Sickle Cell Anemia, Sickle Cell Disease
Conditions
Keywords
sickle cell, sickle cell crisis, sickle cell pain crisis, vaso-occlusive crisis, vaso-occlusion, sickle cell anemia, sickle cell disease, genetic diseases, adenosine 2A Receptor Agonists, Lexiscan, Regadenoson, contrast-enhanced ultrasound, Hydroxyurea
Brief summary
Sickle cell disease (SCD) is an inherited blood disorder that causes the red blood cells to change their shape from a round shape to a half-moon/crescent or sickled shape. Sickle-shaped cells can cause problems by getting stuck in blood vessels, blocking blood flow, and can cause inflammation and injury to important body parts. There are no specific treatments that improve this condition and promote blood flow hindered by sickle cell blockages. Another big challenge in managing sickle cell disease is that there are no good measures to determine changes and improvements in blood flow. Contrast-enhanced ultrasound is a technique currently used to detect blood flow in the heart, muscles, and other organs. It is extremely sensitive and can detect blood flow in the smallest of blood vessels. It would be very useful in helping healthcare providers know whether treatment strategies are improving blood flow during sickle cell blockages. The hypothesis is that contrast-enhanced ultrasound will be a feasible tool for determining changes in blood flow of subjects with sickle cell disease.
Detailed description
Sickle cell disease is an inherited blood disorder that affects one of every 400 African-Americans newborns in the United States. Sickle cell disease causes the red blood cells to change their shape from a round shape to a half-moon sickle shape. Individuals who have sickle cell disease have a different type of protein that carries oxygen in the blood (hemoglobin) than individuals without sickle cell disease. This different type of hemoglobin makes the red blood cell change into a crescent shape under certain conditions. Sickle shaped cells are a problem because the often get stuck on blood vessels blocking the flow of blood, and cause inflammation and injury to important areas of the body. These symptoms can lead to a painful occurrence called a sickle cell crisis. Many individuals have to be admitted into the hospital because of the pain caused by a sickle cell crisis. Regadenoson is a drug that may help prevent inflammation and injury caused by the sickle shaped cells. This drug is approved by the FDA to be used as a bolus during a heart stress test in people unable to exercise enough to put stress on the heart by making it beat faster. In a recent Phase I study, a safe dose for regadenoson was determined for adults with sickle cell disease. This dose was given by a slow IV infusion for a 24-48 hour period. Hydroxyurea is the only FDA approved drug for the treatment of sickle cell disease. Hydroxyurea is a pill taken orally and works well but is not useful during a severe sickle cell crisis. In this study researchers will use a new method, contrast-enhanced ultrasound (CEU), to visualize tiny blood vessels in cardiac and skeletal muscle. Changes in CEU measurements before, during and after administration of regadenoson will be examined. Contrast-enhanced ultrasounds will also be performed in individuals who are not having a sickle cell crisis. Some of those individuals will also undergo CEU while they are having a sickle cell crisis to compare those measurements . Lastly CEU results will be compared between individuals with sickle cell anemia and healthy African-Americans. These CEU's will be used to determine if there are changes in the blood flow of tiny blood vessels in certain conditions. This study wants to know if this new method of contrast-enhanced ultrasound will be a useful tool for physicians to use in individuals with sickle cell anemia. The researchers also want to determine if this new method of CEU can be used to reveal if some treatments for sickle cell anemia work better than others.
Interventions
DRUGregadenoson infusion with contrast-enhanced ultrasound
Subjects who are not having a pain crisis receive a 24-hour infusion of regadenoson. Contrast-enhanced ultrasound will be performed four times during the 24 hour regadenoson infusion
PROCEDUREcontrast-enhanced ultrasound
Subjects who are not having a pain crisis will have contrast-enhanced ultrasound performed up to four times over a two-day period. Time points will resemble the time course used for the Regadenoson Arm, although no investigational drug will be given.
Sponsors
Medical College of Wisconsin
La Jolla Institute for Allergy & Immunology
University of Illinois at Chicago
Oregon Health and Science University
Dana-Farber Cancer Institute
Versiti Blood Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Regadenoson ARM Inclusion Criteria: * Diagnosis of sickle cell anemia confirmed by hemoglobin analysis * Ages 18 to 70 years * Subjects must have laboratory indices as outlined by the protocol * Reliable IV access as determined by physician Sickle Cell Controls ARM Inclusion Criteria: * Diagnosis of sickle cell anemia confirmed by hemoglobin analysis * Ages 18 to 70 years Sickle Cell CEU ARM Inclusion Criteria: * Diagnosis of sickle cell anemia, confirmed by hemoglobin analysis * Males and females age 18-70 years Healthy Control ARM Inclusion Criteria: * African American * Ages 18 to 70 years Technique Optimization Control ARM Inclusion Criteria: -Ages 18 to 70 years
Exclusion criteria
Regadenoson ARM
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Microvascular Blood Flow Rate Change | Between baseline and 24 hours | Primary outcome measure will be a 40% increase in skeletal muscle microvascular blood flow when 24 hour measurements are compared to baseline in subjects receiving Regadenoson. We took measurements in patients who received Regadenoson, as well as Sickle Cell controls. Both arms had microvascular blood flow (volume x velocity) measured at baseline and 24-hours, and those values were compared. A change ratio of \>1 means that the flow rate increased at 24 hours and a change ratio of \<1 means that the flow rate decreased at 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MVBF Ratio of Change During a Pain Crisis | Between baseline and between 7-30 days after pain crisis, if feasible | We planned to examine differences in microvascular blood flow using contrast-enhanced ultrasound (CEU) in adults with sickle cell anemia age 18 and older at baseline state compared to a pain crisis. We were measuring changes in microvascular blood flow in subjects with sickle cell anemia during a pain crisis by examining differences in microvascular blood flow using contrast-enhanced ultrasound at a baseline state, and comparing those measurements to contrast-enhanced ultrasound measurements during a pain crisis. A change ratio of \>1 means that the flow rate increased during a pain crisis and a change ratio of \<1 means that the flow rate decreased during a pain crisis. |
| Microvascular Blood Flow in Sickle Cell Anemia Subjects Versus Control Subjects | 5 years | Examine microvascular blood flow using contrast-enhanced ultrasounds in adult subjects with sickle cell anemia compared to microvascular blood flow of healthy African-American adults |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regadenoson ARM Adult subjects with sickle cell anemia will receive a regadenoson infusion with contrast-enhanced ultrasound
regadenoson infusion with contrast-enhanced ultrasound: Subjects who are not having a pain crisis receive a 24-hour infusion of regadenoson. Contrast-enhanced ultrasound will be performed four times during the 24 hour regadenoson infusion | 20 |
| Sickle Cell Controls ARM Adult subjects with sickle cell anemia will receive contrast-enhanced ultrasound
contrast-enhanced ultrasound: Subjects who are not having a pain crisis will have contrast-enhanced ultrasound performed up to four times over a two-day period. Time points will resemble the time course used for the Regadenoson Arm, although no investigational drug will be given. | 6 |
| Sickle Cell Crisis ARM Adult subjects who had a sickle cell crisis
Adults subjects with sickle cell anemia will receive contrast-enhanced ultrasound
contrast-enhanced ultrasound: Contrast-enhanced ultrasound will be performed on adults with sickle cell anemia at baseline who are not having a pain crisis and performed again during a pain crisis | 6 |
| Healthy Controls Healthy African American control subjects without sickle cell anemia will receive contrast-enhanced ultrasound.
They were not included in the analysis due to the number of participants who did not complete the study (therefore no meaningful ultrasounds to interpret). | 7 |
| Technique Optimization Controls Healthy volunteers will undergo contrast-enhanced ultrasound.
There was no data collected for this arm. | 0 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Incomplete CEU data | 1 | 3 | 5 | 8 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 4 | 4 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 7 |
| Overall Study | Screen failure | 6 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Sickle Cell Controls ARM | Sickle Cell Crisis ARM | Healthy Controls | Total | Regadenoson ARM |
|---|---|---|---|---|---|
| Age, Continuous | 35 years | 26 years | 26 years | 26 years | 25 years |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants | — |
| Region of Enrollment United States | 6 participants | 6 participants | 7 participants | 39 participants | 20 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 7 Participants | 7 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 0 Participants | 32 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 10 | 0 / 21 | 0 / 21 | 0 / 7 |
| other Total, other adverse events | 16 / 32 | 3 / 10 | 4 / 21 | 1 / 21 | 0 / 7 |
| serious Total, serious adverse events | 5 / 32 | 0 / 10 | 3 / 21 | 0 / 21 | 0 / 7 |
Outcome results
Primary
Microvascular Blood Flow Rate Change
Primary outcome measure will be a 40% increase in skeletal muscle microvascular blood flow when 24 hour measurements are compared to baseline in subjects receiving Regadenoson. We took measurements in patients who received Regadenoson, as well as Sickle Cell controls. Both arms had microvascular blood flow (volume x velocity) measured at baseline and 24-hours, and those values were compared. A change ratio of \>1 means that the flow rate increased at 24 hours and a change ratio of \<1 means that the flow rate decreased at 24 hours.
Time frame: Between baseline and 24 hours
Population: There were 20 participants in the Regadenoson arm, and 6 participants acted as sickle cell controls. Sickle Cell Crisis ARM is not included because arm was not measured by CEUS in a similar timeframe as Regadenoson ARM and Sickle Cell Controls ARM, as indicated in Results Baseline Characteristics Arm/Group Description for Sickle Cell Crisis ARM.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regadenoson ARM | Microvascular Blood Flow Rate Change | 1.09 Ratio of change |
| Sickle Cell Controls ARM | Microvascular Blood Flow Rate Change | 0.86 Ratio of change |
Secondary
Microvascular Blood Flow in Sickle Cell Anemia Subjects Versus Control Subjects
Examine microvascular blood flow using contrast-enhanced ultrasounds in adult subjects with sickle cell anemia compared to microvascular blood flow of healthy African-American adults
Time frame: 5 years
Population: African American controls subjects were enrolled. The ultrasounds were not able to be examined and therefore no data generated to provide.
Secondary
MVBF Ratio of Change During a Pain Crisis
We planned to examine differences in microvascular blood flow using contrast-enhanced ultrasound (CEU) in adults with sickle cell anemia age 18 and older at baseline state compared to a pain crisis. We were measuring changes in microvascular blood flow in subjects with sickle cell anemia during a pain crisis by examining differences in microvascular blood flow using contrast-enhanced ultrasound at a baseline state, and comparing those measurements to contrast-enhanced ultrasound measurements during a pain crisis. A change ratio of \>1 means that the flow rate increased during a pain crisis and a change ratio of \<1 means that the flow rate decreased during a pain crisis.
Time frame: Between baseline and between 7-30 days after pain crisis, if feasible
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regadenoson ARM | MVBF Ratio of Change During a Pain Crisis | 0.65 Ratio of change |