Prospective, open-label, multicentre phase 3b study to assess the efficacy and safety of personalized prophylaxis with Human-cl rhFVIII in previously treated adult patients with severe haemophilia A

Haemophilia A is an inherited sex-linked coagulation disorder in which affected
males do not produce functional coagulation factor VIII (FVIII) in sufficient
quantities to achieve satisfactory haemostasis, leading to bleeding diathesis.
Most bleeding episodes occur in the patient*s joints and muscles. Without
adequate treatment, repeated haemarthroses and haematoma lead to long-term
sequelae with severe disability. Other bleeding sites, although less frequent
but more severe, are the central nervous system, the urinary or
gastrointestinal tract, the eyes, and the retroperitoneum. In addition,
patients with haemophilia A are at high risk of developing major and
life-threatening bleeding even after minor surgical interventions, such as
tooth extractions. The optimal treatment of haemophilia A is replacement of
FVIII using FVIII concentrate either obtained by fractionation of human plasma
or manufactured by recombinant DNA technology. Human-cl rhFVIII is a
recombinant human factor VIII concentrate developed by Octapharma. In contrast
to other available recombinant FVIII concentrates in Europe, which are
expressed in hamster cells, Human-cl rhFVIII is expressed in a human cell
line.

Human-cl rhFVIII (brand name Nuwiq.® ) was approved in July 2014 by the
European Medicine Agency (EMA) for the treatment and prophylaxis of bleeding
in patients with haemophilia A (congenital factor VIII deficiency) in all age
groups. It has also been approved in Canada and Australia, and is currently
being reviewed by Health Authorities of other countries (e.g. FDA). The current
study serves to collect further data on Human-cl rhFVIII by evaluating the
approach to individualize prophylactic treatment based on the patient*s
individual PK assessment with Human-cl rhFVIII.

Primary Objective
• To compare the annualised total bleeding rate of individually tailored
prophylaxis with the historical bleeding rate observed in patients having
received on-demand treatment with Human-cl rhFVIII from study GENA-01

Secondary Objectives
1. To compare the annualised spontaneous bleeding rate of individually tailored
prophylaxis with the historical bleeding rate observed in patients having
received on-demand treatment with Human-cl rhFVIII
2. To compare the annualised total bleeding rate in patients with 2x/week (or
less) prophylaxis with the historical bleeding rate observed in patients having
received on-demand treatment with Human-cl rhFVIII
3. To assess the median prophylactic dosing interval
4. To assess the PK of Human-cl rhFVIII in terms of FVIII:C
5. To assess the safety of Human-cl rhFVIII

Additional Objectives
1. To assess the clinical efficacy of Human-cl rhFVIII in the treatment of
breakthrough bleeding episodes (BEs)
2. To assess the clinical efficacy of Human-cl rhFVIII in surgical prophylaxis
3. To assess the correlation of VWF antigen concentration and half-life of
Human-cl rhFVIII
4. To assess the association between ABO blood type and half-life of Human-cl
rhFVIII
5. To assess Human-cl rhFVIII consumption data ( exploratory)

This is a prospective, open-label, multicentre phase 3b study investigating the
efficacy and safety of individually tailored prophylaxis with Human-cl rhFVIII
in previously treated adult patients with severe haemophilia A.

The study consists of three (3) phases, i.e., the PK Evaluation Phase, the
Prophylactic Treatment*Phase I, and the Prophylactic Treatment*Phase II.
• The PK Evaluation Phase will last for 72 hours (i.e., 3 days).
• The purpose of Prophylactic Treatment*Phase I, which will last for 1-3
months, is to treat the patients prophylactically every other day or 3x/week
with a dose of 30-40 IU/kg BW until individual PK data have been analysed and
discussed with the investigator .
• In Prophylactic Treatment*Phase II, patients will be treated prophylactically
for 6 months. The recommended prophylactic doses and dosing intervals are
determined by the Sponsor for each patient based on the analysis of individual
PK data obtained at the Initial PK Visit with the one-stage assay and after
consultation with the investigator.

The study duration for each patient will be approximately 7-9 months, and the
overall study duration will be about 2 years.

The study will be stopped if more than 3 patients develop a neutralizing
antibody ( inhibitor) to Human-cl rhFVIII

Human-cl rhFVIII is a human cell line derived recombinant FVIII concentrate for
intravenous use. Vials contain either 250, 500, 1000, or 2000 international
units (IU) of freeze-dried FVIII concentrate, each to be reconstituted in 2.5
mL water for injections. Human-cl rhFVIII should be injected intravenously by
bolus injection at a maximum rate of 4 mL/min. Continuous infusion is prohibited

Dosing of the IMP:
Initial PK Evaluation (72 hours):
60 ± 5 IU FVIII/kg, according to labelled potency

Prophylactic Treatment*Phase I (1-3 months):
Patients will be treated prophylactically every other day or 3x/week with a
dose of 30-40 IU/kg BW for about 1-3 months until PK data have been analysed
and discussed with the investigator. Dose escalations are allowed in case of an
inadequate frequency and severity of breakthrough bleeding episodes in
accordance with the institution*s standard clinical care.

Prophylactic Treatment*Phase II (6 months):
Patients will be treated prophylactically for 6 months. The recommended
prophylactic doses and dosing intervals are determined by the Sponsor for each
patient based on the analysis of individual PK data obtained at the Initial PK
Visit with the one-stage assay and after consultation with the investigator.

Based on an appropriate PK model, various dosing intervals (usually 12-hour
intervals) and corresponding doses (in IU/kg) will be calculated, which
hypothetically lead to FVIII:C plasma concentrations of at least 0.01 IU/mL at
the end of the respective injection interval.

The goal is to use the maximum regular prophylactic dosing interval that can be
achieved with a maximum dose of preferably not more than 65 IU/kg and that
maintains a trough level of >= 0.01 IU/mL.

Partifipation in this study could take 7-9 months and could include up to 9
visits to the study centre. In between visits the patient also has telefonic
contact with the site personnel
The following procedures will be done during the visits:
• 1x Check inclusion/exclusion criteria
• 1x Documentation of Medical History, as well as other medications the patient
takes
• 4x Vital signs measurement
• 2x Height and body weight measurement
• 2x Physical examination including checking joints
• 8x Blood sampling
• 6x patient diary review
• 4x Documentation of side effects and changes in other medication

Infusion study medication, dosing and frequenxy on an individual basis

A general risk associated with all kinds of factor VIII concentrates (whether
recombinant or produced from human blood) is the possible development of
inhibiting antibodies ('inhibitors') against factor VIII. These are proteins
that the body may make and which prevent the infused factor VIII from working
properly. Inhibitors can reduce the effect of the factor VIII
treatment.Clinical studies performed with Human-cl rhFVIII suggest that the
risk of developing inhibitors to Human-cl rhFVIII is not higher than with other
factor VIII concentrates.

In rare cases, as with other factor VIII concentrates, allergic reactions to
Human-cl rhFVIII might occur. The symptoms might range from burning and
stinging at the injection site, swellings, fever, chills, nausea, vomiting,
flushing, rash, hives, headache, low blood pressure, feeling tired,
restlessness, a faster heart rate, tingling and wheezing, to chest tightness
and shortness of breath. In very rare cases, a severe allergic reaction might
occur.

The following adverse drug reactions were observed in 135 patients (previously
treated with factor VIII) who participated in clinical studies with Human-cl rh
FVIII: paresthesia headache, vertigo, dry mouth, back pain, injection site
inflammation, injection site pain, non-neutralising anti factor VIII antibody.
All these adverse drug reactions occurred only once.

When blood is drawn, pain could be experienced, bruising at the site of
injection, light-headedness, fainting, scarring, and on rare occasion
infections.
When having blood pressure taken, the cuff may squeeze the arm and may cause
irritation.

When having an IV (intravenous) injection, a needle that is attached to a tube
and syringe containing the study drug will be inserted into a vein. Pain may be
experienced, bruising, discoloration of the skin around the injection site,
infection, and clotting.

There may also be other unknown risks, other than those listed above that we
cannot predict. As for any new drug, extra care has to be taken to monitor
possible unexpected medical problems or side effects.