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

Purpose

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 SS RBC adhesion by epinephrine.

Condition	Intervention	Phase
Sickle Cell Disease	Drug: Propranolol Drug: Placebo	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
Official Title:	Phase II Study of Propranolol as Anti-Adhesive Therapy for Sickle Cell Disease

Resource links provided by NLM:

Genetics Home Reference related topics: sickle cell disease

MedlinePlus related topics: Adhesions Sickle Cell Anemia

Drug Information available for: Propranolol hydrochloride Propranolol

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:

Establish the safety and efficacy of long-term therapy with propranolol as an anti-adhesive therapy for SCD [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
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. Each patient participant will be carefully monitored for any adverse events. Specifically, we will monitor the following: hemoglobin, hematocrit, and changes in cardiovascular parameters (HR, BP, 02 saturation). Also occurrence of symptoms and medical complications will be monitored.

Secondary Outcome Measures:

Evaluate changes in soluble markers of endothelial activation and dysfunction. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
Plasma levels of sVCAM-1, sICAM-1, sE-selectin, and sP-selectin will be measured on plasma samples using ELISA kits. We theorize that reduction in SS RBC adhesion to endothelium due to chronic propranolol therapy will reduce endothelial activation and dysfunction, since SS RBC adhesion has been previously shown to induce expression of such markers in vitro. All patient participants will also have genotyping performed on two specific genes, ADRB2 and ADCY6. Polymorphisms in these genes have been associated with adhesion of RBCs to laminin.

Enrollment:	27
Study Start Date:	June 2010
Estimated Study Completion Date:	July 2013
Primary Completion Date:	March 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Propranolol Drug arm	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 Comparator: Sugar pill Placebo arm	Drug: 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).

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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 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, 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01077921

Locations

United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Laura M. De Castro

National Heart, Lung, and Blood Institute (NHLBI)

More Information

Publications:

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.

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.

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. Epub 2008 Jul 29.

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.

Responsible Party:	Laura M. De Castro, Associate Professor, Duke University Medical Center
ClinicalTrials.gov Identifier:	NCT01077921 History of Changes
Other Study ID Numbers:	Pro00018427, K01 HL96434-02., 5 R21 HL096123-02
Study First Received:	February 26, 2010
Last Updated:	April 29, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Duke University:

sickle
adhesion
propranolol

Additional relevant MeSH terms:

Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Propranolol
Anti-Arrhythmia Agents
Cardiovascular Agents

Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Vasodilator Agents

ClinicalTrials.gov processed this record on May 22, 2013