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NCT Number: NCT01077921

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

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.

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Key information

Conditions

Sickle Cell Disease Anemia Anemia, Hemolytic Anemia, Hemolytic, Congenital Anemia, Sickle Cell Cicatrix Congenital, Hereditary, and Neonatal Diseases and Abnormalities Fibrosis Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobinopathies Pathologic Processes Pathological Conditions, Signs and Symptoms Tissue Adhesions

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Propranolol

Drug

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

Drug

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 outcomes

  1. 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

  2. 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

  3. 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 outcomes

  1. 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).

  2. 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).

  3. 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)

  4. 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)

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

Sponsors and collaborators

Lead sponsor

Laura M. De Castro, MD

Other

Collaborators

  • National Heart, Lung, and Blood Institute (NHLBI)

Registry information

Official study title

Phase II Study of Propranolol as Anti-Adhesive Therapy for Sickle Cell Disease

Important dates

Study start
2010
Primary completion
2013
Study completion
2013
First posted
Mar 1, 2010
Registry last updated
Jan 22, 2015

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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