Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, Magnesium Sulfate, Pediatric
Brief summary
The purpose of this study is to determine the safety and efficacy of intravenous magnesium in shortening the duration of a pain crisis and to determine the health-related quality of life and short term outcomes of children treated with intravenous magnesium during an acute pain crisis.
Detailed description
It is well known that children with sickle cell disease are at risk for acute pain crises. The usual treatment for these pain crises, intravenous fluids and pain medicines such as morphine, has changed little over the past three decades. In a pilot study, the addition of intravenous magnesium to standard therapy decreased length of stay; however, this study was not randomized, not blinded, not placebo-controlled, and not adequately powered to assess safety. We will conduct a multi-center, randomized, double-blind, placebo controlled trial of about 208 children, ages 4-21 years. Patients will be randomized to receive intravenous magnesium sulfate or placebo every 8 hours for a total of 6 doses, or until discharge. Patients will return for a routine clinic visit up to 3 months after discharge for a baseline assessment. Patients will also complete health-related quality of life measures at 4 timepoints throughout the study.
Interventions
40 mg/kg (max 2.4 grams), infused at a concentration of 40 mg/ml (1 ml/kg, max 60 ml), every 8 hours for a total of 6 doses
DRUGNormal Saline Placebo
(1 ml/kg, max 60 ml), administered every 8 hours for a total of 6 doses
Sponsors
Pediatric Emergency Care Applied Research Network
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* age 4-21 years, inclusive * Sickle cell anemia (Hb SS) or Sickle beta zero thalassemia disease (Hb Sβ°) * failed intravenous opioid pain management in the emergency department prior to the decision to admit the patient * admitted to the inpatient unit for sickle cell pain crisis
Exclusion criteria
* patient received more than 12 hours of intravenous pain medication prior to enrollment * previous enrollment in this study (only one admission per child is eligible) * history of allergy/intolerance to both intravenous morphine and hydromorphone * known other cause for pain (avascular necrosis, gall bladder disease, priapism, etc.) * patient with greater than 10 admissions for pain crisis in the past year * patient maintained on daily opioids or chronic transfusions for chronic sickle cell pain * transfusion within the previous two months * known kidney or liver failure (elevation of liver function tests does not warrant exclusion) * known pulmonary hypertension * pregnancy * diagnosis of bacterial infection, fever ≥39.5°C, acute chest syndrome, hemodynamic instability or sepsis * current oral magnesium supplementation or current enrollment in another therapeutic study protocol * previously diagnosed clinical stroke * current or planned use of neuromuscular blocker, nifedipine, ritodrine, or terbutaline * allergy to magnesium sulfate * discharge from an inpatient unit within 72 hours of arrival in the emergency department for the current pain crisis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Hospital Length of Stay (Hours) | From the time of the start of first study med infusion until hospital discharge or 12 hours after the last IV opioid, whichever occurs first, up to 10 days post enrollment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypotension Associated With Infusion | Blood pressure will be monitored every 8 hours, concurrent with each infusion, and for 20-30 minutes after infusion completion, until discharge, up to 2 days post enrollment | For each study drug infusion, systolic blood pressure (SBP) was measured just prior to the start of the infusion and again every 10 minutes until 30 minutes until the end of the infusion. Hypotension was defined as a greater than 20% reduction in SBP relative to corresponding baseline measurement for any study drug infusion. |
| Warm Sensation Associated With Study Drug Infusion | Patient-reported warm sensation upon infusion will be monitored every 8 hours, concurrent with each infusion, and for 20-30 minutes after infusion completion, until discharge, up to 2 days post enrollment | Patient spontaneously reported feelings of warmth during any study drug infusion. |
| Number of Morphine Equivalents Per Kilogram of Body Weight Used During Hospitalization | Total morphine equivalents used during the hospitalization will be recorded on the day of discharge, up to 10 days post enrollment | — |
| Development of Acute Chest Syndrome (ACS) | Patients will be monitored daily, on average, during their length of stay until discharge, up to 10 days post enrollment | — |
| Hospital Length of Stay | Start of first study drug infusion to actual hospital discharge | — |
| Rehospitalization | Rehospitalization will be measured at 7 days post discharge and at the follow-up visit (on average, 30 days post discharge) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Magnesium Group Intravenous Magnesium Sulfate
Intravenous Magnesium Sulfate: 40 mg/kg (max 2.4 grams), infused at a concentration of 40 mg/ml (1 ml/kg, max 60 ml), every 8 hours for a total of 6 doses | 104 |
| Placebo Group Normal Saline placebo
Normal Saline Placebo: (1 ml/kg, max 60 ml), administered every 8 hours for a total of 6 doses | 104 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Found to be ineligible | 2 | 5 |
| Overall Study | Hypotension | 1 | 2 |
| Overall Study | No 25-hour magnesium level | 0 | 2 |
| Overall Study | Not consented in time to receive drug | 0 | 1 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Site miscommunication | 0 | 1 |
| Overall Study | Subject transferred to intensive care | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Magnesium Group | Placebo Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 93 Participants | 88 Participants | 181 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 16 Participants | 27 Participants |
| Age, Continuous | 13.4 years STANDARD_DEVIATION 4.5 | 13.8 years STANDARD_DEVIATION 4.8 | 13.6 years STANDARD_DEVIATION 4.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants | 94 Participants | 190 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 99 participants | 94 participants | 193 participants |
| Race/Ethnicity, Customized More than one race | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Unknown or not reported | 3 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized White | 0 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 104 participants | 104 participants | 208 participants |
| Sex: Female, Male Female | 51 Participants | 57 Participants | 108 Participants |
| Sex: Female, Male Male | 53 Participants | 47 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 66 / 101 | 62 / 103 |
| serious Total, serious adverse events | 13 / 101 | 12 / 103 |
Outcome results
Primary
Hospital Length of Stay (Hours)
Time frame: From the time of the start of first study med infusion until hospital discharge or 12 hours after the last IV opioid, whichever occurs first, up to 10 days post enrollment
Population: All participants who received at least one dose of study drug and who did not withdraw from data collection prior to outcome
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magnesium Group | Hospital Length of Stay (Hours) | 56 hours |
| Placebo Group | Hospital Length of Stay (Hours) | 47 hours |
Comparison: Null hypothesis of equal distributions of primary length of stay between treatment arms within all randomization stratap-value: 0.24Van Elteren test
Secondary
Development of Acute Chest Syndrome (ACS)
Time frame: Patients will be monitored daily, on average, during their length of stay until discharge, up to 10 days post enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magnesium Group | Development of Acute Chest Syndrome (ACS) | 16 Paricipants |
| Placebo Group | Development of Acute Chest Syndrome (ACS) | 14 Paricipants |
p-value: 0.78Van Elteren test
Secondary
Hospital Length of Stay
Time frame: Start of first study drug infusion to actual hospital discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magnesium Group | Hospital Length of Stay | 74.5 Hours |
| Placebo Group | Hospital Length of Stay | 60.5 Hours |
p-value: 0.46Van Elteren test
Secondary
Hypotension Associated With Infusion
For each study drug infusion, systolic blood pressure (SBP) was measured just prior to the start of the infusion and again every 10 minutes until 30 minutes until the end of the infusion. Hypotension was defined as a greater than 20% reduction in SBP relative to corresponding baseline measurement for any study drug infusion.
Time frame: Blood pressure will be monitored every 8 hours, concurrent with each infusion, and for 20-30 minutes after infusion completion, until discharge, up to 2 days post enrollment
Population: All participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magnesium Group | Hypotension Associated With Infusion | 4 Participant |
| Placebo Group | Hypotension Associated With Infusion | 1 Participant |
p-value: 0.39Mantel Haenszel
Secondary
Number of Morphine Equivalents Per Kilogram of Body Weight Used During Hospitalization
Time frame: Total morphine equivalents used during the hospitalization will be recorded on the day of discharge, up to 10 days post enrollment
Population: All participants who received at least one dose of study drug and who did not withdraw from data collection prior to either hospital discharge or 12 hours after last intravenous opioid.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Magnesium Group | Number of Morphine Equivalents Per Kilogram of Body Weight Used During Hospitalization | 1.46 mg Morphine/kg |
| Placebo Group | Number of Morphine Equivalents Per Kilogram of Body Weight Used During Hospitalization | 1.28 mg Morphine/kg |
p-value: 0.12Van Elteren test
Secondary
Rehospitalization
Time frame: Rehospitalization will be measured at 7 days post discharge and at the follow-up visit (on average, 30 days post discharge)
Population: All participants who received at least one dose of study drug who had known rehospitalization status within 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magnesium Group | Rehospitalization | 12 Participant |
| Placebo Group | Rehospitalization | 7 Participant |
p-value: 0.11Mantel Haenszel
Secondary
Warm Sensation Associated With Study Drug Infusion
Patient spontaneously reported feelings of warmth during any study drug infusion.
Time frame: Patient-reported warm sensation upon infusion will be monitored every 8 hours, concurrent with each infusion, and for 20-30 minutes after infusion completion, until discharge, up to 2 days post enrollment
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Magnesium Group | Warm Sensation Associated With Study Drug Infusion | 26 Participant |
| Placebo Group | Warm Sensation Associated With Study Drug Infusion | 2 Participant |
p-value: <0.01Mantel Haenszel