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Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia (SEG101)

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ClinicalTrials.gov Identifier: NCT05469828
Recruitment Status : Not yet recruiting
First Posted : July 22, 2022
Last Update Posted : July 22, 2022
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Children's Hospital Los Angeles

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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Crizanlizumab Other: control Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Treatment and Control
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia
Estimated Study Start Date : July 1, 2023
Estimated Primary Completion Date : July 1, 2027
Estimated Study Completion Date : July 1, 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: treatment
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
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).

Active Comparator: control
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
Standard of care




Primary Outcome Measures :
  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. [ Time Frame: Change measured over a 23 week period ]
    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.


Secondary Outcome Measures :
  1. 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 [ Time Frame: Change measured over a 23 week period ]
    Microcirculatory perfusion is measured by laser doppler in perfusion units (PU)

  2. 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 [ Time Frame: Change measured over a 23 week period ]
    Venous oxygen saturation is measured by venous blood gas in pO2 and co-oximetry testing in percent saturation (% sat). Vasoconstriction is measured by plethysmography in percent change (% change).

  3. 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. [ Time Frame: Change measured over a 23 week period ]
    The tricuspid regurgitant jet velocity is a measure of pulmonary pressure and a predictor of mortality in sickle cell anemia measured in m/sec.



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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (Both Patient Groups - 1. SCD on SEG101 and 2. SCD not receiving SEG101)

  • 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

Exclusion Criteria (Both Patient Groups - 1. SCD on SEG101 and 2. SCD not receiving SEG101)

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05469828


Contacts
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Contact: Obdulio Carreras 3233614663 ocarreras@chla.usc.edu

Sponsors and Collaborators
Children's Hospital Los Angeles
Novartis
Investigators
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Principal Investigator: Jon Detterich Children's Hospital Los Angeles
Publications:

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Responsible Party: Children's Hospital Los Angeles
ClinicalTrials.gov Identifier: NCT05469828    
Other Study ID Numbers: CHLA-21-00300
First Posted: July 22, 2022    Key Record Dates
Last Update Posted: July 22, 2022
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn