CVR: Cerebrovascular Reserve and White Matter Disease in Patients With Chronic Anemia

Sponsor
Children's Hospital Los Angeles (Other)
Overall Status
Recruiting
CT.gov ID
NCT03715972
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH), Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other), Vanderbilt University Medical Center (Other)
220
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52.6
4.2

Study Details

Study Description

Brief Summary

This is primarily an observational trial in patients with chronic anemia syndromes (sickle cell disease and thalassemia) and control subjects. The key purpose is to understand how brain blood flow reserve (the ability of the brain to increase its flow in response to stress) is altered in patients with chronic anemia. Since this parameter may depend on anemia severity, we will perform the MRI monitoring prior to and following clinically indicated transfusions in a subset of patients. Most patients will already be prescribed hydroxyurea as part of their standard of care. Since hydroxyurea could impact brain blood flow, there is also a small pilot study (20 patients, nonrandomized, open label) where MRI imaging will be performed prior to and following administration of hydroxyurea up to maximum tolerated dose. The study will enroll 90 adult subjects with transfusion independent sickle cell disease (70 SS, 10 SC, 10 Sβ0) and 60 patients with transfusion-dependent sickle cell disease. It will also include 10 transfusion independent thalassemia patients and 20 transfusion dependent thalassemia patients as well as 40 control subjects recruited from first degree relatives of the sickle cell disease population. All eligible subjects will be asked to provide informed consent before participating in the study.

Condition or Disease Intervention/Treatment Phase

Detailed Description

This is primarily an observational trial in patients with chronic anemia syndromes (sickle cell disease and thalassemia) and control subjects. The key purpose is to understand how brain blood flow reserve (the ability of the brain to increase its flow in response to stress) is altered in patients with chronic anemia. Since this parameter may depend on anemia severity, we will perform the MRI monitoring prior to and following clinically indicated transfusions in a subset of patients. Most patients will already be prescribed hydroxyurea as part of their standard of care. Since hydroxyurea could impact brain blood flow, there is also a small pilot study (20 patients, nonrandomized, open label) where MRI imaging will be performed prior to and following administration of hydroxyurea up to maximum tolerated dose. The study will enroll 90 adult subjects with transfusion independent sickle cell disease (70 SS, 10 SC, 10 Sβ0) and 60 patients with transfusion-dependent sickle cell disease. It will also include 10 transfusion independent thalassemia patients and 20 transfusion dependent thalassemia patients as well as 40 control subjects recruited from first degree relatives of the sickle cell disease population. All eligible subjects will be asked to provide informed consent before participating in the study.

Treatment:

All patients will undergo baseline phlebotomy, brain MRI, and neurocognitive testing. The MRI will include measurements of brain blood flow prior to and following administration of 16 mg/kg of acetazolamide to maximally vasodilate the cerebral vasculature. All transfusion dependent patients will have their MRI performed immediately prior to a routinely scheduled transfusion at their hemoglobin nadir. 20 sickle cell disease patients on chronic simple transfusions and 10 thalassemia patients on chronic simple transfusions will undergo repeat MRI assessment of cerebral blood flow and reactivity following their clinically indicated blood transfusion. 10 sickle cell disease patients on exchange transfusions will undergo repeat MRI assessment of cerebral blood flow and reactivity following their clinically indicated exchange transfusion; this transfusion will be performed to lower their hemoglobin S percentage by 25% points while keeping the total hemoglobin unchanged (isocrit exchange). 20 non transfusion dependent sickle cell disease patients not already receiving hydroxyurea will be placed on hydroxyurea following their baseline exam and titrated to maximal tolerated dose. They will then undergo a repeat MRI within two months of reaching that dose and be given the option to continue on hydroxyurea or stop.

Safety Assessment:

All patients will have a physician present during the MRI examination to monitor vital signs and response to acetazolamide. Patients placed onto hydroxyurea will have monthly study visits with monitoring of complete blood count, vital signs, complete metabolic panel, and hemoglobin electrophoresis. Adverse events will be assessed at every study visit after the first dose through to the last subject visit.

Efficacy Assessments:

Baseline cerebrovascular reserve (CVR) predictors will be assessed by multivariate regression after appropriate transformations. Potential independent predictors include oxygen content, hemoglobin subtype, as well as markers of hemolysis, inflammation, and iron overload.

Study Design

Study Type:
Observational
Anticipated Enrollment :
220 participants
Observational Model:
Cohort
Time Perspective:
Other
Official Title:
Cerebrovascular Reserve and White Matter Disease in Patients With Chronic Anemia
Actual Study Start Date :
Jul 15, 2018
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Anemia Observation

The study will enroll 90 adult subjects with transfusion independent sickle cell disease (70 SS, 10 SC, 10 Sβ0) and 60 patients with transfusion-dependent sickle cell disease. It will also include 10 transfusion independent thalassemia patients and 20 transfusion dependent thalassemia patients. Diamox (acetazolamide) will be administered during MRI.

Drug: Acetazolamide
Acetazolamide will not be considered a treatment; however, it will be used as a tool to help measure cerebralvascular reserve. A dose of 16 mg/kg ACZ will be administered with a maximum of 1400 mg.
Other Names:
  • Diamox
  • Anemia Intervention

    Most patients will already be prescribed hydroxyurea as part of their standard of care. Since hydroxyurea could impact brain blood flow, there is also a small pilot study (20 patients, nonrandomized, open label) where MRI imaging will be performed prior to and following administration of hydroxyurea up to maximum tolerated dose. non transfusion dependent sickle cell disease patients not already receiving hydroxyurea will be placed on hydroxyurea following their baseline exam and titrated to maximal tolerated dose. They will then undergo a repeat MRI within two months of reaching that dose and be given the option to continue on hydroxyurea or stop.

    Drug: Hydroxyurea
    info included in arm group
    Other Names:
  • Hydrea
  • Drug: Acetazolamide
    Acetazolamide will not be considered a treatment; however, it will be used as a tool to help measure cerebralvascular reserve. A dose of 16 mg/kg ACZ will be administered with a maximum of 1400 mg.
    Other Names:
  • Diamox
  • Healthy Controls

    40 control subjects recruited from first degree relatives of the sickle cell disease population. Diamox (acetazolamide) will be administered during MRI.

    Drug: Acetazolamide
    Acetazolamide will not be considered a treatment; however, it will be used as a tool to help measure cerebralvascular reserve. A dose of 16 mg/kg ACZ will be administered with a maximum of 1400 mg.
    Other Names:
  • Diamox
  • Outcome Measures

    Primary Outcome Measures

    1. CVR response to transfusion [3-5 days]

      Cerebral vascular flow reserve will be assessed prior to and following a regularly scheduled blood transfusion

    2. CVR response to hydroxyurea therapy [2-4 months]

      Change in cerebral vascular reserve at baseline and after initiation of hydroxyurea titrated to maximum tolerated dose

    Secondary Outcome Measures

    1. Predictors of CVR response [Single study visit]

      We will determine what factors determine cerebral blood flow response to diamox vasodilator challenge

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    7 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    • Inclusion Criteria:
    1. Diagnosis of sickle cell disease (genotype SS, SC, or SB0), thalassemia (transfusion dependent or transfusion independent), or normal control subject that are ≥18yrs, ethnicity, and sex matched to the sickle cell disease population.

    2. Ability to tolerate a one hour MRI examination.

    3. Age equal to or greater than 7 years old for Anemia groups.

    4. Agreeable to use an approved method of contraception for the entire duration of hydroxyurea usage if accepted onto the hydroxyurea substudy (male or female of childbearing potential)

    Exclusion Criteria:
    1. Hospitalization within one month

    2. Contraindication to acetazolamide use (seizures)

    3. Severe claustrophobia.

    4. Pregnancy or nursing (a negative HCG (pregnancy) test must be obtained prior to MRI)

    5. As a result of medical review, physical examination or screening investigations, the Principal Investigator (PI) considers the subject unfit for the study

    6. No fixed address

    7. In control subjects, chronic hepatitis, diabetes, hypertension, coronary artery disease, cognitively impaired or developmental delay

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 CHLA Los Angeles California United States 90027

    Sponsors and Collaborators

    • Children's Hospital Los Angeles
    • National Heart, Lung, and Blood Institute (NHLBI)
    • Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
    • Vanderbilt University Medical Center

    Investigators

    • Principal Investigator: John C Wood, M.D., PhD, CHLA/USC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    John C. Wood, Professor of Pediatrics and Radiology, Children's Hospital Los Angeles
    ClinicalTrials.gov Identifier:
    NCT03715972
    Other Study ID Numbers:
    • 17-00496
    • 1R01HL136484-01A1
    First Posted:
    Oct 23, 2018
    Last Update Posted:
    Jul 14, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by John C. Wood, Professor of Pediatrics and Radiology, Children's Hospital Los Angeles
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 14, 2022