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Phase 1 Safety, Pharmacokinetics And Pharmacodynamics Study Of Recombinant Factor VIIa Variant (813d) In Adult Subjects With Hemophilia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Catalyst Biosciences
ClinicalTrials.gov Identifier:
NCT01439971
First received: August 26, 2011
Last updated: April 7, 2017
Last verified: April 2017
  Purpose
This study hypothesizes that the study drug, PF-05280602 (at the selected doses) will be safe to administer to subjects with severe Hemophilia A or B with or without inhibitors and will demonstrate evidence of hemostatic activity. This is supported by the preclinical findings in hemophilic animal models.

Condition Intervention Phase
Hemophilia A Biological: PF-05280602 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
The was an ascending dose trial with one open label treatment, intervention model was sequential dose escalation.
Masking: No masking
Primary Purpose: Basic Science
Official Title: An Ascending Single Dose Study To Evaluate The Safety, Tolerability And Pharmacokinetics/Pharmacodynamics Of Pf-05280602, A Recombinant Factor Viia Variant (813d), In Adult Hemophilia A And B Subjects With Or Without Inhibitors

Resource links provided by NLM:


Further study details as provided by Catalyst Biosciences:

Primary Outcome Measures:
  • Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline, Day 2, Day 3, and Day 15 ]
    Supine blood pressure (BP) was measured with the participant's arm supported at the level of the heart, and recorded to the nearest millimeters of mercury (mmHg) after 5 minutes of rest. The same arm (preferably the dominant arm) was to be used throughout the study.

  • Change From Baseline in Body Weight [ Time Frame: Baseline, Day 2, Day 3, and Day 15 ]
  • Change From Baseline in Body Temperature [ Time Frame: Baseline, Day 2, Day 3, and Day 15 ]
    Body temperature was measured by mouth (oral) or ear (tympanic). A temperature greater than 38.5 degree Celsius was considered a fever.

  • Change From Baseline in Respiration Rate [ Time Frame: Baseline, Day 2, Day 3, and Day 15 ]
    Respiration rate measured as respirations per minute (resp/min).

  • Change From Baseline in Supine Pulse Rate [ Time Frame: Baseline, Day 2, Day 3, and Day 15 ]
    Change from baseline is the vital sign value at Day 2, Day 3, and Day 15 minus vital sign value at baseline.

  • Number of Participants With Changes Since Previous Physical Examination [ Time Frame: Baseline (Day 0), Day 1, Day 2, Day 3, Day 15 ]
    Physical examinations were conducted by a physician, trained physician's assistant, or nurse practitioner. A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, genitourinary, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.

  • Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [ Time Frame: Baseline through Day 15 ]
    ECG findings of potential clinical concern were: PR interval greater than or equal to (>=)300 milliseconds (msec), >=25% increase from baseline for baseline values >200 msec, >=50% increase from baseline for baseline values less than or equal to (<=)200 msec; QRS complex >=140 msec or >=50% increase from baseline; QTcF interval (Fridericia's correction) >=450 msec or >=30 msec increase from baseline.

  • Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Withdrawals Due to AEs (Except Hemophilia AEs) [ Time Frame: Baseline through Day 60 ]
    An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Day 15 that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.

  • Number of Participants With Treatment-Emergent Hemophilia AEs and Withdrawals Due to Hemophilia AEs [ Time Frame: Baseline through Day 60 ]
    Hemophilia AEs included spontaneous (no known contributing factor) and traumatic (known or presumed contributing factor/reason) bleeding episodes.

  • Number of Treatment-Emergent AEs and SAEs by Severity (Except Hemophilia AEs) [ Time Frame: Baseline through Day 60 ]
    AE severity were graded as mild, moderate, or severe. Mild severity AEs do not interfere with the participant's usual function. Moderate AEs interfere to some extent with the participant's usual function. Severe AEs interfere significantly with the participant's usual function.

  • Number of Treatment-Emergent Hemophilia AEs by Severity [ Time Frame: Baseline through Day 60 ]
    Mild severity AEs do not interfere with the participant's usual function. Moderate AEs interfere to some extent with the participant's usual function. Severe AEs interfere significantly with the participant's usual function.

  • Number of Participants With Treatment-Emergent Abnormal Troponin-T Levels by Magnitude [ Time Frame: Baseline through Day 15 ]
    Troponin-T is a cardiac marker for the evaluation of possible cardiovascular injury. Troponin-T levels of potential clinical concern are values >1.5 times the upper limit of normal (1.5X ULN) or >=2.5X ULN.

  • Number of Participants With Treatment-Emergent Abnormal Anti-Thrombin III (ATIII) Levels by Magnitude [ Time Frame: Baseline through Day 3 ]
    ATIII is a protein in the blood that blocks abnormal blood clots from forming. Low levels of ATIII can cause abnormal blood clots. ATIII levels of potential clinical concern are values <1X LLN and >1X ULN.

  • Number of Participants With Treatment-Emergent Abnormal Tissue Factor Pathway Inhibitor (TFPI) Levels by Magnitude [ Time Frame: Baseline through Day 3 ]
    TFPI is a polypeptide that can regulate blood coagulation. TFPI levels of potential clinical concern are values <1X LLN and >1X ULN.

  • Number of Participants With Treatment-Emergent Laboratory Test Abnormalities (Normal Baseline) [ Time Frame: Baseline through Day 15 ]
    The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, platelets, leukocytes, total neutrophils, eosinophils, basophils, lymphocytes, monocytes); chemistry (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], glucose, uric acid, sodium, potassium, chloride, bicarbonate, calcium, albumin, total protein, creatine kinase); urinalysis (urine white blood cell [WBC], urine RBC); other (troponin T).

  • Number of Participants With Clinically Significant Laboratory Abnormalities Meeting Stopping Criteria [ Time Frame: Baseline through Day 15 ]
    Clinically significant findings for stopping rules are: hemoglobin <8 grams/deciliter (g/dL) or >20% decrease from normal baseline; WBC >20,000 cells/mm^3 or <1,500 decrease with normal baseline; platelets <100,000/mm^3 or >33% decrease from baseline; total bilirubin >1.5X ULN; AST or ALT >2.5X ULN; alkaline phosphatase >3X ULN; creatinine >1.5X baseline; BUN >31.0 mg/dL; glucose <0.6 or >1.5X reference range; uric acid > ULN; sodium >150 or <130 mEq/L; potassium >5.5 or <3.0 mEq/L; calcium >11.5 or <8.0 mg/dL; albumin <2.0 g/L; total protein <5.0 g/L; positive D-dimer at Day 15; PT prolonged by 3 seconds above baseline; ATIII < LLN and >20% decrease from baseline; troponin-T values above the reference range; fibrinogen <0.75X LLN or >25% decrease from baseline.

  • Number of Participants With Positive Immune Response (Anti-Drug Antibodies [ADA], PF-05280602 Inhibitor, Factor VIIa Inhibitor, Factor VII Inhibitor, and Depletion of Factor VII Activity) [ Time Frame: Baseline through Day 60 ]
    Assays for the determination of a positive immune response was performed. An antibody immune response was defined as a confirmed post-treatment positive ELISA result in combination with a negative baseline sample ELISA result. Positive antibody immune responses to PF-05280602 by ELISA was evaluated for cross reactivity to NovoSeven RT and to Factor VII.


Secondary Outcome Measures:
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)

  • Terminal Elimination Half-Life (t1/2) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    t1/2 is the time measured for the plasma concentration to decrease by one half.

  • Incremental Recovery (IncRec) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    IncRec is the maximum rise in plasma concentration per administered dose.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    AUCinf is area under the plasma concentration-time curve from time 0 extrapolated to infinite time.

  • Mean Residence Time (MRT) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    MRT is AUMCinf/AUCinf, where AUMC is the area under the first moment curve.

  • Volume of Distribution at Steady State (Vss) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.

  • Clearance (CL) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
    Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). Clearance obtained after intravenous infusion dose is influenced by the fraction of the dose absorbed.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Day 1 (pre-dose and 5 min, 10 min, 20 min, 30 min, 1 hr, 3 hr, 6 hr, 9 hr, and 12 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose) ]
  • Maximum Mean Decrease From Baseline in Prothrombin Time (PT) [ Time Frame: Baseline through Day 15 ]
    PT measures how long it takes blood to clot. Maximum mean decrease from baseline at any time point was reported.

  • Maximum Mean Decrease From Baseline in Activated Partial Thromboplastin Time (aPTT) [ Time Frame: Baseline through Day 15 ]
    aPTT is a blood test that characterizes blood coagulation. Maximum mean decrease from baseline at any time point was reported.

  • Maximum Mean Increase From Baseline in Thrombin Anti-Thrombin (TAT) Complexes [ Time Frame: Baseline through Day 3 ]
    TAT complex is a parameter of coagulation and fibrinolysis. The normal reference range of values for TAT is 1 to 4.1 mcg/L. Elevated TAT concentrations may signify predisposition to thrombosis. Maximum mean increase from baseline at any time point was reported.

  • Maximum Mean Increase From Baseline in Prothrombin Fragments 1+2 [ Time Frame: Baseline through Day 3 ]
    Prothrombin fragment 1+2 is a coagulation factor, released when prothrombin is cleaved by activated Factor X. Elevated plasma levels of prothrombin fragment 1+2 indicate high risk of thrombosis. Maximum mean increase from baseline at any time point was reported.

  • Maximum Mean Increase From Baseline in D-Dimers [ Time Frame: Baseline through Day 15 ]
    D-dimer is an indicator of fibrin formation and its subsequent lysis and is a useful biomarker representing overall activation of blood coagulation. Maximum mean increase from baseline at any time point was reported.

  • Maximum Mean Increase From Baseline in Endogenous Thrombin Potential (ETP) [ Time Frame: Baseline through Day 3 ]
    ETP was evaluated using a Thrombin Generation Assay (TGA), a validated automated ex-vivo assay that measures the ability of plasma to generate thrombin. Thrombin generation curves are generated and calculated using dedicated software. ETP is the area under the thrombin generation curve and represents the total amount of generated thrombin. Maximum mean increase from baseline at any time point was reported.

  • Maximum Mean Decrease From Baseline in Thrombin Generation Lag Time [ Time Frame: Baseline through Day 3 ]
    The lag time is defined as the time to reach one sixth of the peak height and is a measure of the initiation phase. It is equivalent to the clotting time. Maximum mean decrease from baseline at any time point was reported.

  • Maximum Mean Increase From Baseline in Peak Thrombin Generation [ Time Frame: Baseline through Day 3 ]
    The peak height is defined as the maximum thrombin concentration produced. Maximum mean increase from baseline at any time point was reported.


Enrollment: 29
Study Start Date: December 2011
Study Completion Date: October 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Biological: PF-05280602
0.5 micrograms per kilogram of PF-05280602, IV infusion, single dose
Experimental: 2 Biological: PF-05280602
4.5 micrograms per kilogram of PF-05280602, IV infusion, single dose
Experimental: 3 Biological: PF-05280602
9.0 micrograms per kilogram of PF-05280602, IV infusion, single dose
Experimental: 4 Biological: PF-05280602
18.0 micrograms per kilogram of PF-05280602, IV infusion, single dose
Experimental: 5 Biological: PF-05280602
30.0 micrograms per kilogram of PF-05280602, IV infusion, single dose

  Eligibility

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

Inclusion Criteria:

  • Male subjects 18 to <65 years old with severe hemophilia A or B with or without inhibitors to FVIII or FIX.
  • Subjects is willing and able to comply with the mandatory washout periods prior to screening and prior to dosing and through 48 hours post dosing. At screening this includes a washout of FIX for 96 hours and FVIII for 72 houts. At dosing this includes a washout of FIX for 96 hours and FVIII and other hemostatic agents for 72 hours through 48 hours post dosing.
  • Subjects must agree and commit to using a a highly effective method of birth control from the time of screening through four weeks after study drug administration.

Exclusion Criteria:

  • Presence of a bleeding disorder in addition to hemophilia A or B.
  • Regular, concomitant therapy with immunomodulating drugs (eg, intravenous immunoglobulin, and routine systemic corticosteroids).
  • History of coronary artery disease, thrombolic disease or diagnosis of prothrombic disorder.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01439971

Locations
United States, California
University of California San Diego Medical Center
San Diego, California, United States, 92103-8651
United States, Connecticut
New Haven Clinical Research Unit
New Haven, Connecticut, United States, 06511
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Oregon
Doernbecher Children's Hospital
Portland, Oregon, United States, 97239
OHSU Investigational Pharmacy
Portland, Oregon, United States, 97239
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
CTRC
Philadelphia, Pennsylvania, United States, 19104
Penn Comprehensive Hemophilia Program - Center for Blood Disorders
Philadelphia, Pennsylvania, United States, 19104
Belgium
Pfizer Clinical Research Unit
Bruxelles, Belgium, B-1070
Hungary
Semmelweis Egyetem Altalanos Orvostudomanyi Kar/ I.sz. Belgyogyaszati Klinika
Budapest, Hungary, 1083
Italy
Dipartimento di Medicina Clinica 1-Centro Regionale per le Malattie del Sangue
Castelfranco Veneto (TV), Italy, 31033
Servizio Farmacia- Ospedale Castelfranco Veneto
Castelfranco Veneto - Treviso, Italy, 31033
Centro Emofilia e Trombosi "Angelo Bianchi Bonomi" U.O.S. Dipartimentale per la Diagnosi e la Terapi
Milano, Italy, 20122
Servizio Farmacia Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Milano, Italy, 20122
Centro Malattie Emorragiche e Trombotiche - Ematologia
Vicenza, Italy, 36100
Farmacia Ospedaliera Ospedale San Bortolo
Vicenza, Italy, 36100
New Zealand
Christchurch Clinical Studies Trust
Christchurch, New Zealand, 08011
South Africa
Phoenix Pharma (Pty) Ltd
Port Elizabeth, Eastern Cape, South Africa, 6001
Turkey
Ege University Tip Fakultesi
Izmir, Turkey, 35100
United Kingdom
Royal Free Hampstead NHS Trust, Royal Free Hospital
London, United Kingdom, NW3 2QG
Haematology Department
London, United Kingdom, W12 0HS
Central Manchester Universtiy Hospitals NHS Foundation Trust
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Catalyst Biosciences
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Catalyst Biosciences
ClinicalTrials.gov Identifier: NCT01439971     History of Changes
Other Study ID Numbers: B3051001
2011-002170-23 ( EudraCT Number )
Study First Received: August 26, 2011
Results First Received: October 20, 2016
Last Updated: April 7, 2017
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Catalyst Biosciences:
Phase 1
Safety
Pharmacokinetic
Pharmacodynamic

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on June 26, 2017