A Phase 3, Multicenter, Randomized, Double-Masked, Vehicle-Controlled, Study to Demonstrate Efficacy and Safety of DFL24498 Eye Drop Solution in Adult Participants with Atopic Keratoconjunctivitis (AKC)

The primary objective is to confirm the efficacy of **DFL24498 ophthalmic solution** in improving the symptom of **ocular itching** in participants with **atopic keratoconjunctivitis** after 6 weeks of treatment. This objective addresses a cardinal symptom that significantly impacts quality of life in patients with this chronic allergic ocular surface disease.

The secondary objectives are:

• To confirm the efficacy of DFL24498 ophthalmic solution in improving **corneal epithelial damage** in participants with atopic keratoconjunctivitis after 6 weeks of treatment.

• To confirm the efficacy of DFL24498 ophthalmic solution in improving **bulbar conjunctival hyperemia** after 6 weeks of treatment.

This clinical trial enrolled a total of **57 participants** diagnosed with **atopic keratoconjunctivitis** (AKC) affecting both eyes. The study population included both **male and female subjects** aged between **18 and 65 years**. Participants were required to have a documented diagnosis of AKC, which included a present or past medical history of other **atopic conditions** such as **atopic dermatitis**, **periocular eczema**, **asthma**, or **allergic rhinitis**, along with chronic **allergic blepharoconjunctivitis** and/or **keratoconjunctivitis**. Key selection criteria included the presence of **ocular itching** with a severity of at least 50 on the **Visual Analog Scale** (VAS), **corneal fluorescein staining** of at least grade 1 as assessed by the modified **Oxford scale**, and **bulbar conjunctival hyperemia** of at least 40 on the VBR 10 scale in the same eye. Participants were also required to have a **composite symptoms score** of 5 or higher, reflecting combined severity of itching, tearing, ocular discomfort, **photophobia**, and mucous discharge. Women of childbearing potential were required to have a negative **pregnancy test** and use acceptable contraception methods throughout the study. The trial population was selected based on the ability and willingness to comply with study procedures and completion of informed consent requirements.

This is a **Phase 3**, multicenter, **randomized**, **double-masked**, vehicle-controlled clinical trial designed to evaluate the efficacy and safety of **DFL24498 eye drop solution** in adult participants with **atopic keratoconjunctivitis**. The investigational medicinal product, **Isocyclosporin A**, will be administered as an **eye drops, solution** formulation via **ophthalmic use**. The study includes a **placebo** (vehicle) control group and utilizes **dexamethasone** as an auxiliary medicinal product. The trial is classified as a category 2 intervention study and is not considered a low-intervention clinical trial.

The primary objective is to confirm the efficacy of DFL24498 ophthalmic solution in improving the symptom of **ocular itching** in participants with atopic keratoconjunctivitis after 6 weeks of treatment. The **primary endpoint** is the change from baseline at week 6 in ocular itching score assessed by **visual analog scale (VAS)**. Secondary endpoints include the change from baseline at week 6 in **corneal epithelial fluorescein staining**, scored by modified Oxford scale, in the study eye, and the change from baseline at week 6 in **bulbar conjunctival hyperemia** assessed by Validated Bulbar Redness (VBR) 10 scale (0 to 100), in the study eye.

Eligible participants are men or women aged 18 to 65 years with a diagnosis of atopic keratoconjunctivitis in both eyes. Key inclusion criteria include a medical history of other atopic conditions such as **atopic dermatitis**, periocular eczema, **asthma**, or **allergic rhinitis**, along with chronic **allergic blepharoconjunctivitis** and/or keratoconjunctivitis. Participants must demonstrate ocular itching of at least 50 as assessed by VAS scale, **corneal fluorescein staining** of at least grade 1 by modified Oxford scale, and bulbar conjunctival hyperemia of at least 40 on the VBR 10 scale in the same eye. A composite symptoms score (CSyS) of 5 or greater is required, representing the sum of severity scores for itching, tearing, ocular discomfort, **photophobia**, and mucous discharge. Women of childbearing potential must have a negative **pregnancy test** at screening and baseline visits and use acceptable contraception methods. All participants must provide informed consent and demonstrate the ability and willingness to comply with study procedures.

The maximum treatment period for the investigational products is 12 weeks. The estimated recruitment start date is December 19, 2025, with an estimated study end date of May 3, 2027. The screening visit serves to assess eligibility criteria and obtain baseline measurements of efficacy and safety parameters. Follow-up visits are conducted to monitor treatment response, evaluate changes in clinical signs and symptoms, and assess safety throughout the study period. The end-of-study visit includes final efficacy assessments and safety evaluations. Participant involvement extends through the treatment period and scheduled follow-up assessments. Early termination from the study may occur under specific conditions as defined in the protocol, including safety concerns, withdrawal of consent, or failure to comply with study requirements.

The investigational medicinal product **Isocyclosporin A** is administered as an **eye drops, solution** formulation for **ophthalmic use**. The active substance is (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S,34R)-30-ethyl-34-[(E,2R)-hex-4-en-2-yl]-4,7,10,12,15,19,25,28-octamethyl-33-(methylamino)-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1-oxa-4,7,10,13,16,19,22,25,28,31-decazacyclotetratriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone hydrochloride, also known as **Isocyclosporin A hydrochloride**. This product is manufactured by Dompé Farmaceutici SpA. The active substance is of chemical origin. The maximum treatment period is 12 weeks. The product is designated as DFL24498 in the study protocol and serves as the test medicinal product in this clinical trial.

The **placebo** control consists of a vehicle formulation matching the investigational product DFL24498. The placebo is designated as Placebo (Vehicle) for investigational DFL24498. This product serves as the comparator treatment in the vehicle-controlled study design. The maximum treatment period for placebo administration is 12 weeks.

**Dexamethasone phosphate** eye drops are utilized as an auxiliary medicinal product in this clinical trial. The active substance is dexamethasone 21-(dihydrogen phosphate), which is of chemical origin. The product is administered via **ophthalmic use**. The **ATC code** for this substance is S01BA01. The maximum treatment period is 12 weeks. This auxiliary treatment may be used in accordance with the study protocol requirements for participants with **atopic keratoconjunctivitis**.

Efficacy will be assessed using multiple parameters to evaluate the therapeutic effect of the investigational treatment in participants with **atopic keratoconjunctivitis**. The primary efficacy endpoint is the change from baseline at week 6 in ocular itching score, which will be measured using a **visual analog scale (VAS)**. Secondary efficacy endpoints include the change from baseline at week 6 in corneal epithelial fluorescein staining, scored by the modified Oxford scale, in the study eye, and the change from baseline at week 6 in bulbar conjunctival hyperemia assessed by the Validated Bulbar Redness (VBR) 10 scale, with scores ranging from 0 to 100, in the study eye.

At baseline, participants must demonstrate ocular itching of at least 50 as assessed by VAS scale, corneal fluorescein staining assessed by modified Oxford scale of at least grade 1, and bulbar conjunctival hyperemia assessed by VBR 10 scale of at least 40 in the same eye. Additionally, participants must have a composite symptoms score (CSyS) of at least 5, calculated as the sum of severity scores graded 0 to 3 for each of the following symptoms: itching, tearing, ocular discomfort, photophobia, and mucous discharge, with a total CSyS range of 0 to 15. The treatment period is planned for 12 weeks, with the primary and secondary efficacy assessments conducted at week 6.