E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060613 |
E.1.2 | Term | Hemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060614 |
E.1.2 | Term | Hemophilia B (Factor IX) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the safety and tolerability of multiple doses of PF-06741086 administered to severe hemophilia A and B subjects. |
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E.2.2 | Secondary objectives of the trial |
•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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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.Patients with an episodic (on demand) treatment regimen prior to Screening, who are 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 have 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. |
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E.4 | Principal 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. ATIII, Protein C, or Protein S deficiency, Factor V Leiden, Prothrombin 20210 mutation, or other known pro thrombotic condition
5. 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.
6. Currently receiving treatment for acute bleeding episodes with rFVIIa or activated prothrombin complex concentrate (eg Factor Eight Inhibitor Bypass Agent [FEIBA]).
7. Regular, concomitant therapy with immunomodulating drugs (eg, intravenous immunoglobulin [IVIG], and routine systemic corticosteroids).
8. 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.
9. 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.
10. Abnormal coagulation activity as defined by the following laboratory results at Screening:
• Prothrombin time (PT) > 1.25 times the ULN.
11. CD4 cell count ≤ 200 /uL.
12. Known hypersensitivity or allergic reaction to hamster protein.
13. Known sensitivity to heparin or heparin-induced thrombocytopenia.
14. 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.
15. 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.
16. 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.
17. 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.
18. Had major surgery, as judged by the investigator, within 3 months prior to the study or have elective surgery planned during the study. |
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E.5 End points |
E.5.1 | 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, ATIII 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 causal relationship of infusion and injection site reactions; Day 1 up to Day 113.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints are all listed in the list of primary endpoints. |
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E.5.2 | 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, AUCτ, 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; Day 1 up to Day 113.
•D-dimer; Day 1 up to Day 113.
•Dilute prothrombin time; 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints are all listed in the list of secondary endpoints. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Brazil |
Bulgaria |
Chile |
Croatia |
France |
Malaysia |
Poland |
South Africa |
Spain |
Switzerland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |