Allogeneic serum micro eye drops compared to conventional sized eye drops: a prospective randomized non-inferiority, investigator-masked, cross-over multicenter clinical study.

Serum eye drops (SEDs) are used to treat patients with severe signs and
symptoms of dry eyes and other diseases, like corneal defects. SEDs are used in
ophthalmic cases where conventional eye drops have insufficient effect. The use
of SEDs in dry eye patients usually has a rapid effect. Most patients claim the
effect to be instantaneous and most symptoms improve by 48 hours.
There is evidence suggesting that serum may enhance corneal epithelial healing.
Some biologically active substances are thought to contribute to the positive
effects, like epidermal growth factor, fibroblast growth factor, fibronectin,
and vitamin A.
Autologous SEDs are used internationally on a regular basis, while allogeneic
SEDs are becoming standard care. In the Netherlands, only autologous SEDs are
used. A prospective double-blinded randomized cross-over trial, comparing the
effectiveness of allogeneic SEDs and autologous SEDs, is currently being
performed at the RadboudUMC in Nijmegen, the Netherlands.
For administration of eye drops, commonly administration systems with a drop
size of 40 to 50 µl are used (further on referred to as conventional sized).
From previous studies done with medicinal eye drops we learned that smaller eye
drops, so called micro drops, can be just as effective and sometimes even
superior to conventional drops in eye disease. This can be explained by the
underlying physiology. The surface of the eye is protected and nourished by the
tear film which has a delicate structure. The first mucous layer serves to
prevent dry spots, the second aqueous layer is an extract from the blood and
the third outer layer is made from lipids to prevent evaporation. By blinking,
the structure of the tear film is continuously maintained. The tear film has a
volume of approximately 10 µL and an additional temporary storage capacity of
approximately 20 µL. There is constant renewal by a flow of about 1-2 µL per
minute. Consequently, a conventional sized eye drop of 40 to 50 µL washes away
most of the tear film which creates irritation and reflex tearing. Only 1 to 7%
of a conventional sized eye drop is taken up by the cornea, 15% is washed away
over the cheeks and 80% flushed through the nasolacrimal tube from where it is
absorbed into the circulation. Alternatively, a micro drop of 5 to 10 µL fits
the eye, leads to less damage of the tear film and creates less irritation and
reflex tears.
If micro drops are just as effective or maybe even superior to conventional
sized eye drops is currently unknown for the use of SEDs. With the proposed
study we would like to compare the feasibility and effectiveness of allogeneic
serum micro eye drops to the conventional sized allogeneic serum eye drops. For
the administration of the serum micro drops the mu-Drop applicator will be used
and for administration of the conventional sized drops the Meise applicator.
Both systems have a closed manufacturing system that allows the production
under GMP conditions. Moreover, the mu-Drop system is designed for single use
that guarantee the microbiological safety. Additionally, because the use of
smaller drops, many more patients can be treated with a single blood donation.
In that way donations are used more efficiently, e.g. serum from one blood
donation can be used to prepare about 1500 mu-Drop applicators, compared to 130
Meise applicators and with an expected average use of 3 applications per day
this is a factor 4 difference between both systems.

The main objective is to determine whether the administration of allogeneic
serum micro eye drops using the mu-Drop device is non-inferior to the
conventional sized drops in terms of effectiveness and safety.

Prospective randomized non-inferiority, investigator-masked, cross-over
multicenter clinical study. For patients the study will be non-blinded. For the
observer the study will be blinded (OSDI score, Schirmer*s test, tear break up
time and corneal punctates will be judged without knowing the study arm). A
non-inferiority design is selected because of expected benefits using smaller
drops, such as economical use of valuable donor serum, better fitting the
physiology of the eye, ease of use of the applicator.

The duration of the entire study is 6 to 12 months and will be performed in an
outpatient setting. Per patient, the on-study time is 3 months. During this
period the patient is asked to keep a diary on the use of serum eye drops and
experience with the applicators.

There are 3 sections in the treatment period:
In the first month, conventional sized or micro allogeneic SEDs administrated
either with Meise or mu-Drop applicators will be provided.
In the second month, regular eye medication (the same as the one(s) used before
onset of the study) will be applied (wash-out period).
In the third month, depending on the treatment the patient received in the
first month, conventional sized or micro allogeneic SEDs administrated either
with Meise or mu-Drop applicators will be provided.

In the month prior to start of the study, the patient has to remain on their
current eye medication, which will be continued during the second month of the
treatment period.
Prior to and at the end of each section of the treatment period, the OSDI
questionnaire will be filled out by the patient. Schirmer*s test will be
performed to determine tear production. The tear break up time will be
measured. Fluorescein will be used to stain the corneal punctates. After
staining, the percentage of affected surface will be estimated in a
standardized way. Only if possible, a photograph of the cornea will be taken to
count the number of corneal punctates. At the end of the study the diary will
be collected from the patient.

N.v.t.

Potential risks of blood-borne diseases are present with donor products, but
the risk is probably much lower as for regular transfusion products, as the
quarantine period effectively eliminates the risk of disease transmission.
In a broader perspective, from previous studies done with medicinal eye drops
we learned that smaller eye drops, so called micro drops, can be just as
effective and sometimes even superior to conventional drops in eye disease. The
current study will provide more data to ensure that evidence based medicine is
used for the treatment of dry eyes with SEDs.