PF-06741086 Multiple Dose Study in Severe Hemophilia

Study Overview
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Brief Summary
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This study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of multiple subcutaneous and/or intravenous doses of PF-06741086 in subjects with severe hemophilia.

Official Title
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A MULTICENTER, OPEN-LABEL, MULTIPLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF SUBCUTANEOUS OR INTRAVENOUS PF-06741086 IN SUBJECTS WITH SEVERE HEMOPHILIA

Conditions
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Hemophilia A or B

Intervention / Treatment
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* Biological: PF-06741086
* Biological: PF-06741086
* Biological: PF-06741086
* Biological: PF-06741086


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe hemophilia A or B (Factor VIII or Factor IX activity ≤ 1%), including patients with inhibitors to Factor VIII or Factor IX Episodic (on-demand) treatment regimen prior to screening At least 6 acute bleeding episodes during the 6-month period prior to screening Exclusion Criteria: Known coronary artery, thrombotic, or ischemic disease Currently receiving treatment for acute bleeding episodes with APCC and cannot substitute treatment with rFVIIa

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06741086 (Cohort 1)<br> | Biological: PF-06741086<br>* PF-06741086 subcutaneous (SC) injection<br>|
| Experimental: PF-06741086 (Cohort 2)<br> | Biological: PF-06741086<br>* PF-06741086 SC injection<br>|
| Experimental: PF-06741086 (Cohort 3)<br> | Biological: PF-06741086<br>* PF-06741086 SC injection<br>|
| Experimental: PF-06741086 (Cohort 4)<br> | Biological: PF-06741086<br>* PF-06741086 SC injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. | Study Day 1 to Day 113 Visit | 
| Number of Participants Discontinued From Study Due to TEAEs | 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. | Study Day 1 to Day 113 Visit | 
| Number of Participants With Abnormal Laboratory Findings-Hematology | 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). | Baseline to Study Day 113 Visit | 
| Number of Participants With Abnormal Laboratory Findings-Clinical Chemistry | 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. | Baseline to Study Day 113 | 
| Number of Participants With Abnormal Laboratory Findings-Urinalysis | Urinalysis included: pH, urine glucose, ketones, urine protein, urine hemoglobin, urobilinogen, urine bilirubin, nitrite, leukocyte esterase, urine erythrocytes, urine leukocytes and bacteria. | Baseline to Study Day 113 Visit | 
| Change From Baseline for Globulin by Dose Cohort | Blood samples were obtained to determine globulin level in serum, total globulin was derived as total protein other than albumin. | Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113. | 
| Change From Baseline for Prothrombin International Normalized Ratio (PT/INR) by Dose Cohort | 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®). | Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113. | 
| Change From Baseline for Activated Partial Thromboplastin Time (aPTT) by Dose Cohort | 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. | Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113. | 
| Change From Baseline for Fibrinogen by Dose Cohort | 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, Study Day 8, 15, 22, 29, 57, 85 and 113. | 
| Change From Baseline for Antithrombin III by Dose Cohort | 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. | Baseline, Study Day 8, 15, 22 and 29. | 
| Change From Baseline for Troponin I by Dose Cohort | Blood samples were collected to measure the level of cardiac-specific troponin I in the blood to help detect heart injury. | Baseline, Study Day 8, 15, 22, 29, 57 and 85. | 
| Number of Participants With Vital Signs Data Meeting Pre-specified Criteria | 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. | Baseline to Study Day 113 Visit | 
| Number of Participants With Electrocardiogram (ECG) Change Meeting Pre-specified Criteria | 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. | Baseline to Study Day 29 Visit. | 
| Number of Participants With Clinically Significant Changes in Physical Examination Findings | 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. | Baseline to Study Day 113 Visit | 
| Number of Participants With Infusion and Injection Site Reactions | 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. | Baseline to Study Day 113 Visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleeding Rate (ABR) | 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%). | Pre-treatment: within 6 months prior to study enrollment; On-study: Day 1 to 9 days after the last dose (Day 78) | 
| Plasma PF-06741086 Concentrations | Plasma PF-06741086 concentrations were analyzed using a validated, sensitive and specific electrochemiluminescence (ECL) method. | 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 | 
| Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-06741086 | AUClast was calculated by linear/Log trapezoidal method. | Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing | 
| Maximum Plasma Concentration (Cmax) of PF-06741086 | Cmax was observed directly from data. | 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 | 
| Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06741086 | Cmin was observed directly from data. | 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 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of PF-06741086 | Tmax was observed directly from data as time of first occurrence. | 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 | 
| Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of PF-06741086 | The dosing interval tau was 1 week. AUCtau was obtained by linear/log trapezoidal method. | Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing | 
| Apparent Clearance After Oral Dose (CL/F) of PF-06741086 | CL/F was calculated by dose/AUCtau. | Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing | 
| Change From Baseline in Total Tissue Factor Pathway Inhibitor (TFPI) | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Change From Baseline in Thrombin Generation (TGA) Lag Time | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Change From Baseline in Thrombin Generation (TGA) Peak | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Change From Baseline in Endogenous Thrombin Generation (TGA) Potential | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Change From Baseline in Prothrombin Fragments 1 + 2 | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Change From Baseline in D-Dimer | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Change From Baseline in Dilute Prothrombin Time | 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. | Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113 | 
| Number of Participants Who Tested Positive for Anti-PF-06741086 Antibody (ADA) | 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. | Baseline up to Study Day 113 | 
| Number of Participants Who Tested Positive for Neutralizing Antibody (NAb) | 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. | Baseline up to Study Day 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemophilia