## Protocol Section
### Identification Module
**NCT ID:** NCT03056079

**Acronym:** COVARIANT

**Brief Title:** Cytokine and Visual Outcome Variations in Eyes Receiving Aflibercept

**Official Title:** Cytokine and Visual Outcome Variations in Eyes Receiving a Variable Dosing Aflibercept Treatment: The COVARIANT Study

#### Organization Study ID Info
**ID:** COVARIANT
#### Organization
**Class:** OTHER
**Full Name:** Unity Health Toronto
### Status Module
#### Completion Date
**Date:** 2024-02-28

**Type:** ESTIMATED

#### Expanded Access Info
**Last Known Status:** RECRUITING
#### Last Update Post Date
**Date:** 2021-04-28

**Type:** ACTUAL

**Last Update Submit Date:** 2021-04-27

**Overall Status:** UNKNOWN

#### Primary Completion Date
**Date:** 2024-02-28

**Type:** ESTIMATED

#### Start Date
**Date:** 2017-02-28

**Type:** ACTUAL

**Status Verified Date:** 2021-04

#### Study First Post Date
**Date:** 2017-02-17
**Type:** ACTUAL
**Study First Submit Date:** 2017-02-01
**Study First Submit QC Date:** 2017-02-13
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Unity Health Toronto

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Objective: To determine the association between baseline aqueous cytokine levels and treatment intervals for patients under a variable dosing regimen with intravitreal aflibercept in patients with neovascular age-related macular degeneration (nAMD), macular edema secondary to retinal vein occlusion (RVO) and diabetic macular edema (DME).

Methods: A prospective, single-centre study will be performed containing 3 sub-studies according to each study population: nAMD, macular edema secondary to RVO and DME. Inclusion criteria are: patients followed at St. Michael's Hospital with the diagnosis of nAMD, macular edema secondary to RVO or DME. Patients will be excluded if visual acuity is worse than counting fingers, with macular pathologies causing any structural changes to the retina, have received anti-VEGF injections or photocoagulation therapy 6 months prior to study, intraocular surgery 3 months prior to study, any history of vitreoretinal surgery or ocular inflammation in the study eye, use of systemic or topical anti-inflammatory or steroids, patients on dialysis for renal failure, allergy to the study drug or fluorescein, \<18 years old, women who are pregnant. All patients will be treated with aflibercept intravitreal injections on a variable dosing regimen: Patients with DME will be examined monthly and receive mandatory injection for the first three months (baseline, weeks 4 and 8). Afterwards, they will continue to be seen monthly and the need for new injections will be decided upon the clinical findings at each visit. An anterior chamber (AC) tap will be done if an injection is required at the visit. Patients with nAMD and RVO will be examined monthly and receive mandatory injection for the first three months. From weeks 12 until 72 (month 18), the visits will be scheduled at increasing 2-weeks intervals based on the stability of the ocular condition and response to treatment. At each visit, an injection and AC tap will be performed. The maximum interval in between injections is 12 weeks. If the disease becomes unstable, the interval in between injections is shortened and, once it stabilizes, the treatment frequency is extended again. In all patients, baseline aqueous humour specimens will be obtained prior to the first aflibercept intravitreal injection and follow-up samples will be taken immediately prior to subsequent injections based on the treatment regimens for cytokine analysis in the end of the follow-up.

### Conditions Module

**Conditions:**

- Age Related Macular Degeneration

- Diabetic Macular Edema

- Retinal Vein Occlusion

- Macular Edema

**Keywords:**

- neovascular age related macular degeneration

- diabetic macular edema

- retinal vein occlusion

- aflibercept

- aqueous humor cytokine

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

**Intervention Model Description:** This study will contain 3 populations of patients which will all receive aflibercept injections: one with neovascular age-related macular degeneration, other with diabetic macular edema and a third with macular edema secondary to retinal vein occlusion.

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 168

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients presenting to St. Michael's Hospital retina clinic with neovascular AMD, macular edema secondary to retinal vein occlusion and diabetic macular edema treated with intravitreal aflibercept in a variable dosing regimen.

**Intervention Names:**

- Drug: Intravitreal aflibercept

**Label:** AMD/RVO/DME

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- AMD/RVO/DME

**Description:** Patients will receive intravitreal aflibercept on a variable dosing regimen and have aqueous humor sample obtained for cytokine analysis at every visit when an intravitreal injection is done.

**Name:** Intravitreal aflibercept

**Other Names:**

- Eylea

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Optimal interval between injections based on aqueous cytokine levels

**Measure:** Association between cytokine levels and optimal treatment interval

**Time Frame:** 18 months

#### Secondary Outcomes

**Description:** Aqueous cytokine curves for each patient based on the relationship between cytokine levels and treatment response

**Measure:** Individualized aqueous cytokine curves relationship with treatment response

**Time Frame:** 18 months

**Description:** Cytokine threshold level below which visual and anatomic outcomes are greatest

**Measure:** Cytokine threshold level with visual and anatomic outcomes

**Time Frame:** 18 months

**Description:** To assess Snellen Best Corrected Visual Acuity (BCVA) change at months 1 and 2, and at the visits scheduled for each injection throughout an 18 months period.

**Measure:** Snellen BCVA change

**Time Frame:** months 1 and 2, and at the visits scheduled for each injection throughout an 18 months period.

**Description:** Visual acuity (ETDRS) change at month 2 (at the third injection), at the visits closest to injection of months 6, 12 and 18.

**Measure:** ETDRS visual acuity change

**Time Frame:** month 2, at the visits closest to injection of months 6, 12 and 18.

**Description:** Anatomic OCT change (Macular Volume, Central Macular Thickness) at months 1 and 2, and at the visits scheduled for each injection throughout an 18 months period.

**Measure:** Optical coherence tomography change

**Time Frame:** months 1 and 2, and at the visits scheduled for each injection throughout an 18 months period.

**Description:** Average number of injections needed in a variable dosing regimen protocol over an 18 months period.

**Measure:** Average number of injections needed

**Time Frame:** 18 months

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Diagnosis of active choroidal neovascularization secondary to AMD in the study eye
* Diagnosis of macular edema secondary to RVO: central macular thickness \>310μm due to intraretinal or subretinal edema in the study eye as measured on OCT
* Diagnosis of DME with central macular thickness \>310μm in the study eye as measured on OCT in patients with diabetes mellitus types 1 or 2

Exclusion Criteria:

* • Previous intravitreal drug injections in either eye within 6 months prior to study enrollment

  * Visual acuity worse than counting fingers
  * Patients with other macular pathologies causing structural changes to the retina
  * Patients with large submacular hemorrhages or extensive fibrosis occupying the majority (\>50%) of the lesion
  * Intraocular surgery in the study eye 3 months prior to study enrollment
  * Previous vitreoretinal surgery in the study eye
  * Previous photodynamic or macular photocoagulation therapy within the past 6 months in the study eye in patients with AMD
  * Previous photocoagulation therapy within 6 months in the study eye or anticipated need for during the course of the study in patients with RVO
  * Presence of active proliferative diabetic retinopathy or patients who have had pan-retinal photocoagulation within 6 months or patients where the need to pan-retinal photocoagulation is anticipated during the course of the study in patients with DME
  * History of intraocular inflammation in the study eye
  * Patients on systemic or topical anti-inflammatory or steroids medications
  * Patients receiving dialysis for renal failure
  * Known allergy to the study drug or fluorescein
  * Patients who are pregnant
  * Unwilling or unable to follow or comply with all study related procedures or to sign consent form

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** rajeev.muni@utoronto.ca

**Name:** Rajeev Muni

**Phone:** 416-867-7411

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Name:** Rajeev H Muni, FRCSC

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Canada

**Facility:** Department of Ophthalmology, St Michael's Hospital

**State:** Ontario

**Status:** RECRUITING

**Zip:** M5C 2T2

**Location 2:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Name:** Peter Kertes

- **Role:** CONTACT

**Country:** Canada

**Facility:** Sunnybrook Health Sciences Centre

**Status:** RECRUITING

#### Overall Officials

**Official 1:**

**Affiliation:** Unity Health Toronto

**Name:** Rajeev Muni

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000012162

- Term: Retinal Degeneration

- ID: D000012164

- Term: Retinal Diseases

- ID: D000005128

- Term: Eye Diseases

- ID: D000020246

- Term: Venous Thrombosis

- ID: D000013927

- Term: Thrombosis

- ID: D000016769

- Term: Embolism and Thrombosis

- ID: D000014652

- Term: Vascular Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC11

- Name: Eye Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC14

- Name: Heart and Blood Diseases

### Condition Browse Module - Browse Leaves

- ID: M11261

- Name: Macular Edema

- Relevance: HIGH

- As Found: Macular Edema

- ID: M7657

- Name: Edema

- Relevance: HIGH

- As Found: Edema

- ID: M15005

- Name: Retinal Vein Occlusion

- Relevance: HIGH

- As Found: Retinal Vein Occlusion

- ID: M11260

- Name: Macular Degeneration

- Relevance: HIGH

- As Found: Age-related Macular Degeneration

- ID: M14997

- Name: Retinal Degeneration

- Relevance: LOW

- As Found: Unknown

- ID: M14999

- Name: Retinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8271

- Name: Eye Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M16686

- Name: Thrombosis

- Relevance: LOW

- As Found: Unknown

- ID: M22071

- Name: Venous Thrombosis

- Relevance: LOW

- As Found: Unknown

- ID: M7784

- Name: Embolism

- Relevance: LOW

- As Found: Unknown

- ID: M19128

- Name: Embolism and Thrombosis

- Relevance: LOW

- As Found: Unknown

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008268

- Term: Macular Degeneration

- ID: D000008269

- Term: Macular Edema

- ID: D000012170

- Term: Retinal Vein Occlusion

- ID: D000004487

- Term: Edema

### Intervention Browse Module - Ancestors

- ID: D000020533

- Term: Angiogenesis Inhibitors

- ID: D000043924

- Term: Angiogenesis Modulating Agents

- ID: D000006133

- Term: Growth Substances

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000006131

- Term: Growth Inhibitors

- ID: D000000970

- Term: Antineoplastic Agents

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M257727

- Name: Aflibercept

- Relevance: HIGH

- As Found: Magnetic Resonance Imaging

- ID: M22318

- Name: Angiogenesis Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M9231

- Name: Growth Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000533178

- Term: Aflibercept

### Misc Info Module

- Version Holder: 2024-05-24
