Study Evaluating Safety Of Patients Switching To ReFacto AF In Usual Care Settings

A Postauthorization Safety Surveillance Study Of Patients Switching To ReFacto AF From ReFacto Or Other Factor VIII Products In Usual Care Settings

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00884390

Enrollment

208

Registered

2009-04-20

Start date

2009-05-31

Completion date

2013-03-31

Last updated

2014-09-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hemophilia A

Keywords

Hemophilia A

Brief summary

The study will be investigating safety in patients who switch to ReFacto AF from ReFacto and other Factor VIII products.

Detailed description

The trial was terminated prematurely on 28 March 2013, due to the inability to recruit the planned number of subjects. The decision to terminate the trial was not based on any safety or efficacy concerns and agreement to close the study in March 2013 was agreed with EMA prior to closure activity.

Interventions

DRUGmoroctocog alfa (AF-CC) (ReFacto AF)

Providing moroctocog alfa (AF-CC) as test article for use during this study.

PROCEDURELaboratory tests

Laboratory samples are collected during study visits, in order to collect safety and efficacy data related to the administration of test article.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

12 Years to No maximum

Healthy volunteers

Inclusion criteria

* Male patients greater than or equal to 12 years of age with severe hemophilia A (FVIII:C less than 1%). * Treatment history of greater than 150 EDs to prior recombinant or plasma-derived FVIII replacement products. * Transitioning to ReFacto AF from ReFacto or other recombinant or plasma-derived FVIII replacement products. * Serum albumin greater than or equal to the lower limit of normal (LLN). * Platelet count greater than or equal to 100,000/µL. * Prothrombin time (PT) less than or equal to1.25 × ULN, or international normalized ratio (INR) less than or equal to 1.5. * HIV positive subjects must have a CD4 count greater than 200/µL and HIV viral load less than 200 particles/µL.

Exclusion criteria

* Presence of any bleeding disorder in addition to hemophilia A. * A positive FVIII inhibitor, according to the local laboratory, at screening; or any Bethesda Inhibitor Titer greater than 0.6, regardless of the normal range for the testing laboratory. * Treated with immunomodulatory therapy (including Immune Tolerance Induction \[ITI\]) during the screening period. * Prior exposure to moroctocog alfa (AF-CC). * Known hypersensitivity to hamster protein.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Clinically Significant Factor VIII Inhibitor Development	100 exposure days to study medication (approx. 2 years)	Number of participants with clinically significant FVIII inhibitor development after switching from ReFacto to moroctocog alfa (AF-CC). Clinically significant inhibitors are defined as a central laboratory confirmed positive inhibitor (≥ 0.6 Bethesda unit (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval) and within 28 days before the initial or within 28 days following the second positive FVIII inhibitor sample collection one of the following: the need for the participant to administer alternative hemostatic products in order to achieve sufficient efficacy, or ≥2 adverse event reports of decreased drug effect (or other adverse event indicating a decrease in the efficacy of the test article). The blood sample collection for these results must also be between the date of first dose of study medication and 28 days after the last dose of study medication.

Secondary

Measure	Time frame	Description
Response Assessment of First On-demand Treatment of New Bleeds	100 exposure days to study medication (approx. 2 years)	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: * Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered. * 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 the infusion, with no additional infusion administered. * 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. * No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens.
Number of ReFacto AF Infusions to Treat Each New Bleed	100 exposure days to study medication (approx. 2 years)	The Infusion Log Diary case report form (CRF) was used to determine the number of test article infusions administered to treat a bleed. This was calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) infusions for the same bleed (same bleed start date/time).
Number of Bleeding Episodes Occurring ≤48 Hours After a Prophylaxis Infusion	100 exposure days to study medication (approx. 2 years)	First, the bleed start time from the Infusion Log Diary CRF was used to determine the number of breakthrough bleeds that occurred ≤48 hours after an infusion marked as Prophylaxis (which had no associated bleed). If there was more than 1 bleed location (ie, ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. If a response was given, or if a bleed time was given, but On Demand was not listed as treatment type, it was still counted as an on-demand bleed for analyses/summaries. Bleeding episodes were not categorized as spontaneous (atraumatic) or traumatic.
Number of Participants With Breakthrough Bleeds	100 exposure days to study medication (approx. 2 years)	The number of participants with any breakthrough bleed was reported.
Annualized Bleeding Rates (ABRs)	100 exposure days to study medication (approx. 2 years)	An ABR for each participant will be calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by his total therapy duration (in days), then multiplied by 365.25.
TFC Following a Prophylaxis Regimen at Baseline for All Participants	100 exposure days to study medication (approx. 2 years)	The total amount (in IU) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each participant.
Average Infusion Dose	100 exposure days to study medication (approx. 2 years)	The average infusion dose for each participant was calculated as his total factor consumption (in IU) divided by the number of infusions administered. Summary statistics were reported for both of these variables separately for those participants classified at baseline as following an on-demand regimen, and for those on a primary or secondary prophylaxis regimen.
Incidence of Less-than-expected-therapeutic Effect (LETE) in the On-demand Setting	100 exposure days to study medication (approx. 2 years)	The calculation of incidence of on-demand LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the On Demand LETE CRF), and the denominator was the number of bleeding episodes treated in an on-demand setting. This denominator could include new bleeding episodes in prophylaxis participants breakthrough bleeds), and if subsequent on-demand doses for such a bleed met the on-demand LETE criteria, then an on-demand LETE was reported.
Incidence of Less-than-expected-therapeutic Effect (LETE) in the Prophylaxis Setting	100 exposure days to study medication (approx. 2 years)	The calculation of incidence of prophylaxis LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the Prophylactic LETE CRF), and the denominator was the number of routine prophylaxis infusions. Each infusion was classified in the infusion log (Prophylaxis/ On Demand/ Preventive), and participants were instructed to select On Demand if the infusion was to treat a bleed, even if the participant typically followed a prophylaxis regimen. Only the infusions classified as Prophylaxis were counted in this denominator.
Total Factor Consumption (TFC) Following a Non-prophylaxis Regimen at Baseline for All Participants	100 exposure days to study medication (approx. 2 years)	The total amount (in International Units \[IU\]) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each participant.

Countries

Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Netherlands, Romania, Spain, Sweden, United Kingdom

Participant flow

Recruitment details

Two hundred and eight (208) participants were enrolled into the study (146 participants into the ReFacto Switch group \[Cohort 1: participants who switched from ReFacto to ReFacto AF\] and 62 participants into the Other Switch group \[Cohort 2: participants who switched from other Factor VIII (FVIII) products other than ReFacto to ReFacto AF\]).

Participants by arm

Arm	Count
ReFacto Switch Participants who switched from ReFacto to ReFacto AF	146
Other Switch Participants who switched from other FVIII products other than ReFacto to ReFacto AF	62
Total	208

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1
Overall Study	Discontinuation of Study by Sponsor	2	2
Overall Study	Lost to Follow-up	0	1
Overall Study	Other	11	1
Overall Study	Physician Decision	2	1
Overall Study	Protocol Violation	4	1
Overall Study	Withdrawal by Subject	4	1

Baseline characteristics

Characteristic	ReFacto Switch	Other Switch	Total
Age, Customized 12-17 years	33 participants	9 participants	42 participants
Age, Customized 18-65 years	113 participants	53 participants	166 participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	146 Participants	62 Participants	208 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	90 / 208
serious Total, serious adverse events	20 / 208

Outcome results

Primary

Number of Participants With Clinically Significant Factor VIII Inhibitor Development

Number of participants with clinically significant FVIII inhibitor development after switching from ReFacto to moroctocog alfa (AF-CC). Clinically significant inhibitors are defined as a central laboratory confirmed positive inhibitor (≥ 0.6 Bethesda unit (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval) and within 28 days before the initial or within 28 days following the second positive FVIII inhibitor sample collection one of the following: the need for the participant to administer alternative hemostatic products in order to achieve sufficient efficacy, or ≥2 adverse event reports of decreased drug effect (or other adverse event indicating a decrease in the efficacy of the test article). The blood sample collection for these results must also be between the date of first dose of study medication and 28 days after the last dose of study medication.