Inhaled Corticosteroids: Effect on Intraocular Pressure in Patients With Controlled Glaucoma

Phase 4

Completed

Conditions: Ocular Hypertension
Glaucoma, Open-Angle

Interventions: Drug: Fluticasone propionate inhaler
Drug: Saline placebo inhaler

Registration Number: NCT02338362

Lead Sponsor: University Health Network, Toronto

Brief Summary: The purpose of this study is to determine whether a commonly prescribed orally inhaled corticosteroid treatment will induce a clinically meaningful elevation in intraocular pressure, when administered to patients with ocular hypertension (OHT) or open-angle glaucoma (OAG). Based on the response to high-dose corticosteroids, this patient group is more likely than the normal population to demonstrate this adverse effect.

Detailed Description: Systemic and topical ophthalmic steroids have long been associated with ocular effects, such as glaucoma or cataracts.\[Alfano JE; Bernstein HN et al. 1962; Bernstein HN et al. 1963; Becker B and Mills DW in Arch Ophthalm 1963; Becker B and Mills DW in JAMA 1963; Armaly MF 1963 (1); Armaly MF 1963 (2); and Buckley RJ\] Periocular steroid injections \[Herschler J; Kalina RE\] and steroids applied to periocular skin \[Aggarwal RK et al.\] have also been reported to increase intraocular pressure (IOP) and raised IOP is the major risk factor for glaucoma.

Ocular hypertension (OHT) is defined as an IOP above 21mmHg in one or both eyes without detectable glaucomatous damage. Primary open-angle glaucoma (POAG) is a chronic and progressive optic neuropathy of unknown etiology characterized by disc cupping, and often associated with visual field defects and elevated IOP. This disease is one of the leading causes of blindness worldwide.\[Kwon YH et al.\] Approximately 18% to 36% of the general population are corticosteroid responders. This response is increased to 46% to 92% in patients with POAG.\[Tripathi RC et al.\] Asthma is the most common chronic respiratory illness in Canada, affecting approximately 10% of the population. For the majority of these patients, long-term inhaled corticosteroids (ICS) are standard of care to prevent acute asthma exacerbations.\[Kim H and Mazza J\] Although the systemic absorption of inhaled and nasal steroids has been established, the clinically relevant ocular side effects are poorly defined. \[Cave A et al.; Allen DB et al.\] A large prospective study in 1995 by Samiy et al reported no statistically significant increase of IOP in 187 patients without glaucoma taking inhaled steroids for various pulmonary conditions.\[Samiy N et al.\] However, six cases of increased IOP associated with combined nasal and inhaled steroid use in non-glaucomatous patients have been reported. \[Dreyer EB; Desnoeck M et al.; Opatowsky I et al.\] A large case-control study in 1997 suggested that current users of high doses of ICS prescribed regularly for 3 or more months were at increased risk of OHT or OAG (OR 1.44; 95% CI 1.01-2.06).\[Garbe E et al.\] In contrast, Gozalez et al. conducted a nested case-control study in 2010 with Quebec data which showed current and continuous use of ICS did not result in increased risk of glaucoma or raised IOP requiring treatment.\[Gonzalez AV et al.\] Similarly, Duh et al. reported no association between inhaled budesonide daily therapy and increased IOP in 1255 asthmatic patients.\[Duh MS et al.\] Further, a prospective population-based cohort study published in 2012 suggested no association between the development of OAG and ICS in the elderly.\[Marcus MW et al.\] In 2013, our group published a randomized double-masked controlled trial that showed no evidence of IOP elevation after 6 weeks use of beclomethasone nasal spray in 19 patients with OHT and POAG.\[Yuen D et al.\] The purpose of the current study protocol would be to extend the study to investigate ICS in the same patient population.

To date, the effect of inhaled corticosteroids in those with pre-existing OHT or POAG remains uncertain. Considering the large number of patients on inhaled steroids, investigating the use of inhaled steroid in glaucoma patients could have significant clinical impact. This study was designed to evaluate the effect of inhaled fluticasone propionate on intraocular pressure (IOP) in patients with OHT or controlled open-angle glaucoma (OAG).

Patient randomization was performed by an independent Research Coordinator in a separate physical space and kept sealed from the principal study investigators, who assessed and recorded outcome measures, until the completion of study data collection. IOP was measured in a masked fashion, using a second observer to record values. Two measurements within 1 mmHg were averaged for each data point. With a sample size of 8 patients per interventional arm, the study is powered at 0.80 to detect an elevation of 3.2 mmHg (≥20%) from mean, assuming a standard deviation of 2.5 mmHg. Baseline data will be compared between groups using the student's t test and Fisher exact test. A 2-sided p value of \<0.05 will be considered statistically significant. The primary outcome measure (mean IOP) will be assessed using a 1-sided Student t test.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Age 18 to 85 years, inclusive
Mild-moderate open-angle glaucoma/ocular hypertension with cup:disc ratio <0.85 vertically and humphrey visual field mean deviation >-12.00 (BOTH EYES must meet this criteria for patient to be included)
Glaucoma well-controlled, defined by IOP < 21 mmHg and at target with no visual field/disc progression for at least 6 months (BOTH EYES must meet this criteria for patient to be included)

Exclusion Criteria

Any form of steroid medication use within the prior 6 weeks
Any previous intra-ocular surgery or refractive surgery in the study eye
no light perception (i.e. blindness) in either eye
unwilling/unable to give consent
unwilling to accept randomization
patient potentially unavailable for follow-up visits

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fluticasone	Fluticasone propionate inhaler	10 participants will be asked to use fluticasone propionate 250 µg metered-dose inhaler 1 puff twice-daily for 6 weeks.
Saline placebo	Saline placebo inhaler	10 participants will be asked to use a saline placebo metered-dose inhaler 1 puff twice-daily for 6 weeks.

Primary Outcome Measures

Name	Time	Method
Mean Intraocular Pressure	week 6	Masked assessment of intraocular pressure using goldmann application tonometry. Mean of 2 measurements within 1 mmHg will be recorded.

Secondary Outcome Measures

Name	Time	Method
Mean Visual Acuity	week 6	best corrected logMAR visual acuity for each eye. 20/20 vision corresponds with a logMAR score of 0, while negative logMAR scores indicate better than 20/20 vision, values \> 0.5 correspond with low vision, and values \> 1.3 correspond with blindness.
Intraocular Pressure Elevation >20% From Baseline	within 6-week observation period	Participants with 2 consecutive intraocular pressure measurements exceeding 20% increase from baseline were discontinued from study.
Side Effects	from baseline to week 6	subjective (reported) and objective (slit lamp examination) side-effects attributable to study medications
Adherence	Completion of study, up to 6 weeks	Adherence was calculated from self-reported study diaries and correlated to a counter that measured number of inhaled puffs built into the placebo metered-dose inhalers