Losartan for Diffuse Myocardial Fibrosis in Sickle Cell Disease

Study Overview
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Brief Summary
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This study is a pilot, phase II, open-label study of the angiotensin II receptor blocker, losartan, in patients with Sickle Cell Disease (SCD) 6 years or older for 12 months. The investigators will enroll 24 patients with SCD over the course of 1 year with a goal to complete all study procedures in 2 years. The short-term goal is to obtain clinical pilot data regarding the safety and efficacy of losartan in stabilizing or decreasing extracellular volume fraction (ECV) after 12 months of therapy.

Official Title
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Losartan for Diffuse Myocardial Fibrosis in Sickle Cell Disease: A Prospective, Phase II Study.

Conditions
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Sickle Cell Disease, Diffuse Myocardial Fibrosis

Intervention / Treatment
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* Drug: Losartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 6 years old or older Diagnosis of HbSS or Sbeta0-thalassemia Ability to cooperate with and undergo CMR without sedation or anesthesia Ability to cooperate with and undergo echocardiogram without sedation or anesthesia Patients who are on a stable dose of sickle cell disease-modifying therapy: Hydroxyurea, Voxelotor, L-Glutamine, or Crizanlizumab, for 3 months prior to enrollment will be eligible. Exclusion Criteria: Current chronic transfusion therapy. Patients who received a simple transfusion for an acute event will be eligible 3 months after completion of transfusion SCD genotypes other than specified in inclusion criteria Any contraindication to CMR such as metallic implants Inability to cooperate with CMR or echocardiography imaging Known congenital heart disease Estimated GFR ≤ to 30 mL/min/1.73 m2 by creatinine clearance Pregnant or lactating females or females of child-bearing potential who are unable to use a medically accepted form of contraception throughout the study Treatment with a renin-angiotensin pathway inhibitor during the 2 weeks prior to enrollment Hypersensitivity to angiotensin receptor II blockers Hyperkalemia (K>5.5 mEq/L) on a non-hemolyzed sample despite low-potassium diet Hepatic dysfunction defined as serum ALT > 5x the upper normal limit for age Current lithium therapy Chronic daily use of NSAID HIV infection.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan<br>Participants will receive oral losartan as tablets or oral solution one time daily. The dosing will depend on age and will be based on drug label and dosing used in studies on patients with SCD. | Drug: Losartan<br>* Losartan dosing for participants <16 years will be 0.7 mg/kg (maximum of 50 mg) once daily. The dose can be increased to 1.4 mg/kg (maximum of 100 mg once daily) after 2 weeks if the dose was tolerated (no hypotension or hyperkalemia). For patients ≥16 years, the starting dose will be 50 mg once daily which can be increased to 100 mg daily if tolerated after 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in extracellular volume fraction (ECV) after 1 year of losartan treatment | Efficacy of losartan in stabilizing or reducing ECV (diffuse myocardial fibrosis) in SCD after one year. | after 1 year of losartan treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Diastolic Function | Efficacy of losartan in improving diastolic function defined by echocardiographic and tissue Doppler assessment . | after 1 year of losartan treatment. | 
| Change in Exercise Capacity | Efficacy of losartan in improving cardiopulmonary exercise testing (CPET) measurements. | after 1 year of losartan treatment. | 
| Predicting Myocardial Fibrosis | Explore the performance characteristics of the following serum biomarkers in predicting myocardial fibrosis in patients with SCD: PICP, PIIINP, TGF-β, CTGF, soluble ST2, galectin-3, and NT-proBNP. | At baseline and after one year of losartan treaement |