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

Sickle Cell Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01077921
• Other study ID #: Pro00018427
• Secondary ID: K01HL096434-025R
• Status: Completed
• Phase: Phase 2
• First received: February 26, 2010
• Last updated: January 19, 2015
• Start date: June 2010
• Est. completion date: December 2013

Study information

• Verified date: January 2015
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis by electrophoresis (HEP) of Hemoglobin (Hgb) SS or Hgb Sß0 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Propranolol
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).
• Placebo
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).

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Laura M. De Castro, MD	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View 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. — View 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. — View 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. Epub 2004 Aug 12. — View 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. Epub 2007 Jul 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes