Title of Study

Prospective, randomized, comparative clinical investigation to evaluate and compare the performance & safety of two different OVDs in patient undergoing cataract surgery.

Protocol No, Version, Date

BIOHYALURPLUS-2022-02, 1.0, 04-Oct-2022

Study Devices

Sodium Hyaluronate ophthalmic viscosurgical device

1. Bio-Hyalur Plus (Sodium Hyaluronate 1.4%)

2. Protectalon (Sodium Hyaluronate 1.4%)

Study Design

This study is a Prospective, randomized, comparative clinical investigation to evaluate and compare the performance & safety of two different OVDs in patient undergoing cataract surgery. Total 140 subjects will be included in study.

Number of patients

The sample size has been calculated by considering the primary endpoint, in terms of the incidence of IOP observations <30 mmHg is 98%. Assuming non-inferiority margin of 10% with allocation ratio of 1:1 a sample size of 112 Eyes (i.e. 56:56) are required at 85% power, with 0.05% level of significance. Considering the drop-out rate up to 20%, total 140 (70:70) patients/eyes will be required to be enrolled in the study.

Number of Centers

1 Center

Duration of clinical investigation

12 Month (9 Month for enrolment and 3 month for follow-up)

Objectives

Primary Objective: To evaluate and compare the performance of Bio- Hyalur Plus against Protectalon 1.4% in patient undergoing cataract surgery.

Secondary Objectives: To evaluate and compare the safety of Bio- Hyalur Plus against Protectalon 1.4% in patient undergoing cataract surgery.

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Study Parameter

1. 1)  Intraocularpressure[Timeframe:Pre-operative,8hours,24 hours, 7 days, 30 days and 90 days post-operative] - Intraocular pressure will be measured by Goldmann Applanation Tonometry in mmHg.

2. 2)  Changes in cell density of the corneal endothelium: [Time Frame: Pre-operative, and 90 day post-operative] - Endothelial cell count (cell/mm2) performed by counting of cells on photographic image of endothelium taken by specular microscope in cell/mm2.

3. 3)  Intraocular Inflammation with Grade of Inflammation [Time Frame: Pre-operative, 24 hours, 7 day, 30 day and 90 day post-operative] - Measurement performed by slit-lamp bio microscopy. Grading of Inflammation will be done based on Aqueous cells and flares as per Standardization Uveitis Nomenclature (SUN);

* Field size should be 1 mm by 1 mm slit beam. The presence or absence of hypopyon should be noted separately in addition to the cellular activity grade.

4. 4)  Cornealthickness(μm)[TimeFrame:Pre-operative,7day, 30 day and 90 day post-operative]- Change in corneal thickness will be measured in micrometre. Measurement performed by SIRIUS topographer.

5. 5)  VisualAcuity[TimeFrame:Pre-operative,30dayand90day post-operative] - Visual Acuity (VA) is measured in LogMAR. LogMAR is the "logarithm of the minimum angle

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of resolution". A lower LogMAR value indicates better visual

acuity. Visual acuity measured by ETDRS chart.

6. 6)  Uncorrecteddistancevisualacuity(UDVA)

7. 7)  Correcteddistancevisualacuity(CDVA)

8. 8)  Corneal Clarity [Time Frame: Pre-operative, 8 hours, 24

   hour, 7 day, 30 day and 90 day post-operative] - It will be evaluated by slit-lamp bio microscope. Grading of corneal clarity on the basis of corneal haze as following;

Grade Detail

0. 0  No corneal haze

1. 1  Iris details visible

2. 2  Pupillary margin visible, iris details not visible

3. 3  Pupillary margin not visible

4. 4  Cornea totally opaque

9) CentralCornealendothelialcelldensity:[TimeFrame:Pre- operative, and 90 day post-operative] - It will be measured by specular microscope

10) CV in cell size in percentage: [Time Frame: Pre-operative, and 90 day post-operative] - It will be measured by specular microscope

11)Cell area:[Time Frame: Pre-operative,and 90 day post- operative] - It will be measured by specular microscope

12) Cell Hexagonality: [Time Frame: Pre-operative, and 90 day post-operative] - It will be measured by specular microscope

13) Lens Clarity: [Time Frame: 8-hours, 24 hours, 7 day, 30 day, 90 day post-operative] - It will be evaluated by slit-lamp bio microscope.

Safety Endpoint:
1) AdverseEvents[TimeFrame:intra-operativevisit,8-hours,

24 hours, 7 day, 30 day, 90 day post-operative and as and when occur]

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2) Iritis by Slit Lamp Examination
3) Fibrin (Grading from 0-none to 4-severe) in anterior chamber

by Slit Lamp Examination

Parameters to be obtained during intra-operative procedure

1. 1)  Investigator Reported Space Maintenance: Maintenance of the anterior chamber/dome during cataract surgery. Space maintenance was reported during Capsulorhexis, Hydro- dissection, Phacoemulsification, and IOL insertion. This will be rated by the surgeon on of the following category:

   •   Full Chamber Maintained

   •   Working Space Maintained  Shallow
      Flat

2. 2)  OVDresidingtimeinAnteriorChamber:Itwillbereportedin Minutes

3. 3)  Removal time of OVD: It will be reported in Seconds

4. 4)  Total Phaco time: It will be reported in Seconds

5. 5)  Effective Phaco time: It will be reported in Seconds

6. 6)  Average Phaco power: It will be reported in percentage

7. 7)  Vacuum: It will be reported in mmHg

8. 8)  Ease of removal use: It will be rated in following parameters based on investigator’s experience.

    Excellent
    VeryGood
    Good
    NeedsImprovement

Study Endpoints

Primary Endpoint

To compare Bio-Hyalur Plus with the Protectalon 1.4% in terms of the incidence of IOP observations above 30 mmHg.

Clinical Parameters

Clinical Parameters:

1 The Endothelial Cell Density Changes from pre-operative to 3 months post-operative for both OVD group.

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2. 2  The grade of inflammation will be tabulated with the frequency and proportion of eyes with each grading for each event over time and cumulatively will be presented for both OVD groups.

3. 3  The grade of corneal clarity will be tabulated with the frequency and proportion of eyes with each grading for each event over time and cumulatively will be presented for both OVD groups.

4. 4  The change in Visual acuity (UCVA & BCVA) from baseline will be presented by descriptive statistics for the 1-month and 3- month postoperative by OVD groups.

5. 5  The frequency and proportion of monocular BCVA will be reported over time by visual acuity line. Monocular BCVA percent 20/40 or better will also be compared to ISO SPE rate.

6. 6  The frequency and proportion of monocular UCVA will be reported over time by visual acuity line.

7. 7  The change in corneal thickness from baseline will be presented by descriptive statistics for the 1-week, 1-month and 3-month post-operative time points by OVD groups.

Eligibility Criteria

Inclusion Criteria:

1. 1)  Unilateral/Bilateral

2. 2)  Age18yearorgreater

3. 3)  Cataractforwhichphacoemulsificationextractionandposterior

   chamber IOL implantation was planned in at least one eye of the

   patient

4. 4)  Clearintraocularmediaotherthancataract

5. 5)  Signedinformedconsent

6. 6)  Patient who are willing to attend all the regular follow-up

   examinations as per the study schedule.

Exclusion Criteria:

1. 1)  Concurrent participation or participation in the last 30 days in any other clinical trial.

2. 2)  Historyofprevioussteroid-inducedIOP

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3. 3)  Patientwithpigmentdispersionsyndrome

4. 4)  Takingmedicationsthatmayaffectvision,IOP,oreaseofcataract

   surgery (e.g., Flomax, glaucoma medications, etc.)

5. 5)  Acute or chronic disease or illness that would increase risk or

confound study results (e.g., diabetes mellitus,

immunocompromised, etc.)

6. 6)  Uncontrolledsystemicoroculardisease.

7. 7)  Historyofoculartraumaorpriorocularsurgery

8. 8)  Corneal abnormalities (e.g., stromal, epithelial or endothelial

   dystrophies)

9. 9)  Knownpathologythatmayaffectvisualacuity;particularlyretinal

   changes that affect vision (e.g., macular degeneration, cystoid

   macular edema, diabetic retinopathy, etc.)

10. 10)  Any visual disorder predicted to cause future acuity loss to a level

    of 0.3 LogMAR or worse

11. 11)  Pseudoexfoliation

12. 12)  Ocular hypertension (>22 mm Hg) or glaucomatous changes in the

    optic nerve.

13. 13)  Endothelial cell counts lower than 1500 cells/mm2 preoperatively

    (based on the lowest value of three cell counts performed by

    technician at investigative site)

14. 14)  Patient is pregnant, planned to become pregnant, lactating or had

    another condition associated with the fluctuation of hormones that

    could lead to refractive changes

15. 15)  Vulnerable subject.

Follow-up schedule

• ï‚·  Pre-operative Visit/Screening Visit

• ï‚·  Surgery Visit/Intra-operative Visit

• ï‚·  Post-operative 8 hours ± 2 hours

• ï‚·  Post-operative 24 hours ± 4 hours

• ï‚·  Post-operative 7 Days ± 2 days

• ï‚·  Post-operative 30 days ± 7 days

• ï‚·  Post-operative 90 days ± 14 days

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Apart from this follow-up schedule, if patient turned up for any additional unscheduled visit to clinic then data for that particular visit will be documented in the Case Report Form (CRF) in appropriate section.

Statistical Analysis

The continuous data will be summarized by treatment groups using descriptive statistics (number of eyes (n), mean, standard deviation (SD), median, minimum and maximum). Categorical data will be summarized by different OVDs using frequency count (n) and percentages (%). All statistical tests will be conducted at the 5% significance level, unless indicated otherwise.

The analysis of performance will be performed on all the patients in mITT and PP population. Any missing post-baseline data will be imputed using the last observation carried forward (LOCF).

Ethical Consideration

The clinical investigation plan, informed consent form and other study related documents must be submitted to the appropriate Ethics Committee (EC) and written approval must be obtained. The investigator will not make any change in the research without EC approval, except when necessary to eliminate immediate hazards to human patients. The Investigator will promptly report to the EC proposed changes and all unanticipated problems involving risks to human patients or others.

These amendments involving significant risk or changes requiring EC approval and written documentation of this approval must be submitted by the investigator before implementation except in case of emergency where the investigator may implement the amendments and then inform the EC as soon as possible.

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Quality Standard

This study will follow Declaration of Helsinki (in accordance with the applicable country’s acceptance), ICH standards for clinical research including ICH-E6 (GCP) and ICH-E3 (Study Reporting); ISO 14155 standards for Conduct of the study. The quality plan will be prepared in accordance with ISO 14155 and ICH-GCP guidelines.

Quality assurance for the data and conduct of the study is primarily the responsibility of the Investigator. The Investigator will ensure that the study complies with the norms of GCP and ISO 14155. The local regulations will be followed in data management quality assurance. Proper due diligence will be conducted before a service is outsourced to any clinical vendor.