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

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)

The goal of the study was 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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease (SCD)
• Intervention / Treatment: Drug: Crizanlizuamb; Drug: Standard of Care

Detailed Description

Approximately 50 patients were to be randomized 1:1 to receive either crizanlizumab (5 mg/kg) + standard of care or standard of care alone. Patients were stratified at randomization based on chronic kidney disease (CKD) risk category (moderate risk or high/very high risk) and hydroxyurea/hydroxycarbamide (HU/HC) prescription (Yes/No). The CKD risk categories used for stratification were based on both Estimated glomerular filtration rate(eGFR) and albuminuria assessed by Albumin/creatinine ratio (ACR).

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil, 90035-003
    • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20.211-030
      • Novartis Investigative Site
  • SP
    • São Paulo, SP, Brazil, 01232-010
      • Novartis Investigative Site
• France
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Paris 15, France, 75015
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Larisa, Greece, 41221
    • Novartis Investigative Site
• Ireland
  • Dublin 8, Ireland, DO8
    • Novartis Investigative Site
• Lebanon
  • Tripoli, Lebanon, 1434
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
• Panama
  • Panama, Panama, 0801
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Adana, Turkey, 01250
    • Novartis Investigative Site
  • Antakya / Hatay, Turkey, 31100
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
  • London, United Kingdom, W12 0HS
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama Birmingham
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Hospital and Health Sciences System .
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Our Lady of the Lake Regional Medic .
  • North Carolina
    • Greenville, North Carolina, United States, 27858
      • East Carolina University BrodySchool of Med 3
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • Univ of Tenn Health Sciences Ctr
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: crizanlizumab + standard of care; 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; 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; Other Names: SEG101; Drug: Standard of Care; HU/HC (hydroxyurea/hydroxycarbamide) and/or ACE (angiotensin-converting enzyme) inhibitors and/or ARBs (angiotensin-receptor blocker)
Active Comparator: standard of care; Patients in the standard of care alone arm will continue to receive their usual standard of care treatment.	Drug: Standard of Care; HU/HC (hydroxyurea/hydroxycarbamide) and/or ACE (angiotensin-converting enzyme) inhibitors and/or ARBs (angiotensin-receptor blocker)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With ≥ 30% Decrease in Albuminuria (ACR) at 12 Months	The effect of SEG101 on clinical disease activity was measured by at least 30% decrease in Albumin to Creatinine Ratio (ACR) from baseline to month 12. A reduction from baseline indicates improvement in patients.	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	The effect of SEG101 on clinical disease activity was measured by the change in albuminuria (ACR) between baseline and month 3, baseline and month 6, baseline and month 9, baseline and month 12. A reduction from baseline indicates improvement in patients.	Baseline to 3, 6, 9, and 12 months
Percentage of Participants With ≥ 30% Decrease in Albuminuria (ACR) at 6 Months	The effect of SEG101 on clinical disease activity was measured by at least 30% decrease in Albumin to Creatinine Ratio (ACR) from baseline to month 6. A reduction from baseline indicates improvement in patients.	Baseline to 6 months
Percentage of Participants With Protein/Creatinine Ratio (PCR) Improvement and Stable PCR at 12 Months	The effect of SEG101 on clinical disease activity was measured by counting patients who had Stable PCR: within ± 20% change from baseline to month 12. PCR improvement: ≥ 20% decrease in PCR from baseline indicates improvement in patients.	Baseline to 12 months
Percentage Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)	The percentage change in eGFR was calculated as the post-baseline eGFR value minus the baseline eGFR divided by the eGFR at baseline. A reduction from baseline indicates improvement in participants.	Baseline to 3, 6, 9, and 12 months
Slope of Albumin to Creatinine Ratio (ACR) Decline	The effect of SEG101 on clinical disease activity was measured by the slope of ACR decline between baseline and Month 12. A reduction from baseline indicates improvement in patients.	Baseline to 12 months
Slope of Estimated Glomerular Filtration Rate (eGFR) Decline	The effect of SEG101 on clinical disease activity was measured by the slope of eGFR between baseline and Month 12. The calculation of eGFR is based on the chronic kidney disease epidemiology collaboration (CKD-EPI) (for patients ≥ 18) and Creatinine-based "Bedside Schwartz" (for patients < 18) equations. A reduction in drop rate from baseline indicates improvement in patients.	Baseline to 12 months
Percentage of Participants With Progression of Chronic Kidney Disease (CKD) at 12 Months	The effect of SEG101 on clinical disease activity was measured by percentage of participants with CKD progression between baseline and Month 12. A reduction from baseline indicates improvement in participants. CKD progression is defined as an increase in CKD progression category, a 25% or greater drop in eGFR from baseline or at least 50% increase in ACR for patients with severe (A3) albuminuria and a doubling of albumin levels in patients with moderate (A2) albuminuria.	Baseline to 12 months
Shift Table for Chronic Kidney Disease (CKD) Progression	The effect of SEG101 on clinical disease activity was measured by percentage of participants with CKD progression between baseline and Month 12. A reduction from baseline indicates improvement in patients.	Baseline and month 12
Immunogenicity: Percentage of Participants With Anti-drug Antibodies (ADA) to Crizanlizumab	The effect of SEG101 on clinical disease activity was measured by percentage of participants shifted to different worst post-baseline categories between baseline and Month 12. An increase in percentage shifting from higher category to lower category indicates improvement in patients. Baseline is defined as the last non-missing value prior to the first dose.	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	The effect of SEG101 on clinical disease activity was measured by summarizing the annualized rate of visits to ER and hospitalizations between baseline and 1 year 4 months. Annualized rate of hospitalizations and ER visits due to VOC =(Number of ER or hospitalizations reported until End date x 365.25)/(End date-date of first dose of study treatment+1). A reduction from baseline indicates improvement in patients.	Baseline to follow-up period (at select time points), assessed up to approximately 1 year and 4 months
Mean Serum Concentration (Ctrough) of Crizanlizumab	The effect of SEG101 on clinical disease activity was measured by checking the concentration of the Drug in serum at different time points. Crizanlizumab pre-dose/trough pharmacokinetic samples were taken at select time points.	Pre-dose and 336 hours post-dose on Week 3 Day 1; pre-dose and 672 hours post dose on Week 11 Day 1, Week 23 Day 1 and Week 39 Day 1; and 672 hours post dose on Week 53 Day 1

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Actual): March 20, 2023
• Study Completion (Actual): March 20, 2023

Study Registration Dates

• First Submitted: August 9, 2019
• First Submitted That Met QC Criteria: August 9, 2019
• First Posted (Actual): August 12, 2019

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: chronic kidney disease; CKD; Sickle Cell Disease; SCD; SEG101; renal function; Crizanlizumab; standard of care; Sickle cell nephropathy; albuminuria (ACR)
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Hematologic Diseases; Renal Insufficiency; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Anemia, Sickle Cell
• Other Study ID Numbers: CSEG101A2203; 2018-003608-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No