loteprednol

1. Clinical Conducted Site: Kalinga Institute Of Medical Sciences,
Kushbhadra Campus, KIIT Campus-5 Bhubaneswar
Department: Ophthalmology
PI: Dr. Manmath Kumar Das
CO-PI: Dr. Shovana Dash
Protocol Title: A Multicentric, Randomized, Double Blind, Double Dummy, Parallel
Group, Two Arm, Comparative, Phase III Clinical Study to Evaluate the Efficacy,
Safety and Tolerability of Loteprednol Etabonate Ophthalmic Suspension 1% w/v of
Ajanta Pharma Ltd. versus Loteprednol Etabonate Ophthalmic Suspension 0.5% w/v
in the treatment of Post-Operative Inflammatory conditions of the Eye.
Protocol ID: APL/CT/22/02 Confidential Version No.: V02

2. INDEX OF PRESENTATION
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Sr. No. Contents Slide No.
1 The Unmet Medical Need in the Country 3
2 Mechanism of Action of Loteprednol Etabonate Ophthalmic Suspension 1% w/v 4
3 Current Regulatory Status of Loteprednol Etabonate Ophthalmic Suspension 1% w/v 5-9
4 Protocol Title 10
5 Details of the Clinical Trial Protocol 11-12
6 Clinical Trial Design 13
7 Study Activity Chart 14-15
8 Subject Eligibility Criteria 16-21
9 Compensation in the Case of Injury or Death 22

3. THE UNMET MEDICAL NEED IN THE COUNTRY
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 Visual system has a delicate microanatomy, which is susceptible to damage even from low levels of intra ocular
inflammation, which if left untreated can result into temporary and permanent visual loss.
 Ophthalmological inflammatory conditions include multiple anterior chamber and posterior chamber pathologies,
like Giant Papillary Conjunctivitis, Seasonal Allergic Conjunctivitis, Vernal Keratoconjunctivitis, Post Ocular
Trauma/Surgery, Iritis, Uveitis etc. affecting all age ranges across.
 Bacterial and seasonal inflammatory pathologies remains a significant problem in tropical countries like India with
hot and humid climatic conditions and unhygienic living conditions.
 Although multiple treatment options like artificial tears, topical NSAIDs, topical and systemic Anti histaminics,
Mast cell stabilizers are available, all of them have limitations of use.
1. Pavesio, Carlos E., and Heleen H. DeCory. "Treatment of ocular inflammatory conditions with loteprednol etabonate." British journal of ophthalmology 92, no. 4 (2008): 455-459.
2. Rathi, Varsha M., and Somasheila I. Murthy. "Allergic conjunctivitis." Community eye health 30, no. 99 (2017): S7.
3. Micieli JA, Arshinoff SA. Cataract surgery. CMAJ. 2011;183(14):1621.

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MECHANISM OF ACTION-LOTEPREDNOL ETABONATE
 Loteprednol etabonate specifically induces phospholipase A2
inhibitory proteins (collectively called lipocortins), which inhibit
the release of arachidonic acid, thereby inhibiting the biosynthesis
of potent mediators of inflammation, such as prostaglandins and
leukotrienes.
 Corticosteroids are thought to act by the induction of
phospholipase A2 inhibitory proteins, collectively called
lipocortins.
 It is postulated that these proteins control the biosynthesis of
potent mediators of inflammation such as prostaglandins and
leukotrienes by inhibiting the release of their common
precursor arachidonic acid. Arachidonic acid is released from
membrane phospholipids by phospholipase A2.

5. CURRENT REGULATORY STATUS
Country – USA
Products: Loteprednol Ophthalmic Suspension 1% w/v
Approval Date: Aug 22, 2018
Company: Kala Pharmaceuticals INC
Brand name: Inveltys
USA Approval
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6. CURRENT REGULATORY STATUS
Country – USA
Products: Loteprednol Ophthalmic Suspension 0.5% w/v
Approval Date: Sep 28, 2012
Company: Bausch & Lomb INC
Brand name: Lotemax
USA Approval
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7. CURRENT REGULATORY STATUS
Country – Germany
Products: Loteprednol Ophthalmic Suspension 0.5% w/v
Approval Date: Mar 31, 2008
Company: Bausch & Lomb GmbH
Brand name: Lotemax
Germany Approval
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8. CURRENT REGULATORY STATUS
Country – Australia
Products: Loteprednol Ophthalmic Suspension 0.5% w/v
Approval Date: Jan 16, 2014
Company: Bausch & Lomb (Australia) Pty Ltd
Brand name: Lotemax
Australia Approval
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9. CURRENT REGULATORY STATUS
Country – India
Products: Loteprednol Etabonate Ophthalmic Solution 0.5%
Approval Date: Mar 15, 2002
1. India Approval_Loteprednol
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10. TITLE:
“A Multicentric, Randomized, Double Blind, Single Dummy, Parallel Group, Two Arm, Comparative,
Phase III Clinical Study to Evaluate the Efficacy, Safety and Tolerability of Loteprednol Etabonate
Ophthalmic Suspension 1% w/v of Ajanta Pharma Ltd. versus Loteprednol Etabonate Ophthalmic
Suspension 0.5% w/v in the treatment of Post-Operative Inflammatory conditions of the Eye.”
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11. DETAILS OF CLINICAL TRIAL PROTOCOL
Indication
Objectives
Arms
Duration
Treatment of Post-Operative Inflammatory conditions of the Eye
Primary Objective
 To evaluate the efficacy of Loteprednol Etabonate Ophthalmic Suspension 1% w/v
in the treatment of Post-Operative Inflammatory conditions of the Eye.
Secondary Objective
 To evaluate the safety of Loteprednol Etabonate Ophthalmic Suspension 1% w/v
in the treatment of Post-Operative Inflammatory conditions of the Eye.
Day 18±2
Arm A: Loteprednol Etabonate Ophthalmic Suspension 1% w/v + Placebo
Arm B: Loteprednol Etabonate Ophthalmic Suspension 0.5% w/v
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Sample Size
Total 206 Subjects (164 Evaluable subjects) Considering 20% of dropout.
Two arms in a ratio of (1:1 - 91:91).
Dose Arm A: Twice Daily + Twice Daily
Arm B: Four Times Daily

12. DETAILS OF CLINICAL TRIAL PROTOCOL
Endpoints
Primary Efficacy Parameter:
• Proportion of Subjects With Complete Resolution of Anterior Chamber (AC) Cells at
visit 5 [ Time Frame: postoperative Day 8]
• Proportion of Subjects With Grade 0 Pain in the Study Eye. [ Time Frame: 8 days ]
Secondary Efficacy Parameter:
• Proportion of study eyes with complete resolution of Anterior Chamber (AC) Flare at
each visit and for each subjects final on treatment visit.
• Proportion of study eyes with Grade 0 pain at each visit and for each subjects final
on treatment visit.
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Safety Parameters:
• The assessment of safety will be based on the frequency of Adverse Events, Serious
Adverse Events and Changes in laboratory parameters.

13. CLINICAL TRIAL DESIGN
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SCREENING VISIT [V1]
-14 Days
Check inclusion/exclusion criteria
≤14 days Surgery day [V2]
Screen failure
Do not enrol the subject
Subject fulfilling all inclusion and none of
exclusion criteria will be enrolled.
RANDOMIZATION VISIT [V3]
(Day 1)
Loteprednol Etabonate Ophthalmic Suspension 1% w/v
OR
Loteprednol Etabonate Ophthalmic Suspension 0.5% w/v
TREATMENT
PERIOD BEGINS
FOLLOW UP VISIT [V4, V5 and V6]
Day 3±2, Day 8±2 and Day 15±2
Day 18±2
FINAL VISIT [V7]

14. STUDY ACTIVITY CHART
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Study procedures Visit 1
(Screening/
Baseline)
Day -14
Visit 2
Surgery
(≤14 days of Visit 1)
Visit 3
Postoperative
Day 1 (18 to 34 hours
post-surgery)
Visit 4
(Follow up)
Day 3 (±1)
Visit 5
(Follow up;
Week 8)
Day 8 (±2)
Visit 6
(Follow up;)
Day 15 (±2)
Visit 7
(Follow up)
Day 18 (±2)
Post treatment
Exam
ICF X - - - - - -
Inclusion/Exclusion criteria X X - - - - -
Randomization - - X - - - -
Demographics X - - - - - -
Medical History X - - - - - -
Vitals (Pulse, Temp., BP and RR) X X X X X X X
Physical Examination X X X X X X X
CBC, SGOT, SGPT X - - - - X -
Serum Creatinine, eGFR,
Routine Urine Analysis,
X - - - - X -
Fundoscopy X - - - - X -
Visual Acuity X - X X X X X
IOP Measurement X - X X X X X
Biomicroscopy X - X X X X X
VAS Scale X - X X X X X
ECG X - - - - X -
HbA1c X - - - - - -
Urine Pregnancy TestSOS X - - - - X -
Note: CBC: Hemoglobin, Total RBC count, Total WBC count, Neutrophils, Basophils, Eosinophils, Lymphocytes, Monocytes and Platelets.

15. STUDY ACTIVITY CHART
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Study procedures Visit 1
(Screening/
Baseline)
Day -14
Visit 2
Surgery
(≤14 days of Visit 1)
Visit 3
Postoperative
Day 1 (18 to 34 hours
post-surgery)
Visit 4
(Follow up)
Day 3 (±1)
Visit 5
(Follow up;
Week 8)
Day 8 (±2)
Visit 6
(Follow up;)
Day 15 (±2)
Visit 7
(Follow up)
Day 18 (±2)
Post treatment
Exam
Drug Dispensing - X - - - - -
Drug Accountability - - X X X X -
Drug Dosing Card Dispensing - - X - - - -
Drug Dosing Card
Accountability for Compliance
- - X X X X -
AE/ ADR/ SAE X X X X X X X
Concomitant Medication X X X X X X X
Assessment of Efficacy - - X X X X -
Assessment of Safety X X X X X X X
Note: CBC: Hemoglobin, Total RBC count, Total WBC count, Neutrophils, Basophils, Eosinophils, Lymphocytes, Monocytes and Platelets.
Note: If during the surgery it is determined that additional manipulations, such as pupil stretching or the use of iris hooks or peripheral relaxing corneal incisions are required, the subject is not
eligible to participate in the trial.

16. SUBJECT ELIGIBILITY CRITERIA
 Inclusion Criteria:
 Male or female 18 to 75 years of age, both ages inclusive.
 Have presence of cataract in at least one eye indicated for extracapsular cataract extraction /phacoemulsification.
 Body Mass Index between 18.0 and 35.0 kg/m2.
 Be able to communicate effectively with the study personnel.
 Be a non-consumer of tobacco (or a mild or moderate consumer) of tobacco.
 Should have undergone medical screening & fit for surgery.
 Have given the written informed consent for participation in the study.
 Be declared eligible to participate in the study by the investigator.
 Be willing and able to comply with all treatment and follow- up/study procedures.
 Be willing and able to comply with all treatment and follow-up/study.
 Be able to read, understand, and provide written informed consent on the Institutional Review Board (IRB)/Ethics Committee
(EC) approved ICF and provide Health Insurance Portability and Accountability Act (HIPAA) authorization.
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17. SUBJECT ELIGIBILITY CRITERIA
 Inclusion Criteria:
 For female subjects, either
• Not be of childbearing potential (female subjects not of childbearing potential must be postmenopausal at least 12 months
prior to Visit 3 or permanently sterilized [eg: tubal occlusion, hysterectomy, bilateral salpingectomy])
Or
• Have a negative urine pregnancy test result at Visit 1 (Screening) and willing to use acceptable contraceptive measures.
 Willing to undergo cataract surgery (Topical anesthesia phaco-emulsification with IOL implantation, not combined with any
other surgery) in the study eye.
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18. SUBJECT ELIGIBILITY CRITERIA
 Exclusion Criteria:
 Suspected or history of hypersensitivity to either of the study medications or any of the ingredients of the formulation.
 Have a severe/serious ocular condition or history/presence of chronic generalized systemic disease that the investigator feels
might increase the risk to the subject or confound the results of the study.
 Female subject who is pregnant or breastfeeding.
 Have a ocular hypertension ≥21 mm Hg, glaucoma or any glaucoma related incisional or laser surgery in the study eye.
 Have had ocular surgery (inclusion laser surgery) in the study eye within 3 months or in the fellow eye within 2 weeks prior to
Visit 1 (Screening).
 Have a current diagnosis of cystoid macular edema in the study eye
 Have any abnormality that prevents reliable Goldmann Applanation tonometry in either eye.
 Have iris atrophy in the operative eye.
 Have lens pseudoexfoliation syndrome with glaucoma or zonular compromise in the study eye.
 Be unable, for any reason to discontinue contact lens use in the study eye during the course of the study.
 Have a history of chronic or recurrent inflammatory eye disease in the study eye (e.g. iritis, scleritis. Uveitis, iridocyclitis, herpes
simplex infection).
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19. SUBJECT ELIGIBILITY CRITERIA
 Exclusion Criteria:
 Have proliferative diabetic retinopathy or moderate to severe non-proliferative diabetic retinopathy in the study eye.
 Have any intraocular inflammation in either eye (cells or flare score greater than Grade 0 at slit lamp examination) or ocular pain
greater than Grade 1 in the study eye at Visit 1 (Screening).
 Have a congenital ocular anomaly in either eye.
 Have a presence of active external ocular disease: infection (bacterial, viral or fungal) or inflammation (including allergic) of the
study eye.
 Have used ocular therapy (either eye) with non steroidal anti inflammatory drugs (NSAIDs), mast cell stabilizers, antihistamines,
or decongestants within 2 days prior to surgery or be expected to require any of these treatments during the 18 days following
cataract surgery.
 Be expected to require treatment with systemic NSAIDs, antihistamines or decongestants during the 18 days following cataract
surgery with the exception of ≤ 81 mg/day of acetyl salicylic acid.
 Be expected to require treatment with any systemic, inhalation, nasal, or ocular (either eye) corticosteroids or gluco-corticosteroids
during the 18 days following cataract surgery or have used ocular immunosuppressants within 30 days prior to surgery.
 Have participated in any drug or device clinical investigation within 30 days prior to participate into the study.
 Any blood donation or significant loss of blood within 56 days of Visit 1.
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20. SUBJECT ELIGIBILITY CRITERIA
 Exclusion Criteria:
 Any history of immunodeficiency disorder, positive HIV, hepatitis B, C, or evidence of acute active hepatitis A (anti-HAV IgM),
or organ or bone marrow transplant.
 Any significant illness that could interfere with study parameters.
 Known history of alcohol and/or drug abuse.
 Unwilling to stop wearing contact lenses during the study.
 Females who are not ready to use acceptable contraceptive methods during the course of study.
 Currently taking prohibited concomitant medications(s) listed and inability/unwillingness to discontinue them for the entire
study period.
 Suspected inability or unwillingness to comply with the study procedures.
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21. DISCONTINUATION CRITERIA
 Subjects at their own request voluntarily or at the request of their legally acceptable representative can be withdrawn from the
study.
 If at any point of the study subject is found to be non-compliant with the study protocol.
 Any adverse events that prevents further administration of treatment.
Patient withdrawn from the study from either arm will be provided standard care of treatment as decided by the
investigator.
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22. COMPENSATION IN THE CASE OF INJURY OR DEATH
 The expenses on medical management and financial compensation in the case of clinical trial injury or death of
the trial subject will be borne by the sponsor.
 Free medical management as long as required.
 Financial compensation to the subject in the case of clinical trial injury.
 Financial compensation to the subject’s nominee(s) in the case of clinical trial related death.
 As per revised government norms [GSR 889 (E), Rule 122 DAB, dated 12-12-2014].
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https://cdsco.gov.in/opencms/opencms/en/Notifications/Gazette-Notifications

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