Pharmacy and Poisons Board
Protocol No: ECCT/21/06/09 Date of Protocol: 08-07-2020
Study Title:

A Phase II, multicenter, randomized, open label two arm study comparing the effect of crizanlizumab + standard of care to standard of care alone on renal function in sickle cell disease patients ≥ 16 years with chronic kidney disease due to sickle cell nephropathy (STEADFAST)
Study Objectives:

Primary objective:

  • To evaluate the effect of crizanlizumab +standard of care compared to standard of carealone on albuminuria (ACR) decrease at 12 months

Secondary objective(s)

  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on change in albuminuria (ACR)
  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on albuminuria (ACR) decrease at
    6 months.
  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on protein to creatinine ratio (PCR) at
    12 months.
  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on the percentage change in eGFR
  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on ACR decline rate.
  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on eGFR decline rate.
  • To evaluate the effect of crizanlizumab + standard of care compared to standard of care alone on the progression of CKD at 12 months.
  • To evaluate overall safety and, tolerability of crizanlizumab + standard of care compared to standard of care alone.
  • To assess the immunogenicity of crizanlizumab over the study period (treatment of 1 year + 105 days of follow-up)
  • To evaluate healthcare resource utilization (visits to emergency room [ER] and hospitalizations) in crizanlizumab + standard of
    care arm compared to standard of care alone
Exploratory objective(s):
  • To assess the effect of crizanlizumab + standard of care compared to standard of care alone on cardiac function, and pulmonary
    hypertension at 12 months.
  • To assess the effect of crizanlizumab + standard of care compared to standard of care alone on selected biomarkers.
  • To assess renal blood flow in a subset of patients treated with crizanlizumab + standard of care versus standard of care alone.
  • To evaluate patient reported outcomes (PROs) using the 36-item Short Form Health Survey Version 2 (SF-36v2) 4-week recall questionnaire in patients treated with crizanlizumab + standard of care versus standard of care alone

 
Laymans Summary:

This is a multicenter, randomized two arm, open label study to compare the effect of crizanlizumab + standard of care to standard of care alone on renal function in SCD patients with CKD due to sickle cell nephropathy (SCN).
Abstract of Study:

This is a multicenter, randomized two arm, open label study to compare the effect of crizanlizumab + standard of care to standard of care alone on renal function in sickle cell disease (SCD )patients with chronic kidney disease (CKD) due to sickle cell nephropathy (SCN).

Sickle cell disease (SCD) is a rare autosomal recessive blood disorder caused by a single missense mutation (Glu6Val) in the β-globin gene. Mutation in the β-globin gene renders the mutant Hb less soluble and prone to polymerization upon deoxygenation. This deforms red-blood cells leading to formation of sickle shaped RBC's that often results in haemolysis, anemia and vaso-oclussion. In SCD, sickle RBCs, leukocytes,platelets, and the endothelium are activated due to the chronic pro-inflammatory state. This  process is mediated by P-selectin a component of the innate immune system. P-selectin is beneficial to the body, however when activation of these cells occurs unnecessarily or is excessive, P-selectin-mediated cell-cell interactions can cause a cascade of events culminatingin disease. The presence of P-selectin expression in the kidneys has been established based on in vitro and in vivo data, and there is evidence that P-selectin is upregulated in the kidney in response to renal ischemia-reperfusion injury in SCD

The study seeks to explore the effect of P-selectin inhibition with crizanlizumab on renal function in sickle cell disease (SCD) patients with chronic kidney disease (CKD) who are receiving standard of care medications for SCD and/or CKD, have albuminuria and Stage 1-3a CKD, and have  evidence of a rapid decline in their estimated glomerular filtration rate (eGFR).The hypothesis is that administration of crizanlizumab, a P-selectin inhibitor, might have a beneficial effect in SCD patients with CKD by blocking P-selectin mediated multicellular adhesion (including leukocytes), and proteinuria, and also reducing vaso-occlusion and potentially its downstream effects in the renal vasculature, which can be clinically demonstrated by a decrease in proteinuria and slowing the decline in glomerular filtration rate (GFR