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 demonstrate the efficacy and safety of PF-06741086 for routine prophylaxis in severe hemophilia A or moderately severe to severe hemophilia B (FVIII activity <1% or FIX activity ≤2%, respectively) participants 12 to <75 years of age with or without inhibitors |
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E.2.2 | Secondary objectives of the trial |
To evaluate additional efficacy of PF-06741086 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be male and 12 to <75 years of age with a minimum body weight of 35 kg at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants with a diagnosis of severe hemophilia A or moderately severe to severe hemophilia B (FVIII activity <1% or FIX activity ≤2%, respectively) documented by a clinical laboratory prior to Enrollment. The severity of hemophilia may be confirmed either by documented historical evidence from a clinical laboratory prior to Screening or by factor activity obtained from a clinical laboratory (which may include the central laboratory for this study) prior to Enrollment.
3. Participants who are enrolled into the Non-Inhibitor Cohort must also meet the following criteria:
• No detectable or documented history of inhibitors (≥0.6 BU/mL or greater than the upper limit of normal [ULN] for the testing laboratory) against FVIII or FIX prior to enrollment (Baseline of Observational Phase).
• Participants receiving routine prophylaxis (defined as treatment by IV injection of factor concentrate to prevent bleeding) treatment with FVIII/FIX replacement, have demonstrated at least 80% compliance with scheduled prophylaxis regimen during 6 months prior to enrollment, and willing to continue to receive routine prophylaxis treatment with FVIII/FIX replacement during the Observational Phase.
(OR)
• Participants with on-demand treatment regimen with ≥6 acute bleeding episodes (spontaneous or traumatic) that required coagulation factor infusion during the 6 months period prior to Enrollment into Observational Phase and willing to continue to receive on demand treatment during the Observational Phase. Surgical bleeding episodes do not apply to this criterion.
4. Participants who are enrolled into the Inhibitor Cohort must also meet the following criteria:
• Documentation of current high titer inhibitor (≥5 BU/mL); or current low titer inhibitor (<5 BU/mL) refractory to FVIII or FIX replacement and with FVIII or FIX recovery <60% of expected within previous 6 months prior to Enrollment into Observational Phase.
• Participants who have documented inhibitors while on factor-replacement therapy but who do not meet the quantitative inhibitor criteria described in the prior bullet at the time of Screening (eg, participant with a previously documented high-titer inhibitor (≥5 BU/mL) and whose condition precludes re-challenge with FVIII or FIX replacement) may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor.
• Hemophilia A participants with on-demand treatment regimen with ≥6 bleeding episodes or hemophilia B participants with ≥4 bleeding episodes (spontaneous or traumatic) necessitating treatment with bypass factor during the 6 months prior to Enrollment into Observational Phase and willing to continue to receive on-demand treatment during the Observational Phase. Surgical bleeding episodes do not apply to this criterion.
• Participants who meet the bleeding criteria noted above and who are on routine prophylaxis (defined as treatment by IV injection of bypass factor to prevent bleeding) and have demonstrated at least 80% compliance with scheduled prophylaxis regimen during the 6 months prior to enrollment, may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor.
Sex
5. Male
Informed Consent
6. Participant or legally authorized representative, or participant’s caregiver capable of giving signed informed consent (or minor assent, when applicable) as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol.
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Previous or current treatment for or history of coronary artery diseases, venous or arterial thrombosis (Common Terminology Criteria for Adverse Events [CTCAE] Grade >1), or ischemic disease (except for catheter associated thrombosis).
2. Known planned surgical procedure during the planned study period.
3. Known hemostatic defect other than hemophilia A or B.
4. Abnormal renal or hepatic function as defined by the following laboratory results at Screening:
a. Alanine transaminase (ALT) >2 × upper limit of normal (ULN)
b. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
c. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C -eg, presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention) is acceptable if the participant otherwise meets entry criteria
d. Serum albumin less than the lower limit of normal (LLN).
e. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (see Section 10.2.1 for formulas used in eGFR calculation).
5. Abnormal hematology values as defined by the following laboratory tests at Screening:
a. Platelet count <100,000/uL
b. Hemoglobin level <10 g/dL
6. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior 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 participant inappropriate for entry into this study.
7. QTcF >450 msec for male participants or QTcF >480 msec in participants with bundle branch block.
8. Individuals with hypersensitivity or an allergic reaction to hamster protein or other components of the study intervention.
Prior/Concomitant Therapy
9. Current routine prophylaxis with bypassing agent (eg, aPCC, BYCLOT, Prothrombin Complex Concentrates [PCC], or rFVIIa), non-coagulation non-factor replacement therapy (eg, emicizumab), or any previous treatment with a gene therapy product for treatment of hemophilia.
• Participants with inhibitors who are being treated using a prophylaxis treatment regimen with a bypass agent will be considered on a case-by-case basis, only after discussion and agreement between the investigator and the Pfizer medical monitor.
• Participants who have previously received non-factor-based hemophilia therapy (eg, fitusiran, concizumab, emicizumab) will be considered on a case-by-case basis, only after discussion and agreement between the investigator and the Pfizer medical monitor.
10. Regular, concomitant therapy with immunomodulatory drugs (eg, IV immunoglobulin [IVIG], and routine systemic corticosteroids, rituximab).
11. Ongoing or planned use of immune tolerance induction during the Observational Phase or Active Treatment Phase, or prophylaxis with FVIII or FIX replacement at any time after initiation of treatment with study intervention during the Active Treatment Phase
12. Participation in other studies involving investigational drug(s) or investigational vaccine(s) within 30 days (or as determined by local requirements) or 5 half-lives prior to study entry or during study participation.
13. Previous exposure to PF 06741086 during to participation in Studies B7841002 and B7841003.
Diagnostic assessments
14. CD4 cell count ≤200/uL if human immunodeficiency virus (HIV)-positive
15. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
Other Exclusions
16. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or participants who are Pfizer employees, including their family members, directly involved in the conduct of the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
The primary efficacy endpoint is the annualized bleeding rate (ABR) of treated bleeding events, which is derived for each participant for each treatment period by using the following formula: ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25). The statistical objective and strategy of demonstrating the efficacy in each cohort is shown below.
Inhibitor Cohort (participants with prior on-demand therapy):
In all regions, to demonstrate superiority in ABR of PF-06741086 prophylaxis observed over the 12-month Active Treatment Phase versus on demand treatment with bypass therapy during the 6 months prior to receiving study intervention.
Non-Inhibitor Cohort:
For regions outside of the EU, superiority in ABR of PF-06741086 prophylaxis observed over the 12-month Active Treatment Phase versus on-demand treatment with FVIII- or FIX- replacement during the Observational Phase prior to receiving study intervention (note this is a secondary endpoint for the EU).
For the EU, non-inferiority in ABR of PF-06741086 prophylaxis observed over the 12-month Active Treatment Phase versus prophylaxis treatment with FVIII- or FIX-replacement during the Observational Phase prior to receiving study intervention (note this is a secondary endpoint for regions outside the EU).
Safety Endpoints
Type I error control would not be applied to the following safety endpoints:
Adverse events (AEs) and Serious Adverse Events (SAEs)
Incidence and severity of thrombotic events
Incidence and severity of thrombotic microangiopathy
Disseminated intravascular coagulation/consumption coagulopathy
Immunogenicity (incidence of antidrug antibody [ADA] and clinically significantly persistent neutralizing antibody [NAb] against PF-06741086)
Incidence and severity of injection site reaction
Changes in physical examination and vital signs
Incidence of clinically significant laboratory value abnormalities
Incidence of severe hypersensitivity and anaphylactic reactions
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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) |
For the Non-Inhibitor Cohort, the primary endpoint with respect to comparisons with prior on-demand therapy for regions outside EU will be a secondary endpoint for the EU. Likewise, the primary endpoint with respect to comparisons with prior prophylaxis therapy for the EU will be a secondary endpoint for the regions outside EU.
The following parameters will be assessed for comparison between PF-06741086 prophylaxis observed over the 12-month Active Treatment Phase versus a respective control group corresponding to each of the 3 statistical objectives (inhibitors [participants with prior on-demand therapy], non-inhibitors [with prior on-demand therapy], and non-inhibitors [with prior prophylaxis therapy]).
Total coagulation factor or bypass product consumption
Incidence of joint bleeds
Incidence of spontaneous bleeds
Incidence of target joint bleeds
Incidence of total bleeds (treated and untreated).
Percentage of participants with no bleeding episodes
Change in joints as measured by the Hemophilia Joint Health Score (HJHS)
• HRQoL:
• Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) (≥17 years of age)/Hemophilia Quality of Life Questionnaire for Children (Haemo-QoL); (Adolescents 12 to <17 years of age);
• Hemophilia Activities List (HAL) (Adult ≥17 years of age)/Pediatric Hemophilia Activities List (pedHAL) (Adolescents 12 to <17 years of age);
• Patient Global Impression of Change – Hemophilia (PGIC-H) (Observational Phase and Active Treatment Phase)
• Health Utilities Measure (EuroQol 5 Dimensions 5 Level [EQ-5D-5L])
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints are all listed in the list of primary 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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Standard of Care for Hemophilia A or B |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Australia |
Hong Kong |
Mexico |
Oman |
Saudi Arabia |
Serbia |
Turkey |
Brazil |
Bulgaria |
Canada |
China |
Croatia |
Germany |
India |
Ireland |
Italy |
Japan |
Korea, Republic of |
Russian Federation |
Spain |
Switzerland |
Taiwan |
United Kingdom |
United States |
France |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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A participant is considered to have completed the study if he has completed all phases of the study including the Day 390 Follow-up phone call during the Active Treatment Phase.
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule of Activities for the last participant in the trial globally. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 16 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 14 |