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 Sickle Red Blood Cell (SS RBC) adhesion by epinephrine.

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


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double Blind (Participant, Care Provider, 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: Sickle Cell Anemia

Drug Information available for: Propranolol hydrochloride Propranolol

Genetic and Rare Diseases Information Center resources: Sickle Cell Anemia

U.S. FDA Resources

Further study details as provided by Laura M. De Castro, MD, Duke University Medical Center:

Primary Outcome Measures:

SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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
SS RBC Adhesion (Epi -2d/cm2- vs. Sham) by Treatment [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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
SS RBC Adhesion (Epi -3d/cm2- vs. Sham) by Treatment [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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

Secondary Outcome Measures:

Overall Change of Plasma Levels of sE-selectin [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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).
Overall Change of Plasma Levels of sP-selectin [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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).
Overall Change of Plasma Levels of sICAM-1 [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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)
Overall Change of Plasma Levels of sVCAM-1 [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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)
Overall Change of Hemoglobin (Hgb) Levels [ Time Frame: Week 0 to 6 and week 8 to 14 ]
Overall change of Hemoglobin (Hgb) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Overall Change of Hematocrit (Hct) Levels [ Time Frame: Week 0 to 6 and week 8 to 14 ]
Overall change of Hematocrit (Hct) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Overall Change of Lactate Dehydrogenase (LDH) Levels [ Time Frame: Week 0 to 6 and week 8 to 14 ]
Overall change of LDH levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Overall Change of Oxygen Saturation (02Sat) Levels [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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
Overall Change of Systolic Blood Pressure Levels [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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
Overall Change of Diastolic Blood Pressure Levels [ Time Frame: Week 0 to 6 and week 8 to 14 ]
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


Enrollment:	31
Study Start Date:	June 2010
Study Completion Date:	December 2013
Primary Completion Date:	December 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 (Adult, Senior)
Sexes Eligible for Study:	All
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 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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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, MD

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. doi: 10.1182/blood-2008-01-134346. 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. doi: 10.1111/j.1365-2141.2008.07008.x.

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.


Responsible Party:	Laura M. De Castro, MD, Associate Professor, Duke University Medical Center
ClinicalTrials.gov Identifier:	NCT01077921 History of Changes
Other Study ID Numbers:	Pro00018427 K01HL096434-02 ( U.S. NIH Grant/Contract ) 5R21HL096123-02 ( U.S. NIH Grant/Contract )
Study First Received:	February 26, 2010
Results First Received:	December 30, 2014
Last Updated:	January 19, 2015

Keywords provided by Laura M. De Castro, MD, Duke University Medical Center:


sickle adhesion propranolol

Additional relevant MeSH terms:


Anemia, Sickle Cell Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn Propranolol Adrenergic beta-Antagonists	Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Anti-Arrhythmia Agents Antihypertensive Agents Vasodilator Agents

ClinicalTrials.gov processed this record on July 21, 2017