Clinical trial NCT01077921: Study of Propranolol as Anti-Adhesive Therapy in Sickle Cell Disease (SCD)
Official title: Phase II Study of Propranolol as Anti-Adhesive Therapy for Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease
Keywords: sickle
adhesion
propranolol
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2010-03-01
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment
timeFrame: Week 0 to 6 and week 8 to 14
measure: SS RBC Adhesion (Epi -2d/cm2- vs. Sham) by Treatment
timeFrame: Week 0 to 6 and week 8 to 14
measure: SS RBC Adhesion (Epi -3d/cm2- vs. Sham) by Treatment
timeFrame: Week 0 to 6 and week 8 to 14
Secondary outcomes:
measure: Overall Change of Plasma Levels of sE-selectin
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Plasma Levels of sP-selectin
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Plasma Levels of sICAM-1
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Plasma Levels of sVCAM-1
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Hemoglobin (Hgb) Levels
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Hematocrit (Hct) Levels
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Lactate Dehydrogenase (LDH) Levels
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Oxygen Saturation (02Sat) Levels
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Systolic Blood Pressure Levels
timeFrame: Week 0 to 6 and week 8 to 14
measure: Overall Change of Diastolic Blood Pressure Levels
timeFrame: Week 0 to 6 and week 8 to 14
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
References:
citation: Zennadi R, Hines PC, De Castro LM, Cartron JP, Parise LV, Telen MJ. Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. Blood. 2004 Dec 1;104(12):3774-81. doi: 10.1182/blood-2004-01-0042. Epub 2004 Aug 12.
citation: Zennadi R, Moeller BJ, Whalen EJ, Batchvarova M, Xu K, Shan S, Delahunty M, Dewhirst MW, Telen MJ. Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo. Blood. 2007 Oct 1;110(7):2708-17. doi: 10.1182/blood-2006-11-056101. Epub 2007 Jul 3.
citation: Zennadi R, Chien A, Xu K, Batchvarova M, Telen MJ. Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium. Blood. 2008 Oct 15;112(8):3474-83. doi: 10.1182/blood-2008-01-134346. Epub 2008 Jul 29.
citation: Eyler CE, Jackson T, Elliott LE, De Castro LM, Jonassaint J, Ashley-Koch A, Telen MJ. beta(2)-Adrenergic receptor and adenylate cyclase gene polymorphisms affect sickle red cell adhesion. Br J Haematol. 2008 Apr;141(1):105-8. doi: 10.1111/j.1365-2141.2008.07008.x.
citation: De Castro LM, Zennadi R, Jonassaint JC, Batchvarova M, Telen MJ. Effect of propranolol as antiadhesive therapy in sickle cell disease. Clin Transl Sci. 2012 Dec;5(6):437-44. doi: 10.1111/cts.12005. Epub 2012 Oct 17.