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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

Tracking Information
First Submitted Date February 20, 2018
First Posted Date October 23, 2018
Last Update Posted Date January 10, 2019
Actual Study Start Date July 15, 2018
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: October 19, 2018)
  • 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
  • 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
Original Primary Outcome Measures Same as current
Change History Complete list of historical versions of study NCT03715972 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: October 19, 2018)
Predictors of CVR response [ Time Frame: Single study visit ]
We will determine what factors determine cerebral blood flow response to diamox vasodilator challenge
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Cerebrovascular Reserve and White Matter Disease in Patients With Chronic Anemia
Official Title Cerebrovascular Reserve and White Matter Disease in Patients With Chronic Anemia
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.
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
Study Design Observational Model: Cohort
Time Perspective: Other
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
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
Condition
  • Thalassemia
  • Sickle Cell Disease
  • Healthy Controls
Intervention
  • 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
Study Groups/Cohorts
  • 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.
    Intervention: Drug: Acetazolamide
  • 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.

    Interventions:
    • Drug: Hydroxyurea
    • Drug: Acetazolamide
  • Healthy Controls
    40 control subjects recruited from first degree relatives of the sickle cell disease population. Diamox (acetazolamide) will be administered during MRI.
    Intervention: Drug: Acetazolamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: October 19, 2018)
220
Original Estimated Enrollment Same as current
Estimated Study Completion Date March 2023
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility 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
Sex/Gender
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
Ages 7 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Mahmoud Tahoun, B.Sc 323.361.1819 mtahoun@chla.usc.edu
Contact: Candice Moulder, MPh, CCRP 3233611646 cmulder@chla.usc.edu
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03715972
Other Study ID Numbers 17-00496
1R01HL136484-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party John C. Wood, Children's Hospital Los Angeles
Study Sponsor Children's Hospital Los Angeles
Collaborators
  • 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
PRS Account Children's Hospital Los Angeles
Verification Date January 2019