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

NCT01077921 | Completed Phase 2 Results

• 3 other identifiers: Pro00018427K01HL096434-025R21HL096123-02
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

Conditions

Sickle Cell Disease

Keywords

sickle; adhesion; propranolol

Outcome Measures

Primary Outcomes (3)

• 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

  Week 0 to 6 and week 8 to 14

• 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

  Week 0 to 6 and week 8 to 14

• 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

  Week 0 to 6 and week 8 to 14

Secondary Outcomes (10)

• Overall Change of Plasma Levels of sE-selectin

  Week 0 to 6 and week 8 to 14

• Overall Change of Plasma Levels of sP-selectin

  Week 0 to 6 and week 8 to 14

• Overall Change of Plasma Levels of sICAM-1

  Week 0 to 6 and week 8 to 14

• Overall Change of Plasma Levels of sVCAM-1

  Week 0 to 6 and week 8 to 14

• Overall Change of Hemoglobin (Hgb) Levels

  Week 0 to 6 and week 8 to 14

Study Arms (2)

Propranolol

EXPERIMENTAL

Drug arm

Drug: Propranolol

Sugar pill

PLACEBO COMPARATOR

Placebo arm

Drug: Placebo

Interventions

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).

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).

Sugar pill

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Laura M. De Castro, MD: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (5)

• 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.

  PMID: 15308566 BACKGROUND

• 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.

  PMID: 17609430 BACKGROUND

• 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.

  PMID: 18664622 BACKGROUND

• 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.

  PMID: 18324973 BACKGROUND

• 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.

  PMID: 23253664 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Tissue Adhesions

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cicatrix; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Laura De Castro, MD, MHSc
• Organization: Duke University Medical Center

laura.decastro@dm.duke.edu

(412) 623-7026

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 26, 2010
• First Posted: March 1, 2010
• Study Start: June 1, 2010
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: January 22, 2015
• Results First Posted: January 22, 2015

Record last verified: 2015-01

Locations

US (1)