PeriOcular and INTravitreal Corticosteroids for Uveitic Macular Edema Trial

Study Overview
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Brief Summary
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To evaluate the relative efficacy of three commonly utilized regional corticosteroids for the regional treatment of uveitic macular edema: periocular triamcinolone acetonide; intravitreal triamcinolone acetonide; intravitreal dexamethasone implant. The primary efficacy measure will be percent change in central subfield thickness as measured by OCT at 8 weeks. Participants will continue in the study for 24 weeks in order to evaluate relative effects of the 3 treatment strategies on the duration of treatment effects, requirement for additional injections, and adverse effects. Note: The planned sample size for the POINT Trial was 267 subjects. On 17 July 2017, with 192 subjects enrolled, the Data and Safety Monitoring Committee (DSMC) reviewed the planned interim analysis and recommended that the goals of the trial could be accomplished by completing follow-up of enrolled subjects without the recruitment of additional subjects. Per the DSMC recommendations, recruitment was suspended and follow-up of enrolled subjects was completed according to the protocol.

Detailed Description
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Macular edema is the most common structural complication and leading cause of visual loss in patients with uveitis. Regional injections of corticosteroids are the most frequently used treatments specifically for uveitic macular edema but there is a lack of high quality evidence to guide choice of drug (e.g., triamcinolone acetonide, dexamethasone) and route of administration (e.g. periocular, intravitreal). The question of how to approach regional treatment of uveitic macular edema is a key question for ophthalmologists treating these patients. The Periocular and Intravitreal Corticosteroids for Uveitic Macular Edema (POINT) Trial is a randomized trial designed to compare the relative efficacy of three regional corticosteroids commonly utilized for the initial regional treatment of uveitic macular edema, periocular triamcinolone (Kenalog® , Bristol-Myers Squibb Company, Princeton, NJ), intravitreal triamcinolone (Triesence™, Alcon Pharmaceuticals, Fort Worth, TX), and the intravitreal dexamethasone implant (Ozurdex®, Allergan, Irvine CA) will be conducted by the MUST Research Group clinical centers throughout the U.S. and one each in Australia and the UK. After signing informed consent and undergoing eligibility evaluation, eligible patients will be randomized to one of the three study treatments to be administered at the first study visit. Randomization is by participant, if both eyes meet eligibility requirements then both eyes receive assigned treatment. The design outcome is the percent change in central subfield macular thickness on OCT from baseline to the 8 week visit. After assessment of the primary outcome at 8 weeks, second injections and best medical judgment will be used if macular edema has not improved as follows: Eye(s) meeting trial eligibility criteria receive initial injection of assigned treatment at P01 visit. Second injection of assigned treatment permitted at 8 week visit for periocular triamcinolone and intravitreal triamcinolone and at 12 week visit for intravitreal dexamethasone if Eye does not meet the improvement definition (a 20% decrease in central subfield thickness of the macula) or Eye has a normal central subfield thickness but has cystoid spaces in the 1 mm central subfield or ME is worse after initial improvement And the following repeat injection criterion are met: • IOP of ≤21 or mm Hg and treatment with ≤3 IOP-lowering agents; Eyes demonstrating no improvement or worsening of ME as measured by the central submacular thickness on OCT (at week 12 for periocular and intravitreal triamcinolone arms and at week 20 for intravitreal dexamethasone arm) are considered primary treatment non-responders.

Official Title
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PeriOcular and INTravitreal Corticosteroids for Uveitic Macular Edema Trial

Conditions
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Macular Edema, Uveitis

Intervention / Treatment
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* Drug: Periocular triamcinolone 40 mg
* Drug: Intravitreal triamcinolone 4 mg
* Drug: Dexamethasone intravitreal implant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eye level inclusion criteria - at least one eye must meet all of the following conditions: Non-infectious anterior, intermediate, posterior or panuveitis; either active or inactive uveitis is acceptable; Macular edema (ME) defined as the presence of central subfield macular thickness greater than the normal range for the OCT machine being used, regardless of the presence of cysts, as assessed by study ophthalmologist; Best corrected visual acuity (BCVA) 5/200 or better; Baseline intraocular pressure > 5 mm Hg and ≤ 21 mm Hg (current use of 3 or fewer intraocular pressure-lowering medications and/or prior glaucoma surgery are acceptable); Baseline fluorescein angiogram that is gradable for leakage in the central subfield Pupillary dilation sufficient to allow OCT testing. Exclusion Criteria: Patient level exclusion criteria: -History of infectious uveitis, or of scleritis, keratitis, or infectious endophthalmitis in either eye; History of central serous retinopathy in either eye; For women of childbearing potential: pregnancy, breastfeeding, or a positive pregnancy test; unwilling to practice an adequate birth control method (abstinence, combination barrier and spermicide, or hormonal) for duration of trial; Use of oral acetazolamide or other systemic carbonic anhydrase inhibitor at baseline; Oral prednisone dose > 10 mg per day (or of an alternative corticosteroid at a dose higher than that equipotent to prednisone 10 mg per day) OR oral prednisone dose ≤ 10 mg per day that has not been stable for at least 4 weeks(note that if patient is off of oral prednisone at baseline (P01 visit), dose stability requirement for past 4 weeks does not apply); Systemic immunosuppressive drug therapy that has not been stable for at least 4 weeks; Known allergy or hypersensitivity to any component of the study drugs; Eye level exclusion criteria - at least one eye that meets all inclusion criteria cannot have any of the following conditions: History of severe glaucoma as defined by optic nerve damage (cup/disc ratio of ≥ 0.9 or any notching of optic nerve to the rim); Media opacity causing inability to assess fundus or perform OCT; Presence of an epiretinal membrane noted clinically or by OCT that per the judgment of study ophthalmologist may be significant enough to limit improvement of ME (i.e., causing substantial wrinkling of the retinal surface)81; Torn or ruptured posterior lens capsule; Presence of silicone oil; Periocular or intravitreal corticosteroid injection in past 8 weeks; Injection of dexamethasone intravitreal implant in past 12 weeks; Placement of fluocinolone acetonide implant (Retisert) in past 3 years;

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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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Periocular triamcinolone 40mg<br>Periocular triamcinolone acetonide (Kenalog), 40 mg Initial injection at Week 0 Second injection permitted at Week 8 IF: Eye does not meet the improvement definition (a 20% decrease in central subfield thickness of the macula) OR eye has a normal central subfield thickness but has cystoid spaces in the 1 mm central subfield OR ME is worse after initial improvement; IOP of ≤21 or mm Hg and treatment with ≤3 IOP-lowering agents; | Drug: Periocular triamcinolone 40 mg<br>* Periocular triamcinolone acetonide, 40 mg injection may be given either by posterior sub-Tenon's approach or by the orbital floor approach, as both appear to have similar efficacy; the approach to the periocular injection will be recorded for analysis if needed.<br>* Other names: Kenalog;|
| Active Comparator: Intravitreal triamcinolone 4mg<br>(preservative-free preparation, Triescence at U.S. clinics; Triesence preferred at non-U.S. clinics but Kenalog allowed) (4 mg) Initial injection at Week 0 Second injection permitted at Week 8 IF: Eye does not meet the improvement definition (a 20% decrease in central subfield thickness of the macula) OR eye has a normal central subfield thickness but has cystoid spaces in the 1 mm central subfield OR ME is worse after initial improvement; IOP of ≤21 or mm Hg and treatment with ≤3 IOP-lowering agents; | Drug: Intravitreal triamcinolone 4 mg<br>* Intravitreal triamcinolone acetonide, 4 mg injection procedures should be carried out under controlled aseptic conditions which include the use of sterile gloves and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide such as betadine, applied to the periocular skin, eyelid and ocular surface are required prior to an intravitreal injection.<br>* Other names: Triescence (in U.S); Kenalog allowed at non-U.S. clinics;|
| Active Comparator: Dexamethasoneintravitreal implant<br>Dexamethasone intravitreal implant (Ozurdex) (0.7 mg) Initial injection at Week 0 Second injection permitted at Week 12 IF: Eye does not meet the improvement definition (a 20% decrease in central subfield thickness of the macula) OR eye has a normal central subfield thickness but has cystoid spaces in the 1 mm central subfield OR ME is worse after initial improvement; IOP of ≤21 or mm Hg and treatment with ≤3 IOP-lowering agents; | Drug: Dexamethasone intravitreal implant<br>* • Standard preparation as described for intravitreal injections.<br>* Other names: Ozurdex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Baseline Central Subfield Thickness Observed at 8 Weeks | The primary outcome is the change in central subfield thickness from baseline to 8 weeks measured on a relative scale as the the proportion of the baseline central subfield thickness. Values less than 1 indicate a decrease in retinal thickness with lower values indicating greater decreases. Smaller values are better. The time point of 8 weeks was chosen for assessment of the primary outcome because it encompasses the window for maximum benefit for all three treatment strategies. Retinal thickness was evaluated using masked assessments of OCT images. | At baseline and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Baseline Central Subfield Thickness Observed at 24 Weeks | The primary outcome is the change in central subfield thickness from baseline to 24 weeks measured on a relative scale as the the proportion of the baseline central subfield thickness. Values less than 1 indicate a decrease in retinal thickness with lower values indicating greater decreases. Smaller values are better.The time point of 24 weeks was chosen to evaluate the duration of response and the need for additional injections.Retinal thickness was evaluated using masked assessments of OCT images. | At baseline and the 24 week visit | 
| Proportion of Eyes With >= 20% Reduction in Macular Thickness (or Normalization Even if <20% Reduction) at 8 Weeks | Proportion of eyes with >=20% reduction in macular thickness (or normalization of macular thickness even if there is <20% reduction) at 8 weeks. | Over 8 weeks of follow-up | 
| Proportion of Eyes With >= 20% Reduction in Macular Thickness (or Normalization Even if <20% Reduction) at 24 Weeks | Proportion of eyes with >=20% reduction in macular thickness (or normalization of macular thickness even if there is <20% reduction) at 24 weeks | Over 24 weeks of follow-up | 
| Proportion of Eyes With Resolution of Macular Edema at 8 Weeks | Proportion of eyes with resolution of macular edema defined as normalization of the macular thickness (i.e., < 260 um on the standardized scale) at 8 weeks. The greater the proportion the more eyes achieved resolution of macular edema. | Over 8 weeks of follow-up | 
| Proportion of Eyes With Resolution of Macular Edema at 24 Weeks | Proportion of eyes with resolution of macular edema defined as normalization of the macular thickness (i.e., <260 um on the standard scale) at 24 weeks. | Over 24 weeks of follow-up | 
| Change in Best-corrected Visual Acuity at 8 Weeks | Mean change in best-corrected visual acuity from baseline to 8 weeks. Participants' visual acuity was measured by certified examiners with best refractive correction in place.Participants were challenged with reading letters on lines of the standard ETDRS eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until no more meaningful readings could be made and were scored by how many letters could be correctly identified. More letters read is associated with higher visual acuity. | Over 8 weeks of follow-up | 
| Change in Best-corrected Visual Acuity at 24 Weeks | Mean change in best-corrected visual acuity from baseline to 24 weeks. Participants' visual acuity was measured by certified examiners with best refractive correction in place.Participants were challenged with reading letters on lines of the standard ETDRS eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until no more meaningful readings could be made and were scored by how many letters could be correctly identified. More letters read is associated with higher visual acuity. | Over 24 weeks of follow-up | 
| Number of Eyes With Vitreous Hemorrhage | Count of eyes with vitreous hemorrhage as an immediate complication of injection. | During 24 weeks of follow-up | 
| Number of Eyes With Retinal Tear or Detachment | Count of eyes with retinal tears or detachments during the course of follow-up. | During 24 weeks of follow-up | 
| Number of Eyes With Endophthalmitis | Count of eyes with an occurrence of endophthalmitis | During 24 weeks of folllow-ip | 
| Cumulative Proportion of Eyes With Severe Vision Loss | Cumulative proportion of eyes with uveitic macular edema who experience severe vision loss (>= 15 standard letters) during the 24 weeks of follow-up. | During 24 weeks of follow-up | 
| Cumulative Proportion of Eyes With an IOP Elevation of >=10 mm Hg Over Baseline | Cumulative proportion of eyes with uveitic macular edema that experience an IOP elevation of >=10 mm Hg higher than the baseline level during 24 weeks of follow-up. | During 24 weeks of follow-up | 
| Cumulative Proportion of Eyes With an IOP Elevation >=24 mm Hg | Cumulative proportion of eyes with uveitic macular edema that experience elevated IOP to >=24 mm Hg during 24 weeks of follow-up. | During 24 weeks of follow-up | 
| Cumulative Proportion of Eyes With an IOP Elevation >=30 mm Hg | Cumulative proportion of eyes with uveitic macular edema that experience elevated IOP to >=30 mm Hg during 24 weeks of follow-up. | During 24 weeks of follow-up |