Novel Cardiac Magnetic Resonance Imaging to Define a Unique Restrictive Cardiomyopathy in Sickle Cell Disease

October 7, 2020 updated by: Children's Hospital Medical Center, Cincinnati
The purpose of this study is to use cardiac magnetic resonance imaging (CMR) and echocardiographic tissue Doppler imaging to demonstrate a unique restrictive cardiomyopathy of sickle cell disease. The investigators will characterize its frequency and how it might change (e.g., presence/absence and severity) over a 2-year period.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Sickle cell disease (SCD) causes progressive cardiopulmonary morbidity, beginning in childhood, which can ultimately be fatal. As a group, cardiopulmonary complications, such as acute chest syndrome and sudden death, are now the most common causes of death in SCD, especially in adolescents and adults.

Patients with SCD have features of both an anemia-related, high cardiac output state and a restrictive cardiomyopathy (RCM). The investigators propose that this unique RCM is an overlooked and understudied complication of SCD. RCM could explain the modest increases in pulmonary artery pressure in patients with SCD, as measured by cardiac catheterization or estimated by tricuspid regurgitant jet velocity (TRJV), which has often been attributed to a primary pulmonary arterial hypertension (PAH). RCM could also be the cause of unexplained sudden cardiac death in SCD, which is a feature of other forms of RCM.

The investigators overarching hypothesis is that increased reactive oxygen species (ROS)-mediated angiotensin-1 receptor (AT1R)-TGFβ1 signaling is pro-fibrotic and, in combination with vaso-occlusive ischemia-reperfusion injury, results in an age-dependent, progressive RCM that can be detected by non-invasive cardiac imaging.

This pilot, longitudinal, observational study uses a novel, comprehensive, multimodal cardiac imaging strategy, combining cutting-edge cardiac magnetic resonance imaging (CMR) and echocardiographic tissue Doppler imaging (TDI), to demonstrate the unique RCM of SCD, characterizing its frequency and the temporal evolution over a 2-year period. The investigators will also correlate the RCM phenotype with biomarkers of ROS and renin angiotensin system (RAS)-TGFβ1 signaling.

This research could change the investigators understanding of how SCD affects the heart and lungs. The investigators propose studies that will change the current concept of primary pulmonary vasculopathy to a cardiomyopathy-centered model with secondary pulmonary vascular changes leading to sudden death. This translational pilot study will deliver a novel, clear, quantifiable CMR phenotype with established diagnostic performance that will be used in phase II/III clinical trials to test anti-fibrotic therapy to prevent or reverse SCD-related RCM.

Study Type

Observational

Enrollment (Actual)

33

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Enrolling a maximum of 40 participants in the entire study across four age strata: A, 6 - 13.9 years; B, 14 - 20.9 years; C, 21 years and older; and D, 6 years and older.

Description

Inclusion Criteria:

  • Sickle cell anemia (HbSS) or sickle-β°-thalassemia (HbSβ°) confirmed by hemoglobin separation and identification techniques
  • Ability to cooperate with and undergo CMR without sedation or anesthesia.
  • Ability to cooperate with and undergo echocardiogram
  • Written informed consent in accordance with the institutional policies and federal guidelines must be provided by the participant (if ≥18 years of age) or parent or legally authorized guardian (if the participant is <18 years of age) Minor participants ≥11 years of age will be requested to provide assent

The following additional inclusion criterion applies to Age Stratum A:

Age 6 to 13.99 years

The following additional inclusion criteria apply to Age Stratum B:

  • Age 14 to 20.99 years
  • Detectible and quantifiable TRJV with reported value

The following additional inclusion criteria apply to Age Stratum C:

  • Age ≥21 years
  • Detectible and quantifiable TRJV with reported value

The following additional inclusion criteria apply to Stratum D:

  • Age ≥6 years.
  • Current use of disease-modifying therapy [hydroxyurea, chronic transfusions, or both (given concurrently, sequentially, or both)] that was initiated at <3 years of age, and for which there has been no interruption of therapy for >6 consecutive months since the initiation of disease-modifying therapy.

Exclusion Criteria:

  • Any contraindication to MRI or physical or behavioral factor that could degrade the quality of MRI data or interfere with a participant's tolerance of the MRI, such as permanent or semi-permanent metallic implants, including pacemakers and defibrillators, or severe claustrophobia
  • Known ventricular septal defect (VSD) documented in medical record
  • Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2 (estimated by serum creatinine or cystatin-C)
  • Pregnancy (documented by serum or urine pregnancy test)

The following additional inclusion criterion applies to strata A, B and C only:

- Current chronic transfusion therapy (defined as regular, approximately monthly, transfusions of packed red blood cells given for at least 6 consecutive months for the treatment of prevention of SCD-related complications with the plan to continue this therapy at the time of potential enrollment).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Age Stratum A
  • Age 6 to 13.99 years
  • Cardiac magnetic resonance imaging (CMR)
Other: Cardiac magnetic resonance imaging (CMR)
CMR is obtained on all participants in all arms/groups
Age Stratum B
  • Age 14 to 20.99 years
  • Detectible and quantifiable TRJV with reported value
  • Cardiac magnetic resonance imaging (CMR)
Other: Cardiac magnetic resonance imaging (CMR)
CMR is obtained on all participants in all arms/groups
Age Stratum C
  • Age ≥21 years
  • Detectible and quantifiable TRJV with reported value
  • Cardiac magnetic resonance imaging (CMR)
Other: Cardiac magnetic resonance imaging (CMR)
CMR is obtained on all participants in all arms/groups
Age Stratum D
  • Age ≥6 years.
  • Current use of disease-modifying therapy [hydroxyurea, chronic transfusions, or both (given concurrently, sequentially, or both)] that was initiated at <3 years of age, and for which there has been no interruption of therapy for >6 consecutive months since the initiation of disease-modifying therapy.
  • Cardiac magnetic resonance imaging (CMR)
Other: Cardiac magnetic resonance imaging (CMR)
CMR is obtained on all participants in all arms/groups

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Frequency of the Diffuse Myocardial Fibrosis Phenotype
Time Frame: Assessed annually over a 2-year period (3 assessments over 2 years)
The occurrence of an abnormally increased extracellular volume (ECV) measurement [i.e., the presence of the diffuse myocardial fibrosis phenotype] as assessed by cardiac magnetic resonance imaging (CMR) using T1 mapping before and after administration of gadolinium. Expressed as number of participants with the diffuse myocardial fibrosis phenotype in each stratum.
Assessed annually over a 2-year period (3 assessments over 2 years)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Stability of the Diffuse Myocardial Fibrosis Phenotype Over Time
Time Frame: Assessed annually over a 2-year period (3 assessments over 2 years)
The occurrence of a change [from the baseline assessment] in the classification [presence or absence] of the diffuse myocardial fibrosis phenotype, which is defined as an abnormally increased extracellular volume (ECV) measurement as assessed by cardiac magnetic resonance imaging (CMR) using T1 mapping before and after administration of gadolinium. Expressed as number of participants who had a change in classification of the diffuse myocardial fibrosis phenotype [e.g., presence to absence, or absence to presence] during the 2-year study in each stratum.
Assessed annually over a 2-year period (3 assessments over 2 years)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Hospital Medical Center, Cincinnati

Investigators

  • Principal Investigator: Charles T Quinn, M.D., Children's Hospital Medical Center, Cincinnati
  • Principal Investigator: Michael D Taylor, MD, Children's Hospital Medical Center, Cincinnati
  • Principal Investigator: Robert J Fleck, M.D., Children's Hospital Medical Center, Cincinnati
  • Principal Investigator: Omar Y Niss, M.D., Children's Hospital Medical Center, Cincinnati

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 31, 2014

Primary Completion (Actual)

January 29, 2018

Study Completion (Actual)

May 20, 2019

Study Registration Dates

First Submitted

May 2, 2014

First Submitted That Met QC Criteria

April 2, 2015

First Posted (Estimate)

April 8, 2015

Study Record Updates

Last Update Posted (Actual)

November 2, 2020

Last Update Submitted That Met QC Criteria

October 7, 2020

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012-4851

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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