A Study to Investigate Aqueous Humor and Multimodal Imaging Biomarkers in Treatment-Naïve Participants With Diabetic Macular Edema Treated With Faricimab

Study Overview
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Brief Summary
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This is an exploratory, prospective, multicenter, open-label, single-arm, interventional, Phase IIb study designed to explore the associations over time between clinical assessments, multimodal imaging assessments, aqueous humor (AH) biomarker patterns, and genetic polymorphisms in participants with diabetic macular edema (DME) who are treated with faricimab.

Official Title
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An Exploratory, Prospective, Multi-Center, Open-Label, Single-Arm, Interventional, Phase IIB Study to Investigate Aqueous Humor and Multimodal Imaging Biomarkers in Treatment-Naïve Patients With Diabetic Macular Edema Treated With Faricimab (RO6867461) - ALTIMETER STUDY

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Faricimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of diabetes mellitus (Type 1 or Type 2), as defined by the World Health Organization (WHO) and/or American Diabetes Association Hemoglobin A1c (HbA1c) ≤10% Patients who are intravitreal (IVT) treatment-naïve in the study eye Diabetic macular edema (DME) defined as macular thickening by spectral-domain optical coherence tomography (SD-OCT) involving the center of the macula. This inclusion criterion is to be assessed by the central reading center (CRC). Decreased visual acuity (VA) attributable primarily to DME Clear ocular media and adequate pupillary dilation to allow acquisition of good quality retinal images to confirm diagnosis Exclusion Criteria: Currently untreated diabetes mellitus or previously untreated patients who initiated oral or injectable anti-diabetic medication within 3 months prior to Day 1 Any known hypersensitivity to any of the components in the faricimab injection, dilating eye drops, or any of the anesthetics and antimicrobial preparations used by the patient during the study Any major illness or major surgical procedure within 1 month before the Day 1. One re-screening for this criterion is permitted History of other diseases, other non-diabetic metabolic dysfunction, physical examination finding, historical or current clinical laboratory finding giving reasonable suspicion of a condition that contraindicates the use of the faricimab or that might affect interpretation of the results of the study or renders the patient at high-risk for treatment complications, in the opinion of the Investigator Active cancer within the past 12 months prior to Day 1 except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score of ≤6 and a stable prostate-specific antigen for >12 months Stroke or myocardial infarction within 12 months prior to the Day 1. One re-screening for this criterion is permitted Any febrile illness within 1 week prior to Day 1. One re-screening for this criterion is permitted Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of faricimab Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 6 months prior to Day 1 or anticipated to require hemodialysis or peritoneal dialysis at any time during the study Any condition resulting in a compromised immune system that is likely to impact the aqueous humor (AH) inflammatory biomarkers. Patients who are currently enrolled in or have participated in any other clinical study involving an investigational product or device, or in any other type of medical research, within 3 months or 5 half-lives prior to Day 1 and up to completion of the current study Substance abuse occurring within 12 months prior to screening, in the Investigator's judgment Use of systemic immunomodulatory treatments within 6 months or 5 half-lives prior to Day 1 Use of any systemic corticosteroids (including inhaled corticosteroids from inhalers used regularly, e.g., pulmonary disease, asthma, or seasonal allergy) within 1 month prior to Day 1 Any prior or concomitant systemic anti-VEGF treatment within 6 months or 5 half-lives prior to Day 1 Use of systemic medications known to be toxic to the lens, retina or optic nerve used during the 6-month period or 5 half-lives prior to Day 1 or likely need to be used Received a blood transfusion within 3 months prior to the screening visit Received any treatment that leads to immunosuppression within 6 months or 5 half-lives prior to Day 1 Ocular Exclusion Criteria for Study Eye: High-risk PDR. This exclusion criterion is to be assessed by the CRC Any history of or ongoing rubeosis iridis Any panretinal photocoagulation or macular laser photocoagulation treatment received in the study eye prior to the screening visit or expected to be received between the screening visit and Day 1 Any history of treatment with anti-VEGF or any periocular or IVT corticosteroids in the study eye and no such treatment planned for the time between screening and Day 1 Any treatment for dry eye disease in the last month prior to Day 1. Lubricating eye drops and ointments are permitted. Any treatment with anti-inflammatory eye drops within 1 month prior to Day 1 Any intraocular surgery within 3 months prior to Day 1 or any planned surgery during the study Any glaucoma surgery/laser procedure involving the iris, trabecular meshwork, or ciliary body prior to the screening visit. Only iris surgery/laser might be allowed if they occurred more than 6 months prior to Day 1. History of vitreoretinal surgery/pars plana vitrectomy, corneal transplant, or radiotherapy Any active or suspected ocular or periocular infections on Day 1 Any presence of active intraocular inflammation on Day 1 or any history of intraocular inflammation Any history of idiopathic, infectious, or noninfectious uveitis Any current or history of ocular disease other than DME that may confound assessment of the macula or affect central vision Any current ocular condition or other causes of visual impairment for which, in the opinion of the Investigator, VA loss would not improve from resolution of macular edema Ocular Exclusion Criteria for Fellow Eye: Patient is currently receiving treatment with brolucizumab or bevacizumab in the non-study eye and is unwilling to switch to a protocol allowed non-study eye treatment during the study Any previous treatment with Iluvien® or Retisert® in the non-study eye Non-functioning non-study eye

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Faricimab<br>Participants will receive 6 doses (one 6 mg faricimab intravitreal [IVT] injection every 28 days [Q4W]) starting at Day 1 and ending on the Day 140 visit. Participants will return for a safety follow-up visit (SFV) after ≥28 days and within <35 days following their last study treatment. | Drug: Faricimab<br>* A 6-milligram (mg) dose of faricimab will be administered intravitreally (IVT) in the study eye once every 4 weeks (Q4W).<br>* Other names: RG7716;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a ≥2-Step Improvement From Baseline on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) in the Study Eye at Week 24 | The ETDRS DRSS score of each participant's study eye was assessed using ultra-wide field color fundus photography (UWF-CFP) taken by trained personnel at the study sites. Analysis of the fundus photographs was performed by the central reading center, and the percentage of participants with a ≥2-step improvement from baseline was summarized along with a two-sided 95% Clopper-Pearson exact confidence interval. Baseline was defined as the participant's last observation prior to initiation of study drug. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Best-Corrected Visual Acuity (BCVA) in the Study Eye at Week 24 | Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. For the Mixed Model for Repeated Measures (MMRM) analysis, the model adjusted for visit, age (continuous), baseline BCVA (continuous), and region (US and Canada and the rest of the world). An unstructured covariance structure was used. In case of convergence issues with the model, an AR (1) covariance structure was used. Treatment policy strategy (i.e., all observed values used) and hypothetical strategy (i.e., all values censored after the occurrence of the intercurrent event) were applied to non-COVID-19 related and COVID-19 related intercurrent events, respectively. Missing data were implicitly imputed by MMRM. | From Baseline to Week 24 | 
| Adjusted Mean Change From Baseline in Central Subfield Thickness in the Study Eye at Week 24 | Central subfield thickness (CST) was defined as the distance between the internal limiting membrane (ILM) and the retinal pigment epithelium (RPE) using Spectral Domain-Optical Coherence Tomography (SD-OCT), as assessed by the central reading center. For the Mixed Model of Repeated Measures (MMRM) analysis, the model was adjusted for visit, age (continuous), baseline CST (continuous), and region (US and Canada and the rest of the world). An unstructured covariance structure was used. In case of convergence issues with the model, an AR (1) covariance structure was used. Treatment policy strategy (i.e., all observed values used) and hypothetical strategy (i.e., all values censored after the occurrence of the intercurrent event) were applied to non-COVID-19 related and COVID-19 related intercurrent events, respectively. Missing data were implicitly imputed by MMRM. | From Baseline to Week 24 | 
| Median Time to First Absence of DME in the Study Eye During the Study | An event was defined as the first absence of diabetic macular edema (DME) in the study eye, defined as first time reaching central subfield thickness (CST; ILM-RPE) <305 microns, after baseline. Baseline was defined as the participant's last observation prior to initiation of study drug. The time to first absence of DME was a Kaplan-Meier estimate. The 95% confidence interval (CI) for the median was computed using the method of Brookmeyer and Crowley. Participants without an event and discontinued from treatment were censored at the last CST assessment. | From Baseline to Week 24 | 
| Percentage of Participants With Absence of Intraretinal Fluid in the Study Eye at Week 24 | The absence of intraretinal fluid (IRF) in the study eye (defined as IRF absent or definite outside center subfield only) was assessed by the central reading center using Spectral Domain-Optical Coherence Tomography (SD-OCT). The percentage of participants with absence of IRF and a two-sided 95% Clopper-Pearson exact confidence interval are reported. | Week 24 | 
| Percentage of Participants With Absence of Subretinal Fluid in the Study Eye at Week 24 | The absence of subretinal fluid (SRF) in the study eye (defined as SRF absent or definite outside center subfield only) was assessed by the central reading center using Spectral Domain-Optical Coherence Tomography (SD-OCT). The percentage of participants with absence of SRF and a two-sided 95% Clopper-Pearson exact confidence interval are reported. | Week 24 |