|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Male paediatric subjects with Haemophilia A who develped high titre
antibodies to human coagulation Factor VIII
|E.1.1.1||Medical condition in easily understood language ||
|Treatment of patients with hereditary deficiency of blood coagulation
factor VIII that developed neutralizing antibodies against Factor VIII is
|E.1.1.2||Therapeutic area ||Diseases [C] - Blood and lymphatic diseases [C15]
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10018941
|E.1.2||Term ||Haemophilia NOS
|E.1.2||System Organ Class ||100000004850
|E.1.3||Condition being studied is a rare disease || No
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|To determine the proportion of subjects who achieve a complete
response (success) following ITI treatment with Biostate.
|E.2.2||Secondary objectives of the trial ||
To assess the safety of Biostate when administered to subjects with
haemophilia A and inhibitors to FVIII in an ITI treatment regimen.
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1. Male subjects diagnosed with haemophilia A (::;2% FVIII level in the
absence of factor replacement, according to their medical history).
2. Age 28 days to <12 years.
3. ITI treatment can be initiated if:
a. An inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated
tests by the central laboratory during the screening period and no
waiting period is required as judged by the investigator.
b. An inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated
tests by the central laboratory during the screening period and the
inhibitor titre decreased from the peak titre during a waiting period
(maximum 11 months) added at the discretion of the investigator.
c. A subject has pre-existing inhibitors, determined no more than 11
months prior to the Screening visit, which decreased from the peak titre,
and an inhibitor level of >5 and <200 BU/mL was confirmed in 2
repeated tests by the central laboratory during the screening period. A
waiting period could still be added if the total duration from inhibitor
XML File Identifier: vFDreSBztfLwGbRZGET6u4sLSvo=
diagnosis until start of IT! treatment (ie, including the screening period)
does not exceed 12 months.
4. The subject and/or his legally acceptable representative understand
the nature of the study and have given written informed consent to
participate in the study.
5. Sufficient peripheral venous access or central venous line.
|E.4||Principal exclusion criteria||
l.DThe subject has received IT! previously.
2.DSubjects with a historical peak inhibitor titre of ~200 BU/mL.
3.DConcomitant treatment with drugs with immunosuppressive side
effects (eg, systemic cortlcosteroids), azathioprine, cyclophosphamide,
high dose immunoglobulin or the use of a protein A column or
plasmapheresis and interferons.
4.DHigh risk of cardiovascular, cerebrovascular, or other
thromboembolic events (excluding catheter thrombosis) as judged by
5. DSubjects who are human immunodeficiency virus (HIV)-l or HIV-2
positive (as reported in the medical records or determined at screening).
6.DThe subject has evidence or a history (within the previous 12
months) of abuse of any drug substance, licit or illicit.
7.DThe subject has a known or suspected hypersensitivity or has
previous evidence of severe side effects to von Willebrand factor
(VWF)/FVIII or FVIII concentrates or human albumin.
S.DThe subject has participated in a clinical study or used an
investigational compound (eg, a new chemical entity not approved for
clinical use) in the past 3 months, unless the study was for haemophilia
A and the subject developed an inhibitor (then, a wash-out period of at
least 4 weeks must be applied), or is planning to enter such a study
during the study period.
9.DSubjects or legal guardians/ representatives with suspected inability
(eg, language problems) or unwillingness to comply with study
10.DThe subject has an acute or chronic medical condition other than
haemophilia A, which may, in the opinion of the investigator, affect the
conduct of the study.
l1.DMental condition rendering the subject (or the subject's legally
acceptable representative) unable to understand the nature, scope and
possible consequences of the study).
12.DAny condition that is likely to interfere with evaluation of the
investigational medicinal product (IMP) or satisfactory conduct of the
13.DEmployee at the study site, or spouse/partner or relative of the
investigator or subinvestigators.
Study Product, Dose, and Mode of Administration:
The IMP Biostate will be intravenously (I.v.) administered at a daily dose
of 200 international units (IU)/kg body weight (b.w.), preferably split
into 2 doses of 100 IU/kg b.w. per day.
For subjects with an undetectable inhibitor titre «0.6 BU/mL) at 2
consecutive assessments, tested at intervals of 2 weeks (±3 days), and
normal recovery (~66% of predicted) for 6-S weeks, the daily Biostate
dose will be reduced by 20 IU/kg b.w. (ie, by 10% of the initial daily ITI
dose), if possible, every 2-4 weeks down to a dose of 100 IU/kg b.w.,
provided the recovery remains normal during that time (assessed
After further gradual reduction of the dose and extension of the administration interval (at the discretion of the investigator), Biostate
will be administered as prophylaxis at a daily dose of 50 IU/kg b.w, on 3
days per week (about every second day).
Any daily dose'~100IU/kg b.w. should preferably be evenly split into 2
doses per day. Daily doses of 100 IU/kg b.w. or lower will be
administered once daily.
Bleeding complications during the tolerization period should be treated
according to centre's standard of care. Study treatment should not be
interrupted for surgical procedures.
|E.5 End points
|E.5.1||Primary end point(s)||
eoResponse to ITI treatment: complete response (success), partial
response (partial success), or ITI failure.
eoFVIII inhibitor titre.
eOTime to complete response (success).
eOTime to inhibitor <0.6 BU/mL for the first time.
eAdverse events (AEs).
eClinical significant changes of laboratory testing (haematology,
biochemistry) as judged by the investigator.
eMarkers of activation of coagulation (thrombin-antithrombin complex
[TAT]) above ULN
eSymptomatic thromboembolic events including catheter thrombosis
eFrequency and nature of bleeding events (severity and number of
bleedings per patient).
eCatheter-related complications (line infections).
ePhysical examination and orthopaedic status.
eClinically significant changes of Vital signs (blood pressure, heart rate,
and body temperature).
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.18.104.22.168||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| No
|E.7.3||Therapeutic confirmatory (Phase III)|| Yes
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || No
|E.8.1.5||Parallel group|| No
|E.8.1.6||Cross over || No
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || No
|E.8.4.1||Number of sites anticipated in Member State concerned||1
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||14
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| No
|E.8.6.2||Trial being conducted completely outside of the EEA|| No
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||3
|E.8.9.1||In the Member State concerned months||5
|E.8.9.1||In the Member State concerned days||
|E.8.9.2||In all countries concerned by the trial years||3
|E.8.9.2||In all countries concerned by the trial months||5