Back to resultsStudy of Propranolol as Anti-Adhesive Therapy in Sickle Cell Disease (SCD)
Primary Purpose
Sickle Cell Disease
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Propranolol
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Disease focused on measuring sickle, adhesion, propranolol
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
Sites / Locations
- Duke University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Propranolol
Sugar pill
Arm Description
Drug arm
Placebo arm
Outcomes
Primary Outcome Measures
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
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
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
Secondary Outcome Measures
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).
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).
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)
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)
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
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
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
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
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
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
Full Information
NCT ID
NCT01077921
First Posted
February 26, 2010
Last Updated
January 19, 2015
Sponsor
Laura M. De Castro, MD
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT01077921
Brief Title
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
2. Study Status
Record Verification Date
January 2015
Overall Recruitment Status
Completed
Study Start Date
June 2010 (undefined)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
December 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Laura M. De Castro, MD
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
sickle, adhesion, propranolol
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
31 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Propranolol
Arm Type
Experimental
Arm Description
Drug arm
Arm Title
Sugar pill
Arm Type
Placebo Comparator
Arm Description
Placebo arm
Intervention Type
Drug
Intervention Name(s)
Propranolol
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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).
Primary Outcome Measure Information:
Title
SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment
Description
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
Time Frame
Week 0 to 6 and week 8 to 14
Title
SS RBC Adhesion (Epi -2d/cm2- vs. Sham) by Treatment
Description
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
Time Frame
Week 0 to 6 and week 8 to 14
Title
SS RBC Adhesion (Epi -3d/cm2- vs. Sham) by Treatment
Description
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
Time Frame
Week 0 to 6 and week 8 to 14
Secondary Outcome Measure Information:
Title
Overall Change of Plasma Levels of sE-selectin
Description
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).
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Plasma Levels of sP-selectin
Description
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).
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Plasma Levels of sICAM-1
Description
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)
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Plasma Levels of sVCAM-1
Description
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)
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Hemoglobin (Hgb) Levels
Description
Overall change of Hemoglobin (Hgb) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Hematocrit (Hct) Levels
Description
Overall change of Hematocrit (Hct) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Lactate Dehydrogenase (LDH) Levels
Description
Overall change of LDH levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Oxygen Saturation (02Sat) Levels
Description
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
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Systolic Blood Pressure Levels
Description
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
Time Frame
Week 0 to 6 and week 8 to 14
Title
Overall Change of Diastolic Blood Pressure Levels
Description
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
Time Frame
Week 0 to 6 and week 8 to 14
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
15308566
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.
Results Reference
background
PubMed Identifier
17609430
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.
Results Reference
background
PubMed Identifier
18664622
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.
Results Reference
background
PubMed Identifier
18324973
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.
Results Reference
background
PubMed Identifier
23253664
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.
Results Reference
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Study of Propranolol as Anti-Adhesive Therapy in Sickle Cell Disease (SCD)
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