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

NCT01439971 | Completed Phase 1 Results DMC

• 2 other identifiers: B30510012011-002170-23
• Study Type: interventional
• Target: 29
• Locations: 8 countries
• Sites: 23

Brief Summary

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.

Conditions

Hemophilia A

Keywords

Phase 1; Safety; Pharmacokinetic; Pharmacodynamic

Outcome Measures

Primary Outcomes (17)

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  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.

  Baseline, Day 2, Day 3, and Day 15

• Change From Baseline in Body Weight

  Baseline, Day 2, Day 3, and Day 15

• Change From Baseline in Body Temperature

  Body temperature was measured by mouth (oral) or ear (tympanic). A temperature greater than 38.5 degree Celsius was considered a fever.

  Baseline, Day 2, Day 3, and Day 15

• Change From Baseline in Respiration Rate

  Respiration rate measured as respirations per minute (resp/min).

  Baseline, Day 2, Day 3, and Day 15

• Change From Baseline in Supine Pulse Rate

  Change from baseline is the vital sign value at Day 2, Day 3, and Day 15 minus vital sign value at baseline.

  Baseline, Day 2, Day 3, and Day 15

• Number of Participants With Changes Since Previous Physical Examination

  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.

  Baseline (Day 0), Day 1, Day 2, Day 3, Day 15

• Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings

  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.

  Baseline through Day 15

• Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Withdrawals Due to AEs (Except Hemophilia AEs)

  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.

  Baseline through Day 60

• Number of Participants With Treatment-Emergent Hemophilia AEs and Withdrawals Due to Hemophilia AEs

  Hemophilia AEs included spontaneous (no known contributing factor) and traumatic (known or presumed contributing factor/reason) bleeding episodes.

  Baseline through Day 60

• Number of Treatment-Emergent AEs and SAEs by Severity (Except Hemophilia AEs)

  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.

  Baseline through Day 60

• Number of Treatment-Emergent Hemophilia AEs by Severity

  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.

  Baseline through Day 60

• Number of Participants With Treatment-Emergent Abnormal Troponin-T Levels by Magnitude

  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.

  Baseline through Day 15

• Number of Participants With Treatment-Emergent Abnormal Anti-Thrombin III (ATIII) Levels by Magnitude

  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.

  Baseline through Day 3

• Number of Participants With Treatment-Emergent Abnormal Tissue Factor Pathway Inhibitor (TFPI) Levels by Magnitude

  TFPI is a polypeptide that can regulate blood coagulation. TFPI levels of potential clinical concern are values \<1X LLN and \>1X ULN.

  Baseline through Day 3

• Number of Participants With Treatment-Emergent Laboratory Test Abnormalities (Normal Baseline)

  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).

  Baseline through Day 15

• Number of Participants With Clinically Significant Laboratory Abnormalities Meeting Stopping Criteria

  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.

  Baseline through Day 15

• 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)

  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.

  Baseline through Day 60

Secondary Outcomes (17)

• Maximum Observed Plasma Concentration (Cmax)

  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)

  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)

• Terminal Elimination Half-Life (t1/2)

  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)

• Incremental Recovery (IncRec)

  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 Extrapolated Infinite Time (AUCinf)

  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)

Study Arms (5)

1

EXPERIMENTAL

Biological: PF-05280602

2

EXPERIMENTAL

Biological: PF-05280602

3

EXPERIMENTAL

Biological: PF-05280602

4

EXPERIMENTAL

Biological: PF-05280602

5

EXPERIMENTAL

Biological: PF-05280602

Interventions

PF-05280602 BIOLOGICAL

0.5 micrograms per kilogram of PF-05280602, IV infusion, single dose

1

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Catalyst Biosciences: lead

Study Sites (23)

University of California San Diego Medical Center

San Diego, California, 92103-8651, United States

Location

New Haven Clinical Research Unit

New Haven, Connecticut, 06511, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Doernbecher Children's Hospital

Portland, Oregon, 97239, United States

Location

OHSU Investigational Pharmacy

Portland, Oregon, 97239, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

CTRC

Philadelphia, Pennsylvania, 19104, United States

Location

Penn Comprehensive Hemophilia Program - Center for Blood Disorders

Philadelphia, Pennsylvania, 19104, United States

Location

Pfizer Clinical Research Unit

Brussels, B-1070, Belgium

Location

Semmelweis Egyetem Altalanos Orvostudomanyi Kar/ I.sz. Belgyogyaszati Klinika

Budapest, 1083, Hungary

Location

Dipartimento di Medicina Clinica 1-Centro Regionale per le Malattie del Sangue

Castelfranco Veneto (TV), Italy, 31033, Italy

Location

Servizio Farmacia- Ospedale Castelfranco Veneto

Castelfranco Veneto - Treviso, Italy, 31033, Italy

Location

Servizio Farmacia Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Milan, Italy, 20122, Italy

Location

Farmacia Ospedaliera Ospedale San Bortolo

Vicenza, Italy, 36100, Italy

Location

Centro Emofilia e Trombosi "Angelo Bianchi Bonomi" U.O.S. Dipartimentale per la Diagnosi e la Terapi

Milan, 20122, Italy

Location

Centro Malattie Emorragiche e Trombotiche - Ematologia

Vicenza, 36100, Italy

Location

Christchurch Clinical Studies Trust

Christchurch, New Zealand, 08011, New Zealand

Location

Phoenix Pharma (Pty) Ltd

Port Elizabeth, Eastern Cape, 6001, South Africa

Location

Ege University Tip Fakultesi

Izmir, Turkey, 35100, Turkey (Türkiye)

Location

Royal Free Hampstead NHS Trust, Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Haematology Department

London, W12 0HS, United Kingdom

Location

Central Manchester Universtiy Hospitals NHS Foundation Trust

Manchester, M13 9WL, United Kingdom

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

The protocol was amended to a starting dose of 4.5 mcg/kg. The positive anti-PF-05280602 antibody was cross-reactive with NovoSeven and native Factor VII and the weak positive immune response at Day 60 may represent a false-positive test result.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Catalyst Biosciences

hlevy@catbio.com

1-650-266-8671

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The was an ascending dose trial with one open label treatment, intervention model was sequential dose escalation.

Study Record Dates

• First Submitted: August 26, 2011
• First Posted: September 23, 2011
• Study Start: December 1, 2011
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: May 12, 2017
• Results First Posted: April 6, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1); BE (1); TU (1); GB (3); IT (6); HU (1); US (9); NZ (1)