Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT03768115 |
| Other study ID # |
R945/54/2012 |
| Secondary ID |
2018/2855 |
| Status |
Withdrawn |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2018 |
| Est. completion date |
October 14, 2020 |
Study information
| Verified date |
October 2020 |
| Source |
Singapore National Eye Centre |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Patients with severe dry eye who have exhausted conventional treatment are not uncommon and
are difficult to manage. They and their physicians are helpless when faced with these
scenarios. A small HPRG group, Health Science Authority (HSA) and IRB approved study of
autologous plasma eye drop therapy for patients with recalcitrant dry eye has been completed
recently by investigators at the Singapore National Eye Centre. The unique feature of the
previous protocol was that the autologous plasma preparation was made and contained in sealed
segments of intravenous tubing until use by the patient. The study showed that the corneal
fluorescein staining of patients who regularly used autologous plasma over a 6 week period
improved significantly. Additionally, there was a significant reduction in the total number
of topical eye drop treatment required. Investigator did not encounter any cases of infected
eye drop preparation or any cases of eye infection. Seventy percent of these patients would
recommend this treatment to their relatives and friends suggesting that this form of
treatment is a valuable additional modality for dry eyes. Now, investigator would like to
extend the short-term pilot study into a long-term single arm clinical trial, in order to
determine the best protocol/logistic for this treatment that is practical and still
effective, and allowing for more than one plasmapheresis during the study. To achieve this,
investigator aim to perform a longitudinal prospective study of patients with severe dry eye
who cannot be satisfactorily managed with conventional dry eye treatments using a proposed
regime for plasmapheresis and plasma storage.
Description:
Dry eye is a multi-factorial disease that is frequently encountered in ophthalmological
practice. Common dry eye symptoms include eye irritation, heaviness of the eyelids, blurred
vision and light sensitivity. The worldwide prevalence of dry eye is generally high. In Asia,
dry eye may affect up to 22% of adults above 40 years in China and Japan. In Asian patients
older than 65 years, prevalence rates of dry eye can be as high as 80% if diagnosis is based
on abnormal tear stability, or as high as 60% on meibomian gland dysfunction (MGD), a major
cause of tear instability.
In a Singapore study, dry eye significantly impacted the quality of life of patients as a
consequence of constant interference with daily activities, such as navigating stairs,
recognizing friends or watching TV. Additionally, patients with severe dry eye reported that
this condition is comparable to dialysis or severe angina, which emphasizes the enormous
impact the dry eye disease has on patients.
Dry eye disease presents a significant socio-economic problem. The overall economic burden of
dry eye management and treatment has been reported to be US$ 3.84 billion per annum in the
American healthcare system and up to US$ 1.1 million per thousand persons per annum in
Europe. The economic cost of dry eye is also high in Singapore. In 2009, the Singapore
National Eye Centre (SNEC) treated 54,051 dry eye patients and the corresponding total cost
for medication amounted to SG$ 181,354 in this single centre (unpublished data). This data
does not account for other over-the-counter lubricants that were purchased by dry eye
patients at pharmacies outside SNEC, so the cost may even be significantly higher.
Most dry eye patients can be successfully managed with lubricants, punctal occlusion, steroid
and/or cyclosporine eye drops. However, some patients with severe dry eye and likely
underlying diseases (for example graft versus host disease, rheumatoid arthritis and
Sjögrens-Syndrome), who have exhausted conventional treatments may amount to 10-20 cases a
year and are difficult to manage. These patients and their physicians are helpless when faced
with these scenarios. These patients have attempted different kinds of eyedrops such as
longer acting gels, doxycycline, punctal plugs, cyclosporine and even topical steroids. Many
of these patient's epitheliopathy, vision, and tear function are at best, stable at a very
unsatisfactory level. Furthermore, all of these patients are currently using eyedrops to the
frequency of half hourly to hourly, and this further affects work productivity and quality of
life. The situation is so critical in these patients that should a form of therapy be
available that can improve the quality of life, such as reducing the number of eyedrops
required per day, it would constitute a definite advance, even if the disease cannot be
reversed, or vision not clearly improved.
A small HPRG group, HSA and IRB approved study of autologous plasma eye drop therapy for
patients with recalcitrant dry eye has been completed by investigators at the Singapore
National Eye Centre (SNEC). The IRB approval no was 2010/137/A dated 12. April 2010. The HSA
CTC approval no was CTC 1000230 dated 22/06/2010. Briefly, the unique feature of the previous
protocol was that the autologous plasma preparation was made and contained in sealed segments
of intravenous tubing until use by the patient. The study showed that the corneal fluorescein
staining of patients who regularly used autologous plasma over a 6-week period improved
significantly. Additionally, there was a significant reduction in the total number of topical
eye drop treatment required. Investigator did not encounter any cases of infected eye drop
preparation or any cases of eye infection. Seventy percent of these patients would recommend
this treatment to their relatives suggesting that this form of treatment is a valuable
additional modality for dry eyes. In addition to these quantitative outcomes, believe that
there are some patients with particularly remarkable results that cannot be quantified
easily. For example, one patient, having had years of unsuccessful treatment with various
formulations, claimed that 'this is the only type of eyedrops that make any difference'. The
scientific evidence for the use of full strength plasma is further strengthened by a recently
published study that showed superiority of undiluted serum over half strength serum in
relieving symptoms of dry eye and epithelial damage.
What would be the next step for the evaluation of autologous plasma treatment in severe dry
eye? This form of treatment in severe dry eye is not appropriate for a randomised controlled
study for the following reasons: First, two randomised studies have shown the efficacy of
autologous serum compared to 'standard therapy, reported in 2004 and 2005. For a proposed
randomised study to be ethical, there has to be equipoise. In this situation, having a
control group of say 'saline' in crimped tubings is not ethical for severe dry eye. Second,
there is no comparison treatment that is available in the Singapore context. The
internationally accepted treatments for severe/recalcitrant dry eye are tarsorrhaphy,
prosthetic replacement of ocular surface ecosystems (PROSE) and autologous serum/plasma. The
PROSE is a form of sclera contact lens that is not available in Singapore and is very
expensive (US$3000-5000). Tarsorrhaphy is a form of surgery (invasive treatment) and is
obviously not suitable for many cases of bilateral severe dry eyes, since closing the eyelids
will prevent proper vision, in addition to cosmetic blemishes. Third, all of the current
severe dry eye patients are using different lubricant formulations up to half hourly, many of
these formulations such as Systane Ultra gels are much more effective than saline. These
patients are constantly requesting for more effective solutions and are understandably
unwilling to use additional saline eyedrops as part of the comparison group, if they are not
randomised to receive autologous plasma. In any arm of a study on severe dry eye, the study
intervention is in addition to the existing treatment (lubricants, doxycycline etc). The one
major reason for decreased quality of life is the requirement for very frequent eyedrops, it
is not surprising that willingness to use yet another eyedrop that is less effective than
their current existing drops is low. Therefore, an attempt to do a randomised study that
requires saline in one arm on such patients will be doomed to fail due to lack of
cooperation. Masking of treatment status is not possible since the control patients would be
aware that they did not have plasmapheresis. The only possibility to do a randomised study
will be in moderate dry eye (rather than severe recalcitrant ones). However, this is not
currently the priority at Singapore National Eye Centre, where the immediate concern is to
address the patients' unmet needs, and the patients with moderate dry eye, unlike their
severe counterparts, have several viable alternatives in the treatment repertoire.
If the most suitable methodology is a single arm prospective study, their outcomes can still
be compared to other severe dry eye patients who for some reason, did not want to
participate. In the current scenario, where there is no real alternative strategy for
treatment of severe dry eye, autologous plasma should be definitely used and evaluated
further. If the regulatory bodies approved this, it would be unethical not to consider this,
since autologous plasma has been shown to be safe and effective in the short term. Some
desperate severe dry eye patients have considered alternative ways of obtaining the
autologous serum, for example, from private clinics and from neighbouring countries. These
treatments may be obtained at much lower costs compared to plasmapheresis, but not
necessarily safer, outside the context of a clinical study. In my opinion, based on managing
these cases over the last 6 years, the relevant question is not whether autologous plasma
should be used, but rather, how such therapy can be used in a protocol that is practical,
convenient and acceptable.
In the above pilot study, the plasma eye drops were prepared at the hematology centre at SGH.
After the completion of the study, investigator has been informed by the hematology centre
that their new accreditation status will prohibit preparation of autologous plasma segments
by crimping within the premises even though they can still perform the plasmapheresis. This
increases the inconvenience of the whole dispensing procedure and may increase the
non-refrigerated time of the harvested plasma. In addition overseas experience, for example,
at the Methodist Hospital in Houston Texas show that it is safer and more efficient for blood
professionals to handle blood products for clinical use rather than other types of health
professionals. For this reason investigator seek the assistance of blood group services at
HSA to perform this part of the study. The facility at HSA has the ability to perform
crimping of the intravenous tube, so it may not be necessary to use the current multi-head
crimper. The current crimper is nevertheless, available for use if desired. A further
enhancement of the procedure can be performed at HSA, using a sealing process that connects
contiguous intravenous tubes without using 3 way taps. This will ensure an entirely closed
environment where the plasma is not exposed to the environment until just before using the
eyedrop.
As autologous plasma treatment is currently advocated in our centre only for
severe/recalcitrant dry eye, it is not expected that the costs of such therapy can be lowered
significantly from the scale of the service since patient number is small at any one time.
Investigator expects that only about 10-20 such patients may appear per year, but these
account for a considerable number of hospital visits per year. The main problem with
autologous plasma as a treatment modality is the one-time cost associated with the
plasmapheresis itself. In order to make the costs of autologous plasma more realistic and
affordable, investigator would like to explore the storage of plasma for a longer time than 6
weeks or 3 months from a single plasmapheresis. As conditions (temperature and hygiene) of
plasma storage is much more predictable at a central storage facility at HSA, investigator
will explore storing half of the extract patient's plasma and dispensing it after the
exhaustion of the initial supply, without necessitating further plasmapheresis and incurring
additional costs.
Many of the dry eye patients use Restasis (topical cyclosporine 0.05% emulsion) which costs
S$70 every three weeks on a long term basis. In the pilot study above, patients on autologous
plasma drops were able to cease Restasis during the time when they use the autologous plasma.
In other words, over the course of about 21 weeks, a patient who uses Restasis would have a
greater expenditure for the medications than a patient who had autologous plasma drops. The
autologous plasma user may also save additionally from the reduced number of eyedrops used
daily, and therefore buying fewer lubricants in 21 weeks. This difference will be even
greater since investigator anticipate that a single plasmapheresis can produce sufficient
eyedrops for a period longer than 21 weeks.
It is believed that plasma eyedrops is superior to conventional eyedrops due to the presence
of various anti-inflammatory proteins such as transforming growth factor-beta in plasma.
Based on the current literature, it is difficult to ascertain the shelf life of the
beneficial proteins after plasma is frozen at -20°C. A pilot study developed a closed,
cascade-filtration system that was an effective method for the production of high-quality,
low-pyrogen autologous serum. This processing method broadly complied with Food and Drug
Administration requirements for reinjection of biological substances. Variable growth factor
stability was observed at +4°C and above. Stability of transforming growth factor beta1,
substance P, nerve growth factor, calcitonin gene-related peptide, insulin-like growth factor
1, and epidermal growth factor was evaluated at -15°C, +4°C, +25°C, +37°C, and +42°C at
different time intervals (hours to weeks). Transforming growth factor beta1, nerve growth
factor, epidermal growth factor, and insulin-like growth factor 1 were more temperature and
time resistant, but substance P and calcitonin gene-related peptide significantly degraded at
+4°C in 24 hours. Endotoxin and lipid peroxidation by-products were not significantly
increased by processing.
A very recently published study by a group with much experience in autologous serum treatment
for dry eye obtained whole blood from 10 volunteers and prepared 100% (AS100), 50% (AS50),
and 20% (AS20) serum eye drops. Epitheliotrophic factors including EGF, fibronectin, vitamins
A and E, albumin, and immunoglobulin A were quantified before and after storage for 7 days at
6°C or 3 and 6 months at -20°C. Human corneal epithelial (HCE) cell lines were used to
investigate proliferation, migration, and overall wound healing potency of the cells in
response to different serum preparations. The proliferation, migration, and wound healing of
HCE cells were measured after incubation with different serum eye drop concentrations and
after different storage conditions. The results show that the concentration of epidermal
growth factor, fibronectin, vitamins A and E, immunoglobulin A, and albumin showed no
significant reduction over the test period. Proliferation, migration, and wound healing of
HCE cells was significantly better after incubation with undiluted serum in comparison with
diluted serum. No significant loss of cytokine concentration, wound healing, and
proliferation effect in HCE culture of AS100, AS50, and AS20 could be detected over the 6
months of storage. This study suggests that storing a portion of the autologous plasma in a
reliable fashion for 6 months should not result in greatly decreased efficacy for dry eye
treatment.
Now, investigator aim to provide an autologous plasma eye drop treatment as a clinical
service provided by Singapore National Eye Centre to any patients who cannot be
satisfactorily managed with conventional dry eye treatments (lubricants, punctal occlusion,
steroid and/or cyclosporine). Specifically, investigator will determine if the significant
beneficial effects of autologous plasma treatment obtained at 6 weeks will persist to 12
months, as a way to evaluate if longer term storage of frozen plasma from a single
plasmapheresis remains effective. Secondly, to will determine if the effectiveness of this
therapy remains at 24 months compared to pre-treatment assessment, and explore whether
specific etiologies of dry eye benefit more from this type of treatment.
Clinical importance At the Singapore National Eye Centre, the principal investigator Dr. Tong
runs a specialised dry eye service. During his clinical consultations, he encounters patients
with severe dry eye who suffer from persistent poor vision. The number of severe dry eye
patients is not high but these patients are devastated by the eye condition. This study is
important because it addresses aspects of using autologous plasma treatment for severe dry
eye, such as feasibility of storing plasma long term in a central freezer, and the data
obtained will determine the best method/protocol for administering the only available
treatment for severe dry eye locally.
1 HYPOTHESIS AND OBJECTIVES Chronic severe and recalcitrant dry eye form a small group of
patients seen at the Singapore National Eye Centre. The symptoms of blurring, decreased
comfort and frequent requirement of eye drops result in reduced quality of life. In a
longitudinal prospective study, investigator aim to observe the long-term safety and efficacy
of autologous plasma eye drop therapy, the only available form of therapy for severe dry eye
patients from the Singapore National Eye Centre.
1.1 Hypothesis To evaluate the long-term efficacy, safety and patient acceptability of
autologous plasma eye drop therapy using a protocol developed at our centre.
1.2 Primary Objectives
1. To evaluate the difference in number of eye drops used daily and dry eye symptom
severity at 6 weeks to 4 months period and subsequent follow up visits at SNEC after
commencement of autologous plasma eye drops in patients with severe/recalcitrant dry eye
in the dry eye clinic at Singapore National Eye Centre who has failed all other
available standard therapy.
1.3 Secondary Objectives
2. To evaluate the difference in number of eye drops used daily and dry eye symptom
severity between the baseline visit and 1 year after the autologous plasma eye drop
treatment has stopped.
3. To explore the treatment outcome in terms of the etiological subtype of the patients
(eg., graft versus host, rheumatoid arthritis, etc) to see if particular subgroups
respond particularly well to this form of treatment.
1.4 Potential Risks and Benefits: 1.4.1 Potential Risks A possible adverse reaction is the
presence of increased redness of the eye and/or increased irritation after commencement of
the treatment. This may or may not be due to contamination and subsequent infection of the
ocular surface. The signs and symptoms will be managed according to clinical findings. In
order to avoid serious infections, especially corneal keratitis, investigator will not
include patients with high risks for infection in this study, such as those patients with a
persistent epithelial defect, wearing of contact lenses, previous ocular surgery such as
penetrating keratoplasty or any other ocular surgery. All adverse reactions will be reported
to the IRB. If eye drop contamination is suspected, eye drops will be sent for microbiology,
in addition to patient swabs or scrapes sent for microbiology.
Another potential problem during plasmapheresis will be headaches, nausea, transient lowering
of blood pressure, tinglings of lips and finger tips, shivers, cramps. Others include,
bruising and bleeding from venepuncture site, rarely transient fits, nerve injury or arterial
puncture.
1.4.2 Potential Benefits Subjects can undergo autologous plasma eye drops treatment for their
dry eye condition.
2 STUDY POPULATION 2.1 List The Number and Nature of Subjects to be Enrolled The number of
subjects will be dependent on the number of patients from SNEC who requires this treatment as
determined by the physician. This is expected to be not more than 10-20 per year. This
amounts to not more than a maximum of 40 patients over 2 years of recruitment.
Attending doctors at Singapore National Eye Centre will determine if treatment is necessary
for patients. Informed written consent will be obtained from all participants.
2.5 Subject Replacement Subjects who have dropped out will not be replaced. 3 STUDY DESIGN To
evaluate the long-term efficacy, safety and patient acceptability of autologous plasma eye
drop therapy using a protocol developed at our centre.
3.1 Study Visits and Procedures 3.1.1 Study Visits and Procedures
1. The study will only include patients who have been referred to the dry eye or cornea
clinic at SNEC and only patients found to be suitable will be recruited into the trial.
2. The clinical indications for starting treatment and follow up visits will be at the
discretion of the principle investigator but the data obtained on designated study
visits will be collected on study case report forms and data entered electronically into
a database for analysis. The eligibility will adhere as much as possible to the
inclusion criteria in the previous study. However, patients with previous plasmapheresis
and autologous plasma treatment (as long as it did not occur within the last 2 weeks)
will now be permitted to participate in this study. To address the first aim of the
study, the symptoms at one year after the patient stopped the autologous plasma
treatment will be compared to that at first follow up visit (6 weeks to 4 months) after
commencement of autologous plasma The patients will be permitted to have a repeat
plasmapheresis after the first one if the patient opts to do that and a second
plasmapheresis deemed indicated by the PI. The duration of treatment from one
plasmapheresis will be longer than the 6 weeks in the previous study as more plasma will
be extracted and half the plasma volume will be stored for later dispensing (described
in detail below). In addition, investigator expect that there may be individual factors
which make continued plasma treatment unnecessary. The extent of inflammation may wax
and wane in patients with severe dry eye, either as part of the natural history or
because of systemic treatment of the condition such as the autoimmune disease. In such
cases, the ocular condition may improve after a certain amount of autologous plasma
treatment and only require conventional eyedrops subsequently. Therefore, the PI will
have the discretion to halt any patient's treatment at any time during the study.
Patients are required to pay for the full costs for this clinical service available at
SNEC, if they are unwilling to continue with this treatment after the collections from
the first plasmapheresis procedures they will be continued to be followed up under this
study till 1 year (±6 months) after they stopped using the autologous plasma. The follow
up visits for this study is dependent on their SNEC appointments as determined by the
PI.
3. From the PI's experience in his clinic, it is expected that less than 10 patients will
be recruited in the first year, after careful scrutiny of the presenting clinical
features. This study does not require the participants to alter any of their
pre-existing dry eye or systemic medications, and will not affect clinical decisions
such as insertion of punctal plugs and so on. Surgeries such as cataract surgeries may
be performed when indicated at any point in the study. If cataract surgery is necessary,
investigator will suspend the autologous plasma treatment for at least one month after
surgery. This is not expected to be a frequent occurrence as cataract surgery in the
presence of a poor cornea epithelium is unlikely to result in patient satisfaction. The
principle investigator may cease the autologous plasma eye drop treatment for any
clinical or social reason (for example, if patients do not have further access to a
freezer) during the follow up. If this happens, treatment may be re-commenced at any
time point by the PI.
4. Beyond the hospital consultation, the patient is required to pay the necessary
consumable, , cooler box, plasmapheresis procedures, crimping and storage of autologous
plasma, transportation and blood testing charges incurred, which will be made known to
the patient. Payment will be made at the SNEC. Patients who meet the criteria outlined
in section 'Inclusion Criteria' will undergo plasmapheresis at SGH Hematology Centre. A
screening for infectious disease will be conducted. If any of the tests is positive for
infectious disease,the patient will not be scheduled for plasmapheresis procedure. The
crimping of intravenous tube will be performed by trained personnel at the HSA.
Counseling on storage and use of autologous tears will be performed at SNEC.
5. Written informed consent will be obtained from all patients prior any procedure. A
standardised documentation of dry eye signs and symptoms will be performed at the
baseline visit. It is expected that these patients will be followed up by the PI at the
clinically indicated frequency, for example, three monthly, etc. The standardised
evaluation form will be implemented during the follow up visits at SNEC when the patient
is using autologous plasma treatment until 1 year (±6 months) after they have stopped
using autologous plasma treatment and the patient will be considered to have exited the
study. However, since dry eye is a chronic disease with possibility of reactivation
later, investigator can allow the participant to re-enter the study in subsequent visits
if the need arises.
Procedures:
Visit 1 (at SNEC and SGH Hematology Centre):
After written informed consent, patients will be screened for good veins at SGH Hematology
Centre. Blood testing at SNEC will be arranged for the patient, preferably on the same day of
doctor's consultation or any of the following days. Patients will be screened with the
inclusion and exclusion checklist as attached (Appendix A). An appointment for plasmapheresis
at SGH Hematology Centre will be scheduled within one month of blood testing. The patient
will be counselled on storage and use of autologous tears by trained staff and written
instructions are given in the patient information sheet. Baseline parameters will be obtained
as in Table 1. Patients with HIV, syphilis, Hepatitis B or Hepatitis C carriers will not be
included in the study and their plasmapheresis appointment at SGH Hematogloy Centre will be
cancelled. They will no longer be participating in the study.
Visit 2 (at SGH Hematology Centre):
Plasmapheresis be conducted at SGH Hematology Centre. Body temperature, , pulse rate and
blood pressure will be assessed at SGH Hematology Centre before the plasmapheresis
procedures. A plasma fluid volume of a maximum of 300ml will be collected from patients in a
closed bag over a period of up to 60 minutes. The Plasma will be transported to HSA blood
services group on the same day for crimping by an experienced technician and storage. Each
segment will contain a volume of 150 to 300μl of plasma.
Patients will receive up to half of the crimped plasma segments from courier service, while
the other half will be stored in a -80°C freezer at HSA. . When patients have almost
completely utilized all the frozen segments, they can contact the SERI coordinator again so
that arrangements (date and time) can be made for the second batch to be delivered to them.
Selected subsequents visit (at SNEC) The study outcomes will be assessed as in Table 1. Once
patients finished the plasma segments and are keen to continue with the treatment (this
occurs any time, they can arrange for the remaining plasma to be delivered to them (without
additional plasmapheresis).
If all the autologous plasma has been exhausted: Anytime during the clinical episodes, if the
PI finds that continued autologous plasma treatment is indicated and the patient is
agreeable, the plasmapheresis can be repeated and the patient will be followed up under this
study until 1 years after the autologous plasma treatment has stopped.
Storage of crimped plasma segments by patients:
Patient will be given half of the plasma that was extracted from patient body on the first
session. The remaining plasma will be safely stored at HSA in a -80°C freezer. Storage at
this central facility is more reliable than at home freezers since such a centralized freezer
is not frequently opened and the temperature can be maintained.
Patients will be instructed to store segments in a double zip-lock plastic bag in their
household freezer. Every morning, patients defrosted their daily desired number of segments
and place them into the fridge at 4°C. Each segment will be opened with alcohol wiped
scissors and must be discarded after a single use. Patients will be taught on the opening of
segments with alcohol wiped scissors and prescribe small square alcohol swabs from the
hospital pharmacy on commencement of the treatment and advice patients on how to obtain
further swabs if the supply runs out. Patients are required to use the autologous plasma
strictly according to the instructions in the patient information sheet strictly.
Usage:
Patients will use autologous plasma only for application as eye drops. The daily dose is
dependent on the patient's requirements. For example, if patients use the plasma 3 times
daily, a total of 3 segments should be defrosted each morning. Patients are allowed to
continue their existing dry eye medications. However, it is important that the plasma eye
drops are instilled at least 5 minutes prior any other eye medications. All existing dry eye
medications will be recorded.
The following procedures may be performed:
Difference of Visual Analogue Scale (VAS) for the ocular discomfort between baseline and
follow-up visits (continuous variable) A VAS will be applied to evaluate dry eye symptoms as
described by Schaumberg et al. (Schaumberg 2007). As shown in Appendix B , the scores will be
recorded separately for frequency and severity of dry eye symptoms. The patient will be asked
to check a point on a 100-mm line that corresponds to the degree of the symptom. The location
of the mark made by the patient for each question will be measured in mm from the left hand
side of the 100 mm line and recorded in mm. For the follow up visits, which measured the
distance between the mark made by the patient and the central anchor, a negative value will
be recorded if left of the anchor and a positive value if right of the anchor.
A global score will be calculated by multiplying the frequency score by the severity score
and taking the square root of the result (to transform back to the original scale).
Tear break up time (TBUT) A drop of normal saline will be instilled on a fluorescein strip
(Fluorets). The strip will then be introduced into the inferior conjunctival fornix on the
right then left eye of the patient.
The patient will blink a few times and close the eyes for few seconds. The patient will be
asked to open the eyes, look ahead at the observer's forehead and not blink for as long as
possible. The break up time will be defined and recorded as the time between the lid opening
and the first appearance of any dry spot on the cornea. The same procedure will be performed
on the left eye.
Corneal fluorescein staining score Assessment of positive fluorescein staining will be
assessed after recording TBUT. A scoring system will be applied to corneal and conjunctival
zones as depicted in Figure 1. Zones with confluent corneal staining and filaments may be
documented.
Schirmers I test (Optional) This will be done with the standard strips currently used at SERI
(5 mm wide with a notch for folding). No prior anaesthetic will be used. The strips will be
positioned over the inferior temporal half of the lower lid margin in both eyes at the same
time.
The patient will be asked to close their eyes. Any excessive irritation signs will be noted.
The extent of the wetting in each strip will be recorded after 5 minutes of testing, and
strips stored at -80˚C until further analysis.
