Pharmacokinetics and Safety of Dexamethasone Eye Drops in Preterm Infants

Study Overview
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Brief Summary
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Background and study aims When an infant is born premature, the blood vessels in the eyes have not developed fully on the retina, and can start to grow incorrectly and result in blindness. To prevent this from happening, premature infants are often screened, and treated with laser or injections into the eye to prevent retinal detachment. A new treatment strategy with steroid eye drops have been found to prevent serious blood vessel growth. The treatment is commonly used in older children and adults to treat different inflammatory conditions, but how the drop is absorbed in premature infants and if there is any risk of side-effects is poorly investigated. The aim of this study is to document how the steroid drop is absorbed and excreted in premature infants and to study if there is a risk of any side effects. Who can participate? Premature infants born before gestational age week 30, that undergo eye-screening at Sahlgrenska University Hospital in Gothenburg and Skånes University Hospital in Malmö and Lund, in the need for steroid eye-drop treatment against pathological vessels. It is not possible to participate if the infant has received systemic steroid treatment 2 weeks prior to the eye-drop treatment, or has an ongoing ocular infection. What does the study involve? The study involves blood and saliva samples according to a specific protocol designed to be able to learn about the uptake and breakdown of the steroid in premature infants. Measurements of blood pressure, growth and a few urine samples will also be collected during the treatment period usually lasting for some weeks. At 2.5 and 5 years of age, visual acuity, refractive errors and retinal thickness measurements will be noted. What are the possible benefits and risks of participating? The infant will receive steroid eye-drops that have been noted to heavily reduce the number of infants that develop retinal changes that require injections or laser treatment. The blood samples have been reduced to an absolute minimum in volume and numbers, but will entail some extra samplings from the infant. The infant will be rigorously checked with regard to any possible side effects from the steroid treatment. Possible but unlikely side effects from the low dose in eye drops are; elevated blood pressure, retarded growth, lowered endogenous steroid production during the eye-drop treatment, increase in blood glucose, and an increase in intra-ocular pressure.

Official Title
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Pharmacokinetics and Safety of Dexamethasone Eye Drops in Preterm Infants With Retinopathy of Prematurity- a Feasibility Study

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Drug: Dexamethasone Ophthalmic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants screened for retinopathy of prematurity (ROP) at Sahlgrenska University Hospital in Gothenburg and at Skåne University Hospital in Malmö and Lund. zone I stage 1 or 2 ROP without plus disease, posterior zone II stage 2 ROP without plus disease, or zone II stage 3 ROP without plus disease. ROP needs to be documented by digital widefield photography and classification confirmed by two ophthalmologist. Exclusion Criteria: ocular infection systemic steroid treatment within two weeks before the start of drop treatment

Ages Eligible for Study
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Maximum Age: 30 Weeks

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
Intervention Model: Single Group Assignment
Interventional Model Description: multicenter interventional phase 1 trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone treated infants<br>15 infants that receive dexamethasone eye drops for treatment of retinopathy of prematurity will be included, and both serum and saliva samples will be collected in order to find out the pharmacokinetic properties of dexamethasone in eye drops according to a pre-specified sampling scheme specifically designed for this purpose by experts in pediatric pharmacokinetics. | Drug: Dexamethasone Ophthalmic<br>* one drop daily in each eye with retinopathy of prematurity of a predefined stage.<br>* Other names: dexafree;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: half-life of plasma concentrations of dexamethasone during treatment with dexamethasone eye drops measured with mass spectrometry. | Half-life of dexamethasone- t½, hours | up to 14 weeks | 
| Pharmacokinetics: maximum plasma concentration of dexamethasone during treatment with dexamethasone eye drops measured with mass spectrometry. | Maximum plasma concentration- Cmax, nmol/L | up to 14 weeks | 
| Pharmacokinetics: saliva koncentrations of dexamethasone during treatment with dexamethasone eye drops. | Half-life of dexamethasone- t½, hours | up to 14 weeks | 
| Pharmacokinetics: saliva koncentrations of dexamethasone during treatment with dexamethasone eye drops measured with mass spectrometry. | Maximum saliva concentration- Cmax, nmol/L | up to 14 weeks | 
| Pharmacokinetics: time to reach maximum plasma concentration of dexamethasone during treatment with dexamethasone eye drops measured with mass spectrometry. | tmax, hours | up to 14 weeks | 
| Pharmacokinetics: time to reach maximum saliva concentrations of dexamethasone during treatment with dexamethasone eye drops measured with mass spectrometry. | tmax, hours | up to 14 weeks | 
| Pharmacokinetics: area under the concentration-time curve for plasma dexamethasone from time point 0 to time t of the last measured concentration above the limit of quantification time. | AUC0-t, nmol.h/L | up to 14 weeks | 
| Pharmacokinetics: area under the concentration-time curve for saliva dexamethasone from time point 0 to time t of the last measured concentration above the limit of quantification time. | AUC0-t, nmol.h/L | up to 14 weeks | 
| Pharmacokinetics: area under the concentration-time curve for plasma dexamethasone from time point 0 to infinity; | AUC0-∞, nmol.h/L | up to 14 weeks | 
| Pharmacokinetics: area under the concentration-time curve for saliva dexamethasone from time point 0 to infinity; | AUC0-∞, nmol.h/L | up to 14 weeks | 
| Pharmacokinetics: apparent total body clearance | CL/F, L/h | up to 14 weeks | 
| Pharmacokinetics: apparent volume of distribution | Vz/F, L | up to 14 weeks | 
| Safety: serum concentrations of endogenous corticosteroids before, during and after treatment with dexamethasone eye drops measured with mass spectrometry. | Endogenous levels of corticosteroids, nmol/L | up to 14 weeks | 
| Safety: saliva concentrations of endogenous corticosteroids before, during and after treatment with dexamethasone eye drops. | Endogenous levels of corticosteroids, nmol/L | up to 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To describe if dexamethasone eye drops delay the intervention for type 1 ROP in cases without regression by calculating the time from detection of type 2 ROP to type 1 ROP | Time from detection of type 2 ROP to type 1 ROP, days | Up to 14 weeks | 
| To describe if dexamethasone eye drop treatment before intervention for type 1 ROP reduces the number of recurrences after the intervention. | recurrences after laser/anti-VEGF treatment, percentage | Up to 14 weeks | 
| To find out if retinal morphology measured with optical coherence tomography is affected by dexamethasone eye drops at 2.5 years of age. | Retinal thickness, micrometers | after 2.5 years | 
| To find out if retinal morphology measured with optical coherence tomography is affected by dexamethasone eye drops at 5 years of age. | Retinal thickness, micrometers | after 5 years | 
| To find out if dexamethasone eye drops affect visual acuity at 2.5 years of age | Visual acuity according to Snellen, fraction | after 2.5 years | 
| To find out if dexamethasone eye drops affect refractive errors at 2.5 years of age | Refractive power, diopters | after 2.5 years | 
| To find out if dexamethasone eye drops affect visual acuity at 5 years of age | Visual acuity according to Snellen, fraction | after 5 years | 
| To find out if dexamethasone eye drops affect refractive errors at 5 years of age | refractive power, diopters | after 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, retinopathy of prematurity, dexamethasone