Combined Dose-Finding and CV Outcomes Study With CSL300 (Clazakizumab) in Adult Subjects With ESKD Undergoing Dialysis

Study Overview
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Brief Summary
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This is a 2-part (phase 2b/3) prospective, interventional, multicenter, randomized, double blind, placebo controlled study. Part 1 (phase 2b) is a dose-finding study for CSL300 vs placebo. Part 2 (phase 3) aims to assess the efficacy of CSL300 on CV outcomes and safety in subjects with ASCVD or diabetes mellitus and evidence of systemic inflammation who are undergoing maintenance dialysis.

Official Title
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A Phase 2b/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Combined Dose-Finding and Cardiovascular Outcome Study to Investigate the Efficacy and Safety of CSL300 (Clazakizumab) in Subjects With End Stage Kidney Disease Undergoing Dialysis

Conditions
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Atherosclerotic Cardiovascular Disease, End Stage Kidney Disease

Intervention / Treatment
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* Drug: CSL300
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female at least 18 years of age A diagnosis of ESKD undergoing maintenance dialysis for at least 12 weeks Serum hs-CRP ≥ 2.0 mg/L A diagnosis of diabetes mellitus OR ASCVD Exclusion Criteria: Subjects who participated in Part 1 (phase 2b) are not eligible to participate in Part 2 (phase 3) Concomitant use of systemic immunosuppressant drugs Abnormal LFTs Any life-threatening disease expected to result in death within 12 months A history of GI perforation, inflammatory bowel disease (except fully excised ulcerative colitis), or peptic ulcer disease

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL300 (low dose)(Phase 2b)<br>Intravenous (IV) administration | Drug: CSL300<br>* Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6<br>* Other names: Clazakizumab;|
| Experimental: CSL300 (medium dose)(Phase 2b)<br>IV administration | Drug: CSL300<br>* Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6<br>* Other names: Clazakizumab;|
| Experimental: CSL300 (high dose)(Phase 2b)<br>IV administration | Drug: CSL300<br>* Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6<br>* Other names: Clazakizumab;|
| Placebo Comparator: Placebo (Phase 2b)<br>IV administration | Drug: Placebo<br>* 0.9% w/v NaCl<br>|
| Experimental: CSL300 (Phase 3)<br>IV administration | Drug: CSL300<br>* Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6<br>* Other names: Clazakizumab;|
| Placebo Comparator: Placebo (Phase 3)<br>IV administration | Drug: Placebo<br>* Part 2 (Phase 3): Matching the excipient content and concentration of the CSL300 product, minus the active ingredient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on the log scale in high-sensitivity C-reactive protein (hs-CRP)(Phase 2b) |  | Up to 12 weeks | 
| Time to first occurrence of CV death or MI (Phase 3) |  | Approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of subjects achieving hs-CRP < 2.0 mg/L (Phase 2b) |  | Week 12 | 
| Change from baseline in log-transformed hs-CRP (Phase 2b) |  | Up to 24 weeks | 
| Mean change from Baseline in SAA (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in sPLA2 (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in fibrinogen (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in PAI-1 (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in Lp (a) (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in Hepcidin (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in hemoglobin (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in ESA (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in ERI (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in iron (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in TIBC (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in TSAT (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in ferritin (Phase 2b) |  | Up to 12 weeks | 
| Area under the plasma concentration versus time curve (AUC) for CSL300 (Phase 2b) |  | Up to 24 weeks | 
| Peak Plasma Concentration (Cmax) for CSL300 (Phase 2b) |  | Up to 24 weeks | 
| Trough Plasma Concentration (Ctrough) for CSL300 (Phase 2b) |  | Up to 24 weeks | 
| Time to Maximum Plasma Concentration (Tmax) for CSL300 (Phase 2b) |  | Up to 24 weeks | 
| Percent of subjects with AE, SAE, including AESIs (Phase 2b) |  | Up to 32 weeks | 
| Mean change from Baseline in WBC (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in neutrophils (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in platelets (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in AST (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in ALT (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in total bilirubin (Phase 2b) |  | Up to 12 weeks | 
| Mean change from Baseline in lipid panel (Phase 2b) | Lipid panel consists of TC, LDL-C, HDL-C, triglyceride | Up to 12 weeks | 
| Titer of confirmed antibodies specific to CSL300 (Phase 2b) |  | Up to 12 weeks | 
| Time to first occurrence of all-cause death or MI (Phase 3) |  | Approximately 5 years | 
| Time to first occurrence of CV death, MI, or ischemic stroke (Phase 3) |  | Approximately 5 years | 
| Time to first occurrence of CV death (Phase 3) |  | Approximately 5 years | 
| Time to first occurrence of CV death, MI or major adverse limb event (Phase 3) |  | Approximately 5 years | 
| Time to first occurrence of all-cause death (Phase 3) |  | Approximately 5 years | 
| Time to first occurrence of CV death, MI, or hospitalization for heart failure (Phase 3) |  | Approximately 5 years | 
| Total number of CV hospitalizations (Phase 3) |  | Approximately 5 years | 
| Total number of HF hospitalizations and urgent visits (Phase 3) |  | Approximately 5 years | 
| Total number of hospitalizations (Phase 3) |  | Approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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End Stage Kidney Disease (ESKD), Myocardial infarction (MI), Atherosclerotic cardiovascular disease (ASCVD), Coronary artery disease, Peripheral artery disease, Diabetes