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

Primary Purpose

Severe Hemophilia

Status

Completed

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

PF-06741086

About this trial

This is an interventional basic science trial for Severe Hemophilia

Eligibility Criteria

18 Years - 74 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

Institute of Hematology, Chinese Academy of Medical Sciences

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

single arm

Arm Description

PF-06741086 300mg subcutaneous(SC)

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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

Change From Baseline in cTnI at Days 2 and 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.

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.

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.

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.

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.

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.

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%.

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.

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%.

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

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

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.

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.

Secondary Outcome Measures

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

Mean plasma concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Maximum Plasma Concentration (Cmax) of Marstacimab

Maximum plasma concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Time for Cmax (Tmax) of Marstacimab

Time for Cmax of marstacimab after participants received a single SC injection of marstacimab 300 mg.

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

Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

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

Area under the concentration time curve from time zero to infinity of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Terminal Half-Life (t1/2) of Marstacimab

Terminal half life (t1/2) of marstacimab after participants received a single SC injection of marstacimab 300 mg. t1/2 is defined as the time for plasma concentration to decrease by one half.

Apparent Volume of Distribution (Vz/F) of Marstacimab

Apparent volume of distribution of marstacimab after participants received a single SC injection of marstacimab 300 mg. Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was influenced by the fraction absorbed. Vz/F was calculated as dose/AUCinf. AUCinf = area under the concentration time curve from time zero to infinity.

Apparent Clearance (CL/F) of Marstacimab

Apparent clearance (CL/F) of marstacimab after participants received a single SC injection of marstacimab 300 mg. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as Dose/ (AUCinf*kel). AUCinf = area under the concentration time curve from time zero to infinity. kel = terminal phase rate constant calculated by a linear regression of the log linear concentration time curve.

Maximum Increase From Baseline for Tissue Factor Pathway Inhibitor (TFPI), Day 1 up to Day 28

TFPI is a protease inhibitor, which acts as an antagonist of the extrinsic coagulation pathway via inhibition of tissue factor-activated coagulation factor VII (FVIIa) and activated factor X (FXa). Plasma total TFPI levels were measured to reflect target binding with marstacimab. TFPI in results represented total TFPI.

Area Under the Curve (AUC) of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TFPI

A change from baseline-time profile was established based on changes from baseline in TFPI at specific time points. Area under the TFPI change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure. TFPI represented total TFPI.

Maximum Increase From Baseline for Prothrombin Fragments 1+2 (PF 1+2), Day 1 up to Day 28

PF1+2 is an in vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for PF 1+2 was provided.

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for PF 1+2

A change from baseline-time profile was established based on changes from baseline in PF 1+2 at specific time points. Area under the PF 1+2 change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Maximum Increase From Baseline for D-Dimer, Day 1 up to Day 28

D-dimer is an in vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for D-Dimer is provided.

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for D-Dimer

A change from baseline-time profile was established based on changes from baseline in D-dimer at specific time points. Area under the D-dimer change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Maximum Decrease From Baseline for Dilute Prothrombin Time (dPT), Day 1 up to Day 28

The dilute prothrombin time (dPT) is an ex vivo endpoint reflective of coagulation pathway activation. Maximum decrease from baseline for dPT is provided.

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for dPT

A change from baseline-time profile was established based on changes from baseline in dPT at specific time points. Area under the dPT change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Maximum Decrease From Baseline for Thrombin Generation Assay (TGA) Lag Time, Day 1 up to Day 28

TGA lag time is an ex vivo endpoint reflective of coagulation pathway activation. Maximum decrease from baseline for TGA Lag Time is provided.

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA Lag Time

A change from baseline-time profile was established based on changes from baseline in TGA lag time at specific time points. Area under the TGA lag time change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Maximum Increase From Baseline for TGA Peak, Day 1 up to Day 28

TGA peak is an ex vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for TGA Peak is provided.

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA Peak

A change from baseline-time profile was established based on changes from baseline in TGA peak at specific time points. Area under the TGA peak change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Maximum Increase From Baseline for TGA Endogenous Thrombin Potential (EGTP), Day 1 up to Day 28

TGA EGTP is an ex vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for TGA Endogenous Thrombin Potential is provided.

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA EGTP

A change from baseline-time profile was established based on changes from baseline in TGA EGTP at specific time points. Area under the TGA EGTP change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Number of Participants With Anti-Drug Antibody (ADA) Against Marstacimab

Summary of ADA incidence by visit is presented. ADA positive was defined as titer >=1.54.

Number of Participants With Neutralizing Antibody (NAb) Against Marstacimab

Summary of NAb incidence by visit is presented. NAb positive was defined as titer >=1.08. ADA-positive participants (defined as titer >=1.54) were analyzed for NAb.

Full Information

NCT ID

NCT04878731

First Posted

April 16, 2021

Last Updated

August 8, 2022

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT04878731

Brief Title

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

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

April 16, 2021 (Actual)

Primary Completion Date

August 10, 2021 (Actual)

Study Completion Date

August 10, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Hemophilia

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

single arm

Arm Type

Experimental

Arm Description

PF-06741086 300mg subcutaneous(SC)

Intervention Type

Biological

Intervention Name(s)

PF-06741086

Intervention Description

single dose SC injection of 300 mg PF-06741086

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Day 1 to Day 42

Title

Number of Participants With Serious Adverse Events (SAEs)

Description

Time Frame

Day 1 to Day 42

Title

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

Description

Time Frame

Day 1 to Day 42

Title

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

Description

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.

Time Frame

Day 1 to Day 42

Title

Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality

Description

Time Frame

Day 1 to Day 28

Title

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

Description

Time Frame

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

Title

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

Description

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.

Time Frame

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

Title

Mean Absolute Value of Activated Partial Thromboplastin Time (APTT)

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

Mean Absolute Value of Fibrinogen

Description

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.

Time Frame

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

Title

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

Description

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.

Time Frame

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

Title

Mean Absolute Value of Antithrombin III (ATIII)

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

Mean Absolute Value of Cardiac Troponin I (cTnI)

Description

Time Frame

Day 1, Day 2, Day 4

Title

Change From Baseline in cTnI at Days 2 and 4

Description

Time Frame

Baseline (Day 1), Day 2, Day 4

Title

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

Description

Time Frame

Day 1 to Day 28

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

Day 1 to Day 28

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

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.

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

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

Description

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.

Time Frame

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.

Title

Number of Participants With Physical Examination Findings

Description

Time Frame

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)

Title

Number of Participants With Injection Site Reactions

Description

Time Frame

Day 1 to Day 7

Secondary Outcome Measure Information:

Title

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

Description

Mean plasma concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Time Frame

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

Title

Maximum Plasma Concentration (Cmax) of Marstacimab

Description

Maximum plasma concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Time Frame

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

Title

Time for Cmax (Tmax) of Marstacimab

Description

Time for Cmax of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Area under the concentration time curve from time zero to infinity of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Time Frame

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

Title

Terminal Half-Life (t1/2) of Marstacimab

Description

Terminal half life (t1/2) of marstacimab after participants received a single SC injection of marstacimab 300 mg. t1/2 is defined as the time for plasma concentration to decrease by one half.

Time Frame

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

Title

Apparent Volume of Distribution (Vz/F) of Marstacimab

Description

Time Frame

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

Title

Apparent Clearance (CL/F) of Marstacimab

Description

Time Frame

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

Title

Maximum Increase From Baseline for Tissue Factor Pathway Inhibitor (TFPI), Day 1 up to Day 28

Description

Time Frame

Day 1 to Day 28

Title

Area Under the Curve (AUC) of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TFPI

Description

Time Frame

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

Title

Maximum Increase From Baseline for Prothrombin Fragments 1+2 (PF 1+2), Day 1 up to Day 28

Description

PF1+2 is an in vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for PF 1+2 was provided.

Time Frame

Day 1 to Day 28

Title

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for PF 1+2

Description

Time Frame

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

Title

Maximum Increase From Baseline for D-Dimer, Day 1 up to Day 28

Description

D-dimer is an in vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for D-Dimer is provided.

Time Frame

Day 1 to Day 28

Title

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for D-Dimer

Description

Time Frame

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

Title

Maximum Decrease From Baseline for Dilute Prothrombin Time (dPT), Day 1 up to Day 28

Description

The dilute prothrombin time (dPT) is an ex vivo endpoint reflective of coagulation pathway activation. Maximum decrease from baseline for dPT is provided.

Time Frame

Day 1 to Day 28

Title

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for dPT

Description

Time Frame

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

Title

Maximum Decrease From Baseline for Thrombin Generation Assay (TGA) Lag Time, Day 1 up to Day 28

Description

TGA lag time is an ex vivo endpoint reflective of coagulation pathway activation. Maximum decrease from baseline for TGA Lag Time is provided.

Time Frame

Day 1 to Day 28

Title

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA Lag Time

Description

Time Frame

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

Title

Maximum Increase From Baseline for TGA Peak, Day 1 up to Day 28

Description

TGA peak is an ex vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for TGA Peak is provided.

Time Frame

Day 1 to Day 28

Title

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA Peak

Description

Time Frame

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

Title

Maximum Increase From Baseline for TGA Endogenous Thrombin Potential (EGTP), Day 1 up to Day 28

Description

TGA EGTP is an ex vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for TGA Endogenous Thrombin Potential is provided.

Time Frame

Day 1 to Day 28

Title

AUC of Change From Baseline Values (Days 1-7, Days 1-14, Days 1-28) for TGA EGTP

Description

Time Frame

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

Title

Number of Participants With Anti-Drug Antibody (ADA) Against Marstacimab

Description

Summary of ADA incidence by visit is presented. ADA positive was defined as titer >=1.54.

Time Frame

Day 1 pre-dose (-2 hours to -5 min prior to dosing); Day 14; Day 21; Day 28

Title

Number of Participants With Neutralizing Antibody (NAb) Against Marstacimab

Description

Summary of NAb incidence by visit is presented. NAb positive was defined as titer >=1.08. ADA-positive participants (defined as titer >=1.54) were analyzed for NAb.

Time Frame

Day 1 pre-dose (-2 hours to -5 min prior to dosing); Day 14; Day 21; Day 28

10. Eligibility

Sex

Male

Gender Based

Yes

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pfizer CT.gov Call Center

Organizational Affiliation

Pfizer

Official's Role

Study Director

Facility Information:

Facility Name

Institute of Hematology, Chinese Academy of Medical Sciences

City

Tianjin

State/Province

Tianjin

ZIP/Postal Code

300020

Country

China

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Links:

URL

https://pmiform.com/clinical-trial-info-request?StudyID=B7841010

Description

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

Learn more about this trial

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

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