Study Evaluating Safety And Efficacy Of Moroctocog Alfa (AF-CC) In Previously Treated Hemophilia A Patients

Study Overview
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Brief Summary
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The study will be investigating pharmacokinetics, safety and efficacy in patients less than 12 years of age with severe hemophilia A that have been previously treated with Factor VIII products ( including blood products).

Official Title
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A Non-randomized, Open-label Study To Evaluate The Pharmacokinetics, Safety And Efficacy Of Refacto Af In Previously Treated Pediatric Subjects Less Than Twelve Years Of Age With Severe Hemophilia A (Fviii:c <1%).

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Moroctocog alfa ( AF-CC)
* Procedure: Laboratory tests


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects less than 12 years of age with a documented history of severe hemophilia A (FVIII:C less than 1%). Subjects who are less than 6 years of age must have had at least 50 Exposure Days (EDs) to prior FVIII products (including blood products). Subjects who are equal to or greater than 6 years of age must have had greater than 150 EDs to prior FVIII products (including blood products). Exclusion Criteria: For laboratory assessments, any measured Bethesda inhibitor titer equal to or greater than 0.6 BU, regardless of the laboratory normal range, or any Bethesda inhibitor titer greater than ULN for the testing laboratory at the time of screening. Any other bleeding disorder in addition to hemophilia A. Treatment with any investigational drug or device within 30 days before the time of signing the parental informed consent/assent form. Major surgery planned to occur during the course of the study. Regular (e.g., daily; every other day) use of agents or medications known to influence platelet function such as aspirin or certain nonsteroidal anti-inflammatory drugs (NSAIDS). Regular, concomitant therapy with immunomodulating drugs (e.g., intravenous immunoglobulin [IVIG], routine systemic corticosteroids), or currently receiving immune tolerance induction (ITI) for inhibitor treatment. The subject is receiving treatment for HIV or hepatitis infection (unless the subject is on a stable antiviral regimen [i.e., consistent treatment regimen for at least 3 months before the parental informed consent/assent form is signed]). Platelet count less than 100,000/µL. Prothrombin time (PT) equal to or greater than 1.25 x ULN, or international normalized ratio (INR) equal to or greater than 1.5. Known hypersensitivity to hamster protein.

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 |
| --- | --- |
| Other: Moroctocog alfa (AF-CC)<br>Open Label | Biological: Moroctocog alfa ( AF-CC)<br>* Dosing is at the discretion of the Investigator<br>* Other names: ReFacto AF;Procedure: Laboratory tests<br>* Factor VIII PK samples, Hematology, Chemistry and Coagulation testing, FactorVIII Inhibitor and Anti Factor VIII antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Significant Factor VIII Inhibitor Development | Clinically significant factor VIII (FVIII) inhibitors were defined as a central laboratory confirmed positive inhibitor of greater than or equal to (>=) 0.6 Bethesda units (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval and one of the following within 4 weeks before the initial or within 4 weeks following the second positive FVIII inhibitor sample collection: 1) the need for the participant to administer alternative hemostatic products in order to achieve sufficient efficacy, 2) >=2 events indicating a decrease in the efficacy of the study treatment. Percentage of participants who developed clinically significant Factor VIII inhibitor after study drug administration were reported. | Baseline up to Month 24 | 
| Incremental Recovery | Incremental recovery was the increase in circulating FVIII activity for every international unit (IU) of ReFacto AF administered per kilogram of body weight. It was measured in international units per deciliter (IU/dL) per international units per kilogram (IU/kg). | Days 1, 15, 50, Months 6, 18 and Final visit (up to Month 24) | 
| Terminal Elimination Half Life of ReFacto AF (t1/2) | T1/2 was the time for the plasma concentration of drug to decrease by one-half of its original concentration. | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | 
| Clearance (CL) | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Annualized Bleeding Rates (ABRs): All Participants | ABR for each participant was calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by the total therapy duration (in days), then multiplied by 365.25. ABR for the participants who reported following a primary or secondary prophylaxis, on-demand regimen or preventive regimen at baseline were reported. | Baseline up to Month 24 | 
| Response to First On-Demand Treatment for New Bleeds: All Participants | A 4-point scale of assessment of 'on-demand' treatment (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) is defined as: 1. Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered. 2. Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode;or, Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following infusion, with no additional infusion administered. 3. Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode. 4. No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens. | Baseline up to Month 24 | 
| Number of On-Demand ReFacto AF Infusions to Treat a New Bleed: All Participants | The infusion log diary case report form (CRF) was used to determine the number of on-demand (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) ReFacto AF infusions administered to treat a new bleed. This was calculated by adding the initial for a new bleed (on-demand) infusion to any subsequent (on-demand) infusions for the same previously treated bleed (same bleed with same start date/time). | Baseline up to Month 24 | 
| Number of Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of ReFacto AF: All Participants | The number of breakthrough bleeds within 48 hours following a prophylaxis dose of ReFacto AF was summarized. The infusion log diary CRF was used to determine the number of infusions administered to treat a new bleed counting only those infusions which were administered <=48 hours after an infusion marked as prophylaxis (which had no associated bleed). | Baseline up to Month 24 | 
| Average Infusion Dose of ReFacto AF: All Participants | The average infusion dose (by weight) for each participant was calculated as his total factor FVIII consumption (in IU) divided by weight (in kg) divided by the number of infusions administered in total study duration. Data was reported separately for participants classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and participants classified at baseline following a primary or secondary prophylaxis regimen. | Baseline up to Month 24 | 
| Total Factor VIII Consumption: All Participants | Total factor VIII consumption for each participant was calculated by sum of the total amount of ReFacto AF (in IU) infused for each ReFacto AF infusion (recorded in the infusion log diary CRF). Data was reported separately for participants classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and participants classified at baseline following a primary or secondary prophylaxis regimen. | Baseline up to Month 24 | 
| Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the On-Demand Setting: All Participants | LETE in on-demand setting was based on response to treatment of a bleeding episode. LETE in the on-demand setting occurred if participant recorded 2 successive no response ratings after 2 successive ReFacto AF infusions. Both infusions were to be administered at an interval of 24 hours for treatment of same bleeding event in absence of confounding factor which included: known presence or subsequent identification of a FVIII inhibitor, known inadequate dose for type and/or severity of bleed in opinion of investigator, delay of greater than 4 hours between onset of bleed to infusion, delay of greater than 24 hours before administration of a follow-up infusion, known compromised ReFacto AF, faulty administration of ReFacto AF, participant had an underlying, predisposing condition responsible for bleed in opinion of investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs),or ongoing trauma responsible for continued bleeding. | Baseline up to Month 24 | 
| Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the Prophylaxis Setting: All Participants | LETE in the prophylaxis setting occurred if there was a spontaneous bleed within 48 hours (<=48 hours) after a regularly scheduled prophylactic dose of ReFacto AF (which was not used to treat a bleed) in the absence of confounding factors. Therefore, LETE in the prophylaxis setting is the occurrence of a bleed. Confounding factors include: Known presence or subsequent identification of a FVIII inhibitor, known inadequate prophylactic dose, known lack of adherence to the prescribed prophylaxis regimen, bleed occurs in a target joint identified at the start of the study, known compromised ReFacto AF, faulty administration of ReFacto AF, an underlying, predisposing condition responsible for the bleed in the opinion of the investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs) or traumatic injury responsible for bleeding. | Baseline up to Month 24 | 
| Number of Occurrences of Less-Than-Expected-Therapeutic Effect (LETE) in the Low Recovery Setting: All Participants | LETE in the low recovery setting was defined as lower than expected recovery of FVIII (in the opinion of investigator), following the infusion of ReFacto AF in the absence of confounding factors for the low recovery. The only confounding factors for low recovery are as follows: known presence or subsequent identification of a FVIII inhibitor, known compromised ReFacto AF, faulty administration of ReFacto AF, including inadequate dosing. | Baseline up to Month 24 | 
| Number of Participants Requiring Escalated Dose of Prescribed Regimen During the Treatment Period: All Participants | Participants who met the dose escalation criteria were prescribed a higher dose and/or more frequent doses as per the investigator's discretion. | Baseline up to Month 24 | 
| Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5) |  | 0.5 hour post-dose on Day 1 | 
| Area Under the Plasma Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. It was calculated as International units*hour per milliliter (IU*hr/mL). | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | 
| Area Under the Plasma Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) | AUClast is the area under the plasma versus time curve from time zero to time of last measurable concentration (AUClast) | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | 
| Volume of Distribution at Steady State (Vss) | Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state. | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | 
| Mean Residence Time (MRT) of ReFacto AF | MRT was calculated as AUMCinf / AUCinf-TI/2, where AUMCinf is the area under the first moment curve from time zero to infinity and TI was the duration of infusion. | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Participants | An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events. | Baseline up to 30 days after last study visit (Month 25) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemophilia A