Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia

NCT05469828 | Not Yet Recruiting Phase 1 FDA Drug

• 1 other identifier: CHLA-21-00300
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

Hypothesis Efficient unloading of oxygen to regions of high metabolic demand requires a healthy microvasculature to sense local oxygen tension and regulate flow, accordingly. In sickle cell disease patients, the investigators have demonstrated oxygen supply-demand mismatch, or SDM, in proportion to anemia severity. SDM occurs in both the peripheral circulation and the brain, and four characteristics: 1) Hyperemia beyond expected for the level of anemia, 2) Corresponding loss of vascular dilatory reserve, 3) Impaired oxygen unloading to the tissues, and 4) Tissue hypoxia. In sickle cell disease, red blood cell (RBC) and white blood cell (WBC) adhere to vascular endothelium triggering transient or irreversible microvascular damage as well as releasing vasoactive substances that contribute to microvascular dysregulation. The investigators postulate that ongoing microvascular damage/dysregulation in the setting of increased total blood flow contributes to SDM. The investigators believe SEG101, by lowering RBC and WBC adhesion to the microvasculature, will improve SDM and tissue oxygenation. Objectives

• Primary - The investigators will test whether SEG101 improves SDM in patients with sickle cell anemia by measuring the change in tissue oxygenation measured by near infrared spectroscopy (NIRS).
• Secondary/Exploratory - The investigators will identify end-organ disease and whether improvement of SDM by SEG101 occurs in patients with sickle cell anemia.

Conditions

Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• The investigators will test whether SEG101 improves Supply-Demand Matching in patients with sickle cell anemia by measuring the change in tissue oxygenation by near infrared spectroscopy from baseline to 3 months and to 6 months.

  Tissue oxygenation is measured by near infrared spectroscopy in rSO2%. The investigators will account for changes in microcirculatory perfusion at rest and post-ischemia by laser doppler.

  Change measured over a 23 week period

Secondary Outcomes (3)

• The investigators will test whether SEG101 improves Supply-Demand Matching in patients with sickle cell anemia by measuring the change in microcirculatory perfusion at rest and post-ischemia

  Change measured over a 23 week period

• The investigators will test whether SEG101 improves Supply-Demand Matching in patients with sickle cell anemia by measuring the change in venous blood saturation and change in vessel endothelial function

  Change measured over a 23 week period

• The investigators will test whether SEG101 improves Supply-Demand Matching in patients with sickle cell anemia in the pulmonary vasculature using tricuspid regurgitant jet velocity as an estimate of pulmonary artery pressure.

  Change measured over a 23 week period

Study Arms (2)

treatment

EXPERIMENTAL

The effects of Crizanlizumab will be assessed in 20 nontransfused SCD subjects. After comprehensive baseline assessment one month prior the time of study initiation, patients will be started on 5mg/kg of body weight to be initiated at week 1 with follow up dosing at week 3 and week 7 then q4weeks until week 23, which will be the last dose given (7 total doses). Safety laboratories will be drawn at each infusion visit. There will be a follow up phone call the day after receiving the medication. Comprehensive blood and vascular testing will be repeated at Week 11 and Week 23 of treatment.

Drug: Crizanlizumab

control

ACTIVE COMPARATOR

A total of 10 SCD subjects will be recruited from the hematology clinic at CHLA, generating a similar distribution of SS and Sß0 hemoglobin. They will be studied twice, once at the beginning of the study, time 0, and once at the end of study, after 6 months. They will undergo the same cerebral, peripheral and cardiopulmonary testing procedures as the patients undergoing therapy. They will also have monthly phone calls to determine clinical outcomes such as crisis frequency, medication use, hospitalizations and other pertinent clinical findings that may arise.

Other: control

Interventions

Crizanlizumab DRUG

patients will be started on 5mg/kg of body weight to be initiated at week 1 with follow up dosing at week 3 and week 7 then q4weeks until week 23, which will be the last dose given (7 total doses).

treatment

control OTHER

Standard of care

control

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• We will enroll only SS and Sß0 sickle cell disease patients
• Both male and female will be included.
• Our population of sickle cell disease is 90% African American and 10% Hispanic, therefore, our study population will reflect that distribution of ethnicity.
• Informed consent from legal guardian and/or patient
• Able to participate without needing sedation for MRI scan
• Age at least 16 years

You may not qualify if:

• Any pain crisis requiring an ER visit and/or admission to the hospital and/or required parenteral pain medication in the previous 4 weeks.
• Any acute transfusion in the previous 4 weeks
• Need for chronic transfusion therapy
• Any known chronic illness that in the judgment of the investigator may compromise subject safety or data integrity. These include but are not limited to rheumatologic disorders, malignancy, severe asthma, chronic hepatic or renal insufficiency.
• Known pregnancy
• Seizure disorder
• Inability to cooperate with MRI examinations
• Contraindication to Crizanlizumab

Sponsors & Collaborators

• Children's Hospital Los Angeles: lead
• Novartis: collaborator

Related Publications (22)

• ITANO HA, PAULING L. A rapid diagnostic test for sickle cell anemia. Blood. 1949 Jan;4(1):66-8. No abstract available.

  PMID: 18103217 BACKGROUND

• PAULING L, ITANO HA, et al. Sickle cell anemia a molecular disease. Science. 1949 Nov 25;110(2865):543-8. doi: 10.1126/science.110.2865.543. No abstract available.

  PMID: 15395398 BACKGROUND

• Chien S, Usami S, Bertles JF. Abnormal rheology of oxygenated blood in sickle cell anemia. J Clin Invest. 1970 Apr;49(4):623-34. doi: 10.1172/JCI106273.

  PMID: 5443167 BACKGROUND

• Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44. doi: 10.1056/NEJM199406093302303.

  PMID: 7993409 BACKGROUND

• Steiner CA, Miller JL. Sickle Cell Disease Patients in U.S. Hospitals, 2004. 2006 Dec. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Feb-. Statistical Brief #21. Available from http://www.ncbi.nlm.nih.gov/books/NBK63489/

  PMID: 21938835 BACKGROUND

• Niss O, Fleck R, Makue F, Alsaied T, Desai P, Towbin JA, Malik P, Taylor MD, Quinn CT. Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia. Blood. 2017 Jul 13;130(2):205-213. doi: 10.1182/blood-2017-02-767624. Epub 2017 May 15.

  PMID: 28507082 BACKGROUND

• Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007 Jan;21(1):37-47. doi: 10.1016/j.blre.2006.07.001. Epub 2006 Nov 7.

  PMID: 17084951 BACKGROUND

• Detterich JA, Kato RM, Rabai M, Meiselman HJ, Coates TD, Wood JC. Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood. 2015 Aug 6;126(6):703-10. doi: 10.1182/blood-2014-12-614370. Epub 2015 Jun 2.

  PMID: 26036801 BACKGROUND

• Friedman D, Szmuszkovicz J, Rabai M, Detterich JA, Menteer J, Wood JC. Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity. J Heart Lung Transplant. 2012 Jun;31(6):642-7. doi: 10.1016/j.healun.2012.02.020. Epub 2012 Mar 21.

  PMID: 22440720 BACKGROUND

• Kato GJ, Hebbel RP, Steinberg MH, Gladwin MT. Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. Am J Hematol. 2009 Sep;84(9):618-25. doi: 10.1002/ajh.21475.

  PMID: 19610078 BACKGROUND

• Delpy DT, Cope MC, Cady EB, Wyatt JS, Hamilton PA, Hope PL, Wray S, Reynolds EO. Cerebral monitoring in newborn infants by magnetic resonance and near infrared spectroscopy. Scand J Clin Lab Invest Suppl. 1987;188:9-17.

  PMID: 2835812 BACKGROUND

• Tenland T, Salerud EG, Nilsson GE, Oberg PA. Spatial and temporal variations in human skin blood flow. Int J Microcirc Clin Exp. 1983;2(2):81-90.

  PMID: 6236158 BACKGROUND

• Thorniley MS, Houston R, Wickramasinghe YA, Rolfe P. Application of near-infrared spectroscopy for the assessment of the oxygenation level of myoglobin and haemoglobin in cardiac muscle in vivo. Biochem Soc Trans. 1990 Dec;18(6):1195-6. doi: 10.1042/bst0181195. No abstract available.

  PMID: 2088860 BACKGROUND

• Nilsson GE, Tenland T, Oberg PA. Evaluation of a laser Doppler flowmeter for measurement of tissue blood flow. IEEE Trans Biomed Eng. 1980 Oct;27(10):597-604. doi: 10.1109/TBME.1980.326582. No abstract available.

  PMID: 6449469 BACKGROUND

• Lee JH, Jang YE, Song IK, Kim EH, Kim HS, Kim JT. Near-Infrared Spectroscopy and Vascular Occlusion Test for Predicting Clinical Outcome in Pediatric Cardiac Patients: A Prospective Observational Study. Pediatr Crit Care Med. 2018 Jan;19(1):32-39. doi: 10.1097/PCC.0000000000001386.

  PMID: 29140967 BACKGROUND

• De Blasi RA, Cope M, Ferrari M. Oxygen consumption of human skeletal muscle by near infrared spectroscopy during tourniquet-induced ischemia in maximal voluntary contraction. Adv Exp Med Biol. 1992;317:771-7. doi: 10.1007/978-1-4615-3428-0_94. No abstract available.

  PMID: 1288203 BACKGROUND

• Adams RJ, McKie VC, Brambilla D, Carl E, Gallagher D, Nichols FT, Roach S, Abboud M, Berman B, Driscoll C, Files B, Hsu L, Hurlet A, Miller S, Olivieri N, Pegelow C, Scher C, Vichinsky E, Wang W, Woods G, Kutlar A, Wright E, Hagner S, Tighe F, Waclawiw MA, et al. Stroke prevention trial in sickle cell anemia. Control Clin Trials. 1998 Feb;19(1):110-29. doi: 10.1016/s0197-2456(97)00099-8.

  PMID: 9492971 BACKGROUND

• Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2;339(1):5-11. doi: 10.1056/NEJM199807023390102.

  PMID: 9647873 BACKGROUND

• Nathan DG. Regulation of fetal hemoglobin synthesis by cell cycle specific drugs. Prog Clin Biol Res. 1985;191:475-500. No abstract available.

  PMID: 2413483 BACKGROUND

• Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016 Feb 18;127(7):820-8. doi: 10.1182/blood-2015-08-618561. Epub 2016 Jan 12.

  PMID: 26758918 BACKGROUND

• Presley TD, Perlegas AS, Bain LE, Ballas SK, Nichols JS, Sabio H, Gladwin MT, Kato GJ, Kim-Shapiro DB. Effects of a single sickling event on the mechanical fragility of sickle cell trait erythrocytes. Hemoglobin. 2010;34(1):24-36. doi: 10.3109/03630260903546999.

  PMID: 20113285 BACKGROUND

• Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002 Dec;8(12):1383-9. doi: 10.1038/nm1202-799. Epub 2002 Nov 11.

  PMID: 12426562 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

crizanlizumab

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Jon Detterich

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Obdulio Carreras

CONTACT

3233614663; ocarreras@chla.usc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Treatment and Control

Study Record Dates

• First Submitted: August 31, 2021
• First Posted: July 22, 2022
• Study Start: July 1, 2024
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029
• Last Updated: August 30, 2023

Record last verified: 2023-05