Efficacy and safety assessment of T1695 ophthalmic suspension, versus Ciclosporin ophthalmic emulsion, in participants with moderate to severe Vernal Keratoconjunctivitis (VKC)

The primary objective of this study is to compare the efficacy of T1695 0.1% ophthalmic suspension administered twice daily versus Ciclosporin 0.1% ophthalmic emulsion administered four times daily at Day 29 on the evolution of keratitis in participants with moderate to severe vernal keratoconjunctivitis. This objective addresses a critical clinical need in managing corneal inflammation associated with this chronic allergic ocular surface disease, where keratitis represents a significant complication that can impact visual outcomes.

The secondary objectives of this study are:

• To compare the efficacy of T1695 0.1% ophthalmic suspension twice daily versus Ciclosporin 0.1% ophthalmic emulsion four times daily at Day 29 on the evolution of symptoms in participants with moderate to severe vernal keratoconjunctivitis.

• To evaluate the efficacy of T1695 0.1% ophthalmic suspension twice daily versus Ciclosporin 0.1% ophthalmic emulsion four times daily on the evolution of all assessments over the 3-month treatment period in participants with moderate to severe vernal keratoconjunctivitis.

• To evaluate the efficacy of T1695 0.1% ophthalmic suspension twice daily versus Ciclosporin 0.1% ophthalmic emulsion four times daily in the follow-up period on the evolution of all assessments in responder participants at Day 85.

• To evaluate the recurrence of active vernal keratoconjunctivitis with T1695 0.1% ophthalmic suspension twice daily versus Ciclosporin 0.1% ophthalmic emulsion four times daily in the follow-up period in responder participants at Day 85.

• To evaluate the safety and tolerability of T1695 0.1% ophthalmic suspension twice daily versus Ciclosporin 0.1% ophthalmic emulsion four times daily in moderate to severe vernal keratoconjunctivitis per period, with specific assessment in responder participants at Day 85 during the follow-up period.

• To evaluate the safety and tolerability of T1695 0.1% ophthalmic suspension twice daily versus Ciclosporin 0.1% ophthalmic emulsion four times daily in moderate to severe vernal keratoconjunctivitis in the follow-up period in non-responder participants at Day 85.

The clinical trial enrolled a total of **48 participants** diagnosed with **Vernal Keratoconjunctivitis (VKC)**. The study population consisted of both **male and female participants** aged **4 years to less than 18 years old**, representing a **vulnerable population** of pediatric patients. Participants were required to have **moderate to severe VKC** with a grading score of 3 or 4 on the **Bonini scale** for clinical grading in each eye at screening, and severe **keratitis** defined as a score of 4 or 5 on the modified **Oxford corneal fluorescein staining score** in each eye at randomization. The trial population was selected based on the presence of active disease with significant symptoms, including a **Visual Analog Scale (VAS)** score of at least 60 mm for VKC symptoms such as **photophobia**, **tearing**, **itching**, and **mucous discharge** in each eye. Participants were also required to have a **Quality of Life in children with VKC (QUICK) questionnaire** score ranging from 32 to 48. Key selection criteria included a history of at least one relapse of active VKC in the past year and current disease status that was either refractory to anti-allergic agents, cortico-dependent, or resistant or insufficiently responsive to ophthalmic **ciclosporin**. Participants needed to be able to safely discontinue existing VKC medication for a specified washout period and be enrolled early during the VKC season to allow for the complete treatment period.

This is a phase IV, randomized, double-blind, controlled clinical trial designed to compare the efficacy and safety of **T1695** ophthalmic suspension containing **tacrolimus monohydrate** administered twice daily versus **ciclosporin** ophthalmic emulsion administered four times daily in participants with moderate to severe **Vernal Keratoconjunctivitis**. The study investigates the treatment of this rare ocular allergic condition in male and female participants aged from 4 years to less than 18 years old. The primary objective is to evaluate the evolution of **keratitis** at Day 29 by assessing changes in **Corneal Fluorescein Staining** grade using the modified Oxford scale. Secondary objectives include evaluation of VKC-associated symptoms such as **photophobia**, tearing, itching, and mucous discharge measured by Visual Analog Scales, assessment of various ocular signs including **bulbar hyperaemia**, Trantas dots, and **tarsal papillae**, as well as monitoring of quality of life using the QUICK questionnaire.

The trial consists of two main treatment periods with an overall maximum treatment duration of 177 days. Participants receive either T1695 eye drops suspension at a maximum daily dose of 4 drops or ciclosporin eye drops emulsion at a maximum daily dose of 8 drops, both administered via the **ocular route**. The study includes a screening visit where participants must present with a grading score of 3 or 4 on the **Bonini scale** for clinical grading of VKC in each eye, or have documented moderate to severe active VKC. At the randomization visit, participants must demonstrate severe keratitis defined as a score of 4 or 5 on the modified Oxford corneal fluorescein staining scale in each eye, VAS scores of at least 60 mm for VKC symptoms, and QUICK questionnaire scores between 32 and 48. Eligible participants must have experienced at least one relapse of active VKC in the past year and be either refractory to anti-allergic agents, cortico-dependent, or resistant to ophthalmic ciclosporin.

Study visits are scheduled throughout the treatment periods to assess efficacy and safety parameters. Follow-up assessments include evaluation of corneal and limbal staining, VKC severity using the Bonini scale, presence of **corneal ulcer**, quality of life questionnaire scores, and responder status at multiple time points including Day 29, Day 85, and subsequent visits. Safety monitoring encompasses ocular and systemic treatment-emergent adverse events, changes in **Intraocular Pressure**, vital signs, **Best Corrected Visual Acuity** expressed in LogMAR, and laboratory parameters including complete blood count, basic metabolic panels, and kidney and liver function tests. Blood concentration measurements of tacrolimus are obtained at baseline before investigational medicinal product instillation and at Day 29 between 1 and 3 hours post-instillation. The study also monitors the use of rescue medication, occurrence of recurrence of active VKC post-Day 85, and time to recurrence.

Participant involvement extends from the screening phase through the treatment periods and follow-up assessments, with recruitment estimated to begin in March 2026 and the study estimated to conclude in January 2027. Early termination from the study may occur due to treatment-emergent adverse events leading to study treatment discontinuation, lack of efficacy requiring alternative therapy, protocol violations, withdrawal of consent, or investigator decision based on safety concerns. The trial design requires participants to be enrolled early during the VKC season to allow completion of the 3-month treatment Period 1 during the active disease season. Participants must be able to safely discontinue prior VKC medications for specified washout periods or switch to treatments with shorter washout periods as permitted by the protocol.

The experimental treatment under investigation is **T1695**, an **ophthalmic suspension** containing **tacrolimus monohydrate** as the active substance. This investigational medicinal product is formulated as **eye drops, suspension** and is manufactured by Laboratoires Thea. The product is designated with the sponsor product code T1695 and EU substance number SUB23141. T1695 is administered via the **ocular route** at a concentration of 0.1%. The dosing regimen consists of **twice daily (BID)** administration, with a maximum daily dose of 4 drops. The maximum total dose over the treatment period is 708 drops, administered over a maximum treatment duration of **177 days**. This formulation has been developed as a **paediatric formulation** for use in participants with moderate to severe **vernal keratoconjunctivitis**.

The **comparator treatment** is **Verkazia 1 mg/mL eye drops, emulsion**, a marketed medicinal product containing **ciclosporin** as the active substance. Verkazia is an authorized medicinal product manufactured by Santen Oy, holding marketing authorization number EU/1/17/1219/004 and MRP number EMEA/H/C/004411 within the European Union. The product is formulated as an **eye drops, emulsion** with an ATC code S01XA18. Ciclosporin 0.1% ophthalmic emulsion is administered via the **ocular route** at a dosing frequency of **four times daily (QID)**, with a maximum daily dose of 8 drops. The maximum total dose over the treatment period is 1416 drops, administered over a maximum treatment duration of **177 days**. This product holds **orphan drug designation** with designation number EU/3/06/360 and is also formulated as a **paediatric formulation**. For the purposes of this clinical trial, the finished product has been repackaged into different secondary and tertiary packaging to comply with the study design requirements, representing a modification compared to the approved marketing authorization.

Both investigational products are chemical substances administered as topical ophthalmic preparations. The study design allows for assessment of efficacy and safety over an identical maximum treatment period for both treatment arms. Participant compliance monitoring will be implemented throughout the treatment duration to ensure adherence to the prescribed dosing schedules.

Efficacy will be assessed using corneal fluorescein staining (CFS) grade as the primary endpoint, evaluated by the modified Oxford scale ranging from 0 to 5 in the study eye. The primary efficacy assessment will measure the change from baseline at day 29 (week 4). Secondary efficacy parameters include changes in Visual Analog Scale (VAS) values ranging from 0 to 100 mm for four symptoms associated with vernal keratoconjunctivitis: photophobia, tearing, itching, and mucous discharge, assessed in both the study eye and contralateral eye. Additional secondary endpoints encompass changes in CFS grade in the contralateral eye, VKC severity using the Bonini scale (0-5), bulbar hyperaemia, Trantas dots, tarsal papillae evaluated via slit lamp examination, and corneal/limbal staining assessed using the VKC-CLEK scale. Quality of life will be measured using the QUICK questionnaire with scores ranging from 16 to 48, and impact on ability to attend school with scores from 1 to 3. Responder status, time to first response, presence of corneal ulcer, use of rescue medication, presence and time to recurrence of active VKC, and far best corrected visual acuity expressed in LogMAR will be evaluated. Efficacy assessments will be conducted at baseline (day 1) and at multiple post-baseline visits including day 29, day 85, and subsequent timepoints. Investigator and participant (or relatives) assessments of ocular tolerance will be performed at each post-baseline visit. Intraocular pressure, vital signs, blood concentration of tacrolimus measured at baseline and day 29, and changes in complete blood count, basic metabolic panels, kidney and liver tests at baseline and day 85 will be monitored throughout the treatment period.