Phase II Combination Steroid and Anti-VEGF for Persistent DME

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT01945866
• Collaborator: Allergan (Industry), Genentech, Inc. (Industry), National Eye Institute (NEI) (NIH)
• Enrollment: 129
• Locations: 56
• Arms: 2
• Actual Duration (Months): 40.1
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Although anti-vascular endothelial growth factor (VEGF) therapy is generally effective as treatment for center-involved diabetic macular edema (DME), a substantial proportion of anti-VEGF-treated eyes with DME do not achieve vision of 20/20 or complete resolution of retinal thickening. Indeed, over 50% of ranibizumab-treated eyes did not achieve a 2 or more line improvement in visual acuity from baseline at 2 years in Protocol I, a previous DRCR.net (Diabetic Retinopathy Clinical Research Network) study. Furthermore, 27% of ranibizumab-treated eyes still had central subfield (CSF) thickness on time-domain optical coherence tomography (OCT) ≥ 300 at 1 year, and more than 40% of ranibizumab-treated eyes did not achieve complete resolution of retinal thickening (< 250 microns) by 2 years. Thus, there is a need for alternative or additional treatments that will improve vision by reducing retinal edema in eyes with persistent DME following previous anti-VEGF therapy. Intravitreal steroid is not as efficacious as ranibizumab in eyes with DME overall, but it has been shown to have a positive effect for DME in some eyes and might add benefit in eyes that are already receiving anti-VEGF.

The main objective of this study is to assess the short-term effects of combination steroid+anti-VEGF therapy on visual acuity and retinal thickness on OCT in comparison with that of continued anti-VEGF therapy alone in eyes with persistent central-involved DME and visual acuity impairment despite previous anti-VEGF treatment. This study will provide important information for the design of a future confirmatory phase III clinical trial on the efficacy of combination steroid and anti-VEGF in eyes with persistent DME and vision impairment following previous anti-VEGF therapy. The primary outcome for efficacy will be the mean change in visual acuity at 24 weeks.

Each study eye is required to complete a 12-week run-in phase. The run-in phase will identify study eyes that truly have persistent DME despite anti-VEGF therapy by requiring an additional 3 injections while also collecting standardized visual acuity and OCT measurements. At the enrollment, 4-week and 8-week visits of the run-in phase, enrolled eyes will receive an intravitreal injection of ranibizumab 3mg. Then at the 12-week run-in visit, if the eye still has persistent DME, it will be randomized to receive either intravitreal sham+intravitreal ranibizumab 0.3 or intravitreal dexamethasone+intravitreal ranibizumab 0.3 injections. The randomized study duration is 24 week, during which a protocol visit takes place every month. The combination injections of sham+ranibizumab or dexamethasone +ranibizumab will be given at the randomization visit (baseline) and at the 12-week visit after randomization. In between, an intravitreal injection of ranibizumab only will be given to study eyes at the 4, 8, 16 and 20 week visits.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: intravitreal ranibizumab 0.3 mg; Drug: dexamethasone intravitreal implant; Procedure: Sham injection	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 129 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Short-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy
• Actual Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Jun 5, 2017
• Actual Study Completion Date: Jun 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sham + intravitreal ranibizumab 0.3 mg Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria.	Drug: intravitreal ranibizumab 0.3 mg; Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria; Other Names: Lucentis ; Procedure: Sham injection; No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Experimental: Intravitreal dexamethasone+intravitreal ranibizumab 0.3mg The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first.	Drug: intravitreal ranibizumab 0.3 mg; Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria; Other Names: Lucentis ; Drug: dexamethasone intravitreal implant; The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first.; Other Names: Ozurdex

Outcome Measures

Primary Outcome Measures

1. Mean Change in Visual Acuity Letter Score [24 weeks after randomization]

   At 24 weeks after randomization, mean change in visual acuity letter score, adjusted for visual acuity at time of randomization

Secondary Outcome Measures

1. At 24 Weeks After Randomization, Number of Eyes With at Least 10 and at Least 15 Letter Gain (Increase) or Loss (Decrease) in E-ETDRS Letter Score Visual Acuity. [24 weeks weeks after randomization]

   ETDRS (Early Treatment Diabetic Retinopathy Study)

2. Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks [24 weeks after randomization]

   Only included participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization.

3. Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization [24 weeks after randomization]

   Change in optical coherence tomography (OCT) central subfield thickness (in microns) was truncated to 3 standard deviations from the mean [-372, +201] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end.

4. Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness [24 weeks after randomization]

   Change in optical coherence tomography (OCT) central subfield (CSF) thickness (in microns) was truncated to 3 standard deviations from the mean [-372, +201] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end.

5. Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus [24 weeks after randomization]

   Gender and OCT machine-specific values for OCT central subfield thickness (in microns) are defined as: <290 in women and <305 in men in Zeiss Cirrus; <305 in women and <320 in men in Heidelberg Spectralis

6. OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks [24 weeks after randomization]

   Including participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 18 years i) Individuals <18 years old are not being included because DME is so rare in this age group that the diagnosis of DME may be questionable.

2. Diagnosis of diabetes mellitus (type 1 or type 2)

3. Any one of the following will be considered to be sufficient evidence that diabetes is present:

4. Current regular use of insulin for the treatment of diabetes

5. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes

6. Documented diabetes by ADA (American Diabetes Association) and/or WHO (World Health Organization) criteria

7. At least one eye meets the study eye criteria listed below.

8. Fellow eye (if not a study eye) meets criteria.

9. Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least the one eye:

1. At least 3 injections of anti-VEGF drug (ranibizumab, bevacizumab, or aflibercept) within the prior 20 weeks.

2. Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen equivalent 20/32 to 20/320).

3. On clinical exam, definite retinal thickening due to DME involving the center of the macula.

4. OCT CSF thickness, within 8 days of enrollment:

1. On Zeiss Cirrus ≥ 290 microns in women; ≥ 305 in men ii) On Heidelberg Spectralis: ≥ 305 microns in women; ≥ 320 in men

1. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCTs.

Exclusion Criteria:

An individual is not eligible if any of the following exclusion criteria are present:

1. History of chronic renal failure requiring dialysis or kidney transplant.

2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).

3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.

4. Participation in an investigational trial within 30 days of enrollment that involved treatment with any drug that has not received regulatory approval for the indication being studied. Note: study participants cannot receive another investigational drug while participating in the study.

5. Known allergy to any component of the study drugs (including povidone iodine prep).

6. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110). If blood pressure is brought below 180/110 by anti-hypertensive treatment, the individual can become eligible.

7. Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 1 month prior to enrollment.

8. Systemic steroid, anti-VEGF or pro-VEGF treatment within 4 months prior to enrollment or anticipated use during the study. These drugs cannot be used during the study.

9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 9 months. Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

10. Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next 9 months.

The following exclusions apply to the study eye only (i.e., they may be present for the non-study eye unless otherwise specified):

1. Macular edema is considered to be due to a cause other than DME. An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are the primary cause of the macular edema.

2. An ocular condition is present such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, non-retinal condition, etc.).

3. An ocular condition is present (other than DME) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).

4. Substantial posterior capsule opacity that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., opacity would be reducing acuity to 20/40 or worse if eye was otherwise normal).

5. History of intravitreal anti-VEGF drug within 21 days prior to enrollment.

6. History of intravitreal or peribulbar corticosteroids within 3 months prior to enrollment.

7. History of macular laser photocoagulation within 4 months prior to enrollment.

8. History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to enrollment or anticipated need for PRP in the 6 months following enrollment into run-in phase.

9. Any history of vitrectomy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina-Vitreous Associates Medical Group	Beverly Hills	California	United States	90211
2	Atlantis Eye Care	Huntington Beach	California	United States	92647
3	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California	United States	92354
4	Northern California Retina Vitreous Associates	Mountain View	California	United States	94040
5	Retina Consultants of Southern California	Redlands	California	United States	92374
6	Retinal Consultants Medical Group, Inc.	Sacramento	California	United States	95841
7	California Retina Consultants	Santa Barbara	California	United States	93103
8	Bay Area Retina Associates	Walnut Creek	California	United States	94598
9	Retina Group of New England	New London	Connecticut	United States	06320
10	New England Retina Associates	Norwich	Connecticut	United States	06360
11	National Ophthalmic Research Institute	Fort Myers	Florida	United States	33912
12	University of Florida College of Med., Department of Ophthalmology	Jacksonville	Florida	United States	32209
13	Central Florida Retina Institute	Lakeland	Florida	United States	33805
14	Ocala Eye Retina Consultants	Ocala	Florida	United States	34474
15	Sarasota Retina Institute	Sarasota	Florida	United States	34239
16	Retina Associates of Florida, P.A.	Tampa	Florida	United States	33609
17	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
18	Thomas Eye Group	Sandy Springs	Georgia	United States	30328
19	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana	United States	46290
20	Medical Associates Clinic, P.C.	Dubuque	Iowa	United States	52002
21	Wolfe Eye Clinic	West Des Moines	Iowa	United States	50266
22	Retina Associates, P.A.	Shawnee Mission	Kansas	United States	66204
23	Elman Retina Group, P.A.	Baltimore	Maryland	United States	21237
24	National Eye Institute/National Institutes of Health	Bethesda	Maryland	United States	20892-2510
25	Ophthalmic Consultants of Boston	Boston	Massachusetts	United States	02114
26	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
27	Retina Vitreous Center	Grand Blanc	Michigan	United States	48439
28	Retina Specialists of Michigan	Grand Rapids	Michigan	United States	49525
29	Retina Center, PA	Minneapolis	Minnesota	United States	55404
30	The Retina Institute	Saint Louis	Missouri	United States	63128
31	The Institute of Ophthalmology and Visual Science (IOVS)	Newark	New Jersey	United States	07103
32	MaculaCare	New York	New York	United States	10021
33	Retina Associates of Western New York	Rochester	New York	United States	14618
34	University of Rochester	Rochester	New York	United States	14642
35	Charlotte Eye Ear Nose and Throat Assoc, PA	Charlotte	North Carolina	United States	28210
36	Retina Associates of Cleveland, Inc.	Beachwood	Ohio	United States	44122
37	Case Western Reserve University	Cleveland	Ohio	United States	44106
38	Retina Northwest, PC	Portland	Oregon	United States	97210
39	Casey Eye Institute	Portland	Oregon	United States	97239
40	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania	United States	19104
41	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
42	Southwest Retina Specialists	Amarillo	Texas	United States	79106
43	Austin Retina Associates	Austin	Texas	United States	78705
44	Retina Research Center	Austin	Texas	United States	78705
45	Retina and Vitreous of Texas	Houston	Texas	United States	77025
46	Baylor Eye Physicians and Surgeons	Houston	Texas	United States	77030
47	Retina Consultants of Houston, PA	Houston	Texas	United States	77030
48	Texas Retina Associates	Lubbock	Texas	United States	79424
49	Valley Retina Institute	McAllen	Texas	United States	78503
50	Retinal Consultants of San Antonio	San Antonio	Texas	United States	78240
51	Retina Associates of Utah, P.C.	Salt Lake City	Utah	United States	84107
52	Virginia Retina Center	Leesburg	Virginia	United States	20176
53	Retina Institute of Virginia	Richmond	Virginia	United States	23235
54	University of Washington Medical Center	Seattle	Washington	United States	98195
55	Spokane Eye Clinic	Spokane	Washington	United States	99204
56	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Jaeb Center for Health Research
• Allergan
• Genentech, Inc.
• National Eye Institute (NEI)

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Sep 25, 2017
• Study Protocol - Nov 16, 2015

More Information

Publications

None provided.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT01945866
• Other Study ID Numbers: DRCR.net Protocol U; EY14231; EY23207; EY18817
• First Posted: Sep 19, 2013
• Last Update Posted: Sep 25, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Jaeb Center for Health Research: Diabetic Macular Edema; Anti-vascular endothelial growth factor; Dexamethasone Intravitreal implant; Ranibizumab intravitreal injection
• Additional relevant MeSH terms: Macular Edema; Edema; Dexamethasone; Ranibizumab

Study Results

Participant Flow

Recruitment Details	Phase 2 multi center randomized trial conducted at 40 US sites; 129 eyes (116 adults) with diabetes between February 2014 and December 2016. Participants with 2 study eyes enrolled one eye in each arm. Therefore, each arm includes no more than 1 study eye per participant; thus the number of eyes is equal to the number of participants in each arm.
Pre-assignment Detail	A 12-week run-in phase was conducted to confirm that eyes with persistent diabetic macular edema (DME) still persisted after additional anti-vascular endothelial growth factor (VEGF) injections. At week 12 of the run-in phase, eyes that had received all run-in injections, and continued to meet specific criteria were eligible for randomization.

Arm/Group Title	Sham + Intravitreal Ranibizumab 0.3 mg	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg
Arm/Group Description	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria. Dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran
Period Title: Overall Study
STARTED	65	64
COMPLETED	63	64
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Sham + Intravitreal Ranibizumab 0.3 mg	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Total
Arm/Group Description	Sham and ranibizumab, 0.3 mg, injections	Combination of ranibizumab, 0.3 mg and intravitreous sustained dexamethasone drug-delivery system (Ozurdex; Allergan), 700 µg, injection	Total of all reporting groups
Overall Participants	64	65	116
Overall Eyes	64	65	129
Age, Customized (years) [Median (Inter-Quartile Range) ]
Age	66	64	65
Sex/Gender, Customized (Eyes) [Count of Units]
Women	36	31	67
Male	28	34	62
Race/Ethnicity, Customized (Eyes) [Count of Units]
White	35	39	74
Black/African American	9	6	15
Hispanic or Latino	16	13	29
Asian	2	6	8
Native Hawaiian or other Pacific Islander	1	0	1
Unknown/not reported	1	1	2
Diabetes Type (Eyes) [Count of Units]
Type 1	2	2	4
Type 2	61	62	123
Uncertain	1	1	2
Duration of Diabetes (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	19	15	17
Insulin Used (Count of Participants)
Count of Participants [Participants]	39 60.9%	40 61.5%	79 68.1%
Hemoglobin A1c (Percent Hemoglobin) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Percent Hemoglobin]	7.4	7.1	7.3
Arterial Blood Pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	98	97	97
Smoking status (Eyes) [Count of Units]
Never	43	44	87
Prior	14	18	32
Current	7	3	10
Body Mass Index (kg/m˄2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m˄2]	33	32	32
Participants with 2 study eyes (participants) [Number]
Number [participants]	13 20.3%	13 20%	26 22.4%
Prior macular laser treatment for DME (Eyes) [Number]
Number [Eyes]	31	31	62
Prior Anti-VEGF for DME (Eyes) [Number]
Aflibercept only	8	7	15
Bevacizumab only	49	48	97
Ranibizumab only	6	3	9
Both aflibercept and bevacizumab	0	4	4
Both aflibercept and ranibizumab	0	1	1
Both bevacizumab and ranibizumab	1	2	3
Total anti-VEGF injections for DME within the 20 weeks before run-in phase (Injections) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Injections]	3	3	3
Randomization visual acuity letter score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	63 (13)	63 (12)	63 (12)
Randomization central subfield thickness (Microns) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Microns]	396 (122)	375 (97)	385 (110)
Change in central subfield thickness from enrollment to randomization (Microns) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Microns]	-50 (102)	-58 (83)	-54 (93)
Improvement in visual acuity(VA) and OCT CST thickness during run-in phase (Eyes) [Number]
Neither VA nor OCT CST is improved	12	15	27
VA and OCT CST are both improved	22	22	44
VA is not improved but OCT CST is improved	16	16	32
VA is improved but OCT CST is not improved	14	12	26
Randomization retinal volume (mm3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm3]	8.6 (2.0)	8.3 (1.6)	8.5 (1.8)
Randomization diabetic retinopathy severity level on clinical examination (Eyes) [Number]
Mild/moderate NPDR	28	30	58
Severe NPDR	12	10	22
PDR and/or prior scatter laser	24	25	49
Change in visual acuity letter score from enrollment to randomization (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3 (7)	3 (6)	3 (7)

Outcome Measures

1. Primary Outcome

Title	Mean Change in Visual Acuity Letter Score
Description	At 24 weeks after randomization, mean change in visual acuity letter score, adjusted for visual acuity at time of randomization
Time Frame	24 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
Mean (Standard Deviation) [Letter Score]	2.7 (9.8)	3.0 (7.1)

2. Secondary Outcome

Title	At 24 Weeks After Randomization, Number of Eyes With at Least 10 and at Least 15 Letter Gain (Increase) or Loss (Decrease) in E-ETDRS Letter Score Visual Acuity.
Description	ETDRS (Early Treatment Diabetic Retinopathy Study)
Time Frame	24 weeks weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
>= 15 Letter Improvement	7	1
>= 10 Letter Improvement	14	9
>= 10 Letter Worsening	8	4
>= 15 Letter Worsening	4	3

3. Secondary Outcome

Title	Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks
Description	Only included participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization.
Time Frame	24 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
Mean (Standard Deviation) [Letter Score]	1.9 (6.3)	2.5 (4.4)

4. Secondary Outcome

Title	Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization
Description	Change in optical coherence tomography (OCT) central subfield thickness (in microns) was truncated to 3 standard deviations from the mean [-372, +201] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end.
Time Frame	24 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
Mean (Standard Deviation) [microns]	-110 (86)	-62 (97)

5. Secondary Outcome

Title	Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness
Description	Change in optical coherence tomography (OCT) central subfield (CSF) thickness (in microns) was truncated to 3 standard deviations from the mean [-372, +201] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end.
Time Frame	24 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
>=1 LogOCT step improvement	34	22
>= 2 LogOCT step improvement	14	8
>=1 LogOCT step worsening	0	1
>=2 LogOCT step worsening	0	1

6. Secondary Outcome

Title	Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus
Description	Gender and OCT machine-specific values for OCT central subfield thickness (in microns) are defined as: <290 in women and <305 in men in Zeiss Cirrus; <305 in women and <320 in men in Heidelberg Spectralis
Time Frame	24 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
Number [Eyes]	32	20

7. Secondary Outcome

Title	OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks
Description	Including participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization.
Time Frame	24 weeks after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg	Sham + Intravitreal Ranibizumab 0.3 mg
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran	Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Measure Participants	63	64
Measure Eyes	63	64
Mean (Standard Deviation) [microns]	-86.9 (65.6)	-33.5 (56.8)

Adverse Events

Time Frame	From Randomization to 24-weeks
Arm/Group Title	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg		Sham + Intravitreal Ranibizumab 0.3 mg		Bilateral
Arm/Group Description	The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. Intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria dexamethasone intravitreal implant: The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ran		Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. intravitreal ranibizumab 0.3 mg: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria Sham injection: No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.		Participants with one eye enrolled in each arm of the study. A participant could only have one eye in each arm/group, therefore participants in the bilateral group received Intravitreal dexamethasone+intravitreal ranibizumab 0.3mg in one eye and Sham + intravitreal ranibizumab 0.3 mg in the other eye.
All Cause Mortality
	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg		Sham + Intravitreal Ranibizumab 0.3 mg		Bilateral
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/51 (0%)		0/13 (0%)
Serious Adverse Events
	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg		Sham + Intravitreal Ranibizumab 0.3 mg		Bilateral
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/52 (13.5%)		7/51 (13.7%)		1/13 (7.7%)
Cardiac disorders
Diastolic dysfunction	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Endocrine disorders
Hypoglycaemia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Eye disorders
Cataract subcapsular	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Retinal detachment	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Infections and infestations
Infection	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Multiple fractures	1/52 (1.9%)	1	0/51 (0%)	0	1/13 (7.7%)	1
Renal and urinary disorders
Acute kidney injury	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/52 (0%)	0	1/51 (2%)	2	0/13 (0%)	0
Upper respiratory tract infection	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Surgical and medical procedures
Stent placement	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Vascular graft	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Vascular disorders
Cerebrovascular accident	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Hypertension	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg		Sham + Intravitreal Ranibizumab 0.3 mg		Bilateral
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/52 (73.1%)		29/52 (55.8%)		11/13 (84.6%)
Blood and lymphatic system disorders
Anaemia	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Thrombocytopenia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Cardiac disorders
Atrial fibrillation	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Atrioventricular block first degree	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Coronary artery stenosis	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Endocrine disorders
Diabetes mellitus inadequate control	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Hypoglycaemia	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Eye disorders
Asthenopia	1/52 (1.9%)	3	0/51 (0%)	0	0/13 (0%)	0
Blepharitis	2/52 (3.8%)	3	0/51 (0%)	0	0/13 (0%)	0
Cataract	3/52 (5.8%)	3	1/51 (2%)	1	0/13 (0%)	0
Cataract cortical	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Cataract nuclear	1/52 (1.9%)	1	0/51 (0%)	0	2/13 (15.4%)	2
Cataract subcapsular	1/52 (1.9%)	1	0/51 (0%)	0	2/13 (15.4%)	3
Conjunctival haemorrhage	4/52 (7.7%)	4	0/51 (0%)	0	1/13 (7.7%)	1
Corneal defect	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Corneal oedema	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Diabetic retinopathy	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Diplopia	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Dry eye	0/52 (0%)	0	1/51 (2%)	1	1/13 (7.7%)	2
Ectropion	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Eye irritation	2/52 (3.8%)	2	1/51 (2%)	1	0/13 (0%)	0
Eye pain	2/52 (3.8%)	2	3/51 (5.9%)	3	0/13 (0%)	0
Eye pruritus	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Eyelid oedema	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Eyelid ptosis	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Foreign body sensation in eyes	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Iritis	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Lacrimation increased	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Metamorphopsia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Ocular discomfort	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Ocular hyperaemia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Photophobia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Photopsia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Retinal exudates	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Vision blurred	7/52 (13.5%)	7	4/51 (7.8%)	5	0/13 (0%)	0
Visual acuity reduced	0/52 (0%)	0	2/51 (3.9%)	3	0/13 (0%)	0
Visual field defect	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Visual impairment	0/52 (0%)	0	1/51 (2%)	2	0/13 (0%)	0
Vitreous adhesions	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Vitreous floaters	8/52 (15.4%)	8	3/51 (5.9%)	3	1/13 (7.7%)	1
Vitreous haemorrhage	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Constipation	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Diarrhoea	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Food poisoning	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Gastritis	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Gastroenteritis viral	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Gastrooesophageal reflux disease	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Nausea	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Tooth infection	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Vomiting	1/52 (1.9%)	2	0/51 (0%)	0	0/13 (0%)	0
General disorders
Pain	0/52 (0%)	0	2/51 (3.9%)	2	0/13 (0%)	0
Pyrexia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Infections and infestations
Gastroenteritis norovirus	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Infection	0/52 (0%)	0	2/51 (3.9%)	2	0/13 (0%)	0
Influenza	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Onychomycosis	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Staphylococcal infection	1/52 (1.9%)	1	0/51 (0%)	0	1/13 (7.7%)	1
Viral infection	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Fall	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Head injury	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Limb injury	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Wound	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Investigations
Blood calcium decreased	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Cardiac murmur	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Intraocular pressure increased	11/52 (21.2%)	12	0/51 (0%)	0	3/13 (23.1%)	3
Metabolism and nutrition disorders
Hypokalaemia	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Vitamin D deficiency	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthritis	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Back pain	1/52 (1.9%)	2	1/51 (2%)	1	0/13 (0%)	0
Foot fracture	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Gout	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Multiple fractures	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Muscle spasms	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Neck pain	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Pain in extremity	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Polymyalgia rheumatica	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Rib fracture	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Synovial cyst	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic cancer	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Nervous system disorders
Carotid artery occlusion	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Dizziness	1/52 (1.9%)	1	0/51 (0%)	0	1/13 (7.7%)	1
Headache	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Myasthenia gravis	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Psychiatric disorders
Depression	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Insomnia	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Renal and urinary disorders
Chronic kidney disease	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Nephrolithiasis	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Urinary tract infection	1/52 (1.9%)	1	1/51 (2%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/52 (0%)	0	0/51 (0%)	0	2/13 (15.4%)	2
Nasopharyngitis	1/52 (1.9%)	1	2/51 (3.9%)	2	1/13 (7.7%)	1
Pharyngitis streptococcal	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Upper respiratory tract infection	1/52 (1.9%)	1	1/51 (2%)	2	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Basal cell carcinoma	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Skin cancer	0/52 (0%)	0	0/51 (0%)	0	1/13 (7.7%)	1
Skin infection	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0
Surgical and medical procedures
Knee operation	0/52 (0%)	0	1/51 (2%)	1	0/13 (0%)	0
Tooth extraction	2/52 (3.8%)	3	0/51 (0%)	0	0/13 (0%)	0
Vascular disorders
Hypertension	1/52 (1.9%)	1	0/51 (0%)	0	0/13 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Trial results can not be discussed until they have been made available to the public