Marstacimab

Derived for each subject for each period (historical and study treatment) by using the following formula: ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25)

ABR is defined as number of bleeding episodes per year. ABR was calculated as number of bleeds requiring treatments/ (days on treatment period/365.25). If a participant did not complete a treatment period, days on treatment ended at last dosing date + 6 days. Treated bleed: If a bleed was treated with factor replacement or bypass agents within 48 hours of start of bleeding, regardless of the type of treatment (preventive, prophylaxis or OD medication). A model-based ABR using a repeated measures negative binomial model is reported for this outcome measure.

ABR is defined as number of bleeding episodes per year. ABR was calculated as number of bleeds requiring treatments/ (days on treatment period/365.25). If a participant did not complete a treatment period, days on treatment ended at last dosing date + 6 days. Treated bleed: If a bleed was treated with factor replacement or bypass agents within 48 hours of start of bleeding, regardless of the type of treatment (preventive, prophylaxis or OD medication). A model-based ABR using a repeated measures negative binomial model is reported for this outcome measure.

ABR is defined as number of bleeding episodes per year. ABR was calculated as number of bleeds requiring treatments/ (days on treatment period/365.25). If a participant did not complete a treatment period, days on treatment ended at last dosing date + 6 days. Treated bleed: If a bleed was treated with factor replacement or bypass agents within 48 hours of start of bleeding, regardless of the type of treatment (preventive, prophylaxis or OD medication). A model-based ABR using a repeated measures negative binomial model is reported for this outcome measure.

An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs included both serious AEs and all other AEs.

AE: any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE: any untoward medical occurrence at any dose that resulted in any of the following outcomes: death; life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or that was considered as an important medical event.

Thrombotic events are when a blood clot (thrombus) forms in a blood vessel in the arm, leg, lung, or head and can be life-threatening. A thrombus can occur in veins (venous thrombosis) or arteries (arterial thrombosis).

Thrombotic microangiopathy: pathological state where micro-vessels are occluded by platelet rich thrombi leading to thrombocytopenia (low platelets) and microangiopathic haemolytic anaemia (red blood cell destruction) and potential end organ damage.

Disseminated intravascular coagulation is characterized by widespread clotting in small blood vessels, and consumption of platelets and clotting factors by the clots, leading to bleeding.

ADA positive: A participant with \>=1 treatment induced or treatment-boosted ADA response. NAb positive: An ADA positive participant with \>=1 treatment induced or treatment boosted NAb response.

Persistent ADA: participant with treatment-induced or treatment-boosted ADA detected at 2 or more times during treatment including any follow-up, where first and last ADA positive samples separated by \>=16 weeks. Transient ADA: treatment-induced or treatment-boosted ADA detected at only 1 time during treatment or follow-up. Persistent NAb: NAb-positive participant with first and last positive NAb samples detected \>=16 weeks posttreatment, irrespective of any negative samples in between. Transient NAb: NAb-positive participant with (1) treatment-induced/treatment-boosted NAb sample detected at only 1 time posttreatment or (2) treatment-induced/treatment-boosted NAb samples detected at 2 or more times where first and last positive samples separated by \<16 weeks, and participant's last sample was NAb or ADA negative.

ISR included: injection site haematoma, injection site pain, injection site bruising, injection site erythema, injection site induration, injection site oedema, Injection site pruritus and Injection site swelling. ISR graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 where grade 1: tenderness with or without associated symptoms (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 and grade 5: death. In this outcome measure only categories with non-zero values reported.

Physical examination included assessments of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Height and weight were also measured and recorded. Clinical significance in physical examinations was determined by investigator.

Vital signs included temperature, pulse rate, respiratory rate, and blood pressure. Blood pressure and pulse rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Respiratory rate was measured by observing and counting the respirations of the participant for 30 seconds and multiplied by 2. Clinical significance of vital signs was determined by investigator.

Hematology included: hemoglobin; leukocytes; neutrophils; and platelets. Chemistry included: potassium; aspartate aminotransferase; creatinine; alkaline phosphatase; total bilirubin; albumin; calcium corrected, estimated decreased; sodium; and calcium. Clinical significance of laboratory parameters was determined by investigator.

Systemic hypersensitivity is a complex immune response where the immune system reacts excessively to an antigen, often leading to severe allergic reactions, including widespread symptoms (which may affect multiple organs), such as rash, swelling of your face, lips, mouth, or tongue, trouble breathing, wheezing, dizziness, fainting, fast heartbeat, pounding in your chest or sweating. Anaphylaxis is a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergy causing substance.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (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 or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. Grades 3 AEs were severe and undesirable adverse events. Grades 4 AEs were life threatening or disabling adverse events.

Following parameters were analyzed for laboratory examination: hematology, clinical chemistry, and urinalysis. The hematology parameters and pre-defined criteria included: neutrophils (10\^3/millimeter\[mm\]\^3) \<0.8\*lower limit of normal (LLN), and basophils (10\^3/mm\^3) \>1.2\*upper limit of normal (ULN). The clinical chemistry parameter and pre-defined criteria included: bilirubin (milligrams \[mg\]/decilitre \[dL\]) \>1.5 ULN, aspartate aminotransferase (units \[U\]/liter \[L\]) \>3.0 ULN, glucose (mg/dL) \>1.5\*ULN. The urinalysis parameter and pre-defined criteria included: urine glucose ≥1, ketones (scalar) ≥1, urine protein ≥1, urine hemoglobin (scalar) ≥1, and hyaline casts per low power field (/LPF). Participants met criteria at any time point were included.

Following parameters were analyzed for vital sign examination: blood pressure (BP), pulse rate (PR), temperature, respiration rate. Categorical vital signs: Temperature \>38.5 degree(s) Celsius (℃), Supine PR: \<40 or \>120 beats per minute (BPM), Systolic BP: \<90 mm Hg, \>=30 mm Hg change from baseline, Diastolic BP: \<50 mm Hg, \>=20 mm Hg change from baseline.

Baseline was defined as the average of triplicate ECG measurements collected prior to dosing on Day 1 in B7841003. Criteria for potentially clinically important changes in ECG were defined as: PR interval value \>=300 millisecond (msec); PR interval baseline \>200 msec and change \>=25%; PR interval baseline \<=200 msec and change \>=50%; QRS complex value \>=140 msec and change \>=50%; QTcF value \>=450 msec and change \>=30 msec. Only the number of participants meeting pre-defined criteria was reported below.

Physical examinations were conducted by a physician, trained physician's assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination was focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. For measuring weight, a scale with appropriate range and resolution was used and must have been placed on a stable, flat surface. Participants removed shoes, bulky layers of clothing, and jackets so that only light clothing remains. They also removed the contents of their pockets and remain still during measurement of weight.

Injection site reactions included but were not limited to: erythema, induration, ecchymosis, pain and pruritus. Grade of severity was defined as follows: Mild: Transient or mild discomfort (\< 48 hours); no medical intervention/therapy required. Moderate: Mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/therapy required. Severe: Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (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 or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator.

An AE was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator.

Hematology evaluation included: hemoglobin, hematocrit, erythrocytes, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils and monocytes. Predefined criteria for hemoglobin and hematocrit: \<0.8\*lower limit of normal (LLN) or \<0.8\*Baseline(Baseline \<1.0\*LLN); for platelets: \<100,000\*10\^3/mm\^3 or \<= 0.77\*Baseline (Baseline \<1.0\*LLN).

Clinical chemistry evaluation included bilirubin, direct and indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, protein, albumin, urea nitrogen, creatinine, urate, triglycerides, sodium, potassium, chloride, calcium, bicarbonate, glucose, creatine kinase, troponin I, cholesterol and fibrinogen.

Urinalysis included: pH, urine glucose, ketones, urine protein, urine hemoglobin, urobilinogen, urine bilirubin, nitrite, leukocyte esterase, urine erythrocytes, urine leukocytes and bacteria.

Blood samples were obtained to determine globulin level in serum, total globulin was derived as total protein other than albumin.

Blood samples were obtained to evaluate this ratio. The prothrombin time (PT) is a test that helps evaluate your ability to appropriately form blood clots. The international normalized ratio (INR) is a calculation based on results of a PT that is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin (Coumadin®).

The activated partial thromboplastin time (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 sample were obtained to evaluate aPTT.

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.

Antithrombin (AT) is a protein produced by the liver that helps regulate blood clot formation (i.e., a naturally-occurring mild blood thinner). Blood samples were collected to measure the activity (function) and the amount (quantity) of antithrombin in an individual's blood is used to evaluate the person for excessive blood clotting.

Blood samples were collected to measure the level of cardiac-specific troponin I in the blood to help detect heart injury.

Criteria for potentially clinically important findings in vital signs data were defined as: 1) supine systolic blood pressure (BP): value \<90 mm Hg or change \>=30 mm Hg increase; 2) Supine diastolic BP: value \<50 mm Hg or change \>=20 mm Hg increase; 3) Supine pulse rate: value \<40 beats/min or \>120 beats/min.

Criteria for potentially clinically important changes in ECG were defined as: PR interval baseline \>200 msec and increase of \>=25%; PR interval baseline \<=200 msec and increase of \>=50%; QRS interval increase of \>=50%. Only the number of participants meeting pre-defined criteria was reported below.

Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Clinical significance was judged by the investigator.

Infusion and injection site reactions included: injection site bruising, injection site erythema, injection site haemorrhage, injection site induration, injection site pain, injection site pruritus, injection site swelling and injection site warmth. Grade of severity was defined as follows: Mild: Transient or mild discomfort (\< 48 hours); no medical intervention/therapy required. Moderate: Mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/therapy required. Severe: Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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%.

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.

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%.

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%.

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.

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.

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.

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.

blood pressure, pulse rate, temperature, respiration rate