The study objectives are to determine the incidence rate of FVIII inhibitors, frequency of adverse events (AEs), and serious adverse events (SAEs) associated with the use of CSL627, to evaluate the PK of 50 IU/kg CSL627, and to evaluate the efficacy…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint of this study is:
* The rate of treatment success for bleeding episodes defined as a rating of
*excellent* or *good* on the investigator*s overall clinical assessment of
hemostatic efficacy fourpoint scale.
The primary efficacy endpoint of the surgical sub-study study is:
* The rate of treatment success during the peri-operative surgical sub-study
defined as an investigator rating of *excellent* or *good* on the four-point
efficacy evaluation of surgical treatment scale.
The primary safety endpoint is:
* The rate of inhibitor formation to FVIII evaluated from the time of first
dose through the End of Study visit.
Secondary outcome
* The proportion of bleeding episodes requiring one, 2, 3 or > 3 infusions of
CSL627 to achieve hemostasis.
Background summary
The study is being conducted to support the approval of CSL627, a new and novel
recombinant FVIII for the following indications:
1. Prevention and treatment of hemorrhagic episodes in patients with hemophilia
A.
2. Surgical prophylaxis of bleeding episodes in patients with hemophilia A.
3. Routine prophylaxis of bleeding episodes in patients with hemophilia A.
Patients with severe hemophilia A (FVIII<1% normal activity) bleed
spontaneously. They are treated with FVIII either plasma-derived or recombinant
to replace the missing clotting factor and arrest the bleeding episode or
prevent bleeding. Doses for this purpose are well established based on the
literature and treatment programs. 30±5 IU/kg is administered for bleeding
episodes which increases the factor VIII activity level to the normal range
(approximately 60%). In some cases dose escalation to closer to 100% activity
(45±5 IU/kg)is needed. Prophylactic regimens are typically 20-40 IU/kg every
second day or 20-50 IU/kg two to three times per week. For surgical procedures
and treatment of major bleeding (e.g. trauma), an initial bolus of 40-50 IU/kg
is often followed by a continuous infusion of 3 to 4 IU/kg/hr followed by
necessary adjustments. Currently all therapy is given intravenously to increase
the activity in the bloodstream which is the only effective way to treat
hemophilia at present.
Study objective
The study objectives are to determine the incidence rate of FVIII inhibitors,
frequency of adverse events (AEs), and serious adverse events (SAEs) associated
with the use of CSL627, to evaluate the PK of 50 IU/kg CSL627, and to evaluate
the efficacy of CSL627 in previously treated subjects with hemophilia A. This
study includes a surgical sub-study evaluating the safety and efficacy of
CSL627 in the prevention and treatment of bleeding during surgical procedures.
Study design
This will be an open label, international multicenter, cross-over design trial,
following the recommendations of the FDA and EMEA. The study will include
centers from North America, Europe and the rest of the world (ROW).
All eligible subjects must have received a FVIII replacement product
(plasma-derived or recombinant) for at least 150 exposure days (EDs) prior to
entering this trial, and have no prior history of inhibitors to FVIII, no first
order family history of inhibitors and no detectible inhibitors
(< 0.6 Bethesda Units [BU]) at screening, as tested by a central laboratory.
Part 3 will assess the safety and efficacy of CSL627 with continued dosing of
new subjects, and will include a repeat PK assessment.
* A surgical sub-study will be conducted.
At least 13 subjects entering Part 3 will participate in a full PK assessment
with a repeat PK assessment between 3 to 6 months. All FVIII activity will be
measured using multiple methods including the one stage clotting (OS) and
chromogenic substrate (CS) assays.
An Independent Data Monitoring Committee (IDMC) will be used in this trial to
monitor the safety of subjects and formation of inhibitors against FVIII and
will provide recommendations to the sponsor during the course of the study to
ensure safety of the subjects (as described in protocol Section 8.3.2.1).
Intervention
All subjects will be treated for a minimum of 6 months and 50 EDs All bleeding
events (either on-demand or prophylaxis) may be treated with CSL627, at a dose
similar to the FVIII product used prior to enrollment for the same type of
bleeding event. Doses in this study will range from 20 to 50 IU/Kg for CSL627
Study burden and risks
The benefits of treatment are stopping and/or preventing bleeding and enabling
a normal and longer life. Based on pre-clinical studies, CSL627 should be able
to deliver the same benefits seen with current FVIII treatments. In addition,
CSL627 should provide an adequate safety profile compared to other current
FVIII marketed products. The risks are that it might be less effective in
increasing factor VIII levels and stopping or preventing bleeding than current
products, and may correlate less well with clotting factor assays used by
clinicians. Treatment with any
antihemophilic factor presents a risk of inhibitor formation, although the
absolute risk of inhibitor formation with CSL627 is unknown.
The associated benefit of treatment with CSL627 outweighs any potential risks
for the subjects participating in this study.
Emil-von-Behring-Str. 76
Marburg 35041
DE
Emil-von-Behring-Str. 76
Marburg 35041
DE
Listed location countries
Age
Inclusion criteria
- Diagnosis of severe hemophilia A defined as <1% FVIII:C documented in medical records.
- Males between * 12 and 65 years of age.
- Subjects who have received or are currently receiving FVIII products (plasma-derived and/or recombinant FVIII) and have had
>150 exposure days (EDs) with a FVIII product
- Written informed consent for study participation obtained before undergoing any study specific procedures.
Exclusion criteria
- Any history of or current FVIII inhibitors
- Any first order family history of FVIII inhibitors
- Use of an Investigational Medicinal Product within 30 days prior to the first rFVIII administration
- Not capable of receiving treatment at home
- Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rFVIII or reference product.
- Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein.
- Any known congenital or acquired coagulation disorder other than congenital FVIII deficiency.
- Platelet count < 100,000/*L at screening.
- HIV positive subjects with a CD4 count < 200/mm3, in their medical history or at screening if available results are older than one year. (HIV positive subjects may participate in the study and antiviral therapy are permitted, at the discretion of the Investigator).
- 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 prior to Day 1.
- Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months prior to Day 1.
- Demonstrated inability (e.g., language problem or mental condition) or unwillingness to comply with study procedures or history of noncompliance.
- Employee at the study site, or spouse/partner or relative of the investigator or subinvestigators.
- Re-entry of subjects previously enrolled or participating in the current study.
- Suspected inability (eg, language problems) or unwillingness to comply with study procedures.
- Mental condition rendering the subject (or the subject's legally acceptable representative[s]) unable to understand the nature, scope and possible consequences of the study).
- Any condition that is likely to interfere with evaluation of the IMP or satisfactory conduct of the study.
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 | EUCTR2011-002393-23-NL |
| ClinicalTrials.gov | NCT01486927 |
| CCMO | NL44546.018.13 |