Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

RESEARCH Protocol

Title of the study:

Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

Introduction and Need for the study

Vernal keratoconjunctivitis (VKC) is a chronic bilateral allergic inflammation of the ocular surface, involving the palpebral and/or bulbar conjunctiva. It is more common in temperate zones of the Mediterranean region, Central and West Africa, the Indian subcontinent, and Central and South America.1 Patients with VKC present with itching, redness, photophobia, ocular discomfort, foreign body sensation, and lacrimation, resulting in visual disturbances. VKC is an IgE-mediated disease leading to accumulation of conjunctival T helper cells promoting IgE synthesis.2 Recent findings implicate a more complex pathogenesis with specific involvement of T helper 2 cells.3

Currently available drugs to treat VKC include antihistamines, mast-cell stabilizers, corticosteroids, and immunomodulators. 4 VKC requires long-term treatment in many cases. Steroids, though beneficial in moderate to severe forms of VKC, cannot be administered for longer periods as it can lead to many complications like glaucoma, cataract, and secondary infections.4

Recently, immunomodulatory agents like cyclosporine and tacrolimus have been used to avoid steroid-related complications. 5 Tacrolimus has an immunomodulatory and anti-inflammatory activity but with much higher potency (up to 100 times) than cyclosporine.6 Tacrolimus suppresses Th2 lymphocyte activation, T helper cell-mediated B-cell proliferation, and formation of cytokines.5,6 Several studies were carried out to assess the success of tacrolimus suspension and tacrolimus ointment for treatment of patients with VKC. Most of these studies evaluated the usefulness of relatively high concentration of topical tacrolimus (topical tacrolimus 0.1%) which was associated with frequent burning sensation and irritation.7,8,9,10 Low dose topical 0.03% Tacrolimus is proved to be safe and effective in the management of patients with refractory VKC. 11,12,13 Therefore, in this study we want to compare the efficacy and safety of topical application of ointment preparation of 0.03% Tacrolimus and 0.1% Tacrolimus in patients with refractory bilateral VKC.

Review of Literature

A study by Caputo R et al concluded that short term topical tacrolimus was effective and safe in refractory vernal keratoconjunctivitis.11 A study by Samir S et al observed that low-dose topical tacrolimus 0.03% solution is effective and safe in the management of patients with refractory VKC.12 A study by Rallis E concluded that low dose topical tacrolimus was effective and safe in refractory vernal keratoconjunctivitis.13

Study Objectives

•To study the efficacy and safety of topical 0.03% Tacrolimus eye ointment in comparison with 0.1% Tacrolimus eye ointment in refractory bilateral VKC

•To compare the clinical outcome between 0.03% Tacrolimus eye ointment and 0.1% Tacrolimus eye ointment in refractory bilateral VKC

Methodology

Study design - A Randomized, Open-label, prospective clinical trial.

Study site – Ophthalmology out patient department, KLE Suchirayu Hospital.

Sample size – 60, 30 in each group 14

Study duration – This study will be conducted for 6 months during May 2022 to December 2022

Inclusion Criteria

1. Age >14yrs

2. Active bilateral VKC responding poorly despite >2 months of treatment with topical anti allergic agents, corticosteroids & cyclosporine.

Exclusion Criteria

Patients with adnexal abnormalities, glaucoma, contact lens wearer, corneal pathology will be excluded from the study. Patients who have received immunosuppressive therapy, patients with known hypersensitivity to Tacrolimus eye ointment, pregnant and lactating women will be excluded from the study.

Method of data collection

Study will be conducted after approval from the Institutional Ethics Committee. Written informed consent was taken from all the study subjects along with parental consent from subjects aged less than 18 years. Study participants will be enrolled into the study according to the inclusion and exclusion criteria. Enrolled participants will undergo complete ophthalmological evaluation including visual acuity, refraction, slit lamp biomicroscopy, fluroscent staining & fundoscopy. They will be randomized into 2 groups according to computerized generated random numbers. The symptoms of VKC like itching, redness, photosensitivity, foreign body sensation & mucus discharge will be assessed and graded; 0-no symptoms, 1-mild, 2-moderate, 3-severe. Objective signs like palpebral & bulbar conjunctival hyperaemia, papillae, limbal tranta’s dots & corneal lesions will be assessed and graded; 0-no signs,1-mild, 2-moderate, 3-severe.

Group A will receive topical 0.03% tacrolimus eye ointment twice daily for 3 weeks & once daily for the next 3 weeks and Group B will receive topical 0.1% tacrolimus eye ointment twice daily for 3 weeks & once daily for the next 3 weeks. All the parameters will be evaluated on day 0 (baseline visit), day 14 (visit 1), day 30 (visit 2) and day 45 (visit 3).

Outcome measures

Primary outcome measure: Changes in mean scores of ocular symptoms and signs at 2nd week, 4th week, 6th week and 8th week from baseline.

Secondary outcome measures:

1.Subjective scoring of symptoms at baseline, 2nd week, 4th week, 6th week and 8th week.

2.Any adverse effects from the treatment reported.

Statistical Analysis

The results obtained in the study will be analysed using Friedman test and chi-square tests. Data will be analysed using appropriate statistical tests. Friedman test & Wilcoxon signed rank test will be used to compare pre & post treatment changes in mean score of symptoms & signs. p-value<0.05 was statistically significant.

References

1. Kumar S. Vernal keratoconjunctivitis: A major review. Acta Ophthalmol. 2009;87(2):133–147.

2. Abu El-Asrar AM, Tabbara KF, Geboes K, Missotten L, Desmet V. An immunohistochemical study of topical cyclosporine in vernal keratoconjunctivitis. Am J Ophthalmol. 1996;121:156–161.

3. Bielory L, Frohman LP. Allergic and immunologic disorders of the eye. J Allergy Clin Immunol. 1992;89(1 pt 1):1–15.

4. Ohji M, Kinoshita S, Ohmi E, Kuwayama Y. Marked intraocular pressure response to instillation of corticosteroids in children. Am J Ophthalmol. 1991;112:450–454.

5. Rallis E, Korfitis C, Gregoriou S, Rigopoulos D. Assigning new roles to topical tacrolimus. Expert Opin Investig Drugs. 2007;16(8):1267–1276.

6. Sawada S, Suzuki G, Kawase Y, Takaku F. Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J Immunol 1987; 139(6): 1797–1803.

7. Al-Amri AM. Long-term follow-up of tacrolimus ointment for treatment of atopic keratoconjunctivitis. Am J Ophthalmol. 2014;157(2):280–286.

8. Fukushima A, Ohashi Y, Ebihara N, et al. Therapeutic effects of 0.1% tacrolimus eye drops for refractory allergic ocular diseases with proliferative lesion or corneal involvement. Br J Ophthalmol. 2014;98:1023–1027.

9. Vichyanond P, Tantimongkolsuk C, Dumrongkigchaiporn P, Jirapongsananuruk O, Visitsunthorn N, Kosrirukvongs P. Vernal keratoconjunctivitis: result of a novel therapy with 0.1% topical ophthalmic FK-506 ointment. J Allergy Clin Immunol. 2004;113(2):355–358.

10. Pucci N, Caputo R, di Grande L, de Libero C, Mori F, Barni S, di Simone L, Calvani A, Rusconi F, Novembre E. Tacrolimus vs. cyclosporine eyedrops in severe cyclosporine-resistant vernal keratoconjunctivitis: A randomized, comparative, double-blind, crossover study. Pediatr Allergy Immunol. 2015 May;26(3):256-261. doi: 10.1111/pai.12360. PMID: 25712437.

11. Shoughy SS, Jaroudi MO, Tabbara KF. Efficacy and safety of low-dose topical tacrolimus in vernal keratoconjunctivitis. Clin Ophthalmol. 2016 Apr 7;10:643-7. doi: 10.2147/OPTH.S99157. PMID: 27103784; PMCID: PMC4827889.

12. Kheirkhah A, Zavareh MK, Farzbod F, Mahbod M, Behrouz MJ. Topical 0.005% tacrolimus eye drop for refractory vernal keratoconjunctivitis. Eye (Lond). 2011 Jul;25(7):872-80. doi: 10.1038/eye.2011.75. Epub 2011 Apr 8. PMID: 21475312; PMCID: PMC3178177.

13. Ryu EH, Kim JM, Laddha PM, Chung ES, Chung TY. Therapeutic effect of 0.03% tacrolimus ointment for ocular graft versus host disease and vernal keratoconjunctivitis. Korean J Ophthalmol. 2012 Aug;26(4):241-7. doi: 10.3341/kjo.2012.26.4.241. Epub 2012 Jul 24. PMID: 22870021; PMCID: PMC3408527.

14. Chen M, Wei A, Ke B, et al. Combination of 0.05% Azelastine and 0.1% Tacrolimus Eye Drops in Children With Vernal Keratoconjunctivitis: A Prospective Study. Front Med (Lausanne). 2021;8:650083. Published 2021 Sep 17. doi:10.3389/fmed.2021.650083

PATIENT INFORMATION SHEET

1. Study Information

Protocol Title: Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

Principal Investigator & Contact Details: Dr Meghana Patil, mob no. 7204351640

2. Purpose of the Research Study

You are invited to participate in a research study. It is important to us that you first take time to read through and understand the information provided in this sheet. Nevertheless, before you take part in this research study, the study will be explained to you and you will be given the chance to ask questions. After you are properly satisfied that you understand this study, and that you wish to take part in the study, you must sign this informed consent form. You will be given a copy of this consent form to take home with you.

You are invited in this study to Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis. This study will recruit 60 subjects from KLE Suchirayu hospital over a period of 6 months

3. What procedures will be followed in this study

Enrolled participants will undergo complete ophthalmological evaluation including visual acuity, refraction, slit lamp biomicroscopy, fluroscent staining & fundoscopy.

4. Your Responsibilities in This Study

If you agree to participate in this study, you should follow the advice given to you by the study team. You should be prepared to visit the hospital 2-3 times and undergo all the assessments that are outlined above.

5. Possible Risks and Side Effect

None

6. Costs & Payments if Participating in the Study

7. Voluntary Participation

Your participation in this study is voluntary. You may stop participating in this study at any time. Your decision not to take part in this study or to stop your participation will not affect your medical care or any benefits to which you are entitled. If you decide to stop taking part in this study, you should tell the Principal Investigator.

However, the data that have been collected until the time of your withdrawal will be kept and analysed. The reason is to enable a complete and comprehensive evaluation of the study.

9. Confidentiality of Study and Medical Records

Information collected for this study will be kept confidential. Your records, to the extent of the applicable laws and regulations, will not be made publicly available.

10. Who To Contact if You Have Questions

Dr Meghana patil - 7204351640

INFORMED CONSENT FORM

Research Study: Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

Principal Investigator: Dr Meghana Patil

I have read and understood the information/ it has been read to me and explained in an understandable language about the research project: Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

•I have had this project explained to me by Dr Meghana Patil. I am satisfied with the answers I have been given. I have been given sufficient time to discuss with family and consider whether to take part in this study. I have had the opportunity to use family support or a friend to help me ask questions and understand the study.

•I understand that taking part in this study is voluntary (my choice) and that I may withdraw from the study at any time and this will in no way affect my continuing health care. I understand that my participation in this study is confidential and that no material which could identify me will be used in any reports on this study.

•I understand that the treatment, or investigation, will be stopped if it should appear harmful to me. I understand the compensation provisions for this study.

•I know who to contact if I have any side effects from the study. I know who to contact if I have questions about the medication used in this study or about the study in general.

Statement by the researcher/person taking consent

I certify that I have explained the study to the volunteer and consider that she/he understands what is involved and freely consents to participation.

Researcher’s signature…………………………………..Date…………………….

8. I, the participant whose signature appears below, have read a transcript of my participation and agree to its use by the researcher as explained.

Participant’s signature……………………………………Date…………………...

PARENTAL CONSENT FORM

Research Study: Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

Principal Investigator: Dr Meghana Patil

I have read and understood the information/ it has been read to me and explained in an understandable language about the research project: Comparison of efficacy and safety of short-term low dose topical 0.03% Tacrolimus eye ointment versus topical 0.1% Tacrolimus eye ointment in patients with refractory bilateral Vernal keratoconjunctivitis.

•I have had this project explained to me and my son/daughter by Dr Meghana Patil. I am satisfied with the answers I have been given. I have been given sufficient time to discuss with family and consider whether my son/daughter will take part in this study. I have had the opportunity to use family support or a friend to help me ask questions and understand the study.

•I understand that taking part of my son/daughter in this study is voluntary (my choice) and that my son/daughter may withdraw from the study at any time and this will in no way affect my continuing health care. I understand that my my son/daughter’s participation in this study is confidential and that no material which could identify my son/daughter will be used in any reports on this study.

•I understand that the treatment, or investigation, will be stopped if it should appear harmful to my son/daughter. I understand the compensation provisions for this study.

•I know who to contact if I have any side effects from the study. I know who to contact if I have questions about the medication used in this study or about the study in general.

Parent’s signature……………………………………Date…………………...

Statement by the researcher/person taking consent

I certify that I have explained the study to the parents of the participant and consider that she/he understands what is involved and freely consents to the participation of their son/daughter.

Researcher’s signature…………………………………..Date…………………….

CASE RECORD FORM

OP number-- Age--- Gender

Occupation

Treatment given: Comorbidities (if any)

Ophthalmological examination findings:

baseline visit 1 visit 2 visit 3

Visual acuity

Refraction

Slit lamp biomicroscopy

Fluroscent staining

Fundoscopy

Ocular symptoms:

Symptoms grading: baseline visit 1 visit 2 visit 3

Itching

Redness

Photosensitivity

foreign body sensation

conjunctival discharge

Ocular signs :

Signs grading: baseline visit 1 visit 2 visit 3

palpebral & bulbar conjunctival hyperamia

papillae

limbal tranta’s dots

corneal lesions

Grading scales for clinical signs

SignsScoreDefinition

Palpebral conjunctiva

Hyperaemia3Impossible to distinguish individual blood vessels

2Dilatation of many vessels

1Dilatation of several vessels

0None

Oedema3Diffuse oedema with opacity

2Thinner diffuse oedema

1Slight oedema

0None

Follicles320 or more follicles

210–19 follicles

11–9 follicles

0None

Papillae3Papillae size: 0.6 mm or more

2Papillae size: 0.3–0.5 mm

1Papillae size: 0.1–0.2 mm

0None

Giant papillae (papillae size ≥1 mm)3Elevated papillae in 1/2 or more of the upper palpebral conjunctiva

2Elevated papillae in <1/2 of the upper palpebral conjunctiva

1Flat papillae

0None

Bulbar conjunctiva

Hyperaemia3Diffuse dilated blood vessels over the entire bulbar conjunctiva

2Dilatation of many vessels

1Dilatation of several vessels

0None

Oedema3Bullous oedema

2Thinner diffuse oedema

1Localised oedema

0None

Limbus

Trantas’ dot39 or more dots

25–8 dots

11–4 dots

0None

Swelling3Found in 2/3 or more of the limbal circumference

2Found in 1/3 to <2/3 of the limbal circumference

1Found in <1/3 of the limbal circumference

0None

Corneal epithelial signs3Shield ulcer or corneal erosion

2Exfoliation superficial punctate keratitis

1Superficial punctate keratitis

0None