Pharmacokinetic, Efficacy, and Safety Study of Recombinant Factor VIII Single Chain (rVIII-SingleChain) in Children With Severe Hemophilia A

Study Overview
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Brief Summary
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This is an international, multicenter, open-label study to assess the efficacy, safety, and pharmacokinetic (PK) profile of rVIII-SingleChain in pediatric patients with severe hemophilia A. A minimum of 25 previously treated subjects ≥ 6 to < 12 years of age and at least 25 subjects < 6 years of age who have undergone > 50 exposure days (EDs) with a previous Factor VIII (FVIII) product are planned to be enrolled. Subjects will be assigned to either an on-demand or prophylaxis treatment regimen and will receive rVIII-SingleChain at a dose to be determined by the investigator. Hemostatic efficacy will be assessed by the subject/caregiver and the investigator who will assess overall efficacy by a 4-point scale.

Official Title
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A Phase III Open-label Pharmacokinetic, Efficacy and Safety Study of rVIII-SingleChain in a Pediatric Population With Severe Hemophilia A

Conditions
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Congenital 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: Diagnosis of severe hemophilia A defined as < 1% Factor VIII (FVIII) concentration (FVIII:C) documented in medical records, Males < 12 years of age, Subjects who have received > 50 EDs with a FVIII product, Prior PK data (at least incremental recovery and half-life) from previous FVIII exposure for subjects participating in the PK part Investigator believes that the subject is willing and able to adhere to all protocol requirements. Investigator believes that the subject's parent(s) or legally acceptable representative(s) is / are willing and able to adhere to all protocol requirements. Exclusion Criteria: Any history of or current FVIII inhibitors Use of an Investigational Medical Product (IMP) within 30 days prior to the first rVIII-SingleChain administration, Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rVIII-SingleChain, Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment, Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values >5 times (x) the upper limit of normal (ULN) at Screening, Subjects with serum creatinine values >2 x ULN at Screening, Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months before Day 1, Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months before rVIII-SingleChain administration.

Ages Eligible for Study
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Maximum Age: 11 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rVIII-SingleChain<br>Subjects will be assigned to either an on-demand or prophylaxis regimen and will receive rVIII-SingleChain as an intravenous (IV) infusion. Subjects assigned to a prophylaxis regimen will be treated with 15 to 50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator's discretion, based on available PK data, the FVIII treatment regimen used before enrollment and/or the subject's bleeding phenotype. The dose for on-demand treatment of a bleeding episode is based on the recommendations of the World Federation of Hemophilia (WFH), with a minimum dose of 15 IU/kg. All subjects were to be treated for a minimum of 50 EDs. For the PK evaluation, the subjects will receive a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period. | Biological: rVIII-SingleChain<br> <br> * Other names: CSL627;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Success | Rate of treatment success where treatment success of a bleeding episode is defined as a rating of excellent or good based on the investigator's overall clinical assessment of hemostatic efficacy (using a 4-point scale of excellent, good, moderate or poor/no response) on the on-demand and prophylaxis regimens combined. The rate of success was based on the number of treated bleeding events; there were 347 treated bleeding events in the Efficacy Population. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleeding Rate | The annualized bleeding rate was defined as the number of bleeding episodes requiring treatment divided by the efficacy evaluation period in days, x 365.25, and is presented separately for the on-demand regimen and the prophylaxis regimens. | Up to 1 year | 
| Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis. |  | Up to 1 year | 
| Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month |  | Up to 1 year | 
| Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year |  | Up to 1 year | 
| Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event |  | Up to 1 year | 
| Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month |  | Up to 1 year | 
| Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year |  | Up to 1 year | 
| Incremental Recovery | Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay. | At 1 hour after the start of infusion | 
| Half-life (t1/2) of rVIII-SingleChain | Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay. | Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing. | 
| Area Under the Concentration Curve (AUC) | AUC to the last sample with quantifiable drug concentration (AUC0-t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay. | Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing. | 
| Clearance (Cl) of rVIII-SingleChain | Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay. | Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing. | 
| Number of Subjects With Inhibitor Formation to rVIII-SingleChain | The number of subjects who develop inhibitors to rVIII-SingleChain, defined as a rVIII-SingleChain antibody titer of at least 0.6 Bethesda Units (BU) per mL after receiving study drug. | At screening, then after dosing at approximately monthly intervals for 6 months, then every 3 months until reaching 50 EDs, and at the end of study visit (up to approximately 12 months). |