Study of Propranolol as Anti-Adhesive Therapy in Sickle Cell Disease (SCD)

Laura M. De Castro, MD31 enrolled

Overview

An open label, prospective, randomized cross-over phase II study in up to 60 sickle cell patients who are either homozygous for Hb S or have HbSB0 thalassemia. Initially, each patient will be treated for 6 weeks with placebo or a standard dose of propranolol (40 mg) every 12 hrs. This will be followed by a 2-week washout period after which, patients will receive the other treatment modality (placebo or propranolol). We Hypothesize that propranolol administered in vivo on a daily basis for 6 weeks (1) will decrease baseline adhesion to endothelial cells and will substantially abrogate epinephrine-stimulated adhesion to endothelial cells, as measured in vitro; (2) will improve biomarkers of endothelial activation and dysfunction; and (3) can be safely used in patients with SCD. Thus, the use of propranolol in SCD may represent a safe and effective means of anti-adhesive therapy in SCD. Study Objectives: Primary Objective: • To establish the safety and efficacy of long-term therapy with propranolol as an anti-adhesive therapy for SCD. Secondary Objective: • To evaluate changes in soluble markers of endothelial activation and dysfunction. Correlative Science Objective: • To determine whether response to propranolol therapy is associated with polymorphisms in genes encoding the proteins involved in the upregulation of Sickle Red Blood Cell (SS RBC) adhesion by epinephrine.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Sickle Cell Disease

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis by electrophoresis (HEP) of Hemoglobin (Hgb) SS or Hgb Sβ0 thalassemia (all patients followed at our clinic have HEP-confirmed diagnosis on file) * Age ≥ 18 years * Blood pressure (BP) Systolic ≥ 95mm Hg and Diastolic ≥ 50mm Hg * Heart rate (HR) ≥ 70 and ≤ 110 bpm * Oxygen saturation by pulse oximeter and at room air ≥ 92% * Hematocrit (Hct) ≥ 20% and Hb \> 6.0 g/dL * Euthyroid status as indicated by normal Thyroid Stimulating Hormone (TSH) * SS RBCs obtained during screening period demonstrating an adhesion response to epinephrine of 40% over non-stimulated baseline adhesion to endothelial cells * Capacity to understand and sign informed consent Exclusion Criteria: * History of vaso-occlusive episode during the 6 wks prior to screening * RBC transfusion during the 3 months prior to study entry * Ongoing pregnancy * History of heart failure, myocardial infarct (MI), bradyarrhythmias, conduction defects * History of asthma or reactive airway disease * History of thyroid disease * Diabetes * Renal insufficiency (BUN \>21 mg/dL and/or Creatinine \>1.4 mg/dL) * Use during the screening or study period of any of the following medications: antihypertensives, diuretics, thyroid replacement therapy, anti-arrhythmia medications, bronchodilators, inhaled steroids, insulin, or hypoglycemic medication * History of allergy to sulfonamides

Outcomes

Primary Outcomes

SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment

The stickiness of SS RBC will be evaluated by a well-established in vitro assay of adhesion of SS RBCs to cultured endothelial cells using a flow chamber. Overall change of adhesion from baseline to post intervention( Week 0 to 6 and week 8 to 14) in unstimulated cells (Sham treated) vs. Stimulated Red Blood Cells (Epi-treated) at 1 dyne/cm2