Recipient Organization
UNIVERSITY OF TENNESSEE
2621 MORGAN CIR
KNOXVILLE,TN 37996-4540
Performing Department
SMALL ANIMAL CLINICAL SCIENCES
Non Technical Summary
Some dogs suffer from a condition of low tear production called keratoconjunctivitis sicca (KCS) or dry eye. Currently there is only one effective treatment of this condition. Not all of the affected dogs respond to this treatment. The purpose of this project is to investigate tacrolimus in the treatment of KCS in dogs.
Animal Health Component
25%
Research Effort Categories
Basic
(N/A)
Applied
25%
Developmental
75%
Goals / Objectives
We have the following objectives: 1) to determine if topical ocular application of tacrolimus (TACRO) is safe in normal dogs, 2) to determine if topical twice-daily application of TACRO is effective in the treatment of keratoconjunctivitis sicca (KCS) and 3) to determine if once daily therapy with TACRO is effective in the treatment of KCS.
Project Methods
This investigation will be conducted in two phases: Phase 1 will determine the safety of topical ophthalmic TACRO in normal dogs. Phase 2 will determine the efficacy of twice daily and once daily topical TACRO in clinical patients with KCS. Both Phase 1 and Phase 2 will be conducted as random, vehicle-controlled, masked investigations. Fourteen normal dogs will be used in Phase 1. Half of the dogs will be treated twice daily in both eyes with 0.03% TACRO in an olive oil. The remaining dogs will be treated twice daily in both eyes with olive oil. The subjects will be monitored for any organ toxicity or systemic absorption of TACRO. Any subject having any systemic toxicity or TACRO blood levels higher than 15 ng/ml will immediately be dismissed from the study. Once daily, before the application of TACRO, each subject will have a complete examination of the anterior segment and adnexa including a Schirmer tear test (STT), fluorescein staining and slit-lamp biomicroscopy.
The dogs will be monitored for 15 minutes after each application of TACRO then every 4-6 hours. If any dog experiences an unacceptable level of discomfort, characterized by incessant rubbing of the face, due to the TACRO it will immediately be dropped from the study. Any subjects, who have severe conjunctival hyperemia, chemosis, corneal edema, blepharospasm, or corneal ulceration, will immediately be dropped from the study. Phase 1 of the proposed investigation will last 14 days and will be completed before beginning Phase 2 of the study. If we determine in Phase 1 that TACRO is not safe in dogs we will not proceed to Phase 2. Phase 2 of the proposed study will be undertaken to determine if TACRO is effective in the treatment of 40 clinical patients with KCS. Patients with KCS, as defined by corneal neovascularization, scarring, or pigmentation and STT value of <10mm wetting in 60 seconds, will be randomly assigned to one of two groups. The control group will be treated with 2% CSA
in olive oil in both eyes twice daily and the treatment group will be treated with 0.03% TACRO in olive oil in both eyes twice daily. Patients will be re-evaluated at 1, 3, 5 and 8 weeks later. The patients will be evaluated by STT, fluorescein staining and slit-lamp biomicroscopy to determine the effectiveness of TACRO and to determine the presence of any ocular toxic effects. Any indication of corneal toxicity or no improvement in either the clinical signs of KCS or the STT in 8 weeks will result in the patient being dropped from the study. Serum chemistry profiles will be performed on each patient at 0, 3 and 8 weeks and therapeutic drug monitoring of TACRO will be performed at 3 and 8 weeks. Any patient who experiences systemic absorption or toxicity due to TACRO, as defined in phase 1, will be dropped from the study immediately. Each patient will be enrolled in the study for 8 weeks. All patients who positively responded to TACRO by an increase of 25% in their STT value or an
improvement in their clinical signs, will be treated once daily for an additional four weeks, to determine if once daily treatment with TACRO is effective in the treatment of KCS.