Sickle Cell Disease, Vaso-occlusive Pain Episode
Conditions
Keywords
Arginine Therapy
Brief summary
The aim of this study is to determine whether giving extra arginine, a simple amino acid, to patients with sickle cell disease seeking treatment for a pain crisis (vaso-occlusive painful events (VOE) will decrease pain scores, decrease the need for pain medications or decrease length of hospital stay or emergency department visit. Funding Source - FDA OOPD.
Detailed description
The purpose of this study is to determine the effects of IV L-arginine hydrochloride therapy in children with sickle cell disease (SCD) and vaso-occlusive pain events (VOE). Specifically, the impact on total opioid use (mg/kg) over the duration of their emergency department (ED) visit and hospital stay will be evaluated.
Interventions
DRUGL-arginine
L-arginine will be dispensed intravenously (IV) in the standard dose of 100 mg/kg three times a day until discharge from the emergency department (ED) or hospital.
DRUGL-arginine Loading Dose
One loading dose of L-arginine will be dispensed intravenously (IV) at 200 mg/kg
OTHERPlacebo
Placebo of intravenous (IV) normal saline 1-2 ml/kg three times a day until discharge from the emergency department (ED) or hospital.
Sponsors
Children's Healthcare of Atlanta
National Center for Complementary and Integrative Health (NCCIH)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Established diagnosis of sickle cell disease (SCD); all genotypes * Pain requiring medical care in an acute care setting (such as the emergency department or ED, hospital ward, day hospital, clinic) not attributable to non-sickle cell causes, that is moderate-to-severe requiring parenteral opioids
Exclusion criteria
* Decision to discharge home from the acute care setting * Hemoglobin less than 5 gm/dL or immediate need for red cell transfusion anticipated within next 12 hours * Hepatic dysfunction of SGPT greater than 3 times the upper value * Renal dysfunction of creatinine greater than 1.0 * Mental status or neurological changes * Acute stroke or clinical concern for stroke * Pregnancy * Allergy to arginine * Two (2) or more ED visits for VOE within the last 7 days prior to CURRENT ED visit * Hospitalization within 14 days * Previous randomization in this arginine RCT (patient consented and screen failed before receiving study drug or placebo remains eligible for future participation). * Use of inhaled nitric oxide, sildenafil or arginine within the last month * PICU admission from the emergency department * Hypotension requiring treatment with clinical intervention * Acidosis with Co2≤ 16 * Newly started on HU for \<3 months * Not an appropriate candidate in the investigator's judgment * Patient refusal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Parenteral Opioid Use in IV Morphine Equivalents | Post study drug delivery to discharge from the hospital (Up to 8 days) | The total amount of parenteral opioids used by participants measured in mg/kg of IV morphine equivalents. The total is calculated after study drug delivery for participants in the emergency department (ED) and during hospital stay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department | Post study drug delivery (Up to 8 hours) | The total number of hours between study drug delivery and the last parenteral opioid. |
| Time to Vaso-occlusive Pain Event (VOE) Resolution in Hospital | Post study drug delivery until discharge (up to 8 days) | The total number of hours between study drug delivery and time of last parenteral opioid use, pain relief improved to tolerate oral pain medications |
| Change in Vaso-occlusive Pain (VOE) Scores | Baseline, Time of discharge (Up to 8 days) | Pain associated with VOE will be measured on a scale of 0-10, by asking subjects to rate their pain level on a subjective scale from 0 to 10, with the ends representing the extreme limits of no-pain (0) and worst pain (10). |
| Length of Emergency Department (ED) Stay | Until discharge or Hospital Admission (Up to 24 hours) | Total hours from time of ED triage to ED discharge or hospital admission. |
| Rate of Emergency Department (ED) Discharge | Post emergency department admission (Up to 24 hours) | Number of participants discharged from ED without a hospital ward admission. |
| Total Opioid Dose (ORAL + Parenteral) in mg/kg IV Morphine Equivalents | Post study drug delivery up to hospital discharge (Up to 8 days) | Total opioid dose (ORAL + Parenteral) in mg/kg IV morphine equivalents after study drug delivery up to hospital discharge (up to 8 days) |
| Total Number of Study Drug Doses | Duration of study (Up to 8 days) | The total number of study drug doses given throughout the study period. |
| Length of Hospital Stay | Discharge (Up to 8 days) | The total number of hours spent in the hospital from study drug delivery to time of discharge. |
| Rate of Blood Transfusion | Duration of study (Up to 8 days) | Number of participants requiring a blood transfusion throughout the study period. |
| Oxygen Saturation Level | At time of Emergency Department Admission | Average oxygen saturation level of participants at time of ED arrival |
| Rate of Return Visits to Emergency Department (ED) Within 72 Hours | Post hospital discharge (within 72 hours) | Number of ED visits from patients who have been discharged within the previous 72 hours. |
| Rate of Hospital Re-admissions Within 72 Hours | Post hospital discharge (within 72 hours) | Number of patients readmitted to the hospital within 72 hours of discharge. |
| Rate of Return Visits to Emergency Department (ED) Within 30 Days | Post hospital discharge (within 30 days) | Number of ED visits from patients who have been discharged within the previous 30 days. |
| Rate of Hospital Re-admissions With 30 Days | Post hospital discharge (within 30 days) | Number of patients readmitted to the hospital within 30 days of discharge. |
| Rate of Acute Chest Syndrome | Duration of study (Up to 8 days) | Number of participants who develop acute chest syndrome (not diagnosed prior to study drug delivery) throughout the study period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| L-Arginine Participants will be randomized to receive an intravenous (IV) infusion of L-arginine (100 mg/kg) three times a day until time of discharge from the emergency department (ED) or hospital.
L-arginine: L-arginine will be dispensed intravenously (IV) in the standard dose of 100 mg/kg three times a day until discharge from the emergency department (ED) or hospital. | 36 |
| Loading Dose and L-Arginine Participants will be randomized to receive an intravenous (IV) infusion of one-time loading dose of L-arginine (200 mg/kg) followed by standard dose (100 mg/kg) three times a day until time of discharge from the emergency department (ED) or hospital.
L-arginine: L-arginine will be dispensed intravenously (IV) in the standard dose of 100 mg/kg three times a day until discharge from the emergency department (ED) or hospital.
L-arginine Loading Dose: One loading dose of L-arginine will be dispensed intravenously (IV) at 200 mg/kg | 36 |
| Placebo Participants will be randomized to receive an intravenous (IV) infusion of placebo (normal saline 1-2 ml/kg) three times a day until time of discharge from the emergency department (ED) or hospital.
Placebo: Placebo of intravenous (IV) normal saline 1-2 ml/kg three times a day until discharge from the emergency department (ED) or hospital. | 36 |
| Total | 108 |
Baseline characteristics
| Characteristic | L-Arginine | Loading Dose and L-Arginine | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 34 Participants | 31 Participants | 35 Participants | 100 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 5 Participants | 1 Participants | 8 Participants |
| Age, Continuous | 13.49 years STANDARD_DEVIATION 3.76 | 13.63 years STANDARD_DEVIATION 3.7 | 12.27 years STANDARD_DEVIATION 4 | 13.13 years STANDARD_DEVIATION 3.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 36 Participants | 35 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 36 Participants | 36 Participants | 36 Participants | 108 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 36 participants | 36 participants | 36 participants | 108 participants |
| Sex: Female, Male Female | 19 Participants | 17 Participants | 20 Participants | 56 Participants |
| Sex: Female, Male Male | 17 Participants | 19 Participants | 16 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 30 / 36 | 31 / 36 | 30 / 36 |
| serious Total, serious adverse events | 4 / 36 | 9 / 36 | 6 / 36 |
Outcome results
Primary
Total Parenteral Opioid Use in IV Morphine Equivalents
The total amount of parenteral opioids used by participants measured in mg/kg of IV morphine equivalents. The total is calculated after study drug delivery for participants in the emergency department (ED) and during hospital stay.
Time frame: Post study drug delivery to discharge from the hospital (Up to 8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine | Total Parenteral Opioid Use in IV Morphine Equivalents | 1.77 mg/Kg | Standard Deviation 1.91 |
| Loading Dose and L-Arginine | Total Parenteral Opioid Use in IV Morphine Equivalents | 1.95 mg/Kg | Standard Deviation 2.09 |
| Placebo | Total Parenteral Opioid Use in IV Morphine Equivalents | 2.36 mg/Kg | Standard Deviation 3.14 |
Secondary
Change in Vaso-occlusive Pain (VOE) Scores
Pain associated with VOE will be measured on a scale of 0-10, by asking subjects to rate their pain level on a subjective scale from 0 to 10, with the ends representing the extreme limits of no-pain (0) and worst pain (10).
Time frame: Baseline, Time of discharge (Up to 8 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-Arginine | Change in Vaso-occlusive Pain (VOE) Scores | Time of hospital discharge Pain Score | 4.5 score on a scale | Standard Deviation 3.46 |
| L-Arginine | Change in Vaso-occlusive Pain (VOE) Scores | Emergency Department (ED) arrival Pain Score | 8.89 score on a scale | Standard Deviation 1.01 |
| L-Arginine | Change in Vaso-occlusive Pain (VOE) Scores | Hospital Discharge Minus ED Arrival | -4.39 score on a scale | Standard Deviation 3.41 |
| Loading Dose and L-Arginine | Change in Vaso-occlusive Pain (VOE) Scores | Time of hospital discharge Pain Score | 4.75 score on a scale | Standard Deviation 3.35 |
| Loading Dose and L-Arginine | Change in Vaso-occlusive Pain (VOE) Scores | Emergency Department (ED) arrival Pain Score | 8.86 score on a scale | Standard Deviation 1.46 |
| Loading Dose and L-Arginine | Change in Vaso-occlusive Pain (VOE) Scores | Hospital Discharge Minus ED Arrival | -4.11 score on a scale | Standard Deviation 3.54 |
| Placebo | Change in Vaso-occlusive Pain (VOE) Scores | Emergency Department (ED) arrival Pain Score | 8.86 score on a scale | Standard Deviation 1.36 |
| Placebo | Change in Vaso-occlusive Pain (VOE) Scores | Hospital Discharge Minus ED Arrival | -4.31 score on a scale | Standard Deviation 3.09 |
| Placebo | Change in Vaso-occlusive Pain (VOE) Scores | Time of hospital discharge Pain Score | 4.56 score on a scale | Standard Deviation 2.97 |
Secondary
Length of Emergency Department (ED) Stay
Total hours from time of ED triage to ED discharge or hospital admission.
Time frame: Until discharge or Hospital Admission (Up to 24 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine | Length of Emergency Department (ED) Stay | 6.29 hours | Standard Deviation 15.84 |
| Loading Dose and L-Arginine | Length of Emergency Department (ED) Stay | 5.67 hours | Standard Deviation 12.33 |
| Placebo | Length of Emergency Department (ED) Stay | 4.08 hours | Standard Deviation 4.26 |
Secondary
Length of Hospital Stay
The total number of hours spent in the hospital from study drug delivery to time of discharge.
Time frame: Discharge (Up to 8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine | Length of Hospital Stay | 71.3 hours | Standard Deviation 50.8 |
| Loading Dose and L-Arginine | Length of Hospital Stay | 76.9 hours | Standard Deviation 49.9 |
| Placebo | Length of Hospital Stay | 84.9 hours | Standard Deviation 90.5 |
Secondary
Oxygen Saturation Level
Average oxygen saturation level of participants at time of ED arrival
Time frame: At time of Emergency Department Admission
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine | Oxygen Saturation Level | 95.5 percentage of oxygenated hemoglobin | Standard Deviation 14.8 |
| Loading Dose and L-Arginine | Oxygen Saturation Level | 98 percentage of oxygenated hemoglobin | Standard Deviation 1.96 |
| Placebo | Oxygen Saturation Level | 98.1 percentage of oxygenated hemoglobin | Standard Deviation 2.14 |
Secondary
Oxygen Saturation Level
The difference in oxygen saturation levels from emergency department arrival to hospital discharge.
Time frame: At time of hospital admission and at time of Hospital discharge (Up to 8 days)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-Arginine | Oxygen Saturation Level | Oxygen saturation measures at time of emergency Department arrival | 95.5 percentage of oxygenated hemoglobin | Standard Deviation 14.8 |
| L-Arginine | Oxygen Saturation Level | Oxygen saturation at Hospital Discharge | 98 percentage of oxygenated hemoglobin | Standard Deviation 2.75 |
| Loading Dose and L-Arginine | Oxygen Saturation Level | Oxygen saturation measures at time of emergency Department arrival | 98 percentage of oxygenated hemoglobin | Standard Deviation 1.96 |
| Loading Dose and L-Arginine | Oxygen Saturation Level | Oxygen saturation at Hospital Discharge | 98.6 percentage of oxygenated hemoglobin | Standard Deviation 2.11 |
| Placebo | Oxygen Saturation Level | Oxygen saturation measures at time of emergency Department arrival | 98.1 percentage of oxygenated hemoglobin | Standard Deviation 2.14 |
| Placebo | Oxygen Saturation Level | Oxygen saturation at Hospital Discharge | 98.4 percentage of oxygenated hemoglobin | Standard Deviation 2.02 |
Secondary
Rate of Acute Chest Syndrome
Number of participants who develop acute chest syndrome (not diagnosed prior to study drug delivery) throughout the study period.
Time frame: Duration of study (Up to 8 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Acute Chest Syndrome | 4 Participants |
| Loading Dose and L-Arginine | Rate of Acute Chest Syndrome | 3 Participants |
| Placebo | Rate of Acute Chest Syndrome | 1 Participants |
Secondary
Rate of Blood Transfusion
Number of participants requiring a blood transfusion throughout the study period.
Time frame: Duration of study (Up to 8 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Blood Transfusion | 3 Participants |
| Loading Dose and L-Arginine | Rate of Blood Transfusion | 2 Participants |
| Placebo | Rate of Blood Transfusion | 5 Participants |
Secondary
Rate of Emergency Department (ED) Discharge
Number of participants discharged from ED without a hospital ward admission.
Time frame: Post emergency department admission (Up to 24 hours)
Population: All patients were admitted to the hospital, none was discharged during Emergency Department stay.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Emergency Department (ED) Discharge | 0 Participants |
| Loading Dose and L-Arginine | Rate of Emergency Department (ED) Discharge | 0 Participants |
| Placebo | Rate of Emergency Department (ED) Discharge | 0 Participants |
Secondary
Rate of Hospital Re-admissions With 30 Days
Number of patients readmitted to the hospital within 30 days of discharge.
Time frame: Post hospital discharge (within 30 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Hospital Re-admissions With 30 Days | 2 Participants |
| Loading Dose and L-Arginine | Rate of Hospital Re-admissions With 30 Days | 7 Participants |
| Placebo | Rate of Hospital Re-admissions With 30 Days | 4 Participants |
Secondary
Rate of Hospital Re-admissions Within 72 Hours
Number of patients readmitted to the hospital within 72 hours of discharge.
Time frame: Post hospital discharge (within 72 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Hospital Re-admissions Within 72 Hours | 2 Participants |
| Loading Dose and L-Arginine | Rate of Hospital Re-admissions Within 72 Hours | 2 Participants |
| Placebo | Rate of Hospital Re-admissions Within 72 Hours | 2 Participants |
Secondary
Rate of Return Visits to Emergency Department (ED) Within 30 Days
Number of ED visits from patients who have been discharged within the previous 30 days.
Time frame: Post hospital discharge (within 30 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Return Visits to Emergency Department (ED) Within 30 Days | 0 Participants |
| Loading Dose and L-Arginine | Rate of Return Visits to Emergency Department (ED) Within 30 Days | 1 Participants |
| Placebo | Rate of Return Visits to Emergency Department (ED) Within 30 Days | 0 Participants |
Secondary
Rate of Return Visits to Emergency Department (ED) Within 72 Hours
Number of ED visits from patients who have been discharged within the previous 72 hours.
Time frame: Post hospital discharge (within 72 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Arginine | Rate of Return Visits to Emergency Department (ED) Within 72 Hours | 0 Participants |
| Loading Dose and L-Arginine | Rate of Return Visits to Emergency Department (ED) Within 72 Hours | 0 Participants |
| Placebo | Rate of Return Visits to Emergency Department (ED) Within 72 Hours | 0 Participants |
Secondary
Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department
The total number of hours between study drug delivery and the last parenteral opioid.
Time frame: Post study drug delivery (Up to 8 hours)
Population: Time to vaso-occlusive pain event (VOE) resolution in emergency department could not be determined as none of the participants had pain resolution in the Emergency department and were hospitalized
| Arm | Measure | Value (MEAN) |
|---|---|---|
| L-Arginine | Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department | NA hours |
| Loading Dose and L-Arginine | Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department | NA hours |
| Placebo | Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department | NA hours |
Secondary
Time to Vaso-occlusive Pain Event (VOE) Resolution in Hospital
The total number of hours between study drug delivery and time of last parenteral opioid use, pain relief improved to tolerate oral pain medications
Time frame: Post study drug delivery until discharge (up to 8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine | Time to Vaso-occlusive Pain Event (VOE) Resolution in Hospital | 57.3 hours | Standard Deviation 50.8 |
| Loading Dose and L-Arginine | Time to Vaso-occlusive Pain Event (VOE) Resolution in Hospital | 55.1 hours | Standard Deviation 42.9 |
| Placebo | Time to Vaso-occlusive Pain Event (VOE) Resolution in Hospital | 69.3 hours | Standard Deviation 85.1 |
Secondary
Total Number of Study Drug Doses
The total number of study drug doses given throughout the study period.
Time frame: Duration of study (Up to 8 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| L-Arginine | Total Number of Study Drug Doses | 298 doses |
| Loading Dose and L-Arginine | Total Number of Study Drug Doses | 330 doses |
| Placebo | Total Number of Study Drug Doses | 329 doses |
Secondary
Total Opioid Dose (ORAL + Parenteral) in mg/kg IV Morphine Equivalents
Total opioid dose (ORAL + Parenteral) in mg/kg IV morphine equivalents after study drug delivery up to hospital discharge (up to 8 days)
Time frame: Post study drug delivery up to hospital discharge (Up to 8 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-Arginine | Total Opioid Dose (ORAL + Parenteral) in mg/kg IV Morphine Equivalents | 2.11 mg/Kg | Standard Deviation 2.18 |
| Loading Dose and L-Arginine | Total Opioid Dose (ORAL + Parenteral) in mg/kg IV Morphine Equivalents | 2.35 mg/Kg | Standard Deviation 2.19 |
| Placebo | Total Opioid Dose (ORAL + Parenteral) in mg/kg IV Morphine Equivalents | 2.82 mg/Kg | Standard Deviation 3.65 |