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

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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Sickle Cell Disease
Interventions Drug: Propranolol
Drug: Placebo
Enrollment 31
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.
Arm/Group Title Propranolol-first Placebo-first
Hide Arm/Group Description 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 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.
Period Title: First Intervention
Started 14 13
Completed 13 12
Not Completed 1 1
Period Title: Washout
Started 13 12
Completed 13 10
Not Completed 0 2
Period Title: Second Intervention
Started 13 10
Completed 13 9
Not Completed 0 1
Arm/Group Title Propranolol-first Placebo-first Total
Hide Arm/Group Description 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 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 Total of all reporting groups
Overall Number of Baseline Participants 14 13 27
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 14 participants 13 participants 27 participants
34.2
(29.4 to 40.8)
26.1
(24.7 to 32.7)
30.4
(25.6 to 39.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants 13 participants 27 participants
Female
8
  57.1%
9
  69.2%
17
  63.0%
Male
6
  42.9%
4
  30.8%
10
  37.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 14 participants 13 participants 27 participants
14 13 27
1.Primary Outcome
Title SS RBC Adhesion (Epi -1d/cm2- vs. Sham) by Treatment
Hide Description 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
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing the placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: Percentage of total RBC
Epinephrine Treated Red blood cells 0  (24.4) -0.3  (20.1)
unstimulated cells (Sham treated) 7.4  (18.7) 2.7  (26)
2.Primary Outcome
Title SS RBC Adhesion (Epi -2d/cm2- vs. Sham) by Treatment
Hide Description 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
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: Percentage of total RBC
Epi-treated Red blood cells 0.2  (13.8) -2.8  (10.7)
unstimulated cells (Sham treated) 2.7  (11.2) 4.4  (13)
3.Primary Outcome
Title SS RBC Adhesion (Epi -3d/cm2- vs. Sham) by Treatment
Hide Description 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
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: Percentage of total RBC
Epi-treated Red blood cells 0.5  (9.7) -2.8  (7.5)
unstimulated cells (Sham treated) -0.1  (9.3) 4.3  (10)
4.Secondary Outcome
Title Overall Change of Plasma Levels of sE-selectin
Hide Description 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).
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: ng/ml
-3.9  (12.1) 3.7  (9.3)
5.Secondary Outcome
Title Overall Change of Plasma Levels of sP-selectin
Hide Description 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).
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: ng/ml
-5  (13.9) -12.8  (54.8)
6.Secondary Outcome
Title Overall Change of Plasma Levels of sICAM-1
Hide Description 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)
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: ng/ml
-6.4  (15.3) 5.4  (28.5)
7.Secondary Outcome
Title Overall Change of Plasma Levels of sVCAM-1
Hide Description 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)
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Mean (Standard Deviation)
Unit of Measure: ng/ml
-16.7  (144.2) -7.2  (117.7)
8.Secondary Outcome
Title Overall Change of Hemoglobin (Hgb) Levels
Hide Description Overall change of Hemoglobin (Hgb) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Median (Inter-Quartile Range)
Unit of Measure: gm/dL
0.2
(0.1 to 0.5)
-0.1
(-0.7 to 0.4)
9.Secondary Outcome
Title Overall Change of Hematocrit (Hct) Levels
Hide Description Overall change of Hematocrit (Hct) levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Median (Inter-Quartile Range)
Unit of Measure: percentage of red blood cells
1
(0 to 2.0)
0
(-2.0 to 1.0)
10.Secondary Outcome
Title Overall Change of Lactate Dehydrogenase (LDH) Levels
Hide Description Overall change of LDH levels from baseline to post intervention( Week 0 to 6 and week 8 to 14) Placebo vs. Propranolol treated
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Median (Inter-Quartile Range)
Unit of Measure: IU/L
24
(-69 to 107)
-5
(-40.5 to 33)
11.Secondary Outcome
Title Overall Change of Oxygen Saturation (02Sat) Levels
Hide Description 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
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Median (Inter-Quartile Range)
Unit of Measure: percentage of oxygen saturation
0
(0 to 2)
0
(-1 to 1.5)
12.Secondary Outcome
Title Overall Change of Systolic Blood Pressure Levels
Hide Description 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
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Median (Inter-Quartile Range)
Unit of Measure: mmHg
-1.0
(-4.0 to 5.0)
-1.0
(-8.0 to 5.5)
13.Secondary Outcome
Title Overall Change of Diastolic Blood Pressure Levels
Hide Description 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
Time Frame Week 0 to 6 and week 8 to 14
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description:
All subjects completing the propranolol treatment phase.
All subjects completing placebo treatment phase.
Overall Number of Participants Analyzed 22 23
Median (Inter-Quartile Range)
Unit of Measure: mmHg
0
(-4.0 to 5.0)
-1
(-7.0 to 5.0)
Time Frame [Not Specified]
Adverse Event Reporting Description All patients who were enrolled and had at least one baseline visit are included in the "at risk" category.
 
Arm/Group Title Propranolol Placebo
Hide Arm/Group Description 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: 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).
All-Cause Mortality
Propranolol Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Propranolol Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   4/27 (14.81%)   3/27 (11.11%) 
Musculoskeletal and connective tissue disorders     
Vaso-occlusive crisis resulting in hospitalization  4/27 (14.81%)  3/27 (11.11%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Propranolol Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   22/27 (81.48%)   19/27 (70.37%) 
Blood and lymphatic system disorders     
Lymphadenopathy  0/27 (0.00%)  1/27 (3.70%) 
Thrombocytopenia  1/27 (3.70%)  1/27 (3.70%) 
Cardiac disorders     
Atrioventricular (AV) block  0/27 (0.00%)  2/27 (7.41%) 
Bradycardia  1/27 (3.70%)  0/27 (0.00%) 
Drop in Blood Pressure  0/27 (0.00%)  1/27 (3.70%) 
Eye disorders     
Bilateral conjunctivitis  0/27 (0.00%)  1/27 (3.70%) 
Gastrointestinal disorders     
Abdominal Paiin  1/27 (3.70%)  2/27 (7.41%) 
Abdominal cramping  1/27 (3.70%)  0/27 (0.00%) 
Abdominal pain and bloating  1/27 (3.70%)  0/27 (0.00%) 
Blood per rectum  1/27 (3.70%)  0/27 (0.00%) 
Diarrhea  1/27 (3.70%)  2/27 (7.41%) 
Diarrhea, intermittent  1/27 (3.70%)  0/27 (0.00%) 
Nausea  1/27 (3.70%)  0/27 (0.00%) 
Nausea and vomiting  1/27 (3.70%)  2/27 (7.41%) 
Stomach ache  1/27 (3.70%)  1/27 (3.70%) 
General disorders     
Extreme tiredness  0/27 (0.00%)  2/27 (7.41%) 
Fatigue  4/27 (14.81%)  4/27 (14.81%) 
Feeling of internal heat  1/27 (3.70%)  0/27 (0.00%) 
Increased Fatigue  1/27 (3.70%)  0/27 (0.00%) 
Shakes  0/27 (0.00%)  1/27 (3.70%) 
ED Visit  0/27 (0.00%)  3/27 (11.11%) 
Infections and infestations     
E Coli Bacteremia  0/27 (0.00%)  1/27 (3.70%) 
Fever  1/27 (3.70%)  0/27 (0.00%) 
MRSA Positive  1/27 (3.70%)  0/27 (0.00%) 
Sinus Infection  1/27 (3.70%)  0/27 (0.00%) 
Sore throat  0/27 (0.00%)  2/27 (7.41%) 
Atypical mycoplasma pneumonia, Suspected  1/27 (3.70%)  0/27 (0.00%) 
Metabolism and nutrition disorders     
Sensitivity to cold  0/27 (0.00%)  1/27 (3.70%) 
Musculoskeletal and connective tissue disorders     
Pain Crisis  6/27 (22.22%)  4/27 (14.81%) 
Pain, Back  0/27 (0.00%)  1/27 (3.70%) 
Pain, Bone  0/27 (0.00%)  1/27 (3.70%) 
Pain, Increased knee pain  0/27 (0.00%)  1/27 (3.70%) 
Pain, Jaw  0/27 (0.00%)  1/27 (3.70%) 
Pain, Joint  0/27 (0.00%)  1/27 (3.70%) 
Pain, Knee  0/27 (0.00%)  1/27 (3.70%) 
Pain, Left chest wall  0/27 (0.00%)  1/27 (3.70%) 
Pain, Leg  1/27 (3.70%)  1/27 (3.70%) 
Pain, Musculoskeletal  1/27 (3.70%)  4/27 (14.81%) 
Pain, back and chest  0/27 (0.00%)  2/27 (7.41%) 
Toothache  0/27 (0.00%)  1/27 (3.70%) 
Vaso-occlusive Crisis  2/27 (7.41%)  2/27 (7.41%) 
Fracture, left foot  1/27 (3.70%)  0/27 (0.00%) 
Fatigue with chest tightness  1/27 (3.70%)  0/27 (0.00%) 
Pain, Hip  1/27 (3.70%)  0/27 (0.00%) 
Pain, Migrating  1/27 (3.70%)  0/27 (0.00%) 
Pain episode  1/27 (3.70%)  0/27 (0.00%) 
Pain, Right foot, plantar  1/27 (3.70%)  0/27 (0.00%) 
Pain, Leg, sharp shooting  1/27 (3.70%)  0/27 (0.00%) 
Pain, Shoulder/Chest  1/27 (3.70%)  0/27 (0.00%) 
Weakness  1/27 (3.70%)  0/27 (0.00%) 
Nervous system disorders     
Dizziness  1/27 (3.70%)  5/27 (18.52%) 
Headache  8/27 (29.63%)  8/27 (29.63%) 
Headache, extreme  0/27 (0.00%)  1/27 (3.70%) 
Dizziness/Vertigo  1/27 (3.70%)  0/27 (0.00%) 
Headache, Intermittent  1/27 (3.70%)  0/27 (0.00%) 
Lightheadness  1/27 (3.70%)  0/27 (0.00%) 
Vertigo  1/27 (3.70%)  0/27 (0.00%) 
Psychiatric disorders     
Worsening depression  0/27 (0.00%)  1/27 (3.70%) 
Renal and urinary disorders     
Pylonephritis due to E. Coli  0/27 (0.00%)  1/27 (3.70%) 
Smelly urine and bladder spasms  0/27 (0.00%)  1/27 (3.70%) 
Reproductive system and breast disorders     
Delayed menstrual period  0/27 (0.00%)  1/27 (3.70%) 
Prolonged menstrual period  0/27 (0.00%)  1/27 (3.70%) 
Respiratory, thoracic and mediastinal disorders     
Congestion, Upper Chest  0/27 (0.00%)  1/27 (3.70%) 
Cough  6/27 (22.22%)  1/27 (3.70%) 
Coughing, congestion  0/27 (0.00%)  1/27 (3.70%) 
Hoarseness  0/27 (0.00%)  1/27 (3.70%) 
Nasal Congestion  1/27 (3.70%)  4/27 (14.81%) 
Sneezing/Allergies  0/27 (0.00%)  1/27 (3.70%) 
Thrush  1/27 (3.70%)  0/27 (0.00%) 
Cold symptoms  2/27 (7.41%)  0/27 (0.00%) 
Shortness of breath on exertion  1/27 (3.70%)  0/27 (0.00%) 
Sore throat, intermittent  1/27 (3.70%)  0/27 (0.00%) 
Runny nose  1/27 (3.70%)  0/27 (0.00%) 
Shortness of breath  1/27 (3.70%)  0/27 (0.00%) 
sinus allergies  2/27 (7.41%)  0/27 (0.00%) 
Congestion, Sinus  1/27 (3.70%)  0/27 (0.00%) 
Sore throat, worsening  1/27 (3.70%)  0/27 (0.00%) 
Skin and subcutaneous tissue disorders     
Rash  0/27 (0.00%)  1/27 (3.70%) 
Skin abrasions due to pruritus  0/27 (0.00%)  1/27 (3.70%) 
Skin abrasions due to pruritis  1/27 (3.70%)  0/27 (0.00%) 
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Laura De Castro, MD, MHSc
Organization: Duke University Medical Center
Phone: (412) 623-7026
EMail: laura.decastro@dm.duke.edu
Layout table for additonal information
Responsible Party: Laura M. De Castro, MD, Duke University
ClinicalTrials.gov Identifier: NCT01077921     History of Changes
Other Study ID Numbers: Pro00018427
K01HL096434-02 ( U.S. NIH Grant/Contract )
5R21HL096123-02 ( U.S. NIH Grant/Contract )
First Submitted: February 26, 2010
First Posted: March 1, 2010
Results First Submitted: December 30, 2014
Results First Posted: January 22, 2015
Last Update Posted: January 22, 2015