Observational Study to Deeply Phenotype Major Organs in Sickle Cell Disease After Curative Therapies

Study Overview
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Brief Summary
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Background: People with sickle cell disease (SCD) have problems with their heart, brain, kidneys, liver, and lungs as they age. These problems may improve after transplant. Researchers want to learn how and why this happens. Objective: To study the benefits of treatments that are intended to cure SCD. Eligibility: People aged 18 and older with SCD who are either receiving curative therapy in the next 3 months or don t have any plans to receive a curative therapy in the next 2 years. Design: At their first visit, participants will be screened with their medical history and a physical exam. Participants will then have a baseline visit. This will take about a week to complete and will include: Blood and heart tests MRI of the brain, heart, and lungs. Participants will lie on a bed that will move into the MRI scanner. Special padding may be placed around their head to keep it still. Interactive games. Participants will complete computer games that test memory, attention, problem solving, language, spatial orientation, processing speed, and emotion. Questionnaire rating quality of life Iothalamate test. An IV catheter will be placed into a vein. A contrast agent will be injected through the IV. Blood will then be collected at different time points. Lung function tests and a 6-minute walk test Vibration controlled transient elastography. A probe placed on the abdomen will measure liver scarring. DOS test. A light attached to the finger or toe will measure blood oxygen. Participants will have an end-of-study visit about 2 years after their baseline visit. This will include repeats of the baseline visit tests.

Detailed Description
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Study Description: This study seeks to evaluate heart, lung, liver, kidney, brain, and neurocognitive function post-hematopoietic stem cell transplant (HSCT) in patients with sickle cell disease (SCD) who undergo curative therapies. Based on our preliminary data, the primary hypothesis is that diastolic function will improve after successful curative therapy as compared to baseline. Secondary analyses will include assessment of cardiopulmonary and kidney function. This study includes assessment of organs before and 2 years after curative therapies with deep phenotyping of the heart, lung, liver, brain, cognitive, and kidney function. Patients who undergo curative therapies will be compared to adults with SCD who receive non-curative therapies at baseline and 2 years later. This protocol will allow us to comprehensively explore sequelae of curative therapies on organ function in patients with SCD. Objectives: Primary Objective: -Evaluate left ventricular end diastolic volume/body surface area (LVEDV/BSA) in patients with SCD who undergo curative therapies as compared to patients who receive non-curative therapies at 2 years after initial testing. Secondary Objectives: Evaluate other markers of cardiopulmonary function in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies. Evaluate change in kidney function over time in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies. Tertiary Objectives: Perform deep phenotyping of heart, lung, liver, kidney, brain and neurocognitive function along with reported genetic variants in adults with SCD who undergo curative therapies as compared to adults with SCD who receive non-curative therapies. Assess markers of inflammation in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies. Evaluate markers of graft rejection and tolerance induction in patients with SCD who undergo curative therapies. Evaluate lipid profiles in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies. Assess whether curative therapies modulate sickle cell-associated coagulopathy as compared to those who receive non-curative therapies. Evaluate regional oxygenation (rS02) with Near Infrared Spectroscopy (NIRS) in patients with SCD who undergo curative therapies as compared to those who receive non-curative therapies. Evaluate novel biomarkers of organ damage in patients who receive curative therapies as compared to those who receive non-curative therapies. Endpoints: Primary Endpoint: Change in LVEDV/BSA Secondary Endpoints: Change in left ventricular end diastolic diameter (LVEDD), ejection fraction, left ventricular mass index, left atrial volume index, global longitudinal strain Change in N-terminal pro b-type natriuretic peptide (NTproBNP). Change in creatinine, cystatin-C, urine protein to creatinine ratio, urine albumin to creatinine ratio, and estimated glomerular filtration rate (eGFR) using the CKD-EPI equation Tertiary Endpoints: Change in myocardial fibrosis, extracellular volume fraction, processing speed, measured GFR, incidence of stroke/silent infarcts, cerebral blood flow, oxygen extraction fraction, and liver stiffness, and correlation of APOL1 risk alleles with renal function and degree of proteinuria Change in c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), inflammatory cytokines (including interferon gamma (IFN-y) and tumor necrosis factor alpha (TNF-a), chemokines, GlycA, and haptoglobin Change in regulatory cells (including regulatory T cells and myeloid-derived suppressor cells) and proteins (including galectin, platelet factor 4, and thrombospondin-1) and suppressive cytokines (interleukin-10 (IL-10), transforming growth factor beta, and IL-7) Change in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle size and number, triglycerides, and apolipoprotein A-I and B Change in Thrombin anti-thrombin complexes, D-dimer, prothrombin fragment 1.2 monocyte cell surface expression of tissue factor (TF), monocyte and endothelial cell-derived TF+ extracellular vesicles (EVs), procoagulant activity of TF+ EVs and proadhesive biomarkers including red blood cell surface phosphatidylserine exposure and circulating heterocellular aggregates Change in rS02 within the peripheral limb with NIRS Correlation of novel genetic biomarkers associated with organ damage in patients with SCD who receive curative therapy or noncurative therapy.

Official Title
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Observational Study to Deeply Phenotype Major Organs in Sickle Cell Disease After Curative Therapies

Conditions
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Mortality in Sickle Cell, Sickle Cell Cardiopulmonary Complications, Sickle Cell Organ Damage, Sickle Cell Life Expectancy and Risk Factors for Early Death, Sickle Cell Lung Disease and Sudden Death

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged >=18 years Current or previous diagnosis of any type of SCD (including HbSS, HbSC, HbSbeta0-thal, HbSbeta+-thal) Ability to travel to the NIH Clinical Center Ability of subject to understand and the willingness to sign a written informed consent document. Ability to undergo required studies except as specified in the Exclusion Criteria. Curative Therapies Group --Plan to receive conditioning for curative therapy at the NIH Clinical Center, Vanderbilt University Medical Center, or Johns Hopkins Hospital Non-Curative Therapy Group -- No plan to undergo curative therapy within 2 years At least one of the following eligibility criteria: History of stroke or abnormal transcranial doppler examination (>= 200 m/s) History of SCD-related renal insufficiency defined as a creatinine level >=1.3 mg/dL and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance < 50mL/min Tricuspid regurgitant velocity >= 2.5 m/s Recurrent tricorporal priapism defined as at least 2 episodes of an erection lasting > 4 hours involving the corpora cavernosa and corpus spongiosa SCD-associated liver disease defined as EITHER ferritin > 1000 mcg/L OR direct bilirubin > 0.4 mg/dL > 1 hospitalization per year for vaso-occlusive crises while on a therapeutic dose of hydroxyurea Any acute chest syndrome while on a therapeutic dose of hydroxyurea Osteonecrosis of 2 or more joints Red cell alloimmunization EXCLUSION CRITERIA: All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation. Prior transplantation (including but not limited to HSCT and kidney transplant) Pregnant or breastfeeding Patients with allergy to iodine or iodinated contrast solutions will not undergo Iothalamate or Iohexal GFR clearance testing but can undergo the other deep phenotype testing Implanted metal object that is not compatible with MRI (e.g.: cerebral aneurysm clip, cochlear implant, or pacemaker) Patients with a pacemaker or automated implantable cardioverter defibrillator will not undergo VCTE but can enroll and undergo the other deep phenotype testing as long as the device is compatible with MRI and MRI testing can be performed Patients requiring peritoneal or hemodialysis Uncontrolled infection or acute illness Criteria specific to the non-curative therapy group: Hydroxyurea initiation or dose adjustment <2 months prior Initiation of chronic transfusion therapy <2 months prior Antihypertensive medication initiation or dose adjustment <1 month prior

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| subjects w sickle cell disease<br>to evaluate heart, lung, liver, kidney, brain, and neurocognitive function post-hematopoietic stem cell transplant (HSCT) in subjects with sickle cell disease (SCD) who undergo curative therapies | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LVEDV/BSA in patients with SCD who undergo curative therapies as compared to patients who receive non-curative treatment | Evaluate whether diastolic function improves significantly more in patients who receive curative therapies as compared to those who receive non-curative treatment. | 2 years after initial testing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in creatinine, cystatin-C, urine protein to creatinine ratio, urine albumin to creatinine ratio, and estimated glomerular filtration rate (eGFR) using the CKD-EPI equation | Evaluate change in kidney function over time in patients with SCD who undergo curative therapies as compared to those who receive non-curative treatment. | 2 years | 
| Change in N-terminal pro b-type natriuretic peptide (NTproBNP). | Evaluate whether cardiopulmonary function improves more in patients who receive curative therapies as compared to non-curative therapy. | 2 years | 
| Change in left ventricular end diastolic diameter (LVEDD), ejection fraction, left ventricular mass index, left atrial volume index, global longitudinal strain | Evaluate whether cardiopulmonary function improves more in patients who receive curative therapies as compared to non-curative therapy. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hydroxyurea, Hydroxyurea-Increased Fetal Hemoglobin, sickle cell anemi, Patterns of mortality in sickle cell disease, Mortality rates and age at death from sickle cell, Natural History