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

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ClinicalTrials.gov Identifier: NCT03715972
Recruitment Status : Recruiting
First Posted : October 23, 2018
Last Update Posted : January 10, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Vanderbilt University Medical Center
Information provided by (Responsible Party):
John C. Wood, Children's Hospital Los Angeles

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
Thalassemia Sickle Cell Disease Healthy Controls Drug: Hydroxyurea Drug: Acetazolamide

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.


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Study Type : Observational
Estimated 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 : July 15, 2018
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023


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 Name: 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 Name: 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 Name: 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 Name: Diamox




Primary Outcome Measures :
  1. CVR response to transfusion [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Single study visit ]
    We will determine what factors determine cerebral blood flow response to diamox vasodilator challenge



Information from the National Library of Medicine

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Ages Eligible for Study:   7 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   for healthy controls we will try to match gender to those that have been enrolled under the anemia cohort
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
Criteria
  • 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

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): NCT03715972


Contacts
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Contact: Mahmoud Tahoun, B.Sc 323.361.1819 mtahoun@chla.usc.edu
Contact: Candice Moulder, MPh, CCRP 3233611646 cmulder@chla.usc.edu

Locations
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United States, California
CHLA Recruiting
Los Angeles, California, United States, 90027
Contact: Mahmoud B Tahoun, BSc    323-361-1819    mtahound@chla.usc.edu   
Contact: Natalie Ornelas    323.361.8827    nornelas@chla.usc.edu   
Principal Investigator: John C Wood, M.D, PhD         
Sub-Investigator: Thomas Coates, M.D         
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
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Principal Investigator: John C Wood, M.D., PhD CHLA/USC

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Responsible Party: John C. Wood, Professor of Pediatrics and Radiology, Children's Hospital Los Angeles
ClinicalTrials.gov Identifier: NCT03715972     History of Changes
Other Study ID Numbers: 17-00496
1R01HL136484-01A1 ( U.S. NIH Grant/Contract )
First Posted: October 23, 2018    Key Record Dates
Last Update Posted: January 10, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by John C. Wood, Children's Hospital Los Angeles:
cerebrovascular reserve
white matter disease in patients with chronic anemia
Additional relevant MeSH terms:
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Leukoencephalopathies
Anemia
Anemia, Sickle Cell
Thalassemia
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hydroxyurea
Acetazolamide
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Anticonvulsants
Carbonic Anhydrase Inhibitors
Diuretics
Natriuretic Agents
Physiological Effects of Drugs