The primary objective is to evaluate the safety of ReFacto AF in previously untreated patients (no prior exposure to factor products or any blood products) of less than 6 years of age.
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary safety outcome measure will be the proportion of subjects who
develop clinically significant FVIII inhibitors during the course of the
study. Clinically significant inhibitors are defined as a central laboratory
confirmed positive inhibitor (* 0.6 BU using the Nijmegen modification of the
Bethesda assay present at 2 consecutive blood draws within a 4-week interval)
and the occurrence of one or more of the following clinical observations:
decreased FVIII recovery, need for alternative hemostatic products, increase in
number of breakthrough bleeds while on preventive or prophylactic treatment, or
more than one report of Less Than Expected Therapeutic Effect (LETE) in the
absence of confounding factors. Mandatory laboratory assessments to screen for
FVIII inhibitor will be performed at the 10-15 ED, and 50 ED visits. Laboratory
assessments for inhibitors are strongly recommended, but are at the discretion
of the investigator at the subsequent 6-Month Interval visits through the Final
Visit. It is recommended that the investigator obtain serial follow-up
inhibitor testing for any subject with a FVIII inhibitor result * 0.6 BU until
the result is < 0.6 BU or the subject reaches the Final Visit. After the
Final Visit, it is recommended that the investigator continue to follow
subjects with ongoing inhibitors until the inhibitor resolves or stabilizes. A
central laboratory Nijmegen modification of the Bethesda assay will confirm
local positive inhibitor assays. Factor VIII ELISA antibody testing will also
be performed by the central laboratory to correlate with positive inhibitor
test results.
The efficacy endpoints include annualized bleeding rates (ABRs) in patients
receiving treatment with Refacto AF, the responses to the first on-demand
treatment with Refacto AF for all new bleeds (4-point scale of assessment) as
assessed by the parent/legal representative, the number of Refacto AF infusions
to treat each new bleed, the number of breakthrough (spontaneous/non-traumatic)
bleeds within 48 hours of a preventive/prophylaxis dose of Refacto AF, the
average infusion dose and total factor consumption, and the incidence of
less-than-expected therapeutic effect (LETE). All subjective assessments will
be provided by the parent/legal representative.
Secondary outcome
Secondary safety outcome measures are the incidence of SAEs and nonserious
AEs. Subject withdrawal for safety reasons will be at the discretion of the
investigator and treating physicians.
Background summary
Hemophilia A is an X-linked recessive disease in which clotting factor VIII
(FVIII) is deficient or inactive. Patients with a low level of FVIII have an
increased tendency to bleed. When the levels of FVIII are very low (<1% of
normal), frequent spontaneous bleeding episodes may occur. Infusing patients
with a concentrated formulation of the missing FVIII protein can control the
bleeding. Until the late 1980s such concentrates were produced exclusively from
human plasma. However, several side effects were seen with these plasma-derived
products, such as the transmission of viral diseases, especially human
immunodeficiency virus (HIV). Rapidly evolving recombinant DNA technology has
enabled the development of several recombinant coagulation products, including
ReFacto. Moroctocog alfa (AF-CC) with the trade name ReFacto AF represents the
next generation of ReFacto that improves theoretical viral safety following
several enhancements, including the removal of albumin from the ReFacto
manufacturing process.
Newborns, infants and very young children with severe hemophilia A typically
require FVIII replacement treatments early in life for various bleeding events,
preventive infusions, or prophylaxis. Historically, it is well-known that
young children, especially those naïve to FVIII, are at greater risk for
developing neutralizing antibodies (inhibitors) and may have altered responses
to replacement therapy than older subjects with hemophilia A. While factors
such as clinical severity, genetic mutations, exposure intensity, and inherent
immunoresponse heterogeneity may be risk factors for such safety issues, it is
also important to ensure that these are not specifically related to different
FVIII replacement products. Since the clinical trials that support approval of
hemophilia treatments are based on limited numbers of subjects, including
children, it is important to continue to characterize product safety in the
pediatric patient population. Thus, previously untreated patients (PUPs)
represent a group of interest as they are at higher risk for inhibitor
development and may have altered response to therapy. Previous studies of
ReFacto AF suggest that subjects less than 12 years of age with hemophilia A
may respond differently to FVIII therapy compared to older subjects with this
disorder. One potential explanation for altered response may be the presence
of sub-clinical inhibitory antibodies, a phenomenon seen with replacement
infusions of therapeutic proteins. Biotechnology-derived proteins, such as
recombinant clotting factor concentrates, may induce humoral immune responses
(antibodies) in patients exposed to these products because the immune system
may recognize these proteins as non-self-immunogens. In order to expand the
safety profile for pediatric patients obtained through the clinical safety and
efficacy trials used for regulatory approval of these products, additional
safety studies are conducted so as to have the opportunity to obtain additional
data on such humoral immune responses or other adverse events that may not be
fully appreciated until larger numbers of pediatric patients are exposed.
Moreover, risk factors for such responses may be host specific, product
specific, or related to route or duration of exposure. A series of recently
completed clinical trials have confirmed that the risk of developing
neutralizing antibodies (inhibitors) to moroctocog alfa (AF-CC) is comparable
to that observed with its predecessor product ReFacto and is no greater than
that seen with other recombinant FVIII products. To fulfill an EMEA requirement
for postauthorization safety surveillance and risk management and to ensure
that ReFacto AF has an acceptable rate of inhibitor development, this study
will also monitor development of clinically significant and
laboratory-confirmed inhibitors in a population of patients with hemophilia A,
that after consultation with their physician, choose to be treated with ReFacto
AF independent of this study. Patients will be monitored in the usual care
setting while following treatment practice recommendations of their prescribing
physician. All male patients < 6 years of age with severe hemophilia A (FVIII:C
<1%) based on clinical records, including newborns will be eligible to enroll.
Study objective
The primary objective is to evaluate the safety of ReFacto AF in previously
untreated patients (no prior exposure to factor products or any blood products)
of less than 6 years of age.
Study design
This nonrandomized, prospective, open-label, study will be conducted in major
hemophilia treatment centers in Europe and other countries. The study will
capture clinical and laboratory observations based on EMEA guidance for
evaluating recombinant FVIII replacement product safety. For the purpose of
this protocol, a previously untreated patient participating in this study will
be referred to as a Subject. This study will enroll subjects who have not
received any factor products or blood products for their hemophilia A. The
subjects will be treated with intravenous infusions of ReFacto AF at a dose and
frequency prescribed by the subjects* treating physician. Factor consumption,
infusion days, treatment regimen, factor dose, purpose of infusion, type of
bleed, location of bleed, and response of bleed to treatment, will be
ascertained using an infusion log maintained by a parent/legal representative.
The parent/legal representative will also complete a 4-point rating scale for
efficacy of infusions. All subjects will be followed for at least 50 exposure
days (EDs) and participation may conclude after the subjects have achieved 100
EDs, or have participated in the study for approximately 26 months, whichever
occurs first.
Intervention
An infusion diary should be maintained for the infusions of ReFacto AF.
Furthermore the subjects will be questionned by the investigator for detection
of adverse events and will be examined. Blood will be withdrawn, they will
receive ReFacto AF and 30 minutes later a second blood sample will be
withdrawn. A physical examination will be conducted and the vital functions
will be determined.
Study burden and risks
In comparison with the standard of care the patient will visit the hospital
more often and blood will be withdrawn more often. Directly before and 30
minutes after dosing blood will be withdrawn to measure the factor VIII
activity in plasma (FVIII:C). These blood samples will be taken via an
venapunction in the arm contralateral to the infusion arm.
The risks are not different from the standard of care.
Arcola Road 500
Collegeville 19426
US
Arcola Road 500
Collegeville 19426
US
Listed location countries
Age
Inclusion criteria
1) Male subjects <6 years of age with severe hemophilia A (FVIII:C <1%) based on clinical records, including newborns.;2) No prior exposure to factor products or any blood products.
Exclusion criteria
1) Presence of any bleeding disorder in addition to hemophilia A.;2) Treatment with any investigational agent or device within the past 30 days.;3) Any condition(s) that compromises the ability to collect study-related observations, or that poses a contraindication to study participation (these conditions include, but are not limited to, inadequate medical history to assure study eligibility; and expectation of poor adherence to study requirements).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-008436-93-NL |
| ClinicalTrials.gov | NCT00950170 |
| CCMO | NL29918.072.11 |