A MULTIPLE DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF SUBCUTANEOUS AND/OR INTRAVENOUS PF-06741086 IN SUBJECTS WITH SEVERE HEMOPHILIA

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2016-001885-27-ES
• Date of registration: 26/10/2016
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc., 235 East 42nd Street, New York, NY 10017
• Public title: A MULTIPLE DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF SUBCUTANEOUS AND/OR INTRAVENOUS PF-06741086 IN SUBJECTS WITH SEVERE HEMOPHILIA
• Scientific title: A MULTICENTER, OPEN-LABEL, MULTIPLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF SUBCUTANEOUS AND/OR INTRAVENOUS PF-06741086 IN SUBJECTS WITH SEVERE HEMOPHILIA
• Date of first enrolment: 03/11/2016
• Target sample size: 24
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001885-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Brazil, Bulgaria, Chile, Croatia, France, Malaysia, Netherlands, Poland, South Africa, Spain, United States

Contacts

• Name: Clinical Trials.gov Call center
• Affiliation: Pfizer Inc.

• Name: Clinical Trials.gov Call center
• Affiliation: Pfizer Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative/parent(s)/legal guardian) has been informed of all pertinent aspects of the study.
2. Males =18 and <65 years of age are eligible for all cohorts. Males =12 and <18 years of age may only be enrolled into a cohort at a dose level and route of administration previously studied in a B7841002 cohort and which has not met the protocol safety criteria for termination of dose escalation.
3. Body Mass Index (BMI) = 17.5 and = 30.5 kg/m2 and total body weight =50 and =100 kg.
4. Diagnosis of severe hemophilia A or B (Factor VIII or Factor IX activity = 1%), with no known Factor VIII or Factor IX inhibitors during the 12-month period prior to Screening.
5. Willing and able to washout from Factor VIII (for at least 72 hours) or Factor IX (for at least 96 hours) replacement therapy prior to Screening laboratory assessments of factor activity and no plans to institute prophylactic factor treatment during the study period.
6. Had at least 6 acute bleeding episodes (spontaneous/traumatic) during the 6-month period prior to Screening. Surgical bleeding episodes do not apply to this criterion.
7. If receiving therapy for human immunodeficiency virus (HIV) or active hepatitis infection, have stable disease and be on a stable regimen at the time of study entry (ie, stable dosing for at least 3 months before consent).
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
9. If with partners currently pregnant or if able to father children, agree to use a highly effective method of contraception throughout the study and for least 28 days after the last dose of investigational product.
Are the trial subjects under 18? yes
Number of subjects for this age range: 2
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 22
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Subjects with any of the following characteristics/conditions will not be included in the study:
1. Females.
2. Known coronary artery, thrombotic, or ischemic disease.
3. Known hemostatic defect other than hemophilia A or B.
4. Detectable or documented history of inhibitors (= 0.6 Bethesda Units [BU]) against Factor VIII or Factor IX during the 12-month period prior to Screening.
5. Currently receiving treatment for acute bleeding episodes with rFVIIa or activated prothrombin complex concentrate (eg Factor Eight Inhibitor Bypass Agent [FEIBA]).
6. Regular, concomitant therapy with immunomodulating drugs (eg, intravenous immunoglobulin [IVIG], and routine systemic corticosteroids).
7. Abnormal renal or hepatic function as defined by the following laboratory results at Screening:
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 3 times the upper limit of normal (ULN).
• Total bilirubin level > 2 mg/dL (> 35 umol/L).
• Serum albumin < the lower limit of normal (LLN).
• Serum creatinine level > 1.25 times the ULN.
8. Abnormal hematology values as defined by the following laboratory results at Screening:
• Platelet count < 100,000 /µL.
• Fibrinogen level < LLN.
• Hemoglobin level < 10 gm/dL.
9. Abnormal coagulation activity as defined by the following laboratory results at Screening:
• Prothrombin time (PT) > 1.25 times the ULN.
10. CD4 cell count = 200 /uL.
11. Known hypersensitivity or allergic reaction to hamster protein.
12. Known sensitivity to heparin or heparin-induced thrombocytopenia.
13. Investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.
14. Participation in other studies involving investigational drug(s) within 30 days (or as determined by the local requirement, whichever is longer) or 5 half-lives prior to study entry and/or during study participation.
15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
16. With partners currently pregnant or able to father children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product.
17. Had major surgery, as judged by the investigator, within 3 months prior to the study or have elective surgery planned during the study.


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Hemophilia A or B
MedDRA version: 19.0 Level: LLT Classification code 10060613 Term: Hemophilia A (Factor VIII) System Organ Class: 100000004850
MedDRA version: 19.0 Level: LLT Classification code 10060612 Term: Hemophilia A System Organ Class: 100000004850
MedDRA version: 19.0 Level: LLT Classification code 10060614 Term: Hemophilia B (Factor IX) System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: PF-06741086
Product Code: PF-06741086
Pharmaceutical Form: Solution for injection
INN or Proposed INN: NA
Other descriptive name: PF-06741086
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Primary end point(s): •Frequency, severity and causal relationship of treatment emergent adverse events (AEs) (treatment emergent adverse events [TEAEs]) and withdrawals due to TEAEs; Day 1 up to Day 113.
•Frequency and magnitude of abnormal laboratory findings (including hematology, PT/INR, aPTT, chemistry, urinalysis, fibrinogen, anti thrombin III activity and cardiac troponin I); Day 1 up to Day 113.
•Changes from baseline in vital sign (blood pressure, pulse rate, temperature and respiration rate) measurements 12 lead electrocardiogram (ECG) parameters and physical examination; Day 1 up to Day 113.
•Frequency, severity and casual relationship of infusion and injection site reactions; Day 1 up to Day 113.

Timepoint(s) of evaluation of this end point: Timepoints are all listed in the list of primary endpoints.

Secondary Objective: •To assess the clinical efficacy of repeat dosing of PF-06741086.
•To characterize the PK profile of PF-06741086.
•To characterize the PD profile of PF-06741086.
•To characterize the immunogenicity of PF-06741086.

Main Objective: To determine the safety and tolerability of multiple doses of PF-06741086 administered to severe hemophilia A and B subjects.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Timepoints are all listed in the list of secondary endpoints.

Secondary end point(s): -Efficacy.
-Frequency and annualized rate of bleeding episodes; Day 1 up to Day 85.
-Pharmacokinetics:
•Plasma PF-06741086 concentrations (Day 1 up to Day 113) and noncompartmental parameters will be calculated as determined by a validated assay:
o Single-dose
o Day 1 to Day 7 (QW): Cmax, Tmax, AUClast, C168h
o Day 1 to Day 28 (QM): Cmax, Tmax, AUClast, C672h.
o Multiple-dose Day 29 to Day 36 (QW) or Day 29 to Day 57 (QM) Cmax,ss, Tmax,ss, AUCt, Vss (for IV administration only), CL (for IV administration only) or CL/F (for SC administration only), and Cmin.
-Pharmacodynamics
•Total TFPI; Day 1 up to Day 113.
•Thrombin generation (including lag time, peak thrombin generation and endogenous thrombin generation potential); Day 1 up to Day 113.
•Prothrombin fragment 1+2 (PF1+2); Day 1 up to Day 113.
•D-dimer; Day 1 up to Day 113.
•Dilute prothrombin time (dPT); Day 1 up to Day 113.
-Immunogenicity
•Frequency of anti drug antibody (ADA) and neutralizing antibody (NAb) production against PF-06741086; Day 1 up to Day 113. Only positive ADA samples and the corresponding baseline sample will be tested in the NAb assay.

Secondary ID(s)

2016-001885-27-PL

B7841002

Source(s) of Monetary Support

Pfizer Inc., 235 East 42nd Street, New York, NY 10017

Ethics review

Status: Approved
Approval date:
Contact: