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Effectiveness and safety of Combination therapy of Ranibizumab and LuseOgliflozin in type 2 diabetes with diabetic Macular Edema, a parallel group comparison with the standard Treatment controlled by Glimepiride, multicenter, randomized, open-label trial (COMET Trial)

COMET Trial (COMET Trial)

Yokote Koutaro

Chiba University Hospital

1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba , JAPAN

kyokote@faculty.chiba-u.jp

Koshizaka Masaya

Chiba University Hospital

1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba , JAPAN

+81-43-226-2092

overslope@chiba-u.jp

Complete

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1) Patients with type 2 diabetes mellitus who are aged of 20 years or older and younger than 80 years when giving their consent
2) patients with diabetic macular edema which affects fovea centralis of macula lutea, and with corrected visual acuity of 0.05 or higher
3) patients with retina thickness of study eye measured by OCT is 350 micrometer or more at the screening test. If the retina thickness of both eyes are 350 micrometer of more, the eye with thicker retina is defined as the study eye.
4) patients with HbA1c of 6.5% or higher and less than 12.0% at the screening test
5) patients with BMI of 18.5 kg/m2 or higher at the screening test
6) patients with eGFR of 30 mL/min/1.73m2 or higher at the screening test
7) patients in whom treatment of diabetes mellitus have not been changed in 8 weeks before the screening test
8) patients who provide written consent form to participate in this study after full explanation of the study

Patients who fall into any of the following criteria are excluded from participating in the study.
<internal medicine>
1)patients with type 1 diabetes mellitus
2)patients with history of hypersensitivity against SGLT2 inhibitor or glimepiride
3)patients with history of coma or precoma due to the diabetes mellitus or hypoglycemia within the 24 weeks before the screening test
4)Patients with severe infections, before or after surgery, or severe trauma which require insulin treatment
5)Patients with severe renal dysfunction (eGFR < 30mL/ min/1.73m2), or patients who undergo dialysis (including peritoneal dialysis)
6)Female patients who are pregnant, possibly pregnant, or planned to be pregnant or breast feeding
7)Patients with urinary tract infection or dehydration, or patients who are prone to urinary tract infection or dehydration
8)Patients with positive urinary ketone body (urine qualitative of 2+ or higher)
9)Patients with history of leg amputation due to leg gangrene
10)Patients with history of bone fracture due to osteoporosis
11) Patients who were treated by thiazolidine, SGLT2 inhibitors, sulfonylurea or glinide within 8 weeks before the screening test
12)Patients who were treated by fibrate or diuretic agents and who changed the usage or dose of them within 8 weeks before the screening test
13)Patients who had systemic administration of steroid within 8 weeks before the screening test
14)Patients with history of cerebrovascular impairment or myocardial infarction within 48 weeks before the screening test
15)Patients with poorly controlled hypertension (clinic blood pressure measured in sitting position is 180 mmHg of higher in systolic blood pressure or 100 mmHg or higher in diastolic blood pressure)

<ophthalmology>
16)patients with history of retina vitreal surgery or scleral buckling
17)Patients with history of filtration surgery to the study eye for glaucoma treatment, or patients who are expected to require the filtration surgery in future
18)Patients with active proliferative diabetic retinopathy in the study eye
19)Patients with history of idiopathic or autoimmune uveitis in the study eye
20)Patients with vitreomacular traction syndrome or epi-retinal membrane in the study eye measured by slit lamp microscope or OCT, which affect the central visual acuity
21)Patients with iris neovessel, vitreous hemorrhage, or traction retinal detachment in the study eye
22)Patients with epi-retinal membrane in the study eye, which affect macular area
23)Patients with morphological impairment at the central area of macula lutea in the study eye, which can affect the improvement of visual acuity after the disappearance of macular edema, such as atrophy of retinal pigment epithelium, fibrogenesis or scarring under the retina, severe retina ischemia or structural hard exudate
24)Patients with history of cataract surgery or other intraocular surgeries to the study eye within 12 weeks before the screening test
25)Patients with history of laser panretinal or macular photocoagulation to the study eye within 12 weeks before the screening test
26)Patients with history of YAG laser posterior capsulotomy to the study eye within 4 weeks before the screening test
27)Patients who received steroid to the study eye or the surrounding of the study eye within 16 weeks before the screening test
28)Patients who received angiogenic inhibitor (pegaptanib, bevacizumab, ranibizumab, aflibercept and others) to any eyes within 12 weeks before the screening test
29)Patients whose transparency of optic media in the study eye is insufficient to obtain fundus or OCT images
30)Patients who received systemic administration of angiogenic inhibitor within 24 weeks before the screening test
31)Patients with complications other than diabetic macular edema, which may cause worsening of visual acuity requiring surgical intervention during the study period, or which can affect the study endpoints
32)Patients with any signs of infectous blepharitis, keratitis, or conjunctivitis in any eyes
33)Patients with history of hypersensitivity against anti-VEGF agent or fluorescein
34)Patients who used kalliginogenase or sairei-to within 8 weeks before the screening test

<common>
35)Patients with other conditions that the investigator/researcher thinks inappropriate for the study

Both

diabetic macular edema, diabetes mellitus

Study agent treatment group: administration of luseogliflozin 2.5mg/day
Control agent treatment group: administration of glimepiride 0.5mg/day

043, 025

Intergroup difference in number of anti-VEGF intravitreal injection to the study eye from baseline to week 48

[Efficacy secondary endpoints]
(1) Change and percent change of following items from baseline to each observation point (every 4 weeks up to week 48) and intergroup difference of them.
1.Proportion of patients who require additional anti-VEGF intravitreal injections to the study eye after the initial anti-VEGF intravitreal injection
2.Proportion of patients who do not require additional anti-VEGF intravitreal injections to the study eye between 4 weeks after the initial anti-VEGF intravitreal injection to each observation point (every 4 weeks up to week 48)
3.Number of retinal microaneurysm photocoagulation (MAPC) to retinal arteriolar macroaneurysm of the study eye from baseline to week 48
4.Central retina thickness of the study eye at each observation point measured by optical coherence tomography (OCT)
5.Corrected visual acuity of the study eye at each observation point converted to logarithm of minimam angle of resolution (logMAR)
6.Presence or absence of hemorrhage at macular area or hard exudate in the study eye at each observation point measured by opthalmoscopy
7.Presence or absence of active leakage from blood vessels surrounding the macula area of the study eye measured by fluorescein angiography
8.Morphology of acular edema and visual acuity, central retina thickness, number of injections of the study eye at each observation point
9.Body weight, body mass index (BMI), blood pressure, pulse, HbA1c, plasma glucose, eGFR and Hct
(2) Intergroup difference of the change of following items during the post-treatment observation period (4 weeks from week 48 to week 52)
1.Central retina thickness of the study eye measured by OCT
2.Correted visual acuity of the study eye converted to logMAR
3.Presence or absence of hemorrhage at macular area or hard exudate in the study eye
4.Presence or absence of active leakage from blood vessels surrounding the macula area in the study eye measured by fluorescein angiography
5.Visual acuity and central retina thickness of the study eye stratified by morphology of acular edema
6.Body weight, BMI, blood pressure, pulse, HbA1c, plasma glucose, eGFR and Hct
[Safety secondary endpoints]
1.Intergroup difference in the frequency and proportion of any adverse events and side effects from baseline to week 48 estimated by MedDRA
2.Intergroup difference in the occurrence of any adverse events and side effects during the post-treatment observation period (4 weeks from week 48 to week 52)
[Exploratory endpoints]
1.Change, percent change, and intergroup difference of following items from baseline to week 24 and week 48
- Insulin and calculated HOMA-R, HOME-bata
- C-peptide and calculated CPI
- Urinary albumin/creatinine ratio
- Biomarker of heart failure (BNP)
- Biomarker of kidney and oxidative stress (urinary L-FABP)
(only in patients who can measure the following items)
- CAVI
- Total body water, intracellular water, extracellular water, lean body mass, muscle mass, bone mineral, body fat percentage and basal metabolism measured by body composition meter (bioelectrical impedance method)
2. Correlation between intergroup difference in change or percent change of following items from baseline to week 24 and week 48 and primary and secondary endpoints
- Body weight, BMI, blood pressure, pulse, HbA1c, plasma glucose, eGFR and Hct
- AST, ALT, gamma-GTP, UA, TC, TG, HDL-C, LDL-C (indirect measurement), T-BIL, BUN, Cre, insulin and calculated HOMA-R and HOMA-bata, C-peptide and calculated CPI, urinary albumin/creatinine ratio, BNP, urinary L-FABP
(only in patients who can measure the following items)
- CAVI
- Total body water, intracellular water, extracellular water, lean body mass, muscle mass, bone mineral, body fat percentage and basal metabolism measured by body composition meter (bioelectrical impedance method)

If patients have macular edema in the fellow eye to which anti-VEGF intravitreal injections are not performed, observe same items of primary and secondary endpoints in the fellow eye.

+81-43-226-2616

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