Study Exploring the Effect of Crizanlizumab on Kidney Function in Patients With Chronic Kidney Disease Caused by Sickle Cell Disease

Study Overview
=================
Brief Summary
-----------------
The goal of the study is to evaluate descriptively the effect of crizanlizumab + standard of care and standard of care alone on renal function in sickle cell disease patients ≥ 16 years with chronic kidney disease due to sickle cell nephropathy.

Official Title
-----------------
A Phase II, Multicenter, Randomized, Open Label Two Arm Study Evaluating the Effect of Crizanlizumab + Standard of Care and Standard of Care Alone on Renal Function in Sickle Cell Disease Patients ≥ 16 Years With Chronic Kidney Disease Due to Sickle Cell Nephropathy (STEADFAST)

Conditions
-----------------
Sickle Cell Disease (SCD)

Intervention / Treatment
-----------------
* Drug: Crizanlizuamb
* Drug: Standard of Care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of SCD (HbSS and HbSβ0-thal SCD genotypes are eligible) Patients with eGFR ≥ 45 to ≤ 140 mL/min/1.73 m2 based on CKD EPI formula (patients ≥ 18) or the Creatinine-based Bedside Schwartz equation (patients < 18) Patients with ACR of ≥ 100 to < 2000 mg/g (taken as an average of the three screening ACR values to determine eligibility) Receiving at least 1 standard of care drug(s) for SCD-related CKD: If receiving HU/HC, the patient must have been receiving HU/HC for at least 6 months and on a stable dose for 3 months, and/or an ACE inhibitor and/or ARB for 3 months and on a stable dose for those 3 months. Hb ≥ 4.0 g/dL, absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L, and platelet count ≥ 75 x 10^9/L Adequate hepatic function as defined by: Alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN) Direct (conjugated) bilirubin ≤ 3.0 x ULN Written informed consent (or assent/ parental consent for minor subjects) prior to any screening procedures Exclusion Criteria: History of stem cell transplant Patients with evidence of AKI within 3 months of study entry (can decrease interval to within 6 weeks of study entry only if renal function has returned to pre-AKI values prior to study entry) Blood pressure > 140/90 mmHg despite treatment Patients undergoing renal replacement therapy (ie. hemodialysis, peritoneal dialysis, hemofiltration and kidney transplantation) Received blood products within 30 days of Week 1 Day 1 Participating in a chronic transfusion program History of kidney transplant Patients with hypoalbuminemia Body mass index of ≥ 35 Currently receiving or received voxelotor within 6 months of screening Patient has received crizanlizumab and/or other selectin inhibitor or plans to receive it during the duration of the study. Other protocol-defined inclusion/exclusion criteria may apply

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: crizanlizumab + standard of care<br>5 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment. | Drug: Crizanlizuamb<br>* Crizanlizumab is a concentrate for solution for infusion, i.v. use. Supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab<br>* Other names: SEG101;Drug: Standard of Care<br>* HU/HC (hydroxyurea/hydroxycarbamide) and/or ACE (angiotensin-converting enzyme) inhibitors and/or ARBs (angiotensin-receptor blocker)<br>|
| Active Comparator: standard of care<br>Patients in the standard of care alone arm will continue to receive their usual standard of care treatment. | Drug: Standard of Care<br>* HU/HC (hydroxyurea/hydroxycarbamide) and/or ACE (angiotensin-converting enzyme) inhibitors and/or ARBs (angiotensin-receptor blocker)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with ≥ 30% decrease in albuminuria (ACR) at 12 months | Percentage of patients with ≥ 30% decrease in ACR at 12 months from baseline. | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in albuminuria (ACR) at 3, 6, 9 and 12 months | Change in ACR from baseline to 3, 6, 9, and 12 months of treatment. | Baseline to 3, 6, 9, and 12 months | 
| Percentage of patients with ≥ 30% decrease in albuminuria (ACR) at 6 months | Percentage of patients with ≥ 30% decrease in ACR at 6 months from baseline | Baseline to 6 months | 
| Percentage of patients with protein to creatinine ratio (PCR) improvement at 12 months | Percentage of patients with PCR improvement at 12 months from baseline. Improvement: ≥ 20% decrease in PCR from baseline | Baseline to 12 months | 
| Percentage of patients with a stable protein to creatinine ratio (PCR) at 12 months | Percentage of patients with stable PCR at 12 months from baseline. Stable: within ± 20% change in PCR from baseline | Baseline to 12 months | 
| Percentage change in estimated glomerular filtration rate (eGFR) | Percentage change in eGFR from baseline to 3, 6, 9, and 12 months of treatment. The percentage change in eGFR is calculated as the post-baseline eGFR value minus the baseline eGFR divided by the eGFR at baseline. | Baseline to 3, 6, 9, and 12 months | 
| Slope of albumin to creatinine ratio (ACR) decline | Slope of ACR decline from baseline to 12 months of treatment based on ACR values at baseline and at 3, 6, 9, and 12 months. The slope of ACR decline will be estimated as a random coefficient in a linear mixed effect model: the model will be fitted to ACR data collected at baseline and at Months 3, 6, 9, and 12. | Baseline to 3, 6, 9, and 12 months | 
| Slope of estimated glomerular filtration rate (eGFR) decline | Slope of eGFR decline from baseline to 12 months of treatment based on eGFR values at baseline and at 3, 6, 9, and 12 months. The slope of eGFR decline will be estimated as a random coefficient in a linear mixed effect model: the model will be fitted to eGFR data collected at baseline and at Months 3, 6, 9, and 12. | Baseline to 3, 6, 9, and 12 months | 
| Percentage of patients with progression of chronic kidney disease (CKD) at 12 months | Percentage of patients with progression of CKD from baseline to 12 months | Baseline to 12 months | 
| Immunogenicity: Levels of anti-drug antibodies (ADA) to crizanlizumab. | Levels of ADA to crizanlizumab at select time points | Baseline to follow-up period (at select time points), assessed up to approximately 1 year and 4 months | 
| Annualized rate of visits to emergency room (ER) and hospitalizations | Annualized rate of visits to ER and hospitalizations due to Acute Kidney Injury (AKI) events, Vaso-occlusive crisis (VOCs), or other Sickle Cell Disease (SCD) complications. | Baseline to follow-up period (at select time points), assessed up to approximately 1 year and 4 months | 
| Trough serum concentration (Ctrough) of crizanlizumab | Crizanlizumab pre-dose/trough pharmacokinetic samples will be taken at select time points | Baseline to follow-up period (at select time points), assessed up to approximately 1 year and 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SCD, SEG101, Crizanlizumab, Sickle cell nephropathy, chronic kidney disease, CKD, albuminuria (ACR), renal function, standard of care