measurement of oral temperature. The criterion for oral temperature of potential clinical concern was oral temperature \> 38.5°C.

  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.

• Change From Baseline in Respiratory Rate at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Respiratory rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Respiratory rate was measured in terms of "breaths per minute", and was measured by observing and counting the respirations of the participant for 30 seconds and multiplied by 2.

  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.

• Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Criteria of Potential Clinical Concern

  Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated heart rate and measured PR, QRS and QT intervals. If a single time point ECG was abnormal, a triplicate ECG was required and obtained approximately 2-4 minutes apart; the average of triplicate ECG measurements collected at pre-dose Day 1 served as each participant's baseline value. Categorical classes for ECG data of potential clinical concern included: (1) QTcF - 450 millisecond (msec)≤ max value \<480 msec, 480 msec ≤ max value \<500 msec, max value ≥500 msec; 30 msec ≤ QTcF max increase from baseline \<60 msec; max increase from baseline ≥60 msec; (2) PR interval - max value ≥300 msec, baseline value\>200 and max increase from baseline ≥25%, baseline value ≤200 and max increase from baseline ≥50%; (3) QRS interval - max value ≥140 msec, increase from baseline ≥50%.

  Day 1 to Day 28

• Change From Baseline in ECG Mean Heart Rate at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Heart rate was measured in terms of "beats per minute". Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. If a single time point ECG was abnormal, a triplicate ECG was required, which were obtained approximately 2-4 minutes apart; the average of the triplicate ECG measurements collected at pre-dose Day 1 served as each participant's baseline value.

  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.

• Change From Baseline in PR Interval at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. Categorical classes for PR interval data of potential clinical concern included: max value ≥300 ms, baseline value\>200 and max increase from baseline≥25%, baseline value ≤200 and max increase from baseline ≥50%.

  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.

• Change From Baseline in QRS Interval at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. Categorical classes for QRS interval data of potential clinical concern included: max value ≥140 ms, increase from baseline ≥50%.

  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.

• Change From Baseline in QT Interval at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals.

  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.

• Change From Baseline in QT Interval Corrected at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. The corrected QT interval (QTc) estimates the QT interval at a standard heart rate of 60 bpm.

  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.

• Change From Baseline in Corrected QT Interval (Fridericia Method) (QTcF Interval) at Days 1, 2, 3, 4, 7, 14, 21 and 28

  Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. QTcF = QT interval corrected using the Fridericia method. Categorical classes for QTcF data of potential clinical concern included: 450 ms≤ max value \<480 ms, 480≤ max value \<500 ms, max value ≥500 ms; 30 ms ≤ QTcF max increase from baseline \<60 ms; max increase from baseline ≥60 ms.

  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.

• Number of Participants With Physical Examination Findings

  A complete PE included assessments of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. A brief PE included assessments of the general appearance, the respiratory and cardiovascular systems, as well as participant reported symptoms. The full PE planned for Screening may have been performed on Day -1 before dosing at the discretion of the Investigator. If a full PE was done at Screening visit, a brief PE was to be conducted on Day-1. After Day -1, brief examinations based on signs and symptoms may have been performed if clinically indicated at the discretion of the Investigator to assess changes from baseline/previous visits of any ongoing symptoms.

  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)

• Number of Participants With Injection Site Reactions

  Grades of injection site reactions were defined according to NCI CTCAE version 5.0. Grade 1=Tenderness with or without associated symptoms (eg, warmth, erythema, itching); Grade 2= Pain, lipodystrophy, edema, phlebitis; Grade 3= Ulceration or necrosis, severe tissue damage, operative intervention indicated; Grade 4=Life-threatening consequences, urgent intervention indicated; Grade 5=death. Participants with any grade of injection site reaction are reported in this outcome measure.

  Day 1 to Day 7

Secondary Outcomes (24)

• Mean Plasma Marstacimab Concentration Versus Time at Days 1, 2, 3, 4, 7, 14, 21 and 28

  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

• Maximum Plasma Concentration (Cmax) of Marstacimab

  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

• Time for Cmax (Tmax) of Marstacimab

  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

• Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Marstacimab

  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

• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinity (AUCinf) of Marstacimab

  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

Study Arms (1)

single arm

EXPERIMENTAL

PF-06741086 300mg subcutaneous(SC)

Biological: PF-06741086

Interventions

PF-06741086 BIOLOGICAL

single dose SC injection of 300 mg PF-06741086

single arm

Eligibility Criteria

• Age: 18 Years - 74 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (1)

Institute of Hematology, Chinese Academy of Medical Sciences

Tianjin, Tianjin Municipality, 300020, China

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Hemophilia A

Interventions

marstacimab

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2021
• First Posted: May 7, 2021
• Study Start: April 16, 2021
• Primary Completion: August 10, 2021
• Study Completion: August 10, 2021
• Last Updated: July 7, 2023
• Results First Posted: July 7, 2023

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)