Comment Period Extended to 3/23/2015 for Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials
Text Size

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

This study has been completed.
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Laura M. De Castro, MD, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT01077921
First received: February 26, 2010
Last updated: January 19, 2015
Last verified: January 2015
History of Changes
  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
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:

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:
  • SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment [ Time Frame: Week 0 to 6 and week 8 to 14 ] [ 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. 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 ] [ 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. 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 ] [ 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. 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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
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 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:

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, K01 HL96434-02., 5 R21 HL096123-02
Study First Received: February 26, 2010
Results First Received: December 30, 2014
Last Updated: January 19, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Duke University:
sickle
adhesion
propranolol

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Propranolol
Adrenergic Agents
Adrenergic Antagonists
 Adrenergic beta-Antagonists
Anti-Arrhythmia Agents
Antihypertensive Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on February 27, 2015