Vascular Endothelial Growth Factor-B (VEGF-B) Blockade With the Monoclonal Antibody CSL346 in Subjects With Diabetic Kidney Disease

Study Overview
=================
Brief Summary
-----------------
This phase 2a, double-blind, randomized, placebo-controlled study will assess the efficacy, safety, tolerability, and pharmacokinetics (PK), of repeat doses of CSL346 in subjects with diabetic kidney disease (DKD) and albuminuria receiving standard of care treatment.

Official Title
-----------------
A Phase 2a, Double-blind, Randomized, Placebo-controlled, Proof of Concept Study of Vascular Endothelial Growth Factor (VEGF)-B Blockade With the Monoclonal Antibody CSL346 in Subjects With Diabetic Kidney Disease

Conditions
-----------------
Diabetic Kidney Disease (DKD)

Intervention / Treatment
-----------------
* Biological: CSL346
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects ≥ 25 years of age with a diagnosis of type 2 diabetes mellitus (T2DM) Urinary ACR ≥ 150 mg/g eGFR > 20 mL/min/1.73m2 Glycosylated HbA1c < 12% Exclusion Criteria: Current diagnosis of type 1 diabetes mellitus History of acute kidney injury or chronic dialysis/renal transplant Uncontrolled hypertension or class III / IV heart failure Left ventricular ejection fraction < 50% by echocardiogram Troponin-I > the upper reference limit b-type natriuretic peptide > 200 pg/mL ALT > 2x the upper limit of normal

Ages Eligible for Study
-----------------
Minimum Age: 25 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: CSL346 (low dose)<br>Administered as a single intravenous (IV) loading dose followed by subcutaneous (SC) infusions | Biological: CSL346<br>* VEGF-B antagonist monoclonal antibody<br>|
| Experimental: CSL346 (high dose)<br>Administered as a single intravenous (IV) loading dose followed by subcutaneous (SC) infusions | Biological: CSL346<br>* VEGF-B antagonist monoclonal antibody<br>|
| Placebo Comparator: Placebo<br>Administered as a single IV loading dose followed by SC infusions | Drug: Placebo<br>* Normal saline<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Urinary Albumin-to-creatinine Ratio (ACR) | Data are presented as the geometric mean (GM) of percent change, which is calculated as the geometric mean of the Week 16 ACR to baseline, expressed as percent change from baseline. | Baseline up to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) |  | Up to 24 weeks | 
| Percentage of Subjects With TEAEs |  | Up to 24 weeks | 
| Number of Subjects With Adverse Events of Special Interest (AESIs) | Data are presented for treatment-emergent AESIs. | Up to 24 weeks | 
| Percentage of Subjects With AESIs | Data are presented for treatment-emergent AESIs. | Up to 24 weeks | 
| Observed Value and Mean Change From Baseline in Serum Creatinine |  | Baseline up to 24 weeks | 
| Observed Value and Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) |  | Baseline up to 24 weeks | 
| Observed Value and Mean Change From Baseline in Systolic Blood Pressure |  | Baseline up to 24 weeks | 
| Observed Value and Mean Change From Baseline in Diastolic Blood Pressure |  | Baseline up to 24 weeks | 
| Maximum Concentration (Cmax) After Intravenous (IV) Loading Dose of CSL346 in Serum Samples |  | Up to 120 minutes after the IV loading dose for CSL346 | 
| Time to Reach Cmax in Serum (Tmax) After IV Loading Dose of CSL346 in Serum Samples |  | Up to 120 minutes after the IV loading dose for CSL346 | 
| Cmax After First Subcutaneous (SC) Dose of CSL346 in Serum Samples |  | From Day 1 to Day 29 | 
| Tmax After First SC Dose of CSL346 in Serum Samples |  | From Day 1 to Day 29 | 
| Area Under the Concentration-time Curve in First Dosing Interval |  | From Day 1 to Day 29 | 
| Trough Concentration After Each Dose |  | 29 days after each dose | 
| Number of Subjects Positive for Anti-drug Antibodies | Data are presented for participants who received treatment with CSL346. Any anti-drug antibodies detected in participants who received treatment with Placebo were considered not specific to CSL346 and of no clinical relevance. | Weeks 4, 8, and 16 | 
| Percentage of Subjects Positive for Anti-drug Antibodies | Data are presented for participants who received treatment with CSL346. Any anti-drug antibodies detected in participants who received treatment with Placebo were considered not specific to CSL346 and of no clinical relevance. | Weeks 4, 8, and 16 |