Topical rVA576 for Treatment of Atopic Keratoconjunctivitis

Study Overview
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Brief Summary
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Topical rVA576 for treatment of atopic keratoconjunctivitis: a randomised placebo-controlled double masked parallel trial (TRACKER)

Detailed Description
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Recombinant rVA576 is a small protein (16.7kDa) which has two independent actions. It inhibits the activation and cleavage of complement C5 and it binds and inactivates leukotriene B4 (LTB4). It acts on the complement system by preventing the cleavage of C5 by C5 convertase into C5a and C5b and so is effective in inhibiting terminal complement activity irrespective of the activating pathway. Atopic keratoconjunctivitis (AKC) is a type of allergic conjunctivitis which involves mast cell activation due to the predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines (Mishra et al. 2011). Recombinant rVA576 eye drops solution is the investigational medicinal product. It is intended for ophthalmic use by topical administration to the eye. Recombinant rVA576 is a compact small protein molecule with a lipocalin-like structure consisting of alpha helices and a beta barrel. There is a surface-active site which binds to the complement C5 molecule with a high affinity (KD 1.85 x 10-8 M) and an internalised active site which binds the small eicosinoid molecule leukotriene B4 (Hepburn et al. 2007).

Official Title
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Topical rVA576 for Treatment of Atopic Keratoconjunctivitis: a Randomised Placebo-controlled Double Masked Parallel Trial (TRACKER)

Conditions
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Atopic Keratoconjunctivitis (AKC)

Intervention / Treatment
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* Drug: rVA576
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 and above Diagnosis of moderate to severe AKC with a composite symptom/sign score from one eye of ≥ 22 out of 33 (see Clinical Scoring 17.1) Will have had maximal topical therapy for at least 3 months without improvement but will not currently be receiving systemic immunotherapy. History of atopy other than ocular (dermatitis, asthma, hay fever) Willing to give informed consent Willing to use adequate contraceptive precautions for the duration of the study and for 90 days thereafter Willing to avoid prohibited medications for the duration of the study Exclusion Criteria: Eye surface disease other than AKC Contact lens use during the study Complete or partial tarsorrhaphy. If such a procedure becomes necessary during the course of the trial patients may remain in the trial providing that at least 50% of the eye surface remains visible to slit lamp examination Ankyloblepharon of any degree at entry to the trial Known or suspected ocular malignancy Active ocular infection at entry to the trial. Patients with eye surface bacterial, viral, fungal or protozoal infection may enter the trial after elimination of the infection as confirmed by eye swabs Known or suspected uveitis Participation in any other clinical trial within 1 month of enrolment Use of any of the following prohibited medications: Eculizumab Any other investigational complement inhibitor whether systemic or topical (e.g. RA101495) Montelukast Zafirlukast Pranlukast Zileuton Hypericum perforatum (St John's wort) Corneal perforation Glaucoma Pregnancy (females) Breast feeding (females) Known allergy to ticks or severe reaction to arthropod venom (e.g. bee or wasp venom) Failure to satisfy the PI of suitability to participate for any other reason

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rVA576<br>Part 1: The first 3 patients selected for the study will be treated with the active drug in an open-label manner at intervals of 1 week and will have weekly clinic visits until Day 14, after which the visit will be every two weeks. When the first 3 patients have completed two weeks of treatment and the safety and tolerability data has been reviewed by the PI and an independent clinician, provided the data is favourable the randomisation process will begin (Part 2). The first 3 patients will continue treatment for a total of 8 weeks and will be assessed throughout the trial by the Principal Investigator according to the Schedule of Events Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial. | Drug: rVA576<br>* 19 Patients with moderate to severe AKC. the study includes two parts: Part 1: The first 3 patients selected for the study will be treated with the active drug in open-label. Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial.<br>* Other names: Coversin;|
| Placebo Comparator: Placebo<br>Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial. | Other: Placebo<br>* Part 2: Sixteen patients will be randomised 1:1. between active and placebo and patients allocated to either group will receive the appropriate product throughout the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Parameter | Incidence of ocular treatment emergent adverse events during the treatment period which have occurred during the 56 days following randomisation. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-instillation comfort | Post-instillation comfort, as graded on patient diary cards at the following intervals Days 1-14, Day 15-28, Day 29-42 and Day 43-56. Eye comfort scoring (0-5): 0 Perfectly comfortable Slight discomfort. Aware of some burning, itching or stinging for up to half a minute after using the eye drop, solution but the discomfort improves without treatment. Moderate discomfort. Burning, itching or stinging lasts for half a minute or longer but improves without treatment. Severe discomfort. Burning, itching or stinging last for at least half a minute and requires washing the eyes to relieve it. Unbearable burning itching or stinging. So severe that you cannot continue treatment. | Day1 to 56 | 
| Visual acuity | Visual acuity by Early Treatment Diabetic Retinopathy Study (ETDRS) charts comparison from Day 1 to Day 56 | Day1 to 56 | 
| Clinical scores | Change from Day 1 in composite clinical scores at Day 14, 28, 42 and 56 Outcome measure information describes more than one measure The primary efficacy endpoint is a composite clinical score made up of 5 symptoms and 6 signs as follows: Symptoms Itching Tearing Discomfort (burning, stinging or foreign body sensation) Discharge Photophobia Signs Bulbar conjunctival hyperaemia Tarsal conjunctival papillary hypertrophy Punctate keratitis Neovascularisation of cornea Cicatrising conjunctivitis Blepharitis | Day1 to 56 | 
| MMP-9 positive | Percentage of patients with MMP-9 positive levels at Days 1, 28, and 56 | Day1 to 56 |