To the Editor,
1.
Sickle cell nephropathy (SCN) represents one of the most serious chronic complications of sickle cell disease (SCD), contributing substantially to morbidity and premature mortality [1, 2]. SCN manifests as hyperfiltration, albuminuria, and progressive loss of kidney function [3], with an estimated 12% of adults with SCD progressing to end‐stage kidney disease (ESKD) over 10 years [4, 5, 6]. Albuminuria, especially urine albumin‐to‐creatinine ratio (ACR) ≥ 100 mg/g, is among the strongest predictors of rapid estimated glomerular filtration rate (eGFR) decline and future kidney failure [7, 8, 9, 10]. Despite this burden, no therapies are approved specifically for SCN. The recommended standard of care (SoC) includes use of angiotensin‐converting enzyme (ACE) inhibitors or angiotensin‐receptor blockers (ARBs) and/or hydroxyurea/hydroxycarbamide (HU/HC), although the supporting evidence is modest, largely from small or short‐term studies not powered for renal outcomes [11, 12, 13]. This underscores the need to evaluate new therapeutic strategies that target the mechanisms driving SCN progression.
P‐selectin mediates vaso‐occlusion by promoting interactions among sickled erythrocytes, leukocytes, and activated endothelium [14]. In preclinical studies, P‐selectin is upregulated after kidney ischemia–reperfusion injury, and blockade reduces neutrophil infiltration and glomerular injury [14, 15, 16]. Crizanlizumab, a humanized anti‐P‐selectin monoclonal antibody, reduced annualized vaso‐occlusive crises (VOCs) in the Phase 2 SUSTAIN trial and was initially approved to reduce VOC frequency in SCD [17, 18]. However, its role in mitigating kidney injury due to SCD has not been evaluated in a dedicated clinical trial.
We report STEADFAST, a multicenter, open‐label, randomized Phase 2 trial (NCT04053764) evaluating crizanlizumab plus SoC versus SoC alone for kidney outcomes in patients with SCN at moderate‐to‐very high risk of CKD progression.
Patients aged ≥ 16 years with confirmed HbSS or HbSβ0 thalassemia (six HbSβ+ genotype patients were enrolled in protocol deviations) were eligible if they had: eGFR 45–140 mL/min/1.73 m2 and ACR ≥ 100 and < 2000 mg/g, on stable SoC (ACE inhibitor and/or ARB ≥ 3 months and/or HU/HC ≥ 6 months). Patients with recent acute kidney injury, kidney replacement therapy, uncontrolled hypertension, or recent voxelotor use were excluded. Patients were stratified by CKD risk category (moderate vs. high/very high, based on ACR and eGFR Table S1) and HU/HC use, and randomized 1:1 to crizanlizumab 5 mg/kg intravenously (Weeks 1 and 3, then every 4 weeks for 12 months) plus SoC, or SoC alone (Figure 1).
FIGURE 1.
Schematic design of the STEADFAST trial. IV = intravenous; N = number; R = randomization; SCD = sickle cell disease; SoC = standard of care.
The primary endpoint was the proportion of patients achieving ≥ 30% reduction in urine ACR at Month 12. Secondary endpoints included changes in ACR and eGFR over time, protein‐to‐creatinine ratio (PCR) response, CKD progression (defined by ≥ 25% eGFR decline and ACR increase), and annualized rates of VOC‐related emergency room (ER) visits and hospitalizations. Exploratory endpoints assessed changes in biomarker levels and improvements in health‐related quality of life (HRQoL). Safety was assessed using CTCAE v5.0.
The trial planned to enroll 170 patients but ended early due to recruitment challenges and a high screen‐failure rate, limiting power to detect between‐arm differences. The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization (ITT). The Safety Set included all patients who received at least one dose of study treatment.
Of 121 screened patients, 58 were randomized to crizanlizumab plus SoC (n = 30) or SoC alone (n = 28). The most frequent reasons for screen failure were ACR or eGFR outside the protocol‐specified ranges. Overall, 57 patients received study treatment and 45 completed the 12‐month treatment period (Figure S1).
The mean age of study participants was 41.5 years and 63.8% were female (Table S1). Most patients had severe genotypes (HbSS or HbSβ0 in 82.7%) and had experienced 0–2 VOCs in the prior year; 77.6% were on HU/HC at baseline. Baseline mean ACR was 528.3 mg/g and mean eGFR was 104.3 mL/min/1.73 m2. Based on the risk of CKD progression, moderate‐risk patients were 36.7% in the crizanlizumab arm and 53.6% in the SoC arm, and high/very high‐risk patients were 50.0% and 32.1%, respectively. The mean ACR was higher in the crizanlizumab arm compared with the SoC arm (565.9 vs. 489.4 mg/g), while the mean eGFR was similar between arms.
At Month 12, a ≥ 30% reduction in ACR from baseline was achieved by 10/30 (33.3%) patients in the crizanlizumab arm and 6/28 (21.4%) in the SoC arm (odds ratio [OR] 1.94; 95% confidence interval [CI], 0.53–7.14). The absolute difference in proportions was 12% (95% CI, −11% to 35%). Given the small sample size and wide CI, this result should be interpreted as a favorable trend rather than evidence of a definitive treatment effect (Table 1).
TABLE 1.
Efficacy endpoints.
| Efficacy endpoints | Crizanlizumab 5.0 mg/kg + SoC (N = 30) | SoC (N = 28) |
|---|---|---|
| Primary efficacy endpoint | ||
| Proportion of patients with ≥ 30% decrease in ACR at 12 months, n (%) | 10 (33.3) | 6 (21.4) |
| Odds ratio (95% CI) a | 1.94 (0.53, 7.14) | |
| Difference in proportion (95% CI) | 0.12 (−0.11, 0.35) | |
| Secondary efficacy endpoints | ||
| Proportion of patients with ≥ 30% decrease in ACR at 6 months, n (%) | 9 (30.0) | 10 (35.7) |
| Odds ratio (95% CI) a | 0.73 (0.23, 2.31) | |
| Difference in proportion (95% CI) | −0.06 (−0.30, 0.18) | |
| Proportion of patients with PCR improvement at 12 months, n (%) b | 10 (33.3) | 10 (35.7) |
| Odds ratio (95% CI) a | 0.94 (0.29, 3.02) | |
| Difference in proportion (95% CI) | −0.02 (−0.27, 0.22) | |
| Proportion of patients with stable PCR at 12 months, n (%) b | 5 (16.7) | 7 (25.0) |
| Odds ratio (95% CI) | 0.75 (0.18, 3.20) | |
| Difference in proportion (95% CI) | −0.08 (−0.29, 0.13) | |
| Proportion of patients with CKD progression at 12 months c | 4 (13.3) | 9 (32.1) |
| Odds ratio (95% CI) a | 0.32 (0.09, 1.21) | |
| Difference in proportion (95% CI) | −0.19 (−0.40, 0.02) | |
Note: N is the total number of patients in the treatment group. It is the denominator for percentage (%) calculation. n, number of patients who are at the corresponding category.
Abbreviations: ACR, albumin‐to‐creatinine ratio; CI, confidence interval; PCR, protein‐to‐creatinine ratio; SoC, standard of care.
The odds ratio is obtained by a logistic regression model including stratification factors HU/HC usage and CKD risk category (as per IRT). 95% CI of the difference is based on an asymptotic method.
PCR improvement is defined as ≥ 20% decrease in PCR from baseline. Stable PCR is defined as PCR within ±20% change from baseline.
CKD progression is defined as (1) an increase in CKD progression category, (2) a 25% or greater drop in eGFR from baseline, or (3) at least a 50% increase in ACR for patients with severe (A3) albuminuria and a doubling of albumin levels in patients with moderate (A2) albuminuria.
Changes in ACR and eGFR (Figure S2a,b) showed favorable trends for the crizanlizumab plus SoC arm, with numerically greater reductions in ACR and a slower decline in kidney function than in the SoC alone arm. PCR improvement or stability at Month 12 was broadly similar between arms. Fewer patients in the crizanlizumab arm met criteria for CKD progression at 12 months (4/30 [13.3%] vs. 9/28 [32.1%]; OR 0.32; 95% CI, 0.09–1.21), suggesting, but not proving, a reno‐protective effect (Table 1). While the total number of VOC‐related ER visits was similar between groups, the annualized rate of hospitalizations and ER visits was lower in the crizanlizumab arm (Table S2).
HRQoL, measured using 36‐item Short Form Health Survey version 2 scores, improved numerically across all domains with crizanlizumab, with > 10‐point differences in general health, physical component score, and physical role compared with SoC alone, but the differences were not statistically significant (data not shown).
As expected, free P‐selectin rapidly fell to near the lower limit of quantification and remained low with crizanlizumab (Figure S3a,b), confirming target engagement, while increasing over time with SoC. Complement marker sC5b‐9 decreased more with crizanlizumab; other biomarkers (blood: NT‐proBNP, C3a, C5a, cystatin C, IFN‐γ, MCP‐1, tryptase, TNF‐α; urine: NGAL/lipocalin‐2, KIM‐1, NAG, nephrin) were similar between arms (Figure S3a–j).
Crizanlizumab plus SoC was generally well tolerated, with a safety profile consistent with prior SCD experience. Overall, AEs were more common with crizanlizumab than SoC (86.2% vs. 71.4%), but grade ≥ 3 AEs were less frequent (13.8% vs. 21.4%), with no grade 4/5 events (Table S3). Common AEs with crizanlizumab were nausea (13.8%) and arthralgia, fatigue, and pruritus (each 6.9%; Table 2). One patient (3.4%) had a grade 3 infusion‐related reaction. Serious AEs were infrequent and similar between arms (one grade 3 SAE each: sickle cell anemia with crisis with crizanlizumab; hyperthyroidism with SoC). One participant discontinued crizanlizumab due to a treatment‐related AE (sickle cell anemia with crisis). Infections (an adverse event of special interest [AESI]) occurred in 72.4% versus 39.3%; hematologic abnormalities were similar (Data S1 for detailed AESI).
TABLE 2.
Adverse events (occurring in > 5% of all patients) and serious adverse events (safety set).
| Adverse events | Crizanlizumab, 5.0 mg/kg + SoC, N = 29 | SoC, N = 28 | All patients, N = 57 | |||
|---|---|---|---|---|---|---|
| All grades | Grade ≥ 3 | All grades | Grade ≥ 3 | All grades | Grade ≥ 3 | |
| Preferred term | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) |
| Number of subjects with at least one event | 25 (86.2) | 4 (13.8) | 20 (71.4) | 6 (21.4) | 45 (78.9) | 10 (17.5) |
| COVID‐19 | 7 (24.1) | 0 | 4 (14.3) | 0 | 11 (19.3) | 0 |
| Headache | 6 (20.7) | 0 | 4 (14.3) | 0 | 10 (17.5) | 0 |
| Arthralgia | 5 (17.2) | 0 | 3 (10.7) | 0 | 8 (14.0) | 0 |
| Influenza | 5 (17.2) | 0 | 4 (14.3) | 0 | 9 (15.8) | 0 |
| Nausea | 4 (13.8) | 0 | 5 (17.9) | 1 (3.6) | 9 (15.8) | 1 (1.8) |
| Tooth infection | 4 (13.8) | 0 | 0 | 0 | 4 (7.0) | 0 |
| Back pain | 3 (10.3) | 0 | 3 (10.7) | 0 | 6 (10.5) | 0 |
| Constipation | 3 (10.3) | 0 | 0 | 0 | 3 (5.3) | 0 |
| Pruritus | 3 (10.3) | 0 | 1 (3.6) | 0 | 4 (7.0) | 0 |
| Pyrexia | 3 (10.3) | 0 | 2 (7.1) | 0 | 5 (8.8) | 0 |
| Urinary tract infection | 3 (10.3) | 0 | 0 | 0 | 3 (5.3) | 0 |
| Cough | 2 (6.9) | 0 | 4 (14.3) | 0 | 6 (10.5) | 0 |
| Fatigue | 2 (6.9) | 0 | 3 (10.7) | 0 | 5 (8.8) | 0 |
| Migraine | 2 (6.9) | 0 | 1 (3.6) | 0 | 3 (5.3) | 0 |
| Pharyngitis | 2 (6.9) | 0 | 1 (3.6) | 0 | 3 (5.3) | 0 |
| Vomiting | 1 (3.4) | 0 | 7 (25.0) | 1 (3.6) | 8 (14.0) | 1 (1.8) |
| Peripheral edema | 0 | 0 | 3 (10.7) | 0 | 3 (5.3) | 0 |
| Serious adverse events | ||||||
| Number of subjects with at least one event | 2 (6.9) | 1 (3.4) | 2 (7.1) | 1 (3.6) | 4 (7.0) | 2 (3.5) |
| Sickle cell anemia with crisis | 1 (3.4) | 1 (3.4) | 0 | 0 | 1 (1.8) | 1 (1.8) |
| Hyperthyroidism | 0 | 0 | 1 (3.6) | 1 (3.6) | 1 (1.8) | 1 (1.8) |
| Influenza | 1 (3.4) | 0 | 0 | 0 | 1 (1.8) | 0 |
| Acute respiratory failure | 0 | 0 | 1 (3.6) | 0 | 1 (1.8) | 0 |
Note: Numbers (n) represent counts of subjects. A subject with multiple severity grades for an AE is only counted under the maximum grade. MedDRA version: 25.0, CTCAE version: 5.0.
Abbreviations: AE, adverse event; SoC, standard of care.
Due to the exploratory nature of the analyses and wide CI, this Phase 2 STEADFAST study does not provide definitive evidence that crizanlizumab has reno‐protective effects but offers important insights into kidney outcomes in adults with SCN. Crizanlizumab treatment showed favorable trends in mean change in ACR from baseline, eGFR and ACR decline rates, proportion of patients with CKD progression and the mean annualized rate of hospitalization or ER visits due to VOCs. ACR also decreased in the placebo group, which may reflect improved adherence to standard‐of‐care medications, including RAAS inhibitors, during trial participation or regression to the mean with the known variability of urinary ACR in SCD. Crizanlizumab showed a favorable safety profile; although overall AEs including infections were more frequent in the crizanlizumab arm, they were mild with no grade 4 or 5 AEs. Unlike prior SCD trials where CKD status was not a primary focus [17, 19], STEADFAST specifically enrolled patients who have clinically significant ACR and heightened risk of CKD progression. By enrolling this high‐risk population, the study aimed to better evaluate crizanlizumab for SCD kidney manifestations and provide insights into its role in SCN management. However, inconsistencies in clinical practice for assessing CKD in SCD patients contributed to a high screen‐failure rate, recruitment challenges, and subsequent early termination.
Currently, no prospective randomized clinical trials have demonstrated long‐term benefits of any treatments for SCN, and no treatments have been approved for this indication in patients with SCD. The observed trends in reducing ACR, eGFR, and CKD progression with crizanlizumab align with the hypothesized impact of P‐selectin inhibition on microvascular vaso‐occlusion and inflammation in the kidney [15, 16]. Although prior [17, 19] and ongoing [20] trials in crizanlizumab were designed primarily to assess VOC‐related outcomes, their collective findings support the biological plausibility that a reduction in vaso‐occlusion through inhibition of P‐selectin‐mediated adhesion may also play a role in mitigating acute microvascular injury to the kidney or reducing the need for nephrotoxic analgesic medications.
In conclusion, while the study was underpowered to establish a reno‐protective effect of crizanlizumab in patients SCN, the observed trends suggest a potential benefit in reducing ACR. Larger, adequately powered randomized trials with longer follow‐up are required to determine whether P‐selectin inhibition can meaningfully modify the natural history of SCN and improve clinically relevant kidney outcomes.
Author Contributions
All authors critically reviewed and revised the manuscript and approved the final version for submission. All authors made critical contributions to the conception, design, data interpretation, drafting, and revision of the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work, ensuring integrity and accuracy.
Funding
This work was supported by Novartis Pharma AG.
Ethics Statement
The STEADFAST trial was approved by the institutional review board or independent ethics committee of each participating center. This study was carried out in accordance with the ethical principles outlined in the Declaration of Helsinki.
Consent
All participants provided written informed consent in accordance with the Declaration of Helsinki prior to the start of treatment.
Conflicts of Interest
K.I.A. reports membership of the Board of Trustees of Vitalant; research funding from Novartis and Novo Nordisk; membership of advisory boards for Agios Pharmaceuticals, Sanofi, Novo Nordisk, Pfizer, Fulcrum Therapeutics, and Octapharma; consultancy for GSK and Protagonist Therapeutics; and membership of the Data Monitoring Committee for Vertex Pharmaceuticals. P.B. reports consultancy for Novartis, Global Blood Therapeutics, Addmedica, Hemanext, Agios, Roche, Bluebird, and Emmaus; and research funding from Addmedica, Fabre Foundation, Novartis, and Bluebird. S.L.S. reports research funding from Pfizer, Global Blood Therapeutics, Novo Nordisk, and Novartis; membership on an entity's advisory committees or consultancy for Agios, BEAM Therapeutics, Novo Nordisk, Novartis, Merck, Pfizer, and Global Blood Therapeutics. V.K.D. reports consultancy for Novartis, Travere Therapeutics, Bayer, Forma Therapeutics, Merck, Amgen, iCell Gene Therapeutics, Vera Therapeutics, Pfizer, and honoraria from UpToDate. A.I. reports consultancy and membership in advisory and/or study steering committees for Novartis, Pfizer, Novo Nordisk, and Roche; research funding from Novartis, Novo Nordisk, Cyclerion, Pfizer, Octapharma, AGIOS, and CSL Vifor. J.D.L. reports consultancy for Novartis and Pfizer. R.D.C. reports consultancy for Novartis, Pfizer, CSL Vifor, Novo Nordisk, AstraZeneca, and Sanofi. C.C.S. reports consultancy for Novartis, Pfizer, and Novo Nordisk. L.D. is an employee of Novartis.
Supporting information
Data S1: Adverse events of special interest.
Table S1: Baseline demographics and clinical characteristics.
Table S2: Annualized rate of hospitalizations and ER visits (FAS).
Table S3: Overview of AEs.
Figure S1: Patient disposition.
Figure S2: (a) Mean change in ACR by treatment over time (FAS) (b) Percentage change in eGFR by treatment over time (FAS).
Figure S3: (a) Time profile of free P‐selectin and (b) change from baseline time profile of free P‐selectin.
Figure S4: Time profiles for different biomarkers analyzed (FAS).
Acknowledgments
The STEADFAST study was sponsored by Novartis Pharma AG. We thank the study participants and their families, as well as the study investigators, research coordinators, and healthcare personnel. Medical writing assistance, under the direction of the authors, was provided by Muthyala Vimal Kumar, PhD and Shashank Jain, PhD (Novartis Healthcare Pvt Ltd) and was funded by Novartis.
Data Availability Statement
Novartis is committed to sharing with qualified external researchers access to patient‐level data and supporting clinical documents from eligible studies. The data that support the findings of this study are available from the corresponding author upon reasonable request. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The availability of the study data is according to the criteria and process described on www.clinicalstudydatarequest.com.
References
- 1. Piel F. B., Steinberg M. H., and Rees D. C., “Sickle Cell Disease,” New England Journal of Medicine 376, no. 16 (2017): 1561–1573. [DOI] [PubMed] [Google Scholar]
- 2. Nath K. A. and Hebbel R. P., “Sickle Cell Disease: Renal Manifestations and Mechanisms,” Nature Reviews. Nephrology 11, no. 3 (2015): 161–171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Ataga K. I., Derebail V. K., and Archer D. R., “The Glomerulopathy of Sickle Cell Disease,” American Journal of Hematology 89, no. 9 (2014): 907–914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Winer J. C., Yee M. E., Ataga K. I., Lebensburger J. D., and Zahr R. S., “Patients With Sickle Cell Disease Who Develop End‐Stage Kidney Disease Continue to Experience Poor Survival—A 19‐Year United States Renal Data System Study,” British Journal of Haematology 199, no. 5 (2022): e43–e47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Ataga K. I., Saraf S. L., and Derebail V. K., “The Nephropathy of Sickle Cell Trait and Sickle Cell Disease,” Nature Reviews. Nephrology 18, no. 6 (2022): 361–377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Niss O., Lane A., Asnani M. R., et al., “Progression of Albuminuria in Patients With Sickle Cell Anemia: A Multicenter, Longitudinal Study,” Blood Advances 4, no. 7 (2020): 1501–1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Astor B. C., Matsushita K., Gansevoort R. T., et al., “Lower Estimated Glomerular Filtration Rate and Higher Albuminuria Are Associated With Mortality and End‐Stage Renal Disease. A Collaborative Meta‐Analysis of Kidney Disease Population Cohorts,” Kidney International 79, no. 12 (2011): 1331–1340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Derebail V. K., Zhou Q., Ciccone E. J., Cai J., and Ataga K. I., “Rapid Decline in Estimated Glomerular Filtration Rate Is Common in Adults With Sickle Cell Disease and Associated With Increased Mortality,” British Journal of Haematology 186, no. 6 (2019): 900–907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Ataga K. I., Derebail V. K., Caughey M., et al., “Albuminuria Is Associated With Endothelial Dysfunction and Elevated Plasma Endothelin‐1 in Sickle Cell Anemia,” PLoS One 11, no. 9 (2016): e0162652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Heerspink H. J. L., Greene T., Tighiouart H., et al., “Change in Albuminuria as a Surrogate Endpoint for Progression of Kidney Disease: A Meta‐Analysis of Treatment Effects in Randomised Clinical Trials,” Lancet Diabetes and Endocrinology 7, no. 2 (2019): 128–139. [DOI] [PubMed] [Google Scholar]
- 11. Bartolucci P., Habibi A., Stehlé T., et al., “Six Months of Hydroxyurea Reduces Albuminuria in Patients With Sickle Cell Disease,” Journal of the American Society of Nephrology 27, no. 6 (2016): 1847–1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Brenner B. M., Cooper M. E., de Zeeuw D., et al., “Effects of Losartan on Renal and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Nephropathy,” New England Journal of Medicine 345, no. 12 (2001): 861–869. [DOI] [PubMed] [Google Scholar]
- 13. Haymann J. P., Hammoudi N., Stankovic Stojanovic K., et al., “Renin‐Angiotensin System Blockade Promotes a Cardio‐Renal Protection in Albuminuric Homozygous Sickle Cell Patients,” British Journal of Haematology 179, no. 5 (2017): 820–828. [DOI] [PubMed] [Google Scholar]
- 14. Embury S. H., Matsui N. M., Ramanujam S., et al., “The Contribution of Endothelial Cell P‐Selectin to the Microvascular Flow of Mouse Sickle Erythrocytes In Vivo,” Blood 104, no. 10 (2004): 3378–3385. [DOI] [PubMed] [Google Scholar]
- 15. Singbartl K., Green S. A., and Ley K., “Blocking P‐Selectin Protects From Ischemia/Reperfusion‐Induced Acute Renal Failure,” FASEB Journal 14, no. 1 (2000): 48–54. [DOI] [PubMed] [Google Scholar]
- 16. Tipping P. G., Huang X. R., Berndt M. C., and Holdsworth S. R., “A Role for P Selectin in Complement‐Independent Neutrophil‐Mediated Glomerular Injury,” Kidney International 46, no. 1 (1994): 79–88. [DOI] [PubMed] [Google Scholar]
- 17. Ataga K. I., Kutlar A., Kanter J., et al., “Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease,” New England Journal of Medicine 376, no. 5 (2017): 429–439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. FDA , Adakveo Prescribing Information (U.S. Food and Drug Administration, 2024). [Google Scholar]
- 19. Abboud M. R., Cançado R. D., de Montalembert M., et al., “Crizanlizumab With or Without Hydroxyurea in Patients With Sickle Cell Disease (STAND): Primary Analyses From a Placebo‐Controlled, Randomised, Double‐Blind, Phase 3 Trial,” Lancet Haematology 12, no. 4 (2025): e248–e257. [DOI] [PubMed] [Google Scholar]
- 20. Campbell A., Silva‐Pinto A., Nnodu O., et al., “A Phase III, Multicenter, Randomized, Placebo Controlled, Double‐Blind Study to Assess Efficacy and Safety of Crizanlizumab (5 mg/kg) Versus Placebo, With or Without Hydroxyurea/Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients With Frequent Vaso‐Occlusive Crises: The Sparkle Study,” Blood 146 (2025): 1198–1198. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1: Adverse events of special interest.
Table S1: Baseline demographics and clinical characteristics.
Table S2: Annualized rate of hospitalizations and ER visits (FAS).
Table S3: Overview of AEs.
Figure S1: Patient disposition.
Figure S2: (a) Mean change in ACR by treatment over time (FAS) (b) Percentage change in eGFR by treatment over time (FAS).
Figure S3: (a) Time profile of free P‐selectin and (b) change from baseline time profile of free P‐selectin.
Figure S4: Time profiles for different biomarkers analyzed (FAS).
Data Availability Statement
Novartis is committed to sharing with qualified external researchers access to patient‐level data and supporting clinical documents from eligible studies. The data that support the findings of this study are available from the corresponding author upon reasonable request. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The availability of the study data is according to the criteria and process described on www.clinicalstudydatarequest.com.