Diffuse Myocardial Fibrosis, Sickle Cell Disease
Conditions
Brief summary
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.
Interventions
DRUGLosartan
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.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. 6 years old or older 2. Diagnosis of HbSS or Sbeta0-thalassemia 3. Ability to cooperate with and undergo CMR without sedation or anesthesia 4. Ability to cooperate with and undergo echocardiogram without sedation or anesthesia 5. 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
1. Current chronic transfusion therapy. Patients who received a simple transfusion for an acute event will be eligible 3 months after completion of transfusion 2. SCD genotypes other than specified in inclusion criteria 3. Any contraindication to CMR such as metallic implants 4. Inability to cooperate with CMR or echocardiography imaging 5. Known congenital heart disease 6. Estimated GFR ≤ to 30 mL/min/1.73 m2 by creatinine clearance 7. Pregnant or lactating females or females of child-bearing potential who are unable to use a medically accepted form of contraception throughout the study 8. Treatment with a renin-angiotensin pathway inhibitor during the 2 weeks prior to enrollment 9. Hypersensitivity to angiotensin receptor II blockers 10. Hyperkalemia (K\>5.5 mEq/L) on a non-hemolyzed sample despite low-potassium diet 11. Hepatic dysfunction defined as serum ALT \> 5x the upper normal limit for age 12. Current lithium therapy 13. Chronic daily use of NSAID 14. HIV infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in extracellular volume fraction (ECV) after 1 year of losartan treatment | after 1 year of losartan treatment. | Efficacy of losartan in stabilizing or reducing ECV (diffuse myocardial fibrosis) in SCD after one year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Diastolic Function | after 1 year of losartan treatment. | Efficacy of losartan in improving diastolic function defined by echocardiographic and tissue Doppler assessment . |
| Change in Exercise Capacity | after 1 year of losartan treatment. | Efficacy of losartan in improving cardiopulmonary exercise testing (CPET) measurements. |
| Predicting Myocardial Fibrosis | At baseline and after one year of losartan treaement | 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. |
Countries
United States
Outcome results
None listed