Conditions: Macular Edema Uveitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 192
Healthy volunteers: yes

Brief summary:
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:
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.

Arms:
arm 1: 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; arm 2: (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; arm 3: 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;

Interventions: intervention 1: Periocular triamcinolone 40 mg intervention 2: Intravitreal triamcinolone 4 mg intervention 3: Dexamethasone intravitreal implant
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: • Standard preparation as described for intravitreal injections.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
PeriOcular and INTravitreal corticosteroids 
for uveitic macular edema (POINT) Trial 
Protocol version 2.1 
16 Feb 2017 
 
 
 
Phase 4 study 
 
Sponsor-investigator 
Janet Holbrook, PhD, MPH 
Director, MUST Coordinating Center 
Associate Professor of Epidemiology 
Johns Hopkins Bloomberg School of Public Health 
415 N. Washington Street 
Baltimore, MD 21231 
  
 
Medical Safety Officer 
Akrit Sodhi, M.D., Ph.D. 
Assistant Professor of Ophthalmology 
Retina Division 
Smith 4039 
Wilmer Eye Institute 
Johns Hopkins Medical Institutions 
400 North Broadway Street 
Baltimore, MD 21231 
 
 
ClinicalTrials.gov identifier: NCT02374060 
 
 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
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Document distribution 
 
 
 
Version 
 
Version date 
 
Distribution 
 
Distribution date 
 
1.0 
 
 
 
20 Nov 2014 
 
JHSPH IRB Office 
 
25 Nov 2014 
1.0 
19 Dec 2014 
JHSPH IRB Office 
19 Dec 2014 
 
 
 
 
1.0 
16 Jan 2015 
JHSPH IRB Office 
16 Jan 2015 
 
 
 
 
1.0 
29 Jan 2015 
Vanguard clinical 
centers 
 
JHSPH IRB Office 
05 Feb 2015 
 
 
06 Feb 2015 
 
 
 
 
 
 
META-MUST DSMC 
13 Feb 2015 
 
 
 
 
1.0 
06 Apr 2015 
JHSPH IRB Office 
14 Apr 2015 
 
 
Clinical Centers 
14 Apr 2015 
 
 
 
 
1.0 
03 Jun 2015 
META-MUST DSMC 
JHSPH IRB Office 
Clinical Centers- 
PPM 4 
 
04 Jun 2015 
04 Jun 2015 
08 Jun 2015 
 
1.1 
06 Aug 2015 
New clinics:  MUHC, 
MEEI, IOWA, OCB, 
SCRA 
All clinical centers 
JHSPH IRB 
 
 
07 Aug 2015 
 
 
11 Aug 2015 (PPM7) 
24 Aug 2015 
 
1.2 
23 Feb 2016 
WILL, MAYO 
UKIO 
CC IRB 
UPMC 
All clinical centers 
23 Feb 2016 
24 Feb 2016 
11 Mar 2016  
28 Mar 2016 
07 Apr 2016 (PPM 14) 
 
 
 
2.0 
28 Jun 2016 
JHSPH IRB 
Clinical centers 
6 July 2016 
6 July 2016 (PPM 18)  
 
2.1 
 
16 Feb 2017 
 
JHSPH IRB 
 
21 Feb 2017 
 
 
Clinical Centers 
24 Mar 2017 (PPM 37) 
 


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Document revision history 
 
19 Dec 2014 
 
Throughout 
• 
Added (Kenalog®) as specification for periocular triamcinolone acetonide 
• 
Added clarification for intravitreal triamcinolone acetonide: Triesence is to be used at U.S. clinics 
and Triesence is preferred at non-U.S. clinics but Kenalog is allowed  
 
 
1.5 Investigators and study centers 
• 
Deleted clinical centers:   
- Massachusetts Eye Research and Surgery Institute, Cambridge, MA 
- University of California-SD, La Jolla, CA 
 
 
3.1 Type of study 
• 
Added second stratification variable:  ≥ .5 disc areas of leakage on fluorescein angiography at 
baseline as assessed by study ophthalmologist 
 
 
3.6 Eligibility criteria 
• 
Clarified inclusion criterion 3 by adding italicized text: 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 
• 
Deleted:  Evidence of leakage on fluorescein angiography at baseline as assessed by study 
ophthalmologist; 
 
 
3.7 Randomization 
• 
Added second stratification variable:  ≥ .5 disc areas of leakage on fluorescein angiography at 
baseline as assessed by study ophthalmologist 
 
 
3.8 Data collection  
• 
Color fundus (disc) images changed to Color fundus/red reflex images 
• 
Deleted:  Slit lamp images  
 
16 Jan 2015 
 
3.8 Data collection 
• 
Clarified that ophthalmic exam includes slit lamp exam and ophthalmoscopy 
 
29 Jan 2015 
 
Abstract 
• 
Removed ‘initial’ in the sentence:  The question of how to approach regional treatment of 
uveitic macular edema is a key question for ophthalmologists treating these patients. 
 
 


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2.1 Objective 
• 
Removed ‘initial’ in the following:  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. 
 
 
3.1 Type of study  
• 
Deleted stratification variable   ≥ .5 disc areas of leakage on fluorescein angiography at baseline 
as assessed by study ophthalmologist  
 
3.6 Eligibility  
• 
Added inclusion criterion: Baseline fluorescein angiogram that is gradable for degree of leakage 
in the central subfield  
 
 
3.7 Randomization 
• 
Deleted stratification variable   ≥ .5 disc areas of leakage on fluorescein angiography at baseline 
as assessed by study ophthalmologist 
 
3.8 Data collection schedule 
• 
“Color fundus/red reflex images” changed to “Fundus reflex images” 
 
6.2 Statistical methods 
In fourth paragraph made the following changes to accommodate removal of leakage on 
fluorescein angiography as stratification variable: All analyses will be performed both 
unadjusted, except for the stratification variable, and adjusted for potential confounders.  Effect 
modification due to factors such as disease location or uveitis activity, fluorescein leakage in the 
central subfield, systemic disease, gender and race also will be explored when appropriate. 
 
16 Feb 2015 
3.6 Eligibility 
• 
Corrected misspelling of gradable  
 
6 Apr 2015 
Title page 
• 
Medical Safety Officer changed from Douglas A. Jabs, MD, MBA to Akrit Sodhi, MD, PhD 
• 
Added: ClinicalTrials.gov Identifier: NCT02374060 
 
1.4 Financial sponsor 
• 
Added: Allergan (Irvine CA) is donating Ozurdex for the NEI, UKIO, and RVEE clinical centers 
 
3.3 Trial schema 


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• 
In footnote “§” changed timeframe of opening of MERIT enrollment from 6 months to 1 year 
after the initiation of POINT 
 
3.6 Eligibility  
• 
Participant-level exclusion criterion 1 (History of infectious uveitis, or of scleritis, keratitis, or 
endophthalmitis in either eye) was split into 2 to clarify that it history of infectious 
endophthalmitis is exclusionary: 
1. History of infectious endophthalmitis or infectious uveitis in either eye; 
2. History of scleritis or keratitis of any type in either eye; 
 
3 Jun 2015 
3.3 Trial schema 
• 
In footnote  “†”  removed “best corrected visual acuity of 20/40 or worse” as condition for 
second injection 
 
3.6 Eligibility  
• 
Inclusion criterion 4 (an eye level criterion) best corrected visual acuity (BCVA) requirement 
changed from “BCVA of 20/40 to 5/200” to “BCVA worse than 20/32 and 5/200 or better”  
 
4.2.2 Second injections of assigned treatment 
• 
Deleted “Best corrected visual acuity of 20/40 or better” as repeat injection criterion 
 
 
6 Aug 2015 
1.5 Investigators and study centers 
• 
Deleted: Texas Retina, Dallas, TX 
• 
Added 
− Southeast Clinical Research Associates, Charlotte Eye Ear Nose &Throat Associates, 
Charlotte, NC 
− Massachusetts Eye and Ear Infirmary/Harvard Medical School, Boston, MA 
− McGill University and McGill University Health Center, Montreal, QC, Canada 
− Ophthalmic Consultants of Boston, Boston, MA 
− University of Iowa Hospitals and Clinics, Iowa City, IA 
− Vision Research/ROPARD Foundation of Associated Retinal Consultants, P.C., Royal Oak, 
MI 
− UW Medicine Eye Institute, University of Washington, Seattle, WA 
 
4.4.3 Possible side effects and complications of treatments, Intravitreal dexamethasone – added  
“elevated intraocular pressure which may require surgery to control” under less frequently reported 
events 
 
3.1 Design, type of study – updated number of clinical centers to 26 


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23 Feb 2016 
1.5 Investigators and study centers 
• 
Deleted  
− Southeast Clinical Research Associates, Charlotte Eye Ear Nose &Throat Associates, 
Charlotte, NC 
− Vision Research/ROPARD Foundation of Associated Retinal Consultants, P.C., Royal Oak, 
MI 
• 
Added: 
− Mid Atlantic Retina, Wills Eye Hospital, Philadelphia, PA  
− Mayo Clinic, Rochester, MN 
 
3.6 Eligibility 
Added new exclusion criterion #11:  (eye level exclusion) Torn or ruptured posterior lens capsule 
 
4.3 Treatment administration guidelines 
• 
Added the word “guidelines” 
• 
Added note:  Ophthalmologist administering treatment may follow local of standard care 
guidelines for topical anesthesia and needle size if they have been reviewed by Study Clinic 
Director as appropriate for use in this trial.   
 
 
28 Jun 2016, version 2.0 
1.4 Financial sponsor 
Clarified that Allergan is donating a limited number of Ozurdex for study patients at U.S. clinical centers 
in special circumstances, e.g. patient’s insurance denies coverage for Ozurdex rather than for use at 
non-U.S. clinical centers 
 
1.5 Investigators and study centers 
• 
Change of Principal Investigator at these clinical centers 
− University of Pennsylvania 
− University of Southern California 
− Washington University 
• 
Added new clinical center University of Pittsburgh Medical Center 
 
3.1 Type of study 
• 
Changed number of clinical centers from 26 to 27 
 
3.3 Trial schema 
• 
Second injection IOP criterion changed from ≤21 mm Hg with ≤ 2 IOP lowering agents to  
≤21 mm Hg with ≤ 3 IOP lowering agents  
 
3.6 Eligibility 
Inclusion criteria 


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• 
3 - Clarified definition of macular edema for eligibility by adding specific eligibility thresholds for 
central subfield macular thickness for different types of OCT machines 
• 
4 - Removed upper limit of best corrected visual BCVA (i.e., worse than 20/32) 
• 
5 – Increased the number of IOP lowering medications permitted from 2 to 3 and added 
clarification that combination medications, i.e.,Cosopt, count as 2 IOP lowering medications 
Exclusion criteria 
• 
3 - New patient-level exclusion added: History of central serous retinopathy in either eye 
• 
6 – Clarification added as italicized for exclusion for oral prednisone dose ≤ 10 mg per day at 
baseline that has not been stable for at least 4 weeks (Note  if patient is off of oral prednisone at 
baseline (P01 visit), dose stability requirement for past 4 weeks does not apply);  
• 
Deleted exclusion criterion:  Topical NSAID use if dose has not been stable for at least 4 weeks. 
 
4.1 Treatment overview  
4.2  Treatment schedule 
• 
Pre-injection IOP criterion changed from ≤21 mm Hg with ≤ 2 IOP lowering agents to  
≤21 mm Hg with ≤ 3 IOP lowering agents 
 
8.  Study timetable 
• 
Removed this section because it is out of date. 
 
16 Feb 2017, version 2.1 
1.5 “Investigators and study centers” changed to “Resource and clinical centers” 
• 
Replaced list of clinical centers and investigators with note that Clinical Centers and Clinic 
Directors are listed in the POINT Manual of Procedures in keeping with the convention that 
clinical centers are not listed in the protocol for multicenter trials with more than 3 clinical 
centers.   
 
3.3 Trial schema 
• 
Clarified that non-responders are eyes demonstrating less than a 20% reduction or worsening of 
ME as measured by central subfield macular thickness on OCT  
• 
For dexamethasone arm, added that non-responders could be enrolled in MERIT at P06, if 
eligible 
• 
Clarified that second injection time points on schema are the earliest time points for second 
injection but that second injections can be done at later time points 
• 
Revised pre-injection IOP criteria for second injections – changed from ≤21 mm Hg to <25 mm 
Hg 
• 
Updated last sentence in footnote explaining purpose of MERIT Trial regarding treatment of 
uveitic macular edema persistent after intravitreal corticosteroids; originally MERIT was to focus 
on uveitic macular edema persistent after intravitreal triamcinolone acetonide.    
 
3.6  Eligibility criteria 
Exclusion criteria  
• 
Patient level exclusion criterion #2 changed  
 
  From 
2.  History of scleritis or keratitis of any type in either eye  
              To 


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2. History of infectious scleritis of any type in either eye. (Note: History of 
noninfectious scleritis that has been active in past 12 months is an eye-level 
exclusion –see #11 below.) 
3. History of keratitis (with the exception of keratitis due to dry eye)in either eye; 
• 
Eye level exclusion criterion added 
11. History of active noninfectious scleritis in past 12 months (Note: History of 
noninfectious scleritis is acceptable if the last episode of active scleritis resolved at 
least 12 months prior to enrollment); 
 
4.1. Treatment overview 
• 
Added to first bullet:  Treatment administration instructions and pre-injection IOP criteria are 
included in sections 4.2 and 4.3. 
• 
Added bullet: Treatment according to the best medical judgment of treating study 
ophthalmologist is permitted as deemed necessary. Repeat injections given before the protocol 
specified time points or other deviations from the treatment protocol (section 3.3.) should be 
reported expeditiously to CC on Unanticipated Event (UA) form, usually within a few days.   
• 
Deleted last bullet:  All injections of study treatments must be administered per protocol 
instructions and follow IOP injection criteria (IOP of ≤21 or mm Hg and treatment with ≤ 3 IOP-
lowering agents).  
4.2.1. Initial injections of assigned treatment 
• 
Added explicit statement that IOP requirements for initial injection must be met on day injection 
administered.  
• 
Added: Note that IOP requirements for the initial injection are the same as for eye eligibility for 
the trial. If study treatment is initiated on the same day as eligibility is confirmed and treatment 
assigned, no additional IOP measurements are needed. If circumstances require patient to return 
to clinic for injection at a later date, IOP must be checked and IOP-lowering agents evaluated 
prior to injection. If the eligibility requirements are not met, the injection should not be given. If 
the treating ophthalmologist elects to proceed with assigned treatment per best medical 
judgment, the deviation from the protocol must be reported to CC on an Unanticipated Event 
(UA) form; the UA form should be submitted as soon as possible, usually within a few days.      
 
4.2.2. Second injections of assigned treatment 
• 
Revised IOP requirements for second injection from “≤21 mm Hg and ≤3 IOP lowering agents” to 
“<25 mm Hg and ≤3 IOP lowering agents” 
 
4.2.3. Treatment for non-responders (i.e., <20% reduction or worsening of ME)  
• 
Clarified the study definition of non-responder: Eyes that demonstrate less than a 20% 
reduction no improvement or worsening of ME as measured by the central subfield thickness on 
OCT at specific time point in the trial 
 
7.2.2 Confidentiality  
• 
Added:  CC will report serious adverse event data for participants randomized to Ozurdex to 
Allergan (Irvine, CA). 
 
Global:  minor edits in reference to changes above and formatting and spelling corrections 


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Abstract 
 
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).   The design outcome is the percent 
change in central subfield macular thickness on OCT from baseline to the 8 week visit.  Follow-
up through 24 weeks will allow evaluation of the duration of response and the need for 
additional injections.  Secondary outcomes include resolution of macular edema, IOP elevation, 
visual acuity, complications of treatment, and cost-effectiveness.  
 
 


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Contents 
Document distribution ........................................................................................................... 2 
Document revision history .................................................................................................... 3 
Abstract ................................................................................................................................ 9 
1. Introduction ...................................................................................................................12 
1.1. Title 12 
1.2. IND exemption ......................................................................................................12 
1.3. Sponsor-investigator .............................................................................................12 
1.4. Financial sponsor .................................................................................................12 
1.5. Resource and clinical centers ...............................................................................12 
1.6. Background and significance ................................................................................12 
2. Objective and study hypothesis .....................................................................................17 
2.1. Objective ..............................................................................................................17 
2.2. Hypothesis ...........................................................................................................17 
3. Design ...........................................................................................................................18 
3.1. Type of study ........................................................................................................18 
3.2. Treatment Arms ....................................................................................................18 
3.3. Trial schema .........................................................................................................19 
3.4. Primary outcome ..................................................................................................20 
3.5. Secondary outcomes ............................................................................................20 
3.6. Eligibility criteria ....................................................................................................21 
3.7. Randomization .....................................................................................................22 
3.8. Data collection schedule .......................................................................................23 
4. Study treatment schedule and administration ................................................................24 
4.1. Treatment overview ..............................................................................................24 
4.2. Treatment schedule ..............................................................................................24 
4.2.1. Initial injections of assigned treatment .........................................................24 
4.2.2. Second injections of assigned treatment ......................................................24 
4.2.3. Treatment for non-responders (i.e., <20% reduction or worsening of ME) ...25 
4.3. Treatment administration guidelines .....................................................................25 
4.3.1. Administration of periocular triamcinolone acetonide ...................................25 
4.3.1.1. Posterior sub-Tenon injection ......................................................................25 
4.3.1.2. Orbital floor injection ....................................................................................26 
4.3.2. Standard preparation for all intravitreal injections ........................................26 


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4.3.3. Administration of intravitreal triamcinolone acetonide (Triesence) ................26 
4.3.4. Administration of dexamethasone implant (Ozurdex) ...................................26 
4.4. Possible side effects and complications of treatments ..........................................27 
4.4.1. Periocular triamcinolone acetonide ..............................................................27 
4.4.2. Intravitreal triamcinolone acetonide .............................................................28 
4.4.3. Intravitreal dexamethasone ..........................................................................28 
4.4.4. Intravitreal injection ......................................................................................28 
5. Adverse event reporting ................................................................................................29 
5.1. Adverse events .....................................................................................................29 
5.2. Serious adverse events ........................................................................................29 
6. Sample size and statistical methods ..............................................................................30 
6.1. Sample size, power and detectable differences ....................................................30 
6.2. Statistical methods ...............................................................................................32 
7. Regulatory and ethical issues ........................................................................................34 
7.1. Recruitment and informed consent procedures ....................................................34 
7.2. IRB/Protection of human subjects .........................................................................34 
7.2.1. Potential risks and procedures to minimize risks to participants ...................34 
7.2.2. Confidentiality ..............................................................................................34 
7.2.3. Inclusion of children .....................................................................................35 
7.2.4. Data and safety monitoring ..........................................................................35 
8. References ....................................................................................................................36 
 
 
 


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1. Introduction 
 
1.1. 
Title 
PeriOcular and INTravitreal corticosteroids for uveitic macular edema (POINT) Trial 
 
1.2. 
IND exemption 
IND exemption granted by FDA on 8 Sep 2013 
 
1.3. 
Sponsor-investigator 
Janet T. Holbrook, PHD, MPH, Director Coordinating Center 
Johns Hopkins University Bloomberg School of Public Health 
Baltimore, MD 
  
1.4. 
Financial sponsor 
U-10 grant, National Eye Institute 
 
Allergan (Irvine CA) is donating a limited number of Ozurdex for study patients at U.S. clinical 
centers in special circumstances, e.g., patient’s insurance denies coverage for Ozurdex. .  
Allergan will have no input into study design, management, data analyses, or interpretation of 
results.  
 
1.5. 
Resource and clinical centers  
 
Resource centers 
 
Center 
Director 
Chairman’s Office 
 
Icahn School of Medicine at  Mount Sinai ,New York, NY 
Douglas A. Jabs, MD, MBA 
Coordinating Center  
 
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 
Janet Holbrook, PhD, MPH 
Reading Center 
 
University of Wisconsin at Madison, Madison, WI 
Michael Altaweel, MD 
 
 
Clinical Centers and Clinic Directors are listed in the POINT Manual of Procedures  
 
 
1.6. 
Background and significance 
Macular edema (ME) is the most common structural complication and cause of visual 
impairment and legal blindness in patients with uveitis.1-3 In a retrospective study from two 
uveitis referral centers in the Netherlands in the early 1990s, 40% of patients with intermediate 
uveitis, posterior uveitis, or panuveitis had ME, and it was the most common cause of visual 
loss among all patients with uveitis, accounting for 41% of visual impairment.3 In the Multicenter 
Uveitis Steroid Treatment (MUST) Trial, ME was present in approximately 40% of eyes with 
uveitis with a similar frequency for patients with intermediate uveitis, posterior uveitis, and 
panuveitis.4-6 The presence of ME is the most common indication for treatment among patients 
with intermediate uveitis.1, 2, 7-9 Furthermore, despite apparent control of inflammation with 
corticosteroids and immunosuppressive drugs such that no inflammatory white cells are present 


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in the anterior chamber or vitreous, many patients exhibit persistent ME requiring supplemental 
therapy, typically with periocular or intravitreal corticosteroid injections.1, 2, 7-10 
 
The management of uveitic ME is principally directed toward treatment of the underlying 
inflammatory condition with appropriate medical therapy and less often, surgical intervention 
together with life-style modifications such as smoking cessation and stress reduction.11-13  
Current medical treatment modalities include nonsteroidal anti-inflammatory drugs, 
immunomodulatory therapies, acetazolamide, octreotide, oral, periocular, or intravitreal 
injections of various corticosteroid preparations, and most recently, intravitreal administration of 
anti-vascular endothelial growth factor (VEGF) inhibitors and methotrexate (MTX).11, 14-17 While 
corticosteroid injections may reduce ME and improve vision, the effect is often variable with a 
limited duration.18, 19 Pars plana vitrectomy (PPV) and PPV in combination with intravitreal 
corticosteroids have been investigated as treatment options for inflammatory ME unresponsive 
to medical therapy; however, the impact of this intervention is not yet clear.20, 21 The frequently 
refractory nature of uveitic ME and its impact on visual function underscores the need to identify 
effective alternative medical therapeutic options. 
 
The pathophysiology of ME associated with uveitis is thought to be a consequence of increased 
vascular permeability from mediators released by inflammatory cells which damage the function 
of the vascular endothelium, retina, and retinal pigment epithelial (RPE) cells with subsequent 
accumulation of fluid into the macula, characteristically distributed in the outer plexiform layer of 
the retina.11 Exactly which mediators are critical in the pathogenesis of inflammatory ME is 
incompletely understood. Corticosteroids have been the first line of treatment for noninfectious 
uveitis in general and of inflammatory ME in particular. The mechanisms of action by which 
corticosteroids mediate their effect are likely their anti-inflammatory, anti-edema, and anti-
angiogenic effects. Corticosteroids inhibit the phospholipase A2 pathway, interfere with the 
release of inflammatory mediators, and decrease VEGF secretion.22, 23 Models of experimental 
autoimmune uveoretinitis in rats and studies in humans with uveitis and ME show an increased 
concentration of vascular endothelial growth factor (VEGF) in the aqueous humor.24-27 VEGF is 
suspected to play a role in the loss of vascular integrity in the eye and is known to be induced 
by inflammatory cytokines, such as interleukin (IL)-1 and IL-6, which have been found to be 
elevated intraocularly in uveitis patients.27, 28 Furthermore, aqueous VEGF concentrations are 
significantly higher in those uveitis patients with CME than those without CME. 25 The recent 
introduction of intravitreally administered nonsteroidal medications with anti-inflammatory 
activity for the treatment of inflammatory ME, such as methotrexate and those which inhibit 
inappropriate VEGF activity, offers potentially effective alternative treatment approaches to ME 
in this population which might obviate the well-known ocular side effects of corticosteroid based 
therapies. 
 
Traditional approaches to the treatment of uveitic ME have included the use of regional 
corticosteroid therapy, delivered periocularly, including posterior sub-Tenon’s (PST) and orbital 
floor injections, or via the intravitreal route.7, 10, 29-41 With respect to periocular delivery, available 
nonrandomized, but comparative, data suggest similar success rate with both approaches.42-44 
The most commonly used drug is triamcinolone acetonide (TA) even though both 
methylprednisolone and TA have been used for periocular injections. The estimated 
pharmacologic effect of a regional corticosteroid injection, whether given by the periocular or 
intravitreal route, appears to be approximately 3 months, although the duration of benefit in 
some patients with uveitis may be longer.  
 
In a retrospective study of 159 eyes that underwent PST for ME from a variety of etiologies and 
were followed for a mean of 12 months, a single injection posed relatively little risk of IOP 


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Introduction │ 14 
 
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complications and cataract progression whereas with repeated administration, these side effects 
increased.45 A study from the Johns Hopkins Medical Institution of 126 patients (156 eyes) with 
uveitic ME who received a single periocular injection of corticosteroid reported clinical resolution 
of ME among 53% and 57% of eyes at 1 month and 3 months respectively. 46 Of the 83 eyes 
that had resolution of ME at 1 month, 50 (60%) had no recurrence of the ME at 3 months after 
the first periocular corticosteroid injection. Among those eyes that had recurrence of ME, the 
median time for recurrence was 20 weeks.  Forty eyes were treated with more than one 
periocular injection due to persistence of ME one month following the first injection.  Of the 21 
eyes treated with a second periocular injection, 81% and 43% had no ME at one and 3 months, 
respectively, after the second injection.  Overall, a 3-line improvement in visual acuity was 
observed in 52% at one month and in 57% at 3-months.  Side effects attributed to periocular 
corticosteroid injections included IOP rise to >30 mm of Hg in 19% (rate = 0.14/eye-year [EY]), 
newly diagnosed cataract in 10% (rate = 0.13/EY), and ptosis in 14% (rate = 0.09/EY).  
 
The largest study evaluating intravitreal triamcinolone acetonide in patients with uveitic ME was 
performed at Moorfields Eye Hospital.33  This retrospective case series of 65 eyes in 54 patients 
found an improvement in ME and visual acuity in 83% of eyes and a mean 12-letter gain (2.4 
lines) in BCVA with intravitreal triamcinolone acetonide with a mean follow-up of 8 months.  The 
most important side effect was raised IOP with 43% experiencing IOP rise >10 mm of Hg.  
Although not strictly comparable, these data suggest that intravitreal triamcinolone acetonide 
may be superior to periocular TA for the treatment of uveitic ME, but that the frequency of ocular 
complications may be greater.  Similarly, a study comparing the ocular side effects of PST to 
intravitreal triamcinolone acetonide in ME from a variety of causes demonstrated a significantly 
increased frequency of IOP> 30 mm Hg and the more frequent need for antiglaucoma 
medication among the intravitreal triamcinolone acetonide  group with risk factor for the 
development of elevated IOP including; higher baseline IOP, younger age, and the presence of 
uveitis.47  
 
Indeed, the major limitations of intravitreal triamcinolone acetonide are related to the relatively 
high rates of adverse ocular effects and to its limited duration of action.  The rate of cataract 
development has been reported to range from 15-30% after a single injection48-51 and increases 
with repeated injections.52, 53  Steroid induced IOP elevations have been reported to arise in 
25% and 45% of patients33, 48-50, 54 are dose dependent55, 56 and may be more frequent among 
children.18  In most instances, elevated IOP is transient and may be controlled with 
antiglaucoma medications; however, surgical intervention may be required.36, 57  While the long-
term prognosis of uveitic ME treated with intravitreal triamcinolone acetonide  is uncertain, a 
recent report demonstrated improved BCVA with no evidence of tachyphylaxis to repeated 
intravitreal triamcinolone acetonide injections or increased rates of IOP elevation, while cataract 
progression requiring surgery was seen in all phakic patients by the fifth injection.58  In addition, 
intravitreal triamcinolone acetonide has been shown to be effective in the management of 
persistent ME despite adequate control of intraocular inflammation with response rates of up to 
85%.16, 52, 59, 60 There are currently two formulations of preservative free TA that have been 
approved by the Federal Drugs Administration (FDA) for intraocular use, Triesence™ (Alcon, 
Fort Worth, Texas, USA) and Trivaris™ (Allergan Inc., Irvine, California, USA ). 
 
In an effort to avert the limited duration of action of intravitreal triamcinolone acetonide  and 
exposure to systemic medications, sustained release devices have been developed and 
approved by the FDA including the dexamethasone implant, a copolymer containing 
dexamethasone, lactic and glycolic acid, which degrades slowly into carbon dioxide and water 
over a period of 6 months following an office based injection into the vitreous cavity.61-67  The 
safety and efficacy of a single intravitreal injection of two dexamethasone implant doses (0.7mg 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Introduction │ 15 
 
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and 0.35mg) has been recently reported from the HURON study, a large, 26 week, phase III, 
prospective, multicenter, masked, sham-controlled randomized clinical trial among 229 patients 
with noninfectious intermediate or posterior uveitis.68  Patients were randomized 1:1:1 to receive 
either a high dose dexamethasone (0.7mg) implant, low dose dexamethasone (0.35mg) implant, 
or sham injections.  While both implant doses were shown to be effective in controlling vitreous 
inflammation and in improving visual acuity, the higher dose implant proved to have a longer 
duration of action without a significant increase in untoward ocular side-effects and is the dose 
currently in clinical use.  Vitreous haze scores of zero were achieved in 47% and 36% of the 
high and low dose implants respectively as compared with 12% among sham treated eyes at 8 
weeks, a benefit which persisted among the high dose group to 26 weeks when compared to 
sham.  At 8 weeks, 43% of treated eyes versus 7% in the sham group had at least a 15 letter 
improvement from baseline BCVA while the proportion of eyes achieving this level was 2- to 6- 
fold greater in the dexamethasone implant groups as compared to the sham group throughout 
the study period.  The central macular thickness as measured by optical coherence tomography 
(OCT) was significantly lower at weeks 8 and 26 in both dexamethasone implant groups 
compared to baseline but not statistically different among the sham group.  While the mean 
reduction in macular thickness from baseline was significantly greater in the dexamethasone 
implant treated eyes at week 8, this was not sustained at week 26.  The percentage of eyes with 
IOP ≥25 mm Hg peaked at 7.1% for the high dose implant, 8.7% for the low dose implant, and 
4.2% for the sham group with the ≤ 23% of eyes in the high dose group requiring antiglaucoma 
medication and none requiring surgical intervention.  Likewise, at 26 weeks, there was no 
statistically significant increase in the rate of cataract between treatment groups (15% high 
dose, 12% low dose, 7% sham) with no patient requiring surgery. 
 
Subsequent small, retrospective case series confirm the safety and efficacy of the 
dexamethasone implant in eyes with noninfectious posterior uveitis with an improved 
inflammatory activity, visual acuity and a reduction in mean central retinal thickness; however, 
the durability of the effect may be shorter (3-4 months) in clinical practice than that reported in 
the HURON trial and require repeated injections.69-71  While the side effect profile of the 
dexamethasone implant may appear to be superior to intravitreal triamcinolone acetonide, it is 
important to note that steroid responders were excluded from the HURON trial and patients 
received a single injection, hence, the effect of multiple injections on cataract and IOP remains 
unknown.  Finally, while preclinical data indicate that the vitreous and retinal concentrations of 
dexamethasone are similar in non-vitrectomized and vitrectomized eyes, it is of interest as to 
whether the dexamethasone implant will have an advantage in the latter situation in which 
clearance of intravitreal triamcinolone acetonide is known to be more rapid.19, 64, 72 
 
Taken together these data suggest that intravitreal triamcinolone may be a more effective initial 
treatment than periocular triamcinolone although its side effects may be greater and that the 
intravitreal dexamethasone may have lower rates of side effects than those of intravitreal 
triamcinolone.  However, differing methodologies and different enrollment criteria substantially 
hamper comparing the data from these different studies. One of the most substantial differences 
is the methodology used to evaluate macular edema.  Clinical estimates of macular edema 
improvement are heavily influenced by visual acuity improvement and may overestimate the 
resolution rate and the apparent efficacy of interventions on macular edema.  Fluorescein 
angiography and OCT measure somewhat different aspects of macular edema, vascular 
leakage and retinal thickness, respectively.  Although the two methods correlate, the correlation 
is moderate, as compensated leakage may not result in thickening, and thickening may occur 
without evident leakage.4  Of the three methods (OCT, fluorescein angiography, clinical 
examination), clinical examination is least likely to detect macular edema.4  Visual acuity loss 
correlates better with retinal thickness than with the two-dimensional area of leakage.73  Even 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Introduction │ 16 
 
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though vision is influenced by multiple factors, such as media opacity, change in macular 
thickness on OCT correlate with visual acuity improvement74, suggesting that as a single 
measure of macular edema response for comparative studies, retinal thickness on OCT is a 
good one.  Furthermore, a relatively short-term trial with macular thickness on OCT as a 
comparative measure may be adequate to evaluate relative efficacy.  Somewhat longer-term 
follow-up (e.g. 6 months) will be needed to evaluate the duration of response and the need for 
additional injections. The POINT Trial was designed to compare the relative efficacy of 
periocular triamcinolone, intravitreal triamcinolone, and intravitreal dexamethasone as the initial 
regional approach to treatment of macular edema using central subfield macular thickness on 
OCT as the primary outcome measure with assessment of the relative efficacy at 8 weeks and 
evaluation of the duration of response and the need for additional injections over 24 weeks of 
follow-up.   
 
 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Objective and study hypothesis │ 17 
 
P:\Doc\MUST\POINT\protocol\17 02 16_2.1\17 02 16 POINT protocol 2 1.docx 
 
 
2. Objective and study hypothesis 
 
2.1. 
Objective 
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. 
 
 
2.2. 
Hypothesis 
  Primary hypotheses: 
(1) Intravitreal triamcinolone injections will have greater efficacy than periocular 
triamcinolone as a treatment for uveitic macular edema. 
(2) Intravitreal injections of the dexamethasone pellet will have greater efficacy than 
periocular triamcinolone injections as a treatment for uveitic macular edema. 
(3) Intravitreal injections of the dexamethasone pellet will be non-inferior to intravitreal 
triamcinolone as a treatment for uveitic macular edema. 
  Secondary hypothesis: 
(1) Intravitreal injections of the dexamethasone pellet will have a lower rate of IOP elevation 
than intravitreal triamcinolone injections over the 24 weeks of follow-up. 
 
 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Design │ 18 
 
P:\Doc\MUST\POINT\protocol\17 02 16_2.1\17 02 16 POINT protocol 2 1.docx 
 
3. Design 
 
3.1. 
Type of study 
• 
Three-armed, parallel design randomized comparative trial 
• 
Allocation ratio 1:1:1 
• 
Randomization stratified by the presence or absence of concomitant systemic therapy 
for uveitis (e.g., oral corticosteroids and/or immunosuppressive drugs) 
• 
Unit of randomization is patient, not eye; if both eyes meet eligibility criteria, both receive 
the assigned treatment 
• 
Multicenter 
• 
Fixed sample size, 267 (89 per treatment group) 
• 
Anniversary close-out at the 24 week clinic visit  
• 
Reading center graders assessing primary outcome and visual acuity examiners masked 
to treatment 
• 
Open-label; treating physicians and patients unmasked to treatment (the therapies are 
different in appearance and have potentially different injection schedules) 
 
 
3.2. 
Treatment Arms 
• 
Periocular triamcinolone acetonide (Kenalog) (40 mg) 
• 
Intravitreal triamcinolone acetonide (preservative-free preparation, Triescence at U.S. 
clinics; Triesence preferred at non-U.S. clinics but Kenalog allowed) (4 mg) 
• 
Dexamethasone intravitreal implant (Ozurdex) (0.7 mg) 
 
 
 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Design ൟ 19 
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POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Design │ 20 
 
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3.4. 
Primary outcome 
The primary outcome is the percent change in central subfield thickness from the baseline OCT 
measurement at the 8-week visit.  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. The results will be transformed to represent relative change. Assessment 
of OCT outcomes will be performed by masked readers. 
 
3.5. 
Secondary outcomes  
• 
Rate of IOP elevation of >21 mm Hg or ≥ 10 mm Hg from baseline during the 24 weeks 
of follow-up  
• 
Percent change in macular thickness as measured by OCT over the 24 weeks of follow-
up 
• 
Proportion of eyes with macular edema events over the 24 weeks of follow-up 
- ≥20% reduction in macular thickness (or normalization of macular thickness even 
if there is <20% reduction)  
- ”Resolution”, defined as normalization of the macular thickness to within +2 
standard deviations of the normative mean for the OCT machine used 
- Worsening defined as a 20% increase in macular thickness from the lowest value 
after an injection 
- “Recurrence” defined as >20% increase in the central subfield measurement on 
OCT to an abnormal value in an eye that previously had resolution of ME 
• 
Mean change in BCVA over the 24 weeks of follow-up.  
Best-corrected visual acuity score will be measured at every study visit under 
standardized lighting conditions by certified study examiners masked to study treatment 
using logarithmic (ETDRS) visual acuity charts, according to the method described by 
Ferris, et al.75 
• 
Inflammation as graded using the semi quantitative scales used in the MUST Trial i.e., 
clinician grading of the presence and extent of anterior chamber cells, anterior vitreous 
cells, and vitreous haze based on previously published standard ordinal scales (0, trace, 
1+, 2+, 3+, 4+)76-78 using the scales endorsed by the Standardization of Uveitis 
Nomenclature Working Group when applicable79 
• 
Safety outcomes including elevated IOP ( >30 mm Hg thresholds ); new onset posterior 
subcapsular (PSC) cataract or progression of pre-existing PSC (using the Age-Related 
Eye Disease Study [AREDS] scheme80; vitreous hemorrhage; retinal tear/detachment; 
endophthalmitis; severe vision loss (≥15 Early Treatment Diabetic Retinopathy Study 
[ETDRS] letters) during the 24 weeks of follow-up. 
• 
Cost-effectiveness of treatments for uveitic macular edema during the 24 weeks of 
follow-up will be assessed by enumerating costs of treatments and procedures for uveitis 
during the 24 week follow-up; participants’ utilities will be measure with the EuroQol 
questionnaire. 
• 
Visual function related quality of life as measured by the NEI Visual Function 
Questionnaire (25 item version).  
 
 


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Design │ 21 
 
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3.6. 
Eligibility criteria 
Inclusion criteria: 
      Patient level inclusion criterion: 
 
1. 18 years of age or older; 
 
       Eye level inclusion criteria - at least one eye must meet all of the following conditions  
 
2. Non-infectious anterior, intermediate, posterior or panuveitis; either active or inactive 
uveitis is acceptable; 
 
3. Macular edema (ME) defined as the presence of central subfield macular thickness 
greater than the normal range for the OCT machine being used (>300 μm for Zeiss 
Cirrus/Topcon 3DOCT or >320 μm for Heidelberg Spectralis), regardless of the 
presence of cysts, as assessed by study ophthalmologist;  
 
 
4. Best corrected visual acuity (BCVA) 5/200 or better;  
 
 
5. 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 – note that combination medications, i.e., Cosopt, count as 2 IOP 
lowering medications); 
 
6. Baseline fluorescein angiogram that is gradable for degree of leakage in the central 
subfield  
 
7. Pupillary dilation sufficient to allow OCT testing. 
 
Exclusion criteria: 
      Patient level exclusion criteria: 
1. History of infectious endophthalmitis or infectious uveitis in either eye; 
 
2. History of infectious scleritis of any type in either eye. (Note: History of noninfectious 
scleritis that has been active in past 12 months is an eye-level exclusion –see #11 
below.) 
 
3. History of keratitis (with the exception of keratitis due to dry eye)in either eye; 
 
4. History of central serous retinopathy in either eye; 
 
5. 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;  
 
6. Use of oral acetazolamide or other systemic carbonic anhydrase inhibitor at baseline; 
 
7. 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 at baseline 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);   


POINT PROTOCOL VERSION 2.1 (16 FEB 2017) 
Design │ 22 
 
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8. Systemic immunosuppressive drug therapy that has not been stable for at least 4 
weeks; 
 
9. 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:  
 
10. 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); 
 
11.  History of active noninfectious scleritis in past 12 months (Note: History of 
noninfectious scleritis is acceptable if the last episode of active scleritis resolved at 
least 12 months prior to enrollment); 
 
12. Media opacity causing inability to assess fundus or perform OCT; 
 
13. 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; 
 
14. Torn or ruptured posterior lens capsule 
 
15. Presence of silicone oil; 
 
16. Periocular or intravitreal corticosteroid injection in past 8 weeks; 
 
17. Injection of dexamethasone intravitreal implant in past 12 weeks; 
 
18. Placement of  fluocinolone acetonide implant (Retisert) in past 3 years; 
 
 
 
3.7. 
Randomization 
After the patient has given written informed consent, eligibility has been confirmed and baseline 
data have been keyed and passed an electronic eligibility review, the patient will be randomly 
assigned to one of the three treatment groups, via a web-based system, returning the treatment 
assignment result in real time.  Receipt of treatment assignment will be confirmed by user re-
entry of the treatment assignment.  Beginning at this point, the patient’s data will be included for 
primary analyses, regardless of subsequent actual treatment and/or extent of adherence to 
therapy. Randomization will be accomplished using an auditable, documented scheme 
generating a reproducible order of assignment. Randomization schedules will be developed by 
the Coordinating Center (CC), using permuted blocks of varying lengths, designed to yield 
expected assignment ratio of 1:1:1. Randomization will be stratified by the presence or absence 
of concomitant systemic therapy for uveitis (e.g., oral corticosteroids and/or immunosuppressive 
drugs). 
 


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3.8. 
Data collection schedule 
Visit ID 
P01 
P02 
P03 
P04 
P05 
P06 
Time 
Baseline 
4-wk 
8-wk 
12-wk 
20-wk 
24-wk 
Medical/ophthalmic history 
X 
X 
X 
X 
X 
X 
Treatment history 
X 
X 
X 
X 
X 
X 
Best-corrected visual acuity 
X 
X 
X 
X 
X 
X 
Tonometry 
X 
X 
X 
X 
X 
X 
Ophthalmic exam (slit lamp 
exam and ophthalmoscopy) 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
 
 
 
 
 
OCT 
X 
X 
X 
X 
X 
X 
Fundus reflex images 
X 
 
 
 
 
X 
Fluorescein angiogram 
X 
 
 
 
 
 
EuroQol Questionnaire 
X 
X 
X 
X 
X 
X 
Visual Functioning 
Questionnaire - 25 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
Pregnancy testing† 
X 
 
 
 
 
 
†   Required for women of childbearing potential 
 


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4. Study treatment schedule and administration 
 
 
4.1. 
Treatment overview 
• 
The timing and administration of initial injections and earliest permissible second 
injections of assigned treatment are specified by the protocol.  Treatment administration 
instructions and pre-injection IOP criteria are included in sections 4.2 and 4.3. 
• 
Additional guidance is provided for treatment of non-responders and simultaneous 
enrollment of eligible patients in the MERIT Trial at certain time points.  
• 
The protocol does not prescribe treatment options for every situation 
• 
Treatment according to the best medical judgment of treating study ophthalmologist is 
permitted as deemed necessary. Repeat injections given before the protocol specified 
time points (section 3.3.) or other deviations from the treatment protocol should be 
reported expeditiously to CC on Unanticipated Event (UA) form, usually within a few 
days.    
 
 
4.2. 
Treatment schedule 
 
4.2.1. 
Initial injections of assigned treatment 
• 
Patients will be randomized to receive an injection of one of three treatments; doses and 
routes of administration are those standardly used in clinical care:   
- Triamcinolone acetonide 40 mg given by the periocular route 
- Triamcinolone acetonide 4 mg given by intravitreal route  
- Intravitreal placement injection of the 0.7 mg dexamethasone implant  
• 
Injection of assigned treatment should be given on the day of randomization or as soon 
after randomization as possible 
• 
IOP requirements for injection of initial study treatment must be met on the day the 
treatment is administered: 
-   ≤21 or mm Hg and treatment 
-  ≤ 3 IOP-lowering agents (combination meds, e.g., Cosopt, count as 2 agents) 
 
Note that the IOP requirements for the initial injection are the same as for eye eligibility 
for the trial. If study treatment is initiated on the same day as eligibility is confirmed and 
treatment assigned, no additional IOP measurements are needed. If circumstances 
require patient to return to clinic for injection at a later date, IOP must be checked and 
IOP-lowering agents evaluated prior to injection. If the eligibility requirements are not 
met, the injection should not be given. If the treating ophthalmologist elects to proceed 
with assigned treatment per best medical judgment, the deviation from the protocol 
must be reported to CC on an Unanticipated Event (UA) form; the UA form should be 
submitted as soon as possible usually within a few days.      
  
 
4.2.2. 
Second injections of assigned treatment 
Second injections of assigned treatment are permitted at or after specified time points if 
macular edema has not improved and re-treatment criteria are met.  The time points and IOP 
limitations for second injections of periocular triamcinolone and intravitreal triamcinolone are 
consistent with typical clinical care approaches. 
• 
Time points for second injection: 
- Periocular triamcinolone acetonide :  8 weeks after OCT (i.e., after 
ascertainment of primary outcome data) 


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- Intravitreal triamcinolone acetonide: 8 weeks after OCT  
- Intravitreal dexamethasone: 12 weeks after OCT 
 
• 
Reasons to give second injection: 
- Eye does not meet the improvement definition (a 20% decrease in central 
subfield thickness of the macula) 
- ME is worse after initial improvement 
- Eye has a normal central subfield thickness but has cystoid spaces in the 1 mm 
central subfield 
 
• 
Re-treatment IOP requirements: 
- <25  mm Hg   
- ≤ 3 IOP-lowering agents (combination meds, e.g., Cosopt, count as 2 agents) 
 
4.2.3. 
Treatment for non-responders (i.e., <20% reduction or worsening of ME)  
Eyes that demonstrate less than a 20% reduction  or worsening of ME as measured by the 
central subfield thickness on OCT at time points specified below will be considered primary 
treatment failures and will be handled in the following manner: 
 
• 
Eyes in periocular triamcinolone arm at 12 weeks  
- Intravitreal triamcinolone acetonide 4mg if following conditions met:  
 
IOP of  <25 mm Hg and treatment with ≤3 IOP-lowering agents 
- Follow to close-out visit (week 24) 
 
• 
Eyes in intravitreal triamcinolone acetonide arm at 12 weeks  
- Offer enrollment in the MERIT Trial if eligible OR treat according to best medical 
judgment  
- Follow to close-out visit (week 24) 
 
• 
Eyes in the intravitreal dexamethasone arm at 20 weeks 
- Treat according to best medical judgment  
- Follow to the close-out visit (week 24) 
 
 
4.3. 
Treatment administration guidelines 
Note:  Ophthalmologist administering treatment may follow local of standard care guidelines for topical 
anesthesia and needle size if they have been reviewed by Study Clinic Director as appropriate for use in 
this trial.   
 
4.3.1. 
Administration of periocular triamcinolone acetonide  
The 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. 
  
4.3.1.1. 
Posterior sub-Tenon injection 
• 
Saturate a cotton-tipped applicator with topical anesthetic (e.g., in 1 or 2% lidocaine) and 
place under the upper lid for posterior sub-Tenon’s approach  
• 
Instruct patient to look inferonasally with eye to receive injection 
• 
Retract upper lid 


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• 
Introduce needle (e.g., 16-mm 25 gauge needle) into the sub-Tenon space, bevel side 
down 
• 
Advance needle with a lateral to and fro motion to ensure the tip does not engage sclera 
• 
When needle is judged to be behind the macula, deliver 40-mg (1-mL) bolus of 
triamcinolone acetonide43 
 
4.3.1.2. 
Orbital floor injection 
• 
Saturate a cotton-tipped applicator  with topical anesthetic (e.g., 1 or 2% lidocaine) and 
place in inferior fornix where needle will be directed 
• 
Introduce needle (e.g., 25-mm 25 gauge) at the lateral third of the inferior orbital rim 
• 
Pass needle posteriorly parallel to the orbital floor periosteum to approximately 25 mm 
depth 
• 
Slowly deliver 40-mg (1-mL volume) bolus of triamcinolone acetonide43 
 
 
4.3.2. 
Standard preparation for all intravitreal injections 
Intravitreal 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. 
 
 
4.3.3. 
Administration of intravitreal triamcinolone acetonide (Triesence) 
• 
Standard preparation as described for intravitreal injections in section 4.3.2.  
• 
Saturate a sterile cotton-tipped applicator with 0.5% proparacaine hydrochloride drops 
and hold the swab against the planned intravitreal injection site for 10 seconds in 
preparation for the subconjunctival injection of 1% lidocaine hydrochloride ophthalmic 
solution for injection (without epinephrine).  Alternatively, an injection may be given with 
just topical anesthesia. 
• 
Use a sterile 4×4 pad in a single wipe to absorb excess liquid and to dry the periocular 
skin. 
• 
Instruct subject to direct gaze away from syringe prior to intravitreal injection. 
• 
An intravitreal injection using a 30-gauge needle is given 4 mm posterior to the limbus 
after marking that distance on the ocular surface. Inject medication slowly aiming 
inferiorly to minimize the dispersal of medication in the visual axis that could affect the 
patient’s vision. 
• 
Place a cotton swab on the site as the needle is injected to help prevent extrusion of 
medication 
• 
Following the intravitreal injection, patients should be monitored for elevation in IOP 
- Monitoring may consist of a gross assessment of visual acuity 
- Check for perfusion of the optic nerve head immediately after the injection 
and/or tonometry within 30 minutes following the injection 
 
4.3.4. 
Administration of dexamethasone implant (Ozurdex) 
• 
Standard preparation as described for intravitreal injections in section 4.3.3 above 
• 
Saturate a sterile cotton-tipped applicator with 0.5% proparacaine hydrochloride drops 
and hold the swab against the planned intravitreal injection site for 10 seconds in 
preparation for the subconjunctival injection of 1% lidocaine hydrochloride ophthalmic 


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solution for injection (without epinephrine).  Alternatively, an injection may be given with 
just topical anesthesia. 
• 
Open the foil pouch over a sterile field and gently drop the applicator on a sterile tray  
• 
Carefully remove the cap from the applicator 
• 
Hold the applicator in one hand and pull the safety tab straight off the applicator; do not 
twist or flex the tab 
• 
Hold long axis of the applicator parallel to the limbus and engage the sclera at an 
oblique angle with the bevel of the needle up (away from the sclera) to create a shelved 
scleral path  
• 
Advance tip of the needle within the sclera for about 1 mm (parallel to the limbus), then 
re-direct toward the center of the eye and advance until penetration of the sclera is 
completed and the vitreous cavity is entered; do not advance the needle past the point 
where the sleeve touches the conjunctiva.  
• 
Slowly depress the actuator button until an audible click is noted. Before withdrawing the 
applicator from the eye, make sure that the actuator button is fully depressed and has 
locked flush with the applicator surface. 
• 
Remove the needle in the same direction as used to enter the vitreous 
• 
Following the intravitreal injection, patients should be monitored for elevation in IOP   
- Monitoring may consist of a gross assessment of visual acuity 
- Check for perfusion of the optic nerve head immediately after the injection 
and/or tonometry within 30 minutes following the injection.82 
 
 
4.4. 
Possible side effects and complications of treatments 
 
4.4.1. 
Periocular triamcinolone acetonide 
Possible side effects and complications associated with periocular triamcinolone acetonide 
injections are similar to those associated with intravitreal injections of triamcinolone acetonide, 
but rates are lower because the drug is not injected directly into the eye. 
 
• 
Commonly reported events 
- Elevated intraocular pressure 
- Cataract development 
 
• 
Less frequently reported events  
- Ocular discomfort 
- Transient visual blurring 
- Subconjunctival hemorrhage 
- Ptosis with posterior sub-Tenon’s injections (risk increases with multiple 
injections) 
 
• 
Rare and serious events 
- Glaucoma or severe IOP elevation requiring surgical therapy 
- Breach of sclera 
- Endophthalmitis (occurs with inadvertent breach of sclera and injection of drug 
into the eye (less than 1 in 1000 cases) 
- Subretinal deposition of drug 
- Retinal tear with or without retinal detachment 
- Vitreous hemorrhage 
 
 


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4.4.2. 
Intravitreal triamcinolone acetonide 
• 
Commonly reported events (≥ 20% of patients)  
- Elevated intraocular pressure in up to 40% of cases 
- Cataract development or progression of existing cataract 
- Subconjunctival hemorrhage 
 
• 
Less frequently reported events 
- Mild short-term ocular discomfort 
- Short-term visual disturbances  
- Severe increase in eye pressure (~10% of patients), some of whom may require 
glaucoma surgery83 
 
• 
Rare and serious events  
- Endophthalmitis (infectious and non-infectious) 
- Perforation of the globe where there is thinning of the outer covering of the eye 
- Vitreous hemorrhage 
- Retinal detachment  
- Retinal tear 
 
 
4.4.3. 
Intravitreal dexamethasone 
• 
Commonly reported events (≥ 20% of patients) 
- Elevated intraocular pressure which may require medication to lower 
- Subconjunctival hemorrhage 
 
• 
Less frequently reported events 
- Mild short-term ocular discomfort 
- Short-term visual disturbances 
- Vitreous detachment 
- Headache 
- Cataract development  
- Elevated intraocular pressure which may require surgery to control 
- In eyes with non-intact posterior capsule implant migration to anterior chamber  
  
• 
Rare  and serious events  
- Endophthalmitis 
- Perforation of the globe where there is thinning of the outer covering of the eye 
- Vitreous hemorrhage 
- Retinal detachment  
− Retinal tear 
−  
4.4.4. 
Intravitreal injection 
Risks of an intravitreal injection that may be associated with the injection procedure itself have 
been included along with each type of drug injection above. 
 
 


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5. Adverse event reporting 
5.1. 
Adverse events   
Adverse events (AEs) and complications of study treatment will be recorded on study data 
forms and submitted to the CC.  The CC Safety Officer and the DSMC Safety Officer will 
review all adverse events and make recommendations to the DSMC as to any actions that may 
be needed.  
 
 
5.2. 
Serious adverse events 
A serious adverse event (SAE) is an adverse event that results in one of the following 
outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or 
congenital anomaly/birth defect. Also, important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention (treatment) to prevent any of the outcomes 
previously listed in this definition.  
 
Clinical centers will report all SAEs to the Coordinating Center expeditiously regardless of the 
relationship to study treatment.  When an investigator or clinical center staff member becomes 
aware of an SAE, it will be reported to the Coordinating Center (CC) within 72 hours with 
follow up reporting until the event is terminated.  The SAE report will include an assessment 
by the clinical investigator at the managing clinical center as to whether the event is related to 
treatment.  Upon receipt at the CC, the SAE report will be sent to the CC Safety Officer for 
immediate review and determination as to whether the event meets the criteria for a safety 
report and whether expedited review by the DSMC Safety Officer is warranted.  
 
All serious and unexpected events possibly related to study treatment will be reported as safety 
reports to the NEI project officer, the FDA, the pharmaceutical supplier (where appropriate), 
and all clinical centers in accordance with FDA regulations. The CC and clinical centers will 
submit all safety reports as expedited reports to their IRBs.  Reports of SAEs not deemed to be 
unexpected will be submitted to the CC’s IRB, to the IRB of the clinical center in which the 
event was reported, as well as to any other study center IRBs which require such reports. 
 
 


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6. Sample size and statistical methods 
The primary outcome measurement for the POINT Trial is percent change from baseline in 
retinal thickness at 8 weeks.  The primary analysis will be based on the assigned treatment 
and all randomized individuals will be included in the analysis (intention-to-treat) with 
additional sensitivity analyses based on treatment received.  Individuals will be randomized to 
treatment groups, i.e., all eligible eyes from an individual will receive the same treatment. 
 
 
6.1. 
Sample size, power and detectable differences 
The units of analysis for the primary outcome for POINT are eyes as opposed to individuals.  
Since we expect approximately 25% of individuals to have bilateral disease, our sample size 
calculations take advantage of the information from both eyes by incorporating the effect of 
correlated, multiple measurements from the same individual.  To arrive at the target sample 
sizes, we first calculated the number of independent eyes needed to power a specific aim (i.e. 
act as though each participant had only one study eye) and then used the following 
adjustment to calculate the required number of individuals:  
 
 
NS = NIE * [(1 + r)/ (2*p + (1+r)(1-p))] 
 
where NS denotes the required number of individuals, NIE denotes the number of independent 
eyes, p denotes the percentage of individuals with bilateral disease (and so two study eyes), 
and r denotes the correlation between eyes86. Estimates for the correlation (r) between 
outcome measurements for an individual are based upon preliminary data from the MUST 
Trial and FS. 
 
Power calculations for the primary hypotheses are based upon pair-wise comparisons of the 
three treatment arms: intravitreal injection of triamcinolone, dexamethasone pellet, and 
periocular injection of triamcinolone.  A Bonferroni correction will be used to adjust for multiple 
comparisons, i.e. a two-sided type I error rate of 0.05/3 = 0.01667 will be used to determine 
statistical significance.  The sample sizes needed to provide 90% power for the superiority 
hypotheses (intravitreal injection or dexamethasone pellet versus periocular injection) and 80% 
power for the non-inferiority hypothesis (intravitreal injection versus dexamethasone pellet) were 
computed separately for each comparison and then the maximum sample size was selected.  
The primary outcome is the change in retinal thickness at the central subfield at 8 weeks.  Given 
the skewness in the distribution of retinal thickness, a log-transformation will be used to analyze 
the primary outcome74, 87; hence, the comparisons will be represented on a relative scale (i.e. 
percent of baseline) and transformed to obtain the percent change from baseline.   A 20% 
change in retinal thickness is associated with clinically meaningful changes in visual acuity.74  In 
the MUST Trial, approximately 25% of individuals had bilateral macular edema and the 
correlation between-eyes was 0.40 for log retinal thickness.4, 6  The standard deviation for 
change in log retinal thickness was approximately 0.33 in the MUST Trial; a conservative 
estimate since the treatment of macular edema was not standardized and the timing of the 
assessment, at 6 months after randomization, was not linked to the implementation of treatment 
for macular edema.  Based upon the 6-month OCT evaluation in the MUST Trial, we allowed for 
a 10% loss to follow-up. 
For the first two superiority hypotheses, we evaluated the power to show that each of the 
treatment methods for intravitreal corticosteroids (triamcinolone injections and dexamethasone 
pellets) is superior to periocular triamcinolone injections at 8 weeks.  In previous studies, 
treatment with the dexamethasone pellet has resulted in a decrease in retinal thickness of 30%-


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50%, so a 40% decrease or log change in retinal thickness of log (0.60) = -0.5108 was selected.  
Intravitreal triamcinolone is expected to have a similar level of improvement; whereas periocular 
triamcinolone is expected to have a smaller but clinically meaningful change, i.e. a 25% 
reduction or log change of log(0.75) = -0.2877.  Based upon a standard deviation of log-retinal 
thickness of 0.33, a sample size of 89 independent eyes per treatment group, i.e. 89 individuals 
with one eye for each individual, provides 98% power to detect a 40% reduction in retinal 
thickness for an intravitreal corticosteroid treatment as compared to a 25% reduction for 
periocular triamcinolone at 8 weeks with a two-sided type I error rate of 0.01667 (i.e. 0.05/3).  
This number increases to 99 individuals after inflating it for a 10% loss to follow-up.  By including 
outcomes from both eyes for participants with bilateral macular edema (assuming a between 
eye correlation of 0.4 and 25% bilateral disease), we can reduce our sample size to 89 
individuals enrolled in each arm (267 total).  That is, 10 fewer participants per arm after 
accounting for losses to follow-up than are required if we only include a single eye per 
participant.  
For the third hypothesis, we evaluated the power to show that the dexamethasone pellet is non-
inferior to injected triamcinolone. Previous research has indicated that the threshold for 
reproducibility is 10% and that a 20% change is associated with changes in visual acuity.74, 88 
Therefore, we chose a non-inferiority margin of 10%, i.e. we would consider the dexamethasone 
pellet to be non-inferior if the percent reduction in retinal thickness was 30% or more (log [0.7]) 
as opposed to a 40% (log [0.60]) in the intravitreal injection group, i.e. the difference in the log 
retinal change was at most 0.15 (log[0.7] – log[0.6]).  A sample size of 89 independent eyes per 
treatment group will provide 80% power to demonstrate non-inferiority with a one-sided type I 
error rate of 0.01667.  We would reject the null hypothesis of inferiority if the upper bound of the 
96.7% confidence interval of the difference in log retinal change from baseline at 8 weeks was 
less than 0.15 (log[0.7] – log[0.6]) or equivalently if the ratio of the percent of baseline for the 
two groups was less than 1.16 (0.7/0.6).  Assuming a between-eye correlation of 0.4, 25% 
bilateral disease, and a 10% loss to follow-up, we will need to enroll 89 individuals in each 
treatment arm to attain 80% power, i.e. the inclusion of both eyes for bilateral disease off-sets 
the sample size inflation necessary to account for losses to follow-up. 
An important secondary outcome for the comparison of intravitreal triamcinolone injection 
versus the dexamethasone pellet will be change in IOP.  In prior studies, treatment with 
intravitreal triamcinolone resulted in IOP elevation for 40% of study eyes.33, 51 In contrast, reports 
of IOP elevation with dexamethasone pellet have been more variable but consistently lower, 
ranging from 5% to 17%.62, 68 A sample size of 89 independent eyes per treatment group, which 
is equivalent to 89 individuals per arm allowing for bilateral disease and losses to follow-up, will 
provide 99% power to detect an increase in the percent of eyes with an IOP elevation from 12% 
in the dexamethasone pellet arm to 40% in the intravitreal triamcinolone injection arm with a 2-
sided, type I error rate of 0.05.   
Clinical resolution is one of the standard outcomes in macular edema trials.  Based upon the 
MUST Trial and other research, this improvement likely represents a measureable reduction in 
OCT measurement rather than complete resolution.4, 6, 74, 89 A single PST triamcinolone injection 
resulted in clinical improvement for 50-55% of eyes between one and three months.30, 46 
Intravitreal triamcinolone and the dexamethasone pellet are expected to result in improvements 
of 35% and 25%, respectively.  Based upon the assumptions outlined above, the sample size of 
89 independent eyes per treatment group, which is equivalent to 89 individuals per arm allowing 
for bilateral disease and losses to follow-up, would allow us to detect an increase from 50% to 
85% or 75% with 99.9% or 93% power, respectively, assuming a 2-sided type I error rate of 0.05 
for this important secondary outcome. 
   


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6.2. 
Statistical methods 
The primary analysis will adhere to the intention to treat principle regardless of treatment 
deviations made either in error or per the best medical judgment of the treating ophthalmologist. 
Evaluation of continuous outcomes over time (such as log change in retinal thickness or best 
corrected visual acuity) and binary outcomes over time (such as normal/abnormal IOP) will use 
a repeated measures analysis with Gaussian or logit links that account for the nested 
correlations between observations over time and between eyes of the same patient.90 A 
saturated mean model, including visit and visit by treatment interaction terms, will be used.  An 
unstructured covariance matrix will be used to model the within-eye repeated measurements 
augmented by random effects to induce cross-sectional between-eye associations.  
Alternatives, including a first-order, auto-regressive process (an AR(1) model) along with a 
random intercept, will be considered if the unstructured covariance model is unstable.  This 
structure allows for correlation to decrease with increasing time-separation down to a level set 
by the random intercept. 
Significance for superiority hypotheses in POINT will be determined by comparing the p-value of 
the interaction term for the week 8 visit with 0.01667 (i.e. 0.05/3).  Significance for the non-
inferiority hypothesis in POINT will be assessed by comparing the upper bound of the 96.7% 
confidence intervals for estimate of the difference in change in log retinal thickness at 8 weeks, 
which is estimated by the 8-week interaction term, with the defined non-inferiority boundary of  
0.15 on the log scale, which is equivalent to a 10% difference in percent reduction (40% vs 30% 
reduction) for the two groups.   
Evaluation of risk factors for time-to-event outcomes such as incidence of cataracts, as well as 
time to remission will be performed using Cox proportional hazards regression as well as 
parametric time-to-failure models, such as gamma models91. Implementation of these models 
that allows for clustering (within patients and within eyes), assessment of recurrent events, and 
incorporation of time-dependent covariates will be used.  When the relevant follow-up time in the 
analysis reflects the clinical time scale (e.g. time since diagnosis of uveitis), it is necessary to 
incorporate the prevalent cases (longstanding diagnosis of uveitis) into the analysis.  To 
accommodate the prevalent cases we will use the staggered entry technique92, which is one 
method of adjusting for potential survival bias.  The analysis compares the event rates among 
patients with similar duration of disease and then combines over these comparisons. Event 
rates for multiple recurring events, e.g. the number of adverse events, will be modeled using 
Poisson regression or Negative Binomial regression93, including a random effects term to 
account for the between eye correlation.   
All analyses will be performed both unadjusted, except for the stratification variable, and 
adjusted for potential confounders.  Effect modification due to factors such as disease location 
or uveitis activity, fluorescein leakage in the centeral subfield, systemic disease, gender and 
race also will be explored when appropriate.  Robust standard errors will be computed using 
statistical program-based approaches when available and a bootstrap with the individual as the 
sampling unit, when a pre-programmed approach is not available. 
POINT has a focused set of primary research questions and related analyses.  Bonferonni 
corrections will be applied to control the type I error rates for the primary hypotheses within each 
study.  However, a large number of comparisons are planned for secondary outcomes and 
caution is needed in the reporting of interpretation of the results.  Our primary focus for analyses 
of these outcomes will be on the parameter estimates and confidence intervals as opposed to p-
values as recommended by Wang et al94. Several methods of adjusting P-values for multiple 
comparisons exist, however no clear consensus as to the most appropriate method is available 
and it is difficult if not impossible to quantify ahead of time the number of comparisons that will 
be performed.  In general, issuing cautions is sufficient, but for identifiable and related sets of 


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estimates we will do adjustments.  We expect that related sets of estimates will have a high 
positive correlation, making a Bonferroni correction extremely conservative.  Therefore, we will 
estimate the covariance matrix for these related sets using a bootstrap approach and also 
estimate the null distribution of the minimum P-values for the multivariate distribution of Z-scores 
using a global null hypothesis permutation distribution. 
The best protection against bias caused by missing data is to prevent it.  We will work with 
coordinators and participants, as we have done in previous trials, to ensure that missing data 
are infrequent.  Regardless, we will perform a variety of sensitivity analyses to determine the 
potential for bias due missing data.  For a crude estimate of the range of potential impact, ‘best’ 
and ‘worst’ case single imputation techniques will be implement.  In addition, more sophisticated 
approaches (e.g. multiple imputation and pattern mixture) will also be used to assess the impact 
of missing data95, 96.  For the principal sensitivity analysis, we will retain all features of the 
primary analysis other than how missing values for visits beyond the last one with a measured 
value are handled.  As is implicit in the primary analysis where missing data indicators are used 
(e.g. “.” in SAS, “NA” in R), we will treat all missing values as Missing at Random (MAR).  We 
will impute other missing values to generate 10 pseudo-complete records for each such 
individual by sampling from a joint predictive distribution for the missing data given the observed 
data.  We will use a covariance matrix equal to the estimated covariance matrix from the primary 
analysis, but will “take control” of the prediction mean.  Varying the mean of the predictive 
distribution allows us to assess the sensitivity of our results to a variety of missing data 
scenarios.  The pattern mixture model approach stratifies participants on their pattern of missing 
data, estimates stratum-specific parameters and then combines estimates over strata using 
inverse variance weights.  The approach is similar to stratified analysis to adjust for potential 
confounders and allows for comparison of stratum-specific estimates.  We stratify by three 
patterns: complete data, at least one internal measurement missing, and closeout weight 
missing (along with any other missingness).    
 
 


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7. Regulatory and ethical issues 
7.1. 
Recruitment and informed consent procedures 
Eligible patients will be recruited from the patient populations seen at and referred to the MUST 
Research Group clinical centers, the majority of which are in the US and one each is in London, 
England, UK, Melbourne, Australia, and Montreal, Canada.  Typically, patients will be identified 
in the course of usual clinical practice by the study physicians. When a potentially eligible 
patient is identified, the study physician and study coordinator will describe the study to and 
discuss the study with the patient.  Patients considering enrollment will be given the consent 
statement and IRB-approved informational materials and allowed time to decide about joining 
the study. After patients have time to review materials and discuss enrollment with family 
members when appropriate, the clinic coordinator or study physician will obtain written informed 
consent, using a written, local IRB-approved consent document  based on a prototype prepared 
by the CC and approved by the CC’s IRB, the JHSPH IRB Office.  The trial is registered on 
www.ClinicalTrials.gov (NCT02374060).  Recruitment efforts and eligibility criteria for POINT are 
subject to review and approval by IRBs and the DSMC. 
 
 
7.2. 
IRB/Protection of human subjects 
7.2.1. 
Potential risks and procedures to minimize risks to participants 
The injection procedures, dosage of medication and treatment algorithm within the study will be 
consistent with standard clinical treatment, e.g., sterile technique. To minimize risks associated 
with increased ocular pressure post-injection, patients with uncontrolled ocular hypertension or 
glaucomatous changes will be excluded from the trial.  Patients in the trial will not be exposed to 
risk beyond what they would be exposed to with standard clinical care for their condition.  
Adverse events encountered will be managed by the best medical judgment of the treating 
physician. 
 
7.2.2. 
Confidentiality 
Confidentiality of patient data will be maintained in accordance with legal regulations.  This 
includes the storage of protected health information (PHI) in locked cabinets or rooms and 
limited access to secure data areas by certified study personnel.  Name, social security number, 
address, and other such personal data will be kept solely at the clinical center where the patient 
receives her/his clinical care.  All transmission of data to the Coordinating Center for analysis is 
done by study ID codes alone.  A dataset limited so as to contain a minimal amount of protected 
health information–that required to make the data useful for accomplishing the purposes of the 
POINT Trial–may be disclosed, as needed, to collaborating study sites, the NEI, and the FDA. 
Rarely, for reasons of good clinical practice or legal reasons, data with personal information 
may need to be reviewed by regulatory bodies such as the IRB, FDA, or DSMB. If such an audit 
occurs, care will be taken to protect confidentiality of participants. Clinically relevant information 
from the study may be placed in the patient's medical record.  The CC will report serious 
adverse event data for participants randomized to Ozurdex to Allergan (Irvine CA).  Release of 
protected health information to any other persons or organizations will require additional written 
consent of the patient affected, except as required by law. 
 
 A privacy acknowledgment designed to conform to the specifications of HIPAA regulations and 
approved by the local governing authorities invested with oversight of HIPAA regulations at 
each participating site, will be signed by the participant before his/her enrollment in the study.  
This acknowledgement will be included in the consent form or as a stand-alone document per 
local institutional requirements.  
 
 


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7.2.3. 
Inclusion of children  
Patients under 18 years of age will not be included; the intravitreal dexamethasone pellet is not 
approved for use in pediatric patients. 
 
7.2.4. 
Data and safety monitoring 
Treatment effects and safety monitoring will be conducted by a study Data and Safety 
Monitoring Committee (DSMC).  The DSMC will consist mostly of members of the standing 
DSMC, which monitored the Multicenter Uveitis Steroid Treatment (MUST) Trial and now is 
monitoring the MUST Follow-up Study.  However, the Chair of the MUST DSMC, who is a 
biostatistician, is unable to serve because of potential conflicts of interest.  Hence a new 
biostatistician has been appointed and the Chair of the DSMC for this protocol will be one of the 
clinical experts.  The committee consists of voting members with expertise in biostatistics, 
clinical trial design, ophthalmology, and medical ethics who were appointed by NEI and non-
voting members (i.e., Study Officers).  Initially, the DSMC will meet at least twice a year, once 
in-person and once by conference call.   For each DSMC meeting, data will be summarized in a 
report prepared by the CC.   These reports will include information related to monitoring the 
safety and effectiveness of the study treatments and will include tables and graphs that 
summarize baseline, outcome, and adverse event data by treatment assignment, and if 
indicated, within specific subgroups.  Analyses will be included as requested by the DSMC.  
Pertinent information from outside sources such as a reprint of a recent publication reporting on 
results of other, related studies will also be included as available. The DSMC report will also 
include an overall study performance report, designed for monitoring the effectiveness of the 
participating centers.   
 
The DSMC Safety Officer will be appointed from among the physician voting members of the 
DSMC, who periodically will review summaries of serious adverse event data prepared by the 
CC between DSMC meetings to make a determination as to whether the event is unexpected 
and possibly related to treatment.   
 


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