| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| To treat damage (swelling) of the retina (the light sensitive part of the eye) caused by complications of diabetes. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Ocular Physiological Phenomena [G14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057915 |
| E.1.2 | Term | Diabetic macular oedema |
| E.1.2 | System Organ Class | 10015919 - Eye disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the safety and efficacy of the 700 µg DEX PS DDS Applicator System (700 µg dexamethasone) and 350 µg DEX PS DDS Applicator System (350 µg dexamethasone) compared with a Sham DEX PS DDS Applicator System (needle-less applicator) in patients with diabetic macular edema. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and efficacy of the 700 µg DEX PS DDS Applicator System (700 µg dexamethasone) compared with the 350 µg DEX PS DDS Applicator System
(350 µg dexamethasone) in patients with diabetic macular edema. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, at least 18 years of age
2. Diagnosis of diabetes mellitus (type 1 or type 2). Any one of the following will be considered to be sufficient evidence that diabetes is present:
- Current regular use of insulin for the treatment of diabetes
- Current regular use of oral hypoglycemic agents for the treatment of diabetes
- Diabetes defined as (ADA guidelines):
• Symptoms of diabetes (polyuria, polydipsia, and unexplained weight loss) plus plasma glucose concentration at any time of the day regardless of time since last meal ≥ 200 mg/dl (11.1 mmol/l) or
• Eight-hour fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/l) or
• Two-hour postload (75 g) glucose ≥ 200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test
3. Diabetic macular edema in the study eye defined as clinically
observable macular edema involving the center of the macula (fovea)
associated with diabetic retinopathy, with any of the following
characteristics:
a) Prior medical therapy for diabetic macular edema
b) Prior macular laser(s) for diabetic macular edema with the most
recent laser at least 3 months prior to Baseline/ Qualification
where, in the opinion of the investigator, the patient will be able to
improve 15 or more letters in BCVA from baseline with the
resolution of the macular edema despite the presence of macular
laser scars
c) In the investigator’s opinion the patient would not benefit from
macular laser treatment
d) The patient refuses laser treatment
4. BCVA score between 34 letters (approximately 20/200 Snellen equivalent) and
68 letters (approximately 20/50 Snellen equivalent) in the study eye measured by the ETDRS method at qualification/baseline
5. Retinal thickness of ≥ 300 μm by OCT in the 1mm central macular
subfield of the study eye at qualification/baseline as determined by the
investigator
6. Patients who have received intravitreal triamcinolone acetonide must
satisfy the following:
• The intended dose for each injection was 4 mg or less
• The most recent dose was at least 6 months prior to
qualification/baseline visit
• No treatment-related adverse event was seen that, in the
opinion of the investigator, has the potential to worsen or
reoccur with study treatment
7. Female patients of childbearing potential must have a negative urine pregnancy test at the randomization (day 0) visit
8. Written informed consent has been obtained
9. Written Authorization for Use and Release of Health and Research Study Information (US sites only) has been obtained
10. Written Data Protection Consent (European sites only) has been obtained
11. Written documentation has been obtained, in accordance with state and country privacy requirements, where applicable |
|
| E.4 | Principal exclusion criteria |
1. Uncontrolled systemic disease or current immunosuppressive diseases
(e.g. HIV+ or AIDS)
2. Initiation of medical therapy for diabetes or a change from oral
hypoglycemic agents to insulin therapy within 4 months prior to the
qualification/baseline visit
3. Blood HbA1c level greater than 10% at the qualification/baseline visit
4. Renal failure requiring hemodialysis or peritoneal dialysis within 6
months prior to the qualification/baseline visit
5. Adjusted glomerular filtration rate (GFR) less than 50 mL/min based on
the Modified Diet in Renal Disease (MDRD) formula adjusted for body
surface area, at the qualification/baseline visit
6. Any ocular condition in the study eye that in the opinion of the
investigator would prevent a 15-letter improvement in visual acuity
(e.g., severe macular ischemia, extensive macular laser scarring or
atrophy)
7. Presence of branch retinal vein occlusion, central retinal vein occlusion,
uveitis, pseudophakic cystoid macular edema or any other condition in
the study eye which could be contributing to macular edema
8. Presence of an epiretinal membrane or vitreo-retinal interface changes in
the study eye which, in the opinion of the investigator, is the primary
cause of macular edema, or is severe enough to prevent improvement in
visual acuity despite reduction in macular edema
9. History of IOP elevation in response to steroid treatment in either eye
that resulted in any of the following:
1) a ≥ 10 mm Hg increase in IOP from baseline with an absolute IOP
≥25 mm Hg
2) required therapy with 3 or more anti-glaucoma medications
10. History of glaucoma or optic nerve head change consistent with
glaucoma damage, and/or glaucomatous visual field loss in the study
eye. Patients with a history of previous angle-closure or similar
conditions that have been successfully treated with either a laser or
surgical peripheral iridotomy are allowed as long as the visual fields
and optic nerves have been stable for > 1 year prior to study entry and
the patient has been and can be safely dilated
11. Ocular hypertension in the study eye at qualification/baseline with any
of the following:
1) IOP > 23 mm Hg if taking no anti-glaucoma medications
2) IOP > 21 mm Hg if taking one anti-glaucoma medication
3) Use of 2 or more anti-glaucoma medications (combination products
should be considered 2 medications)
Note: Anti-glaucoma medications or lack thereof must be stable for at
least 4 weeks prior to qualification/baseline.
12. Aphakia or presence of anterior chamber intraocular lens in the study
eye
13. Active optic disc or retinal neovascularization in the study eye at
qualification/baseline
14. Active or history of choroidal neovascularization in the study eye
15. Presence of rubeosis iridis in the study eye at qualification/baseline
16. Any active ocular infection (ie, bacterial, viral, parasitic, or fungal) in
either eye at qualification/baseline
17. History of herpetic infection in the study eye or adnexa
18. Presence of active or inactive toxoplasmosis in either eye at
qualification/baseline
19. Presence of visible scleral thinning or ectasia in the study eye
20. Media opacity in the study eye at qualification/baseline that precludes
clinical and photographic evaluation (including but not limited to
preretinal or vitreous hemorrhage, lens opacity)
21. Intraocular surgery, including cataract surgery, and/or laser of any type
in the study eye within 90 days prior to qualification/baseline
22. History of central serous chorioretinopathy in either eye
23. History of pars plana vitrectomy in the study eye
24. Anticipated need for ocular surgery or laser in the study eye within 1
year following the qualification/baseline visit (e.g., panretinal
photocoagulation (PRP), cataract surgery)
25. History of use of intravitreal steroids in the study eye other than
triamcinolone acetonide
26. History of use of intravitreal bevacizumab, ranibizumab, or pegaptanib
in the study eye within 3 months prior to qualification/baseline visit
27. History of use of any intravitreal agent in the study eye other than
triamcinolone acetonide, bevacizumab, ranibizumab, or pegaptanib, or
intravitreal doses of triamcinolone acetonide > 4mg, bevacizumab >
1.25 mg, ranibizumab > 0.5 mg, or pegaptanib > 0.3 mg
28. Periocular depot of steroids to the study eye within 6 months prior to
qualification/baseline
29. Use of systemic steroids (e.g., oral, intravenous, intra-articular,
epidural, intra-bursal) within 1 month prior to the qualification/baseline
visit or anticipated use at any time during the study. Inhaled and
intranasal steroids are allowed
30. For patients who participate in therapeutic drug monitoring evaluation
only: use of dexamethasone within 1 month prior to
qualification/baseline or anticipated use during the first 90 days in any
form/route of administration
DUE TO SPACE RESTRICTIONS, ONLY EXCLUSION CRITERIA 1-30 ARE LISTED. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable for countries/regions other than the United States will be BCVA average change from baseline during the study (AUC approach) using observed data in the study eye.
Best Corrected Visual Acuity (BCVA) is the primary efficacy variable and will be measured using the ETDRS method. It will be measured in both eyes (study eye and non-study eye) at the qualification visit and each follow-up visit. BCVA will be performed following manifest refraction, except 1, 7 and 21 days after the study treatment or re-treatment,. At days 1, 7 and 21 after a treatment or re-treatment, visual acuity (VA) evaluations may be performed using refraction obtained at baseline or at the preceding re-treatment visit, respectively. These VA evaluations will be considered as safety measures but not as efficacy measures. All other VA evaluations will be considered as both safety and efficacy measures. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Mean BCVA change from baseline at each scheduled follow-up visit.
- Proportion of patients with a BCVA improvement of 10 or more letters from baseline
- Proportion of patients with a BCVA improvement of 15 or more letters from baseline
- Average proportion of patients with a BCVA improvement of 15 or more letters from baseline 3 month after each injection.
- Analysis of BCVA change from baseline at each scheduled follow-up visit in the distribution of 7 categories: (1) ≥ 15 letters better, (2) ≥ 10 and < 15 letters better, (3) ≥ 5 and < 10 letters better, (4) no change (ie, change of -4 to +4 letters), (5) ≥ 5 and
< 10 letters worse, (6) ≥ 10 and < 15 letters worse and (7) ≥ 15 letters worse.
- Other secondary efficacy analyses include contrast sensitivity, FA, FP and retinal thickness by optical coherence tomography (OCT). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Colombia |
| Czech Republic |
| France |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Korea, Democratic People's Republic of |
| New Zealand |
| Philippines |
| Poland |
| Portugal |
| Singapore |
| South Africa |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 96 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 96 |
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