Anemia, Sickle Cell
Conditions
Keywords
Sickle Cell Disease, ACS, Acute Chest Syndrome, Hgb SS, Hgb Sβ0, Dexamethasone
Brief summary
People with sickle cell disease (SCD) may develop acute chest syndrome (ACS), which is a common and serious lung condition that usually requires hospitalization. Dexamethasone is a medication that may decrease hospitalization time for people with ACS, but it may also bring about new sickle cell pain. This study will evaluate the effectiveness of a dexamethasone regimen that includes a gradual dose reduction at decreasing hospitalization and recovery time in people with SCD and ACS.
Detailed description
SCD is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain, which are called sickle cell crises. ACS is a life-threatening, lung-related complication of SCD that can lower the level of oxygen in the blood. Repeat occurrences of ACS can cause lung damage. It is the second most common cause of hospitalizations among people with SCD and accounts for more than 25% of premature deaths in people with SCD. Symptoms of ACS include fever, chest pain, cough, and breathing difficulties. ACS can appear suddenly and often requires immediate hospitalization and treatment, including antibiotics, supplemental oxygen, and blood transfusions. Previous studies have shown that dexamethasone, a type of steroid medication that blocks inflammation, can decrease hospitalization time for people with ACS; however, some participants in these earlier studies were re-hospitalized due to new sickle cell pain. Slowly decreasing the dosage of dexamethasone over a period of time may decrease the chance that new sickle cell pain will occur. The purpose of this study is to evaluate the effectiveness of a dexamethasone regimen that includes a gradual dose reduction at decreasing hospitalization and recovery time in people with SCD and ACS. This study will enroll people with SCD who are hospitalized and have been diagnosed with ACS within the past 24 hours. Participants will be randomly assigned to receive either dexamethasone or placebo on a daily basis for 8 days. Every 2 days the medication dose will be gradually reduced. While in the hospital, participants will receive usual care for ACS, including antibiotics, pain control medication, intravenous fluids, and other needed treatments. Each day, participants will undergo a physical exam, a pain assessment score, a test to measure the oxygen level in the body, blood collection, and, if needed, a chest x-ray. Vital signs and blood pressure measurements will be taken every 4 hours. Study staff will document the amount of pain medication, blood transfusions, oxygen, and breathing treatments participants receive. Upon leaving the hospital, follow-up visits will occur 1 week after participants were originally admitted to the hospital (participants who are still hospitalized at this time will not attend this visit) and 1 month after hospital discharge. At both visits, information on hospital visits for pain treatment and blood transfusions will be collected, and evaluations performed earlier in the study will be repeated. The second visit will also include lung function tests.
Interventions
DRUGDexamethasone
Individuals meeting entry criteria will be randomized to receive dexamethasone 0.3 mg/kg (12 mg maximum single dose). The study drug will be given by mouth every 12 hours until discharge from the hospital or for a maximum of 4 doses (2 days), whichever occurs first. Thereafter, study drug will be tapered over 6 days for a total duration of therapy not to exceed 8 days.
DRUGPlacebo
Individuals meeting entry criteria will be randomized to receive 0.3 mg/kg (12 mg maximum single dose) of placebo. The study drug will be given by mouth every 12 hours until discharge from the hospital or for a maximum of 4 doses (2 days), whichever occurs first. Thereafter, study drug will be tapered over 6 days for a total duration of therapy not to exceed 8 days.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of sickle cell anemia (Hgb SS) or sickle-β0-thalassemia (Hgb Sβ0) * Current episode of ACS, defined as a new lobar or segmental pulmonary infiltrate seen on a chest radiograph and two or more of the following findings: 1. Temperature of 38.5°C or higher 2. Tachypnea (i.e., rapid breathing) 3. Dyspnea or increased work of breathing 4. Chest wall pain 5. Oxygen saturation of less than 90% in room air by pulse oximetry * Current episode of ACS diagnosed in the 24 hours prior to study entry * Ability to take medication in capsule form
Exclusion criteria
* Prior participation in this study * Diagnosed with any medical condition that will likely be worsened by corticosteroid therapy, including any of the following conditions: 1. Diabetes mellitus 2. High blood pressure 3. Esophageal or gastrointestinal ulceration or bleeding 4. Known avascular necrosis * Diagnosis of ACS in the 6 months prior to study entry * Treatment with oral or parenteral corticosteroid therapy for any reason in the 14 days prior to study entry * Use of inhaled corticosteroids or systemic corticosteroids for respiratory illness in the 3 months prior to study entry * Long-term lung condition that requires treatment with corticosteroids * Participation in a program of chronic transfusions that ended fewer than 4 months ago. A program of chronic transfusions includes a regimen of serial simple or exchange transfusions given at least every 6 weeks for at least three consecutive transfusions for the prevention of SCD-related complications. * Pregnant * Treatment with any investigational drug in the 90 days prior to study entry * History of either tuberculosis or a positive skin test for tuberculosis * Known HIV infection or a current systemic fungal infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log (Natural) of Duration of Signs and Symptoms of Acute Chest Syndrome (ACS) or Duration of Hospitalization, Whichever is Less | Measured from first dose to end of the hospital stay, no maximum number of days | Resolution of symptoms of ACS includes respiratory rate \<= upper limit of normal +2, no work of breathing (retractions, nasal flaring, and use of accessory muscles), thoracic pain \<= 4, no use of supplemental oxygen, no use of ventilary support, and saturation of peripheral oxygen (Sp02) \>= steady state value -2. Symptoms were measured every 4 hours from the first dose of study drug to resolution of symptoms or hospital discharge. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rating of Pain | Measured at the end of the hospital stay | Change from baseline rating of pain from randomization (baseline) to discharge from the hospital, evaluated every 4 hours. Pain was rated on the Oucher Scale for the pediatric population or numeric rating scale for the adult population, both 0 to 10 with 0 indicating no pain and 10 indicating severe pain. |
| Duration of Hospitalization | Measured at the end of hospital stay, no maximum number of days | Duration in hours from treatment start time to hospital discharge. |
| Duration of Supplemental Oxygen | Measured at the end of hospital stay | Time period between the supplemental oxygen start date/time and first dose date/time, whichever is later, and the supplemental oxygen stop date/time |
| Duration of Hypoxemia (Low Blood Oxygen) | Measured at the end of hospital stay | Sum of time periods when subject was hypoxemic (Sp02 value less than 92%) since the first dose date/time |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from October 2006 through June 2008 at 10 sites across the United States. Due to the acute nature of the disease under study, subjects were recruited in a hospital, frequently in the Emergency Department.
Pre-assignment details
No events excluded patients following enrollment, but prior to group assignment. Group assignments were made at enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Dexamethasone 0.3 mg/kg (12 mg maximum single dose) every 12 hours until discharge from the hospital or for a maximum of 4 doses, whichever comes first. Thereafter, study drug will be tapered over 6 days (not to exceed 8 days). | 6 |
| Placebo 0.3 mg/kg (12 mg maximum single dose) every 12 hours until discharge from the hospital or for a maximum of 4 doses, whichever comes first. Thereafter, study drug will be tapered over 6 days (not to exceed 8 days). | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Dexamethasone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 3 Participants |
| Age Continuous | 15.8 years STANDARD_DEVIATION 12.81 | 18.8 years STANDARD_DEVIATION 14.08 | 17.3 years STANDARD_DEVIATION 12.93 |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 2 / 6 |
| serious Total, serious adverse events | 1 / 6 | 0 / 6 |
Outcome results
Primary
Log (Natural) of Duration of Signs and Symptoms of Acute Chest Syndrome (ACS) or Duration of Hospitalization, Whichever is Less
Resolution of symptoms of ACS includes respiratory rate \<= upper limit of normal +2, no work of breathing (retractions, nasal flaring, and use of accessory muscles), thoracic pain \<= 4, no use of supplemental oxygen, no use of ventilary support, and saturation of peripheral oxygen (Sp02) \>= steady state value -2. Symptoms were measured every 4 hours from the first dose of study drug to resolution of symptoms or hospital discharge.
Time frame: Measured from first dose to end of the hospital stay, no maximum number of days
Population: Subject without major protocol violation and received treatment.
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Log (Natural) of Duration of Signs and Symptoms of Acute Chest Syndrome (ACS) or Duration of Hospitalization, Whichever is Less | 2.4 hours (log transformed) | Standard Deviation 1.23 |
| Placebo | Log (Natural) of Duration of Signs and Symptoms of Acute Chest Syndrome (ACS) or Duration of Hospitalization, Whichever is Less | 3.5 hours (log transformed) | Standard Deviation 0.6 |
Comparison: The null hypothesis of no difference in the log duration of signs and symptoms or hospitalization between the two treatment groups was tested using an F test from a generalized mixed model with fixed effects for treatment group, age group and ACS severity. Please note that the study was stopped prematurely so only 11 of the 112 originally planned were included in the analysis.p-value: 0.127Mixed Models Analysis
Secondary
Duration of Hospitalization
Duration in hours from treatment start time to hospital discharge.
Time frame: Measured at the end of hospital stay, no maximum number of days
Population: Subject without major protocol violation and received treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Duration of Hospitalization | 41.5 Hours | Standard Deviation 9.03 |
| Placebo | Duration of Hospitalization | 62.3 Hours | Standard Deviation 14.27 |
Comparison: The null hypothesis of no difference in the log duration of signs and symptoms or hospitalization between the two treatment groups was tested using an F test from a generalized mixed model with fixed effects for treatment group, age group and ACS severity. Please note that the study was stopped prematurely so only 11 of the 112 originally planned were included in the analysis.p-value: 0.02Mixed Models Analysis
Secondary
Duration of Hypoxemia (Low Blood Oxygen)
Sum of time periods when subject was hypoxemic (Sp02 value less than 92%) since the first dose date/time
Time frame: Measured at the end of hospital stay
Population: Subject without major protocol violation and received treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Duration of Hypoxemia (Low Blood Oxygen) | 13.8 Hours | Standard Deviation 0 |
| Placebo | Duration of Hypoxemia (Low Blood Oxygen) | 38.4 Hours | Standard Deviation 22.18 |
Comparison: The null hypothesis of no difference in the log duration of signs and symptoms or hospitalization between the two treatment groups was tested using an F test from a generalized mixed model with fixed effects for treatment group, age group and ACS severity. Please note that the study was stopped prematurely so only 11 of the 112 originally planned were included in the analysis.p-value: 0.77Mixed Models Analysis
Secondary
Duration of Supplemental Oxygen
Time period between the supplemental oxygen start date/time and first dose date/time, whichever is later, and the supplemental oxygen stop date/time
Time frame: Measured at the end of hospital stay
Population: Subject without major protocol violation and received treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexamethasone | Duration of Supplemental Oxygen | 17.5 Hours | Standard Deviation 0 |
| Placebo | Duration of Supplemental Oxygen | 41.2 Hours | Standard Deviation 22.22 |
Comparison: The null hypothesis of no difference in the log duration of signs and symptoms or hospitalization between the two treatment groups was tested using an F test from a generalized mixed model with fixed effects for treatment group, age group and ACS severity. Please note that the study was stopped prematurely so only 11 of the 112 originally planned were included in the analysis.p-value: 0.876Mixed Models Analysis
Secondary
Rating of Pain
Change from baseline rating of pain from randomization (baseline) to discharge from the hospital, evaluated every 4 hours. Pain was rated on the Oucher Scale for the pediatric population or numeric rating scale for the adult population, both 0 to 10 with 0 indicating no pain and 10 indicating severe pain.
Time frame: Measured at the end of the hospital stay
Population: Subject without major protocol violation and received treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexamethasone | Rating of Pain | Thoracic | -3.8 Units on a scale | Standard Error 1.34 |
| Dexamethasone | Rating of Pain | Non-thoracic | -2.0 Units on a scale | Standard Error 1.35 |
| Placebo | Rating of Pain | Thoracic | -4.1 Units on a scale | Standard Error 1.26 |
| Placebo | Rating of Pain | Non-thoracic | -1.4 Units on a scale | Standard Error 1.28 |
Comparison: The null hypothesis of no difference in the log duration of signs and symptoms or hospitalization between the two treatment groups was tested using an F test from a generalized mixed model with fixed effects for treatment group, age group and ACS severity. Please note that the study was stopped prematurely so only 11 of the 112 originally planned were included in the analysis.p-value: 0.801Mixed Models Analysis