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

Study Overview
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Brief Summary
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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.

Official Title
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Phase II Study of Propranolol as Anti-Adhesive Therapy for Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Propranolol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propranolol<br>Drug arm | Drug: Propranolol<br>* Treatment will be with a standard propranolol dose of 40 mg every 12 hrs.Each patient will participate in 6 weeks of treatment with placebo or study drug (propranolol), followed by a 2-week wash-out period and then 6 weeks of treatment with the other modality (placebo or propranolol).<br>|
| Placebo Comparator: Sugar pill<br>Placebo arm | Drug: Placebo<br>* Treatment will be with a standard propranolol dose of 40 mg every 12 hrs.Each patient will participate in 6 weeks of treatment with placebo or study drug (propranolol), followed by a 2-week wash-out period and then 6 weeks of treatment with the other modality (placebo or propranolol).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Week 0 to 6 and week 8 to 14 | 
| SS RBC Adhesion (Epi -2d/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 2 dyne/cm2 | Week 0 to 6 and week 8 to 14 | 
| SS RBC Adhesion (Epi -3d/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 3 dyne/cm2 | Week 0 to 6 and week 8 to 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Change of Plasma Levels of sE-selectin | Biomarkers of Endothelial Activation and Dysfunction: Overall change of Plasma levels of sE-selectin measured in triplicate on plasma samples using commercially available ELISA kits from baseline to post intervention ( Week 0 to 6 and week 8 to 14). | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Plasma Levels of sP-selectin | Biomarkers of Endothelial Activation and Dysfunction: Overall change of Plasma levels of sP-selectin measured in triplicate on plasma samples using commercially available ELISA kits from baseline to post intervention ( Week 0 to 6 and weeks 8 to 14). | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Plasma Levels of sICAM-1 | Biomarkers of Endothelial Activation and Dysfunction: Overall change of Plasma levels of sICAM-1 measured in triplicate on plasma samples using commercially available ELISA kits from baseline to post intervention ( Week 0 to 6 and week 8 to 14) | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Plasma Levels of sVCAM-1 | Biomarkers of Endothelial Activation and Dysfunction: Overall change of Plasma levels of sVCAM-1 measured in triplicate on plasma samples using commercially available ELISA kits from baseline to post intervention ( Week 0 to 6 or week 8 to 14) | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Hemoglobin (Hgb) Levels | Overall change of Hemoglobin (Hgb) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Hematocrit (Hct) Levels | Overall change of Hematocrit (Hct) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Lactate Dehydrogenase (LDH) Levels | Overall change of LDH levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Oxygen Saturation (02Sat) Levels | Overall change of Oxygen Saturation (02Sat) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Systolic Blood Pressure Levels | Overall change of Systolic Blood Pressure levels from baseline to post intervention (Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated | Week 0 to 6 and week 8 to 14 | 
| Overall Change of Diastolic Blood Pressure Levels | Overall change of Diastolic Blood Pressure levels from baseline to post intervention (Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated | Week 0 to 6 and week 8 to 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle, adhesion, propranolol