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PF-06741086 Multiple Dose Study in Severe Hemophilia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02974855
Recruitment Status : Completed
First Posted : November 29, 2016
Results First Posted : December 4, 2019
Last Update Posted : December 4, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Hemophilia A or B Biological: PF-06741086 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : March 8, 2017
Actual Primary Completion Date : December 3, 2018
Actual Study Completion Date : December 3, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PF-06741086 (Cohort 1) Biological: PF-06741086
PF-06741086 subcutaneous (SC) injection

Experimental: PF-06741086 (Cohort 2) Biological: PF-06741086
PF-06741086 SC injection

Experimental: PF-06741086 (Cohort 3) Biological: PF-06741086
PF-06741086 SC injection

Experimental: PF-06741086 (Cohort 4) Biological: PF-06741086
PF-06741086 SC injection




Primary Outcome Measures :
  1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: 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.

  2. Number of Participants Discontinued From Study Due to TEAEs [ Time Frame: 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.

  3. Number of Participants With Abnormal Laboratory Findings-Hematology [ Time Frame: 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).

  4. Number of Participants With Abnormal Laboratory Findings-Clinical Chemistry [ Time Frame: 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.

  5. Number of Participants With Abnormal Laboratory Findings-Urinalysis [ Time Frame: 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.

  6. Change From Baseline for Globulin by Dose Cohort [ Time Frame: 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.

  7. Change From Baseline for Prothrombin International Normalized Ratio (PT/INR) by Dose Cohort [ Time Frame: 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®).

  8. Change From Baseline for Activated Partial Thromboplastin Time (aPTT) by Dose Cohort [ Time Frame: 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.

  9. Change From Baseline for Fibrinogen by Dose Cohort [ Time Frame: 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.

  10. Change From Baseline for Antithrombin III by Dose Cohort [ Time Frame: 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.

  11. Change From Baseline for Troponin I by Dose Cohort [ Time Frame: 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.

  12. Number of Participants With Vital Signs Data Meeting Pre-specified Criteria [ Time Frame: 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.

  13. Number of Participants With Electrocardiogram (ECG) Change Meeting Pre-specified Criteria [ Time Frame: 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.

  14. Number of Participants With Clinically Significant Changes in Physical Examination Findings [ Time Frame: 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.

  15. Number of Participants With Infusion and Injection Site Reactions [ Time Frame: 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.


Secondary Outcome Measures :
  1. Annualized Bleeding Rate (ABR) [ Time Frame: 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%).

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

  3. Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-06741086 [ Time Frame: Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing ]
    AUClast was calculated by linear/Log trapezoidal method.

  4. Maximum Plasma Concentration (Cmax) of PF-06741086 [ 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 ]
    Cmax was observed directly from data.

  5. Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06741086 [ 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 ]
    Cmin was observed directly from data.

  6. Time to Reach Maximum Plasma Concentration (Tmax) of PF-06741086 [ 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 ]
    Tmax was observed directly from data as time of first occurrence.

  7. Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of PF-06741086 [ Time Frame: 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.

  8. Apparent Clearance After Oral Dose (CL/F) of PF-06741086 [ Time Frame: Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing ]
    CL/F was calculated by dose/AUCtau.

  9. Change From Baseline in Total Tissue Factor Pathway Inhibitor (TFPI) [ Time Frame: 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.

  10. Change From Baseline in Thrombin Generation (TGA) Lag Time [ Time Frame: 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.

  11. Change From Baseline in Thrombin Generation (TGA) Peak [ Time Frame: 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.

  12. Change From Baseline in Endogenous Thrombin Generation (TGA) Potential [ Time Frame: 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.

  13. Change From Baseline in Prothrombin Fragments 1 + 2 [ Time Frame: 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.

  14. Change From Baseline in D-Dimer [ Time Frame: 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.

  15. Change From Baseline in Dilute Prothrombin Time [ Time Frame: 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.

  16. Number of Participants Who Tested Positive for Anti-PF-06741086 Antibody (ADA) [ Time Frame: 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.

  17. Number of Participants Who Tested Positive for Neutralizing Antibody (NAb) [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02974855


Locations
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United States, Colorado
UC Denver Hemophilia and Thrombosis Center - Pharmacy
Aurora, Colorado, United States, 80045
UC Denver Hemophilia and Thrombosis Center
Aurora, Colorado, United States, 80045
United States, Illinois
Pharmacy
Chicago, Illinois, United States, 60612
Rush University Medical Center
Chicago, Illinois, United States, 60612
Chile
Hospital Dr. Sotero del Rio
Santiago, Chile, 8207257
Croatia
Klinicki bolnicki centar Zagreb
Zagreb, Croatia, 10000
Poland
Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne
Gdansk, Poland, 80-952
South Africa
Phoenix Pharma (Pty) Ltd
Port Elizabeth, Eastern CAPE, South Africa, 6001
Haemophilia Comprehensive Care Centre
Johannesburg, Gauteng, South Africa, 2193
Switzerland
UniversitatsSpital Zurich, Klinik fur Hamatologie
Zurich, Switzerland, 8091
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] October 2, 2017
Statistical Analysis Plan  [PDF] October 20, 2017


Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02974855    
Other Study ID Numbers: B7841002
2016-001885-27 ( EudraCT Number )
First Posted: November 29, 2016    Key Record Dates
Results First Posted: December 4, 2019
Last Update Posted: December 4, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
hemophilia
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn