This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of emicizumab in patients of all ages with mild (FVIII level between > 5% and < 40%) or moderate hemophilia A (FVIII level between >= 1% and
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety endpoints:
• Incidence and severity of adverse events, with severity determined according
to WHO Toxicity Grading Scale
• Incidence of thromboembolic events
• Incidence of thrombotic microangiopathy (TMA)
• Change from baseline in physical examination findings
• Change from baseline in and vital signs
• Change from baseline in ECG parameters
• Incidence of laboratory abnormalities
• Incidence and severity of injection-site reactions
• Incidence of adverse events leading to drug discontinuation
• Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events
• Incidence and significance of anti-emicizumab antibodies
• Incidence of de novo development of FVIII inhibitors
Efficacy endpoints:
• Number of treated bleeds over time (i.e., bleed rate)
Secondary outcome
Secondary Efficacy endpoints:
• Number of all bleeds (i.e., those treated and untreated with FVIII) over time
• Number of joint bleeds over time
• Number of target joint bleeds over time (target joints are defined as joints
with
• 3 bleeds occurring in the same joint during the last 24 weeks)
• Number of spontaneous bleeds over time (spontaneous bleed rate)
• Joint health, as assessed through use of the Hemophilia Joint Health Score
(HJHS) at specified timepoints
• Health-related quality of life (HRQoL), as assessed through use of the
Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH) Questionnaire
over time
• Preference for emicizumab compared with previous FVIII regimen, as assessed
through use of the Emicizumab Preference Survey (EmiPref) at Week 17
• Effect of emicizumab prophylaxis treatment on physical activity compared with
physical activity at baseline
PK endpoint:
• Plasma concentration of emicizumab at specified timepoints
Immunogenicity endpoints:
• Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs
during the study
• Number and proportion of patients who develop anti-FVIII inhibitors (titer >=
0.6 BU/mL) at specified timepoints
Biomarkers:
The exploratory biomarker objective for this study is to investigate the effect
of emicizumab on PD parameters, including but not limited to thrombin
generation, FVIII activity, FVIII protein, D-dimer, and prothrombin fragment
1+2 (PF1+2) at regular intervals throughout the study and at times of treated
bleeds. Changes over time in biomarkers related to bone and joint health may
also be explored.
Health Status Utility Endpoint:
• Change from baseline in EuroQol 5-Dimension 5-level Questionnaire (EQ-5D
index utility and visual analog scale (VAS) scores at specified timepoints
Background summary
Hemophilia A is bleeding disorder that occurs in approximately 1 in 5000 live
male births. Patients with hemophilia A have a deficiency or absence of blood
coagulation factor VIII (FVIII), an essential component of the intrinsic
pathway in the coagulation cascade.
The absence or functional deficiency of FVIII leads to a lifelong bleeding
tendency. Common clinical signs of hemophilia A include easy bruising;
prolonged bleeding after trauma or surgery; spontaneous bleeding into joints,
muscles, or soft tissues; and intracranial hemorrhage. The severity of the
disease roughly correlates with the residual endogenous level of FVIII activity.
Whereas patients with mild and moderate disease generally report a
significantly lower number of joint bleeds compared with those with severe
hemophilia, there are patients with non-severe disease who present with
recurrent articular bleeds.
In patients who experience multiple spontaneous bleeds (regardless of their
specific FVIII level), a prophylactic approach is beneficial as it will prevent
the occurrence of bleeds and their consequences. Given the clinically
meaningful efficacy of emicizumab in the prevention of bleeds and the major
benefit it offers over available agents, emicizumab is considered an
appropriate option in the medical armamentarium for individuals with non-severe
hemophilia A who require prophylaxis.
This study will evaluate the safety, efficacy, pharmacokinetics, and
pharmacodynamics of emicizumab in patients of all ages with mild or moderate
hemophilia without inhibitors against FVIII whose bleeding phenotype warrants
prophylactic treatment.
Study objective
This study will evaluate the safety, efficacy, pharmacokinetics, and
pharmacodynamics of emicizumab in patients of all ages with mild (FVIII level
between > 5% and < 40%) or moderate hemophilia A (FVIII level between >= 1% and
<= 5%) without inhibitors against FVIII whose bleeding phenotype warrants
prophylactic treatment. Specific objectives and corresponding endpoints for the
study are outlined in section 2 of the protocol. Summarized:
• The safety objective for this study is to evaluate the safety profile of
emicizumab in patients with non-severe hemophilia A without inhibitors.
• The primary efficacy objective for this study is to evaluate the efficacy of
emicizumab.
• The PK objective for this study is to characterize the emicizumab PK profile.
• The immunogenicity objective for this study is to evaluate the immune
response to Emicizumab.
• The exploratory biomarker objective for this study is to investigate the
effect of emicizumab on PD parameters.
• The exploratory health status utility objective for this study is to evaluate
health status utility scores of patients treated with emicizumab.
Study design
Study BO41423 is a multicenter, open-label, single-arm study designed to
evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of
emicizumab in patients with mild or moderate hemophilia A without inhibitors
against FVIII.
Intervention
Emicizumab (also known as ACE910, RO5534262, and HEMLIBRA) is a recombinant,
humanized, bispecific, immunoglobulin G4 monoclonal antibody that binds with
moderate affinity to activated factor IX (FIXa) and factor X (FX), mimicking
the co-factor function of FVIII.
Four loading doses of emicizumab 3 mg/kg will be administered subcutaneously QW
for 4 weeks followed by patient preference of one of the following maintenance
regimens:
• 1.5 mg/kg QW;
• 3 mg/kg Q2W;
• 6 mg/kg Q4W.
The three maintenance dose regimens have shown equivalent average steady-state
exposure, and demonstrated consistent efficacy and safety, and are approved in
several countries for the treatment of Hemophilia A with or without FVIII
inhibitors. As patients with mild or moderate Hemophilia A have residual FVIII
levels of >= 1%, it is of interest to collect safety data over a longer time
period.
Therefore, in this study, the observation time to primary analyses was extended
to approximately 52 weeks compared with prior Phase III studies investigating
emicizumab.
Study burden and risks
The general burden on the patient consists, among other things, of blood
sampling (each visit), and the administration of the study drug (depending on
the treatment regimen chosen, varying from every week to every 4 weeks) that
may lead to various adverse events.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
• Signed Informed Consent Form (signed by patient*s legally authorized
representative for patients who have not attained the age of majority)
• Signed Assent Form when appropriate, as determined by patient's age and
individual site and country standards
• Willingness and ability to comply with schedules visits, treatment plans,
laboratory tests and other study procedures
• Diagnosis of mild (FVIII level between >5% and <40%) or moderate (FVIII level
between >= 1% and <= 5%) congenital Hemophilia A without FVIII inhibitors
• Weight >= 3 kg
• Need for prophylaxis based on investigator assessment
• A negative test for inhibitor (i.e., < 0.6 BU/mL) within 8 weeks prior to
enrollment
• No documented inhibitor (i.e., < 0.6 BU/mL), FVIII half-life < 6 hours, or
FVIII recovery < 66% in the last 5 years
• Patients who completed successful immune tolerance induction (ITI) at least 5
years before screening are eligible, provided they have had no evidence of
inhibitor recurrence (permanent or temporary) as may be indicated by a
detection of an inhibitor, FVIII half-life <6 hours or FVIII recovery <66%
since completing ITI.
• Documentation of the details of prophylactic or episodic FVIII treatment and
of number of bleeding episodes for at least the last 24 weeks prior to
enrollment
• Adequate hematologic function, defined as platelet count >= 100,000 cells/µL
and hemoglobin >= 8 g/dL (4.97 mmol/L) at the time of screening
• Adequate hepatic function defined as total bilirubin <= 1.5 X age-adapted
upper limit of normal (ULN) (excluding Gilbert syndrome) and both AST and ALT <=
3 x age-adapted ULN at the time of screening, and no clinical signs or known
laboratory/radiographic evidence consistent with cirrhosis
• Adequate renal function, defined as serum creatinine <= 2.5x age-adapted ULN
and creatinine clearance >= 30 mL/min by Cockroft-Gault formula
• For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraception as defined in section 4.1.1
of the Clinical Protocol
Exclusion criteria
• Inherited or acquired bleeding disorder other than mild (FVIII level between
> 5% and < 40%) or moderate (FVIII level between >= 1% and <= 5%) congenital
hemophilia A
• History of illicit drug or alcohol abuse within 48 weeks prior to screening,
in the investigator*s judgment
• Previous (within the last 12 months) or current treatment for thromboembolic
disease (with the exception of previous catheter-associated thrombosis for
which anti-thrombotic treatment is not currently ongoing) or signs of
thromboembolic disease
• Other conditions (e.g., certain autoimmune diseases) that may currently
increase the risk of bleeding or thrombosis
• History of clinically significant hypersensitivity associated with monoclonal
antibody therapies or components of the emicizumab injection
• Planned surgery during the emicizumab loading dose phase (surgeries in
patients on emicizumab from Week 5 onwards are allowed)
• Known HIV infection with CD4 counts < 200 cells/µL
• Concomitant disease, condition, significant abnormality on screening
evaluation or laboratory tests, or treatment that could interfere with the
conduct of the study, or that would in the opinion of the investigator, pose an
additional unacceptable risk in administering study drug to the patient
• Receipt of any of the following
o An investigational drug to treat or reduce the risk of hemophilic bleeds
within 5 half-lives of last drug administration with the exception of prior
emicizumab prophylaxis (prior investigational or commercial emicizumab use is
not an exclusion criterion)
o A non-hemophilia-related investigational drug within last 30 days or 5
half-lives, whichever is shorter
o Any other investigational drug currently being administered or planned to be
administered
• Inability to comply with the study protocol in the opinion of the investigator
• Pregnant or breastfeeding, or intending to become pregnant during the study
(women of childbearing potential must have a negative serum pregnancy test
result within 7 days prior to initiation of study drug)
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 | EUCTR2019-002179-32-NL |
| CCMO | NL71583.056.19 |
| Other | nog onbekend |