Cerebrovascular Reserve and White Matter Disease in Patients with Chronic Anemia (CVR)

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Thalassemia; Healthy Controls
• Intervention / Treatment: Drug: Acetazolamide; Drug: Hydroxyurea

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 Type: Observational
• Enrollment (Actual): 165

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • CHLA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

sickle cell disease: non-transfused, simple transfused, exchange transfusion Non-sickle Cell Anemia: Non- transfused and transfused healthy controls

Description

• 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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	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: 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; Drug: Hydroxyurea; info included in arm group; Other Names: Hydrea
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CVR response to transfusion	Cerebral vascular flow reserve will be assessed prior to and following a regularly scheduled blood transfusion	3-5 days
CVR response to hydroxyurea therapy	Change in cerebral vascular reserve at baseline and after initiation of hydroxyurea titrated to maximum tolerated dose	2-4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictors of CVR response	We will determine what factors determine cerebral blood flow response to diamox vasodilator challenge	Single study visit

Collaborators and Investigators

• Sponsor: Children's Hospital Los Angeles
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Vanderbilt University Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: John C Wood, M.D., PhD, CHLA/USC

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2018
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: February 20, 2018
• First Submitted That Met QC Criteria: October 19, 2018
• First Posted (Actual): October 23, 2018

Study Record Updates

• Last Update Posted (Actual): October 30, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: cerebrovascular reserve; white matter disease in patients with chronic anemia
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Thalassemia; Anemia; Leukoencephalopathies; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Diuretics; Natriuretic Agents; Anticonvulsants; Carbonic Anhydrase Inhibitors; Antisickling Agents; Acetazolamide; Hydroxyurea
• Other Study ID Numbers: CHLA-17-00496; 1R01HL136484-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No