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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01077921
Recruitment Status : Completed
First Posted : March 1, 2010
Results First Posted : January 22, 2015
Last Update Posted : January 22, 2015
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Laura M. De Castro, MD, Duke University

Tracking Information
First Submitted Date  ICMJE February 26, 2010
First Posted Date  ICMJE March 1, 2010
Results First Submitted Date  ICMJE December 30, 2014
Results First Posted Date  ICMJE January 22, 2015
Last Update Posted Date January 22, 2015
Study Start Date  ICMJE June 2010
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 19, 2015)
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: February 26, 2010)
Establish the safety and efficacy of long-term therapy with propranolol as an anti-adhesive therapy for SCD [ Time Frame: 16 weeks ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 19, 2015)
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: February 26, 2010)
Evaluate changes in soluble markers of endothelial activation and dysfunction. [ Time Frame: 16 weeks ]
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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Propranolol as Anti-Adhesive Therapy in Sickle Cell Disease (SCD)
Official Title  ICMJE Phase II Study of Propranolol as Anti-Adhesive Therapy for Sickle Cell Disease
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE
  • 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).
  • 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).
Study Arms  ICMJE
  • Experimental: Propranolol
    Drug arm
    Intervention: Drug: Propranolol
  • Placebo Comparator: Sugar pill
    Placebo arm
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 19, 2015)
31
Original Estimated Enrollment  ICMJE
 (submitted: February 26, 2010)
40
Actual Study Completion Date  ICMJE December 2013
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01077921
Other Study ID Numbers  ICMJE Pro00018427
K01HL096434-02 ( U.S. NIH Grant/Contract )
5R21HL096123-02 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Laura M. De Castro, MD, Duke University
Study Sponsor  ICMJE Laura M. De Castro, MD
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE Not Provided
PRS Account Duke University
Verification Date January 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP