PF-06741086 Multiple Dose Study in Severe Hemophilia

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.

Time frame: Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.

Population: This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number analyzed refers to number of participants evaluable for specified rows of time points.

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.

Time frame: Baseline, Study Day 8, 15, 22 and 29.

Population: This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number analyzed refers to number of participants evaluable for specified rows of time points.

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, Study Day 8, 15, 22, 29, 57, 85 and 113.

Population: This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number analyzed refers to number of participants evaluable for specified rows of time points.

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

Time frame: Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.

Population: This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number analyzed refers to number of participants evaluable for specified rows of time points.

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®).

Time frame: Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.

Population: This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number analyzed refers to number of participants evaluable for specified rows of time points.

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

Time frame: Baseline, Study Day 8, 15, 22, 29, 57 and 85.

Population: This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number analyzed refers to number of participants evaluable for specified rows of time points.

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.

Time frame: Study Day 1 to Day 113 Visit

Population: The analysis population included all participants who received at least 1 dose of investigational product.

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.

Time frame: Baseline to Study Day 113

Population: This analysis population included all participants who received at least 1 dose of investigational product. Number analyzed refers to number of participants evaluable for specified rows.

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).

Time frame: Baseline to Study Day 113 Visit

Population: This analysis population included all participants who received at least 1 dose of investigational product.

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

Time frame: Baseline to Study Day 113 Visit

Population: This analysis population included all participants who received at least 1 dose of investigational product. Number analyzed refers to number of participants evaluable for specified rows.

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.

Time frame: Baseline to Study Day 113 Visit

Population: This analysis population included all participants who received at least 1 dose of investigational product.

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.

Time frame: Baseline to Study Day 29 Visit.

Population: This analysis population included all participants who received at least 1 dose of investigational product.

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.

Time frame: Baseline to Study Day 113 Visit

Population: This analysis population included all participants who received at least 1 dose of investigational product.

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.

Time frame: Study Day 1 to Day 113 Visit

Population: The analysis population included all participants who received at least 1 dose of investigational product.

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.

Time frame: Baseline to Study Day 113 Visit

Population: This analysis population included all participants who received at least 1 dose of investigational product.

Pre-treatment ABR = number of bleeding episodes within 6 months prior to study enrollment (total number of bleeding episodes in hemophilia history CRF) × 2; On-study ABR = number of bleeding episodes occurred within 9 days after the last dose / (\[last dose date + 9 - first dose date + 1\] / 365.25) The historical On Demand group was constructed using the following internal Pfizer studies: ReFacto AF 3082B2-4432 (B1831004), BeneFIX B1821010, and BeneFIX 3090A1-400 (B1821004). Participants who were on On Demand treatment in B1831004, as well as data from the On Demand period in B1821004 and B1821010 were used to construct the historical On Demand group. The resulting dataset were further filtered to match the key inclusion/exclusion criteria of Study B7841002 based on age and factor activity (18 \<=age \<=65 and factor activity \<=1%).

Time frame: Pre-treatment: within 6 months prior to study enrollment; On-study: Day 1 to 9 days after the last dose (Day 78)

Population: This efficacy analysis was conducted in the Per Protocol Analysis Set (PPAS) that included all participants who received at least 1 dose of investigational product and did not have any major protocol deviations.

CL/F was calculated by dose/AUCtau.

Time frame: Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing

Population: The PK parameter analysis population included all enrolled participants treated who had at least 1 quantifiable concentration and in whom at least 1 of the PK parameters of interest was calculated.

AUClast was calculated by linear/Log trapezoidal method.

Time frame: Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing

Population: The PK parameter analysis population included all enrolled participants treated who had at least 1 quantifiable concentration.

The dosing interval tau was 1 week. AUCtau was obtained by linear/log trapezoidal method.

Time frame: Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing

Population: The PK parameter analysis population included all enrolled participants treated who had at least 1 quantifiable concentration and in whom at least 1 of the PK parameters of interest was calculated.

An in vivo pharmacodynamic measure of thrombin generation (fibrin degradation). D-dimer is a fibrin degradation product, a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. D-dimer is one of the protein fragments produced when a blood clot gets dissolved in the body. It is normally undetectable or detectable at a very low level unless the body is forming and breaking down blood clots. Then, its level in the blood can significantly rise.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

An ex vivo pharmacodynamic measure of thrombin generation (via extrinsic pathway). Clotting time is measured using a dilute prothrombin time reagent consisting of a unique formulation of relipidated recombinant tissue factor and calcium.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

An ex vivo pharmacodynamic measure of thrombin generation. The endogenous TGA potential represents the total amount of active thrombin formed during thrombin generation and the peak height the maximal amount of thrombin formed.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

An in vivo pharmacodynamic measure of thrombin generation (prothrombin cleavage). Prothrombin fragment 1+2 (F 1+2) is the amino terminus fragment of the prothrombin molecule. It is a polypeptide with a half-life of approximately 90 minutes. F 1+2 is released from prothrombin when prothrombin is converted to thrombin by the prothrombinase complex.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

An ex vivo pharmacodynamic measure of thrombin generation (initiation of thrombin generation), the lag time is the time needed to form the first traces of thrombin.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

An ex vivo pharmacodynamic measure of thrombin generation (initiation of thrombin generation). The peak represents the highest thrombin concentration that can be generated. There may be patients who reach the peak faster or slower than others and this may represent hyper- or hypocoagulability, respectively.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

Total amount of tissue factor pathway inhibitor (TFPI) (bound and unbound) in plasma. 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). Human plasma samples were analyzed for total TFPI concentrations using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometric method (LC-MS/MS). Mixed model repeated measures (MMRM) was used to analyze the change from baseline on TFPI.

Time frame: Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113

Population: The analysis population included all enrolled participants who received at least 1 dose of study medication and had a baseline measurement and at least 1 post-dose measurement for at least 1 pharmacodynamic endpoint.

Cmin was observed directly from data.

Time frame: Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing, pre-dose on Day 29, 24 and 96 hours post Day 29 dosing

Population: The PK parameter analysis population included all enrolled participants treated who had at least 1 quantifiable concentration. Number analyzed refers to number of participants evaluable for specified rows.

Cmax was observed directly from data.

Time frame: Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing, pre-dose on Day 29, 24 and 96 hours post Day 29 dosing

Population: The PK parameter analysis population included all enrolled participants treated who had at least 1 quantifiable concentration. Number analyzed refers to number of participants evaluable for specified rows.

Human plasma ADA samples were analyzed for the detection of anti PF-06741086 antibodies by using semi-quantitative electrochemiluminescence (ECL) method. The criterion for positive result of ADA samples was ADA titer \>=1.53. Treatment induced are negative prior to dosing and become positive during/after dosing. Treatment boosted are positive prior to dosing but titer increases during/after dosing.

Time frame: Baseline up to Study Day 113

Population: This analysis population included all participants who received at least 1 dose of investigational drug.

Human plasma NAb samples were analyzed for the presence or absence of NAb to PF-06741086 using semi-quantitative electrochemiluminescence (ECL) method. Treatment induced are negative prior to dosing and become positive during/after dosing. Treatment boosted are positive prior to dosing but titer increases during/after dosing.

Time frame: Baseline up to Study Day 113

Population: Only positive ADA samples and the corresponding baseline sample were tested in the NAb assay.

Plasma PF-06741086 concentrations were analyzed using a validated, sensitive and specific electrochemiluminescence (ECL) method.

Time frame: pre-dose on Study Day 1, 24hours (h), 72h post Study Day 1 dosing, pre-dose on Study Day 8, 15 and 22, pre-dose on Study Day 29, 24h, 96h post Study Day 29 dosing, pre-dose on Study Day 57, 168h, 840h post Study Day 57 dosing

Population: The PK concentration population included all enrolled participants treated who had at least 1 quantifiable concentration. Number analyzed refers to number of participants evaluable for specified rows of categories.

Tmax was observed directly from data as time of first occurrence.

Time frame: Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing, pre-dose on Day 29, 24 and 96 hours post Day 29 dosing

Population: The PK parameter analysis population included all enrolled participants treated who had at least 1 quantifiable concentration. Number analyzed refers to number of participants evaluable for specified rows.