Efficacy and Safety of Ocudox Lid Wipes Compared to Traditional Lid Cleaning
Condition: Dry Eye
MeSH terms: Dry Eye Syndromes
Study type: Interventional
Phase: Phase 1

Summary: 
      The use of povidone iodine solution for prophylaxis of endophthalmitis is well established
      for intraocular procedures like cataract surgery and for injections of anti-VEGF agents for
      retinal diseases such as age-related macular degeneration. Unfortunately iodine is unfriendly
      to the ocular surface, and when repeated often enough (some patients require up to monthly
      injections of anti-VEGF agents for the entire year), corneal epitheliopathy and secondary dry
      eye results. Unfortunately, there is no good alternative to cleaning patient's eyelid at the
      moment. Ocudox is a relatively new antibacterial product (spraying on eyelid wipe) which
      contains Neutrox (pure hypochlorous acid) that kills many microbes, but remain very friendly
      and non-toxic for the ocular surface.
    

Detailed description: 
      In a multicentre study involving 71 eyes, reported at a conference abstract (ARVO), Avenova
      (similar ingredients as Ocudox) reduces bacteria on ocular skin surface by more than 90%
      without altering the diversity of bacteria on the ocular skin surface in any significant way.
      This lowering of the bacterial load was particularly noteworthy for all staphylococci,
      including S. epidermidis, the most frequently recovered species. At 20 minutes following
      treatment, 138 unique bacterial strains belonging to 26 different species were recovered.

      However, the efficacy of anti-microbial action has not been compared to the gold standard of
      a single wipe with povidone iodine solution. Investigator intend to compare pre and post
      treatment of Ocudox and a single use of povidine iodine solution at Day 14 in terms of the
      alteration of the conjunctival microbiome of the eye and the effect on the ocular surface.

      Clinical significance The study has implications on the prophylaxis of infection in many
      common ophthalmic procedures conducted in Singapore National Eye Centre and many places in
      the world.

        1. OBJECTIVES The aim of this study is to compare pre and post-treatment of the application
           of Ocudox to a single use of povidine iodine solution at Day 14in terms of the
           alteration of the conjunctival microbiome and the integrity of the eye.

        2. EXPECTED RIKS AND BENEFITS There would be no expected risk involved as all the
           evaluations are non-invasive. However, there will be some slight discomfort from measure
           tear volume or tear collection (Schirmer's strips) and also slight discomfort from
           culturing procedure.

      There are no known benefits from participation in this study. However, this project may have
      the potential to prevent infection in many common ophthalmic procedures conducted in
      Singapore National Eye Centre and many places in the world.

      3. STUDY POPULATION 3.1. List the number and nature of subjects to be enrolled. Due to the
      nature of the preliminary study, six participants with Meibomian Gland Dysfunction (MGD) will
      be recruited from Singapore National Eye Centre. Participants will be randomised into either
      Ocudox group or single use povidine iodine solution.

      n= 3 (Ocudox group) n= 3 (Single use povidine iodine solution)

      3.2. Criteria for Recruitment and Recruitment Process

      1. Participants meet all the inclusion criteria listed below. 2. Clear of exclusion criteria.
      Permission would be sought from the attending doctors before participants are being
      recruited.

      Eligible participants will be counselled on the study by the study coordinator. If the
      participant is interested, the study coordinator will then accompany the participant to SERI
      level 5 for the relevant assessments. Informed written consent will be obtained from all
      participants.

      3.3. Inclusion Criteria Participants must meet all of the inclusion criteria to participate
      in this study.

      1. Participants must be 50 to 60 years old with Meibomian Gland Dysfunction (MGD) 2. Clear of
      exclusion criteria 3. Willing to perform all eye examinations in this study 3.4. Exclusion
      Criteria Participants meeting any of the exclusion criteria will be excluded from this study.

        1. Participants diagnosed with diabetes

        2. No recent eye surgery or eye procedure within 1 month

        3. Participants who are unsuitable for Oculus K5M recording such as musculoskeletal
           problems

        4. Participants who are unable to tolerate Oculus K5M recording machine

        5. Is pregnant, lactating or planning a pregnancy

        6. Any other specified reason as determined by clinical investigator

      4. STUDY DESIGN AND PROCEDURES/METHODOLOGY This is a randomised interventional trial with
      Ocudox eyelid wipes and povidine iodine solution.

      Study visits and duration:

      Trial arms No. of study visits Study duration Ocudox eyelid wipes 3 21±3 days Povidine iodine
      solution 3 21±3 days Recruitment duration: One year

      Treatment arms and randomisation:

      There will be 2 trial arms (parallel groups) in this study:

      A. Ocudox eyelid wipes n=3 B. Povidine iodine solution n=3

      Randomisation and Blinding

      The randomisation procedure used will entail:

        1. Presence of two witnesses

        2. Drawing of lots

        3. Randomization codes for the 2 groups will be noted. For e.g. 001A, 002B, etc.

        4. Study information related to randomisation will be filed and kept at SERI

        5. Only unblinded personnel have access to the randomization code file

      There will be blinded and unblinded study team members in this study. Blinded study team
      members will only be performing the procedures as described below. Unblinded study team
      members will dispense the study product, counsel participants on directions for using Ocudox
      eyelid wipes and also to clean the eyelid and conjunctiva if randomised to Povidone Iodine,

      Directions for using Ocudox eyelid wipes:

      Participant who received Ocudox eyelid wipes will be instructed to clean the eyelid according
      to manufacturer's protocol during the study period (twice a day). A diary chart will be given
      to all participants at the end of baseline visit. Participants will be asked to fill up the
      diary chart whenever Ocudox eyelid wipes was used.

      Directions for cleaning with Povidone Iodine:

      • Pour 10ml of 10% Povidone Iodine into a 50ml Falcon tube.

        -  Dilute 10% of Povidone Iodine to 5% by pouring 10ml of saline and 10ml of Povidone
           Iodine into a 50ml Falcon tube

        -  Prepare gauze and dip into the 10% Povidone Iodine solution

        -  Clean participant's exterior eye at least 2-3 times

        -  Next, flush the interior of the participant's eye with 5% Povidone Iodine

        -  Using a pasture pipette, flush the interior of the participant's eye

        -  Wait for 5 minutes

        -  After 5 minutes, rinse off with saline solution

        -  Thereafter, wait for 1 minute before adding tetracaine

        -  After adding tetracaine, wait for another minute before collection of microbiome swab.

      Equipment used:

      Oculus Keratograph 5M will be used on the baseline visit and post-treatment visits.

      Workflow procedure:

      Ocular symptoms will be examined subjectively using standard patient evaluation of eye
      dryness (SPEED). Oculus Keratograph 5M will be conducted to assess tear meniscal height
      (TMH), conjunctival redness and Non-invasive Tear Break-Up time (NIKBUT). Meibomain gland
      evaluator will be used to assess the number of expressible glands. Bacteria on the eye
      surface will be cultured from one of the conjunctivas (white part of the eyes) and Schirmers
      I test will carry out to examine tear secretion and tear collection.

      Outcomes:

      Differences in Tear Meniscus Height, Ocular Redness, Non-invasive Tear Break-up time readings
      and findings of DNA/RNA between study visits and study groups.

      Figure 2. Study workflow

      Details of study procedures shown below:

      i) SPEED questionnaires Investigator will use the previously validated standard patient
      evaluation of eye dryness (SPEED) questionnaire, which consists of 2 questions on frequency
      and severity of dry eye graded on a scale of 0-3 on frequency, and grades 0-4 on severity.
      Scores from all sub-questions will be added, and the greater the total score (0-28), the more
      frequent or severe the dry eye (2).

      ii) Non-invasive tear break-up time Both Oculus Keratograph 5M (Oculus, Wetzlar, Germany)
      will be used to perform the non-invasive tear break up time (NIKBUT) (3). Briefly, seated
      patients blink freely while fixing on a target ahead. Once ready, patients blink twice and
      then refrain from further blinking. The fully automated instrument will capture any break or
      distortion in the image of the projected rings on the cornea and the timings will be
      automatically recorded. One reading will be taken per eye (4).

      iii) Conjunctiva redness & Tear meniscus height Oculus Keratograph 5M (Oculus, Wetzlar,
      Germany) will be used to measure conjunctival redness. After scanning the ocular surface and
      images captured, grading of the conjunctival hyperemia (0-4) will be automatically performed
      with subtraction of major conjunctival blood vessels, and temporal bulbar, nasal bulbar and
      average readings will be obtained. Higher redness scores indicate more hyperemia(5). Height
      of the tear meniscus can be measured by dragging the ruler option icon and the measured value
      will appear in mm.

      iv) Meibomain Gland Evaluator Meibomian glands will be assessed by gently squeezing the lower
      eyelids using a device that delivers standardised pressure to the eyelids (Meibomian gland
      expresser, TearScience, France). Texture of the expressed secretion will be graded as liquid
      or viscous. The number of expressible glands will be recorded.

      v) Collection of microbiome One specimens of microbiome will be collected from both eyes
      First: a drop of non-preserved tetracaine will be instilled into the conjunctival fornix.
      After the stinging sensation has resolved, a sterile cotton swap will be used to collect the
      microbes from the lower conjunctival fornix using a gentle rolling action (up to 8 strokes).
      The procedure is then repeated for the opposite eye.

      These swaps will then be soaked in DNA/RNA Shield (Zymo) reagent and immediately homogenised
      for 1 minute, stop at 30 seconds, and keep on ice for 1 minute, and homogenized for another
      30 seconds. Homogenised samples will be stored at 4°C. This ensures an optimal and sufficient
      DNA/RNA yield for our purpose. Subsequent nucleic acid extraction, PCR, sequencing, and
      bioinformatics procedures will be performed by our collaborators. Storage: intended to be
      analysed within a year, not more than 5 years.

      Analysis: Investigator intend to compare composition of known microbes at the specie and
      genus level after obtaining the reads in the non-human DNA metagenomics signatures.

      vi) Schirmers I test Schirmer I test will be done with the standard 5 mm wide Test Strips
      (Clement Clark) with a notch for folding, without prior anaesthesia. The strips will be
      positioned over the inferior temporal half of the lower lid margin in both eyes, and
      participants' eyes will then close. The extent of the wetting will be recorded after 5
      minutes, and strips stored at -80˚C until further analysis(7).
    

Intervention name(s): Eyelid cleaning
Intervention type(s): Procedure
Intervention description(s): This is a pure hypochlorous acid that kills many microbes, but remain very friendly and non-toxic for the ocular surface.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Ocudox lid wipes
Masking: Single (Investigator)
Primary purpose: Prevention