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

CSL Behring246 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

246

Conditions

Hemophilia A Severe Hemophilia A

Interventions

Eligibility

Sex: MALE

Medical Language ↔ Plain English

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

Locations (64)

Study Site 8400213

San Diego, California, United States

Study Site 8400241

Aurora, Colorado, United States

Study Site 8400118

Hartford, Connecticut, United States

Study Site 8400116

Miami, Florida, United States

Study Site 8400184

Chicago, Illinois, United States

Study Site 8400204

Outcomes

Primary Outcomes

Incidence of Inhibitor Formation to FVIII in Previously Treated Patients (PTPs) With 100 Exposure Days (EDs) to CSL627

Time frame: 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.

Time frame: 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.

Time frame: Up to 5 years

Annualized Spontaneous Bleeding Rate in PUPs

The annualized spontaneous bleeding rate for PUPs taking prophylaxis and on-demand treatment regimens.

Time frame: Up to 5 years

Secondary Outcomes

Percentage of Bleeding Episodes Treated Successfully in PTPs

Time frame: 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

Time frame: Up to 5 years

Percentage of Bleeding Episodes Requiring 1, 2, 3, or > 3 Injections of CSL627 to Achieve Hemostasis in PTPs and PUPs

Time frame: Up to 5 years

Mean Number of On-demand Infusions of CSL627

Time frame: Up to 5 years

Mean On-demand Dose Administered of CSL627

Time frame: Up to 5 years

Mean Prophylaxis Dose Administered of CSL627

Time frame: Up to 5 years

Mean Total Amount of CSL627 Administered During Surgery Period in PTPs

Time frame: Day of surgery up to 336 hours post-surgery

Total Amount of CSL627 Administered During Surgery Period in PUPs

Time frame: 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".

Time frame: 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

Time frame: Up to 5 years

Percentage of PTPs and PUPs Developing Antibodies Against CSL627

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: At the closest visit after 10 and after 50 EDs (up to 5 years)

Incidence of Total Inhibitor Formation to FVIII in PUPs

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Up to 5 years