PF-06741086 Multiple Dose Study in Severe Hemophilia

Phase 2

Completed

Conditions: Hemophilia A or B

Interventions: Biological: PF-06741086

Registration Number: NCT02974855

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 27

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
PF-06741086 (Cohort 1)	PF-06741086	-
PF-06741086 (Cohort 2)	PF-06741086	-
PF-06741086 (Cohort 3)	PF-06741086	-
PF-06741086 (Cohort 4)	PF-06741086	-

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (10): Hospital Dr. Sotero del Rio
🇨🇱
Santiago, Chile
Klinicki bolnicki centar Zagreb
🇭🇷
Zagreb, Croatia
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
UC Denver Hemophilia and Thrombosis Center - Pharmacy
🇺🇸
Aurora, Colorado, United States
UC Denver Hemophilia and Thrombosis Center
🇺🇸
Aurora, Colorado, United States
Pharmacy
🇺🇸
Chicago, Illinois, United States
Phoenix Pharma (Pty) Ltd
🇿🇦
Port Elizabeth, Eastern CAPE, South Africa
Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne
🇵🇱
Gdansk, Poland
UniversitatsSpital Zurich, Klinik fur Hamatologie
🇨🇭
Zurich, Switzerland
Haemophilia Comprehensive Care Centre
🇿🇦
Johannesburg, Gauteng, South Africa