Study Rationale: Dry eye disease (DED), also called keratoconjunctivitis sicca, is a
multifactorial disease of the ocular surface characterized by loss of homeostasis of the
tear film and accompanied by symptoms such as ocular discomfort and visual disturbance.
The reported prevalence of DED estimates vary widely, from 5% to 33%, which may reflect
both differing populations and inconsistent diagnostic criteria. Patients with
moderate-to-severe DED may experience a reduced quality of life due to ocular pain,
difficulty in performing daily activities, and depression. First-line therapy for
treating dry eye consists of over the counter (OTC) artificial tear drops, gels,
ointments, or lubricants.
Sodium hyaluronate (commonly referred to as hyaluronic acid or HA) is a naturally
occurring polymer and is ubiquitous throughout the interstitial cellular space in humans.
It helps retain moisture in different types of tissue throughout the human body and aids
lubrication between layers of tissue to eliminate friction - thus making it an ideal
physiological tear film substitute.
As a result of its coiled structure and large hydrophilic domains, HA attracts and
retains a large amount of water, and therefore possesses the ability to retard water
evaporation. Following instillation, HA-based solutions effectively moisturize the eye
surface and prolong the beneficial wetting effect over time.
Hyaluronic acid does not alter the normal surface of the eye like other types of tear
substitutes. It closely mimics the properties of a normal, healthy tear film, with a
longer retention time on the corneal surface than a cellulose-based tear substitute.
HA gels have also been used successfully in ophthalmic surgery for many years. As a
result of their unique physical and chemical properties, HA solutions are similar to
natural tears. For that reason, they are widely used in ophthalmology as lubricant eye
drops for the treatment of sensations of ocular dryness.
For these reasons, an interventional, confirmative, post marketing clinical follow-up
(PMCF) study was planned to evaluate the performance and safety of HA-based ophthalmic
solutions (i.e. Irilens; Iridina; Afomill Lubricating Eye Drops) used to relieve dry eyes
symptoms.
Study Objective: The objectives of this PMCF study are confirmation of the performance,
collection of additional safety data regarding expected adverse events and detection of
potential unexpected adverse events associated with use of three investigational products
(IPs) containing HA as key ingredient.
The IPs are on the market with the following brand names:
Primary • To evaluate the performance of IPs used as intended to relieve dry eye
symptoms.
Secondary
To evaluate the efficacy of IPs used as intended to relieve symptoms of DED.
To evaluate the safety and tolerability of the IPs.
To evaluate the patient satisfaction of the IPs.
Methodology: Potential candidates, that according the investigator judgment could be
treated with one of IPs, will be identified, with the assessment of their eligibility
criteria. Each subject, after signing the Informed Consent Form, will enter the screening
and baseline phase (the 2 visits will coincide) during which baseline procedures will be
completed.
At baseline visit (V0), as per clinical practice, only one of the below reported IPs
products can be assigned to the enrolled subject, depending on investigator clinical
evaluation and decision:
The patient will perform 2 on site visits: V0 and V2/EOS. To monitor the safety, 1 phone
contact is planned (V1) to check for potential adverse events and concomitant medications
intake.
Data coming from additional assessments (e.g. blood tests), if done per clinical practice
to perform DED diagnosis and evaluations, might be collected and used.
Number of subjects Planned: About 90 patients in total. Treatment duration: After
baseline visit and IP dispensing, the treatment duration (according to the Investigation
Product IFU) will be prolonged until the V2 (EOS visit; 25+ 5 days).
Safety Analysis Set (SAS): The "Safety Analysis Set" (SAS): this set included all
enrolled patients who took at least one dose of IP.
Full Analysis Set (FAS): The "Full Analysis Set" (FAS): this set included all enrolled
patients who took at least one dose of IP, and with a baseline and at least one
post-baseline performance assessment.
Per protocol (PP): The "Per-Protocol" (PP) set: would include all the FAS patients who
(a) met all inclusion/exclusion criteria liable to affect the performance assessment, (b)
did not present serious deviations of the protocol that may affect efficacy.
I
IPs medical devices:
Irilens (with 0.4% HA as key ingredient);
Iridina (with 0.4% HA as key ingredient);
Afomill Lubricating Eye Drops (with 0.2% HA as key ingredient and distilled water of
Chamomile).
They are ophthalmic solutions with pH, isotonicity and osmolarity compatible with eye
tissue and tear fluid.
Irilens, Iridina and Afomill Lubricating Eye Drops are suitable in the treatment of dry
eyes symptomatology due to use of contact lenses, environmental reasons, excessive hours
of study or computer work. Irilens and Iridina are suitable also after eye surgery.
Dose/dosage: All IPs are available as 10 ml multi-dose bottles. Irilens contains sodium
chlorite as vanishing preservative. Iridina is a preservative-free ophthalmic solution.
Afomill Lubricating Eye Drops contains Phmb 0.0002% as preservative.
Irilens is also available as preservative-free 0.5 ml mono-dose vials. The IP dosage for
each individual case will be defined according to investigator judgment.
Administration:
The application of IP on eye surface should be performed in accordance to the indication
for use.
According to the Investigator judgement, based on the subject clinical conditions and the
indications reported on the IFU, one of the investigational products can be assigned to
the subject to be enrolled in the trial.
The first administration and the intervals at which the treatment should be repeated, to
be done as per investigator judgment and according the IFU, depend on various factors
regarding the physiology of the patients (e.g. type of eye-tear film, anatomy, age),
their lifestyle (e.g. use of computer, wearing of contact lenses).
Primary efficacy endpoint
• To evaluate the performance of IPs to relieve symptoms of dry eye, the Shirmer I test
(ST) might be completed at baseline (V0) and end of study visit (EOS/V2). The evaluation
will be performed stratified by study IPs.
Secondary efficacy endpoints
To assess the efficacy of IPs used as intended to relieve symptoms of dry eye, the
difference of "Ocular surface index" (OSDI) Questionnaire between baseline (V0) and
end of study visit (EOS/V2) will be evaluated stratified by study IPs.
To assess the efficacy of IPs used as intended to relieve symptoms of dry eye, the
Tear breakup time (TBUT) test might be completed at baseline (V0) and end of study
visit (EOS/V2). The evaluation will be performed stratified by study IPs.
To evaluate the safety and tolerability of the IPs a Visual Analogue Scale (VAS)
will be used.
The patient satisfaction will be evaluated with a 5-points Likert Scale.
Safety:
Safety will be monitored through eye examination and adverse events including assessment
of relationship to the IP.
Time-points for efficacy and safety: Baseline (V0) and follow up visit(s) performed.
Statistical methods:
Supposing a minimum difference of 20% (equals to 1 mm of difference) between after
treatment and at baseline visit in terms of mean ST value, with a standard deviation (SD)
equal to 1.7 mm, a correlation between baseline and end of treatment of 50%, and a type I
error of 5%, 25 patients are sufficient to reach a statistical power greater than 80% for
each IPs.
Moreover, planning to enroll a total of 30 patients would allow for a 15% drop-out rate.
Considering all IPs included, 90 patients should be enrolled in the study. In general,
all the variables will be descriptively analyzed by treatment groups and visit (mean,
median, standard deviation, minimum and maximum for continuous variables after normality
check of distribution with Kolmogorov-Smirnov test, frequency distribution for
categorical variables). All the analysis will be detailed in the Statistical Analysis
Plan (SAP) which will be finalized in Version 1.0 before the Data Base Lock (DBL).
In details, the safety data will include (at least) physical examinations, laboratory
data and adverse events.
