A Study to Evaluate THR-687 Treatment for Diabetic Macular Oedema.

Study Overview
=================
Brief Summary
-----------------
This study is conducted to select the THR-687 dose level (Part A of the study) and to assess the efficacy and safety of the selected dose level compared to aflibercept (Part B of the study).

Detailed Description
-----------------
In Part A, approximately 12 subjects are planned to be randomized (1:1 allocation) to THR-687 1.2mg and THR-687 2.0mg. In Part B, in the cohort of Treatment Naïve subjects are planned to be randomized (2:1 allocation) to THR-687 selected dose level from Part A and Aflibercept 2.0mg. In Part B, in the cohort of Previously Treated subjects are planned to be randomized (1:1 allocation) to THR-687 selected dose level from Part A and Aflibercept 2.0mg. All subjects in the study will receive study treatment in one selected study eye only.

Official Title
-----------------
A Phase 2, Randomised, Multicentre Study to Assess the Dose Level of Multiple THR-687 Injections and to Evaluate the Efficacy and Safety of THR-687 Versus Aflibercept for the Treatment of Diabetic Macular Oedema (DME)

Conditions
-----------------
Diabetes Mellitus, Diabetic Retinopathy, Diabetic Macular Edema

Intervention / Treatment
-----------------
* Drug: THR-687 dose level 1
* Drug: THR-687 dose level 2
* Drug: THR-687 selected dose level
* Drug: Aflibercept


Participation Criteria
=================
Eligibility Criteria
-----------------
The subjects in this study will be subjects with central-involved DME (CI-DME). Both treatment-naïve and previously treated subjects will be included. Inclusion Criteria: Written informed consent obtained from the subject prior to screening procedures Male or female aged 18 years or older at the time of signing the informed consent Type 1 or type 2 diabetes BCVA ETDRS letter score ≥ 39 in the study eye CI-DME with CST of ≥ 300µm in men (or equivalent in women), measured from RPE to ILM inclusively, on SD-OCT, in the study eye BCVA ETDRS letter score ≥ 34 in the fellow eye Exclusion Criteria: Macular edema due to causes other than DME in the study eye Concurrent disease in the study eye, other than DME, that could require medical or surgical intervention during the study period or could confound interpretation of the results Any condition in the study eye that could confound the ability to detect the efficacy of the investigational medicinal product Previous confounding medications / interventions, or their planned administration during the study Presence of iris neovascularisation in the study eye Uncontrolled glaucoma in the study eye Previously received THR-687 or any other experimental therapy for DME, in either eye Any active or suspected ocular or periocular infection, or active intraocular inflammation, in either eye Untreated Diabetes Glycated haemoglobin A (HbA1c) > 12% Uncontrolled hypertension

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, THR-687 1.2 mg<br> | Drug: THR-687 dose level 1<br>* 3 intravitreal injections of THR-687 dose level 1, 1 month apart<br>|
| Experimental: Part A, THR-687 2.0mg<br> | Drug: THR-687 dose level 2<br>* 3 intravitreal injections of THR-687 dose level 2, 1 month apart<br>|
| Experimental: Part B, treatment naïve subjects, THR-687 selected dose level<br>Due to the discontinuation of the study after Part A, the dose level for Part B has not been selected | Drug: THR-687 selected dose level<br>* 3 intravitreal injections of THR-687 selected dose level, 1 month apart, possibly followed by a 4th intravitreal injection with the same dose level of THR-687 at Month 3, or Month 4, or Month 5, if any of the PRN criteria are met.<br>|
| Active Comparator: Part B, treatment naïve subjects, aflibercept 2.0mg<br> | Drug: Aflibercept<br>* 3 intravitreal injections of aflibercept, 1 month apart, possibly followed by a 4th intravitreal injection with aflibercept at Month 3, or Month 4, or Month 5, if any of the PRN criteria are met.<br>* Other names: Eylea®;|
| Experimental: Part B, previously treated subjects, THR-687 selected dose level<br>Due to the discontinuation of the study after Part A, the dose level for Part B has not been selected | Drug: THR-687 selected dose level<br>* 3 intravitreal injections of THR-687 selected dose level, 1 month apart, possibly followed by a 4th intravitreal injection with the same dose level of THR-687 at Month 3, or Month 4, or Month 5, if any of the PRN criteria are met.<br>|
| Active Comparator: Part B, previously treated subjects, aflibercept 2.0mg<br> | Drug: Aflibercept<br>* 3 intravitreal injections of aflibercept, 1 month apart, possibly followed by a 4th intravitreal injection with aflibercept at Month 3, or Month 4, or Month 5, if any of the PRN criteria are met.<br>* Other names: Eylea®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in BCVA ETDRS Letter Score, at Month 3, in Treatment-naïve Subjects in Part B of the Study |  | At Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Average of the Change From Baseline in BCVA ETDRS Letter Score From Day 8 Through Month 3 Using the Trapezoidal Rule (AUC), in Treatment-naïve Subjects in Part B of the Study |  | at Month 3 | 
| Change From Baseline in BCVA ETDRS Letter Score, by Study Visit, in Treatment-naïve Subjects in Part B of the Study |  | Up to Month 8 | 
| Change From Baseline in Central Subfield Thickness (CST), Based on Spectral Domain Optical Coherence Tomography (SD-OCT), as Assessed by the Central Reading Center (CRC), by Study Visit, in Treatment-naïve Subjects in Part B of the Study |  | Up to Month 8 | 
| Incidence of Ocular and Non-ocular Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events will be reported from the date of Informed Consent until End of the Study visit (up to Month 6 in Part A and up to Month 8 in Part B) or at the early study discontinuation visit and will be coded using MedDRA. Adverse Events will be summarized by System Organ Class and Primary Term. Incidence by subject represents at least one occurrence of the Primary Term with an onset on or after the date of the first study treatment. If a subject has multiple occurrences of an adverse event (P-term), the subject is presented only once in the respective subject count. | Up to End of Study (Part A up to Month 6 and Part B up to Month 8) |