An Open-label Safety and Efficacy Study of Recombinant FVIII in Patients With Severe Hemophilia A

Study Overview
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Brief Summary
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This multicenter, open-label, phase 3 extension study will investigate the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in at least 200 previously treated patients (PTPs) with severe congenital hemophilia A and previous exposure to FVIII products who achieve at least 100 exposure days (EDs) to rVIII-SingleChain in this study, as well as in previously untreated patients (PUPs) with no previous exposure to any FVIII product who achieve at least 50 EDs to rVIII-SingleChain in this study. A substudy (open to both PTPs and PUPs) will investigate the use of rVIII-SingleChain in surgery. A substudy (open to PUPs who develop an inhibitor to rVIII-SingleChain) will investigate the use of rVIII-SingleChain in immune tolerance induction (ITI) therapy.

Official Title
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A Phase III Open Label, Multicenter, Extension Study to Assess the Safety and Efficacy of Recombinant Coagulation Factor VIII (rVIII-SingleChain, CSL627) in Subjects With Severe Hemophilia A

Conditions
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Hemophilia A, Severe Hemophilia A

Intervention / Treatment
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* Biological: rVIII-SingleChain


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PTPs: Males of any age who have been diagnosed with severe congenital hemophilia A (FVIII activity levels < 1%) and who participated in a previous CSL-sponsored clinical study with rVIII-SingleChain. Males 0 to <65 years age who have been diagnosed with severe congenital hemophilia A (FVIII activity levels < 1%), who have at least 50 EDs to any FVIII product, and who are not currently enrolled in a CSL-sponsored clinical study with rVIII-SingleChain. PUPs: Males 0 to <18 years of who have been diagnosed with severe congenital hemophilia A (FVIII activity levels < 1%) No prior exposure to any Factor VIII product (with the exception of short-term use of blood products). ITI substudy: PUPs who have developed a confirmed inhibitor to rVIII-SingleChain in the main study. Exclusion Criteria: Known or suspected hypersensitivity to rVIII-SingleChain or to any excipients of rVIII-SingleChain or Chinese hamster ovary (CHO) proteins. Currently receiving a therapy not permitted during the study. Serum creatinine > 2 x upper limit of normal, alanine aminotransferase or aspartate aminotransferase > 5 x upper limit of normal at Screening (if specified) Any first-order family (eg, siblings) history of FVIII inhibitors For PTPs not rolling over directly from a CSL-sponsored clinical study with rVIII-SingleChain: any history of or current FVIII inhibitors
Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Previously treated patients (PTPs)<br>The investigator will assign subjects to either prophylaxis or on-demand treatment regimens for rVIII-SingleChain by intravenous injection. The investigator will determine the rVIII-SingleChain dose and dosing schedule for the subject based upon the subject's pharmacokinetic (PK) profile, rVIII-SingleChain PK data, previous FVIII treatment regimen, and bleeding phenotype, if available. | Biological: rVIII-SingleChain<br>* Recombinant single-chain coagulation factor VIII<br>* Other names: CSL627;|
| Experimental: Previously untreated patients (PUPs)<br>The investigator will assign subjects to either prophylaxis or on-demand treatment regimens for rVIII-SingleChain by intravenous injection. The investigator will determine the rVIII-SingleChain dose and dosing schedule at their discretion, taking into consideration the World Federation of Hemophilia (WFH) guidelines, the type of bleeding episode, location of the bleeding, subject's age, and other disease characteristics. | Biological: rVIII-SingleChain<br>* Recombinant single-chain coagulation factor VIII<br>* Other names: CSL627;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Inhibitor Formation to FVIII in Previously Treated Patients (PTPs) With 100 Exposure Days (EDs) to CSL627 |  | At the closest visit after 100 EDs (up to 5 years). | 
| Number of Previously Untreated Patients (PUPs) With High-titer Inhibitor Formation to FVIII With at Least 50 EDs to CSL627 | High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL. | At the closest visit after 50 EDs (up to 5 years). | 
| Percent Treatment Success for Major Bleeding Episodes in PUPs | Percentage of major bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of excellent or good on the investigator's clinical assessment of hemostatic efficacy 4-point scale excellent, good, moderate or poor/no response. Major bleeding episodes are defined as bleeding episodes for which a subject is required to seek treatment at the hemophilia center or that threatens the subject's life or loss of limb. | Up to 5 years | 
| Annualized Spontaneous Bleeding Rate in PUPs | The annualized spontaneous bleeding rate for PUPs taking prophylaxis and on-demand treatment regimens. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Bleeding Episodes Treated Successfully in PTPs | Percentage of bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of excellent or good on the investigator's clinical assessment of hemostatic efficacy 4-point scale excellent, good, moderate or poor/no response. | Up to 5 years | 
| Annualized Bleeding Rate in PTPs and PUPs | The annualized bleeding rate for PTPs and PUPs taking prophylaxis and on-demand treatment regimens | Up to 5 years | 
| Percentage of Bleeding Episodes Requiring 1, 2, 3, or > 3 Injections of CSL627 to Achieve Hemostasis in PTPs and PUPs |  | Up to 5 years | 
| Mean Number of On-demand Infusions of CSL627 |  | Up to 5 years | 
| Mean On-demand Dose Administered of CSL627 |  | Up to 5 years | 
| Mean Prophylaxis Dose Administered of CSL627 |  | Up to 5 years | 
| Mean Total Amount of CSL627 Administered During Surgery Period in PTPs |  | Day of surgery up to 336 hours post-surgery | 
| Total Amount of CSL627 Administered During Surgery Period in PUPs |  | Day of surgery up to 336 hours post-surgery | 
| Hemostatic Efficacy of rVIII-SingleChain for PTPs and PUPs Who Undergo Surgery | The investigator will rate the efficacy of the rVIII-SingleChain treatment during surgery based on a hemostatic efficacy four point rating scale of excellent, good, moderate or poor/no response. | From the start of surgery through the post-operative recovery (generally up to 14 days after surgery) | 
| Incidence of Inhibitor Formation to FVIII in PTPs After 10 EDs and After 50 EDs |  | Up to 5 years | 
| Percentage of PTPs and PUPs Developing Antibodies Against CSL627 |  | PTPs: At the closest visit after 100 EDs (up to 5 years). PUPs: At the closest visit after 50 EDs (up to 5 years). | 
| Percentage of PTPs and PUPs Developing Antibodies to Chinese Hamster Ovary (CHO) Proteins |  | PTPs: At the closest visit after 100 EDs (up to 5 years). PUPs: At the closest visit after 50 EDs (up to 5 years). | 
| Number of PUPs With High-titer Inhibitor Formation to FVIII After 10 EDs With CSL627 | High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL. | At the closest visit after 10 EDs (up to 5 years) | 
| Number of PUPs With Low-titer Inhibitor Formation to FVIII After 10 EDs and After 50 EDs With CSL627 | Low-titer inhibitor is defined as an inhibitor titer of less than 5 Bethesda units/mL. | At the closest visit after 10 and after 50 EDs (up to 5 years) | 
| Incidence of Total Inhibitor Formation to FVIII in PUPs |  | Up to 5 years | 
| Percent Treatment Success for Non-major Bleeding Episodes in PUPs | Percentage of bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of excellent or good on the investigator's clinical assessment of hemostatic efficacy 4-point scale excellent, good, moderate or poor/no response. Non-major bleeding episodes are those not requiring treatment at the hemophilia center or not threatening subject's life or loss of limb. | Up to 5 years | 
| Percentage of PUPs With Clinically Significant Abnormal Vital Signs Values After First Infusion of CSL627 | Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator. | Up to 6 hours after first infusion | 
| Percentage of PUPs With Treatment-emergent Clinically Significant Abnormal Vital Signs Values | Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator. | Up to 5 years |