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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01077921

Enrollment

Registered

2010-03-01

Start date

2010-06-30

Completion date

2013-12-31

Last updated

2015-01-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Sickle Cell Disease

Keywords

sickle, adhesion, propranolol

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.

Interventions

DRUGPropranolol

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).

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment	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	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	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

Measure	Time frame	Description
Overall Change of Plasma Levels of sVCAM-1	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	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	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 Plasma Levels of sE-selectin	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 Oxygen Saturation (02Sat) Levels	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	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	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
Overall Change of Lactate Dehydrogenase (LDH) Levels	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 Plasma Levels of sP-selectin	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	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)

Countries

United States

Participant flow

Recruitment details

Subjects were recruited from the Duke adult sickle cell clinic. Those that consented underwent a screening visit to determine eligibility. If eligible they were enrolled on the study and received study drug within 30 days of screening

Pre-assignment details

Eighty-four patients were approached for the study, of those 28 declined to participate, 14 remained undecided. Forty-two patients consented. Thirthy-one of those consenting were enrolled and 27 randomized to the study.

Participants by arm

Arm	Count
Propranolol-first Cross-over study comprising treatment with propranolol for 6 weeks with a standard dose of 40 mg every 12 hrs, followed by a 2 weeks period washout, then similar treatment period with placebo followed by another 2 weeks washout period	14
Placebo-first Cross-over study comprising treatment with placebo for 6 weeks, followed by a 2 weeks period washout, then similar treatment period with propranolol with a standard dose of 40 mg every 12 hrs., followed by another 2 weeks washout period	13
Total	27

Baseline characteristics

Characteristic	Propranolol-first	Placebo-first	Total
Age, Continuous	34.2 years	26.1 years	30.4 years
Region of Enrollment United States	14 participants	13 participants	27 participants
Sex: Female, Male Female	8 Participants	9 Participants	17 Participants
Sex: Female, Male Male	6 Participants	4 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	22 / 27	19 / 27
serious Total, serious adverse events	4 / 27	3 / 27

Outcome results

Primary

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