Arginine Therapy for Sickle Cell Disease Pain

• ClinicalTrials.gov Identifier: NCT02536170
• Recruitment Status: Completed
• First Posted: August 31, 2015
• Results First Posted: June 6, 2022
• Last Update Posted: June 6, 2022
• Sponsor: Emory University
• Collaborators: Children's Healthcare of Atlanta; National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): Claudia R. Morris, Emory University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Conditions: Sickle Cell Disease; Vaso-occlusive Pain Episode
• Interventions: Drug: L-arginine; Drug: L-arginine Loading Dose; Other: Placebo
• Enrollment: 108

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description	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.	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	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.
Period Title: Overall Study
Started	36	36	36
Completed	36	36	36
Not Completed	0	0	0

Baseline Characteristics

Arm/Group Title		L-Arginine	Loading Dose and L-Arginine	Placebo	Total
Arm/Group Description		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.	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	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.	Total of all reporting groups
Overall Number of Baseline Participants		36	36	36	108
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	36 participants	36 participants	108 participants
	<=18 years	34 94.4%	31 86.1%	35 97.2%	100 92.6%
	Between 18 and 65 years	2 5.6%	5 13.9%	1 2.8%	8 7.4%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	36 participants	36 participants	36 participants	108 participants
		13.49 (3.76)	13.63 (3.7)	12.27 (4.0)	13.13 (3.84)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	36 participants	36 participants	108 participants
	Female	19 52.8%	17 47.2%	20 55.6%	56 51.9%
	Male	17 47.2%	19 52.8%	16 44.4%	52 48.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	36 participants	36 participants	108 participants
	Hispanic or Latino	0 0.0%	0 0.0%	1 2.8%	1 0.9%
	Not Hispanic or Latino	36 100.0%	36 100.0%	35 97.2%	107 99.1%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	36 participants	36 participants	36 participants	108 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	36 100.0%	36 100.0%	36 100.0%	108 100.0%
	White	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	36 participants	36 participants	36 participants	108 participants
		36	36	36	108

Outcome Measures

1. Primary Outcome

Title	Total Parenteral Opioid Use in IV Morphine Equivalents
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: mg/Kg
	1.77 (1.91)	1.95 (2.09)	2.36 (3.14)

2. Secondary Outcome

Title	Length of Hospital Stay
Description	The total number of hours spent in the hospital from study drug delivery to time of discharge.
Time Frame	Discharge (Up to 8 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: hours
	71.3 (50.8)	76.9 (49.9)	84.9 (90.5)

3. Secondary Outcome

Title	Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department
Description	The total number of hours between study drug delivery and the last parenteral opioid.
Time Frame	Post study drug delivery (Up to 8 hours)

Outcome Measure Data

Analysis Population Description

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/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: hours
	NA [1] (NA)	NA [1] (NA)	NA [1] (NA)

[1]

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

4. Secondary Outcome

Title	Time to Vaso-occlusive Pain Event (VOE) Resolution in Hospital
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: hours
	57.3 (50.8)	55.1 (42.9)	69.3 (85.1)

5. Secondary Outcome

Title	Change in Vaso-occlusive Pain (VOE) Scores
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: score on a scale
Emergency Department (ED) arrival Pain Score	8.89 (1.01)	8.86 (1.46)	8.86 (1.36)
Time of hospital discharge Pain Score	4.5 (3.46)	4.75 (3.35)	4.56 (2.97)
Hospital Discharge Minus ED Arrival	-4.39 (3.41)	-4.11 (3.54)	-4.31 (3.09)

6. Secondary Outcome

Title	Length of Emergency Department (ED) Stay
Description	Total hours from time of ED triage to ED discharge or hospital admission.
Time Frame	Until discharge or Hospital Admission (Up to 24 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: hours
	6.29 (15.84)	5.67 (12.33)	4.08 (4.26)

7. Secondary Outcome

Title	Rate of Emergency Department (ED) Discharge
Description	Number of participants discharged from ED without a hospital ward admission.
Time Frame	Post emergency department admission (Up to 24 hours)

Outcome Measure Data

Analysis Population Description

All patients were admitted to the hospital, none was discharged during Emergency Department stay.

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%

8. Secondary Outcome

Title	Total Opioid Dose (ORAL + Parenteral) in mg/kg IV Morphine Equivalents
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: mg/Kg
	2.11 (2.18)	2.35 (2.19)	2.82 (3.65)

9. Secondary Outcome

Title	Total Number of Study Drug Doses
Description	The total number of study drug doses given throughout the study period.
Time Frame	Duration of study (Up to 8 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Number; Unit of Measure: doses
	298	330	329

10. Secondary Outcome

Title	Rate of Acute Chest Syndrome
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	4 11.1%	3 8.3%	1 2.8%

11. Secondary Outcome

Title	Rate of Blood Transfusion
Description	Number of participants requiring a blood transfusion throughout the study period.
Time Frame	Duration of study (Up to 8 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	3 8.3%	2 5.6%	5 13.9%

12. Secondary Outcome

Title	Oxygen Saturation Level
Description	Average oxygen saturation level of participants at time of ED arrival
Time Frame	At time of Emergency Department Admission

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: percentage of oxygenated hemoglobin
	95.5 (14.8)	98 (1.96)	98.1 (2.14)

13. Secondary Outcome

Title	Oxygen Saturation Level
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Mean (Standard Deviation); Unit of Measure: percentage of oxygenated hemoglobin
Oxygen saturation measures at time of emergency Department arrival	95.5 (14.8)	98 (1.96)	98.1 (2.14)
Oxygen saturation at Hospital Discharge	98 (2.75)	98.6 (2.11)	98.4 (2.02)

14. Secondary Outcome

Title	Rate of Return Visits to Emergency Department (ED) Within 72 Hours
Description	Number of ED visits from patients who have been discharged within the previous 72 hours.
Time Frame	Post hospital discharge (within 72 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%

15. Secondary Outcome

Title	Rate of Hospital Re-admissions Within 72 Hours
Description	Number of patients readmitted to the hospital within 72 hours of discharge.
Time Frame	Post hospital discharge (within 72 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	2 5.6%	2 5.6%	2 5.6%

16. Secondary Outcome

Title	Rate of Return Visits to Emergency Department (ED) Within 30 Days
Description	Number of ED visits from patients who have been discharged within the previous 30 days.
Time Frame	Post hospital discharge (within 30 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	1 2.8%	0 0.0%

17. Secondary Outcome

Title	Rate of Hospital Re-admissions With 30 Days
Description	Number of patients readmitted to the hospital within 30 days of discharge.
Time Frame	Post hospital discharge (within 30 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	L-Arginine	Loading Dose and L-Arginine	Placebo
Arm/Group Description:	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.	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	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.
Overall Number of Participants Analyzed	36	36	36
Measure Type: Count of Participants; Unit of Measure: Participants
	2 5.6%	7 19.4%	4 11.1%

Adverse Events

Time Frame	Information on adverse events will be assessed from the time study participation begins through the end of study follow up (up to 30 days, or after 21 doses or until discharge, whichever comes first).
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	L-Arginine		Loading Dose and L-Arginine		Placebo
Arm/Group Description	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.		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		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.
All-Cause Mortality
	L-Arginine		Loading Dose and L-Arginine		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/36 (0.00%)		0/36 (0.00%)		0/36 (0.00%)
Serious Adverse Events
	L-Arginine		Loading Dose and L-Arginine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/36 (11.11%)		9/36 (25.00%)		6/36 (16.67%)
Blood and lymphatic system disorders
Re-admission: Non sickle Cell event †	1/36 (2.78%)	1	0/36 (0.00%)	0	0/36 (0.00%)	0
Cardiac disorders
Re-admission: Acute Chest Syndrome †	1/36 (2.78%)	1	2/36 (5.56%)	2	1/36 (2.78%)	2
Prolonged hospitalization: Acute Coronary Syndrome †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
Renal and urinary disorders
Prolonged hospitalization: Priapism †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
Vascular disorders
Re-admission: Vaso-Occlusive Pain Event †	2/36 (5.56%)	3	7/36 (19.44%)	13	3/36 (8.33%)	4
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	L-Arginine		Loading Dose and L-Arginine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/36 (83.33%)		31/36 (86.11%)		30/36 (83.33%)
Blood and lymphatic system disorders
Splenic Sequestration †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
Transfusion †	3/36 (8.33%)	3	2/36 (5.56%)	2	5/36 (13.89%)	5
Elevated ALT †	5/36 (13.89%)	5	5/36 (13.89%)	5	4/36 (11.11%)	4
Elevated AST †	6/36 (16.67%)	6	9/36 (25.00%)	9	7/36 (19.44%)	7
Elevated Bilirrubin †	3/36 (8.33%)	3	4/36 (11.11%)	4	2/36 (5.56%)	2
Elevated Alkaline Phosphatase †	0/36 (0.00%)	0	2/36 (5.56%)	2	0/36 (0.00%)	0
Elevated creatinine †	0/36 (0.00%)	0	0/36 (0.00%)	0	0/36 (0.00%)	0
Decreased Neutrophil count †	0/36 (0.00%)	0	1/36 (2.78%)	1	0/36 (0.00%)	0
Anemia/ Decreased Hemoglobin †	7/36 (19.44%)	7	7/36 (19.44%)	7	8/36 (22.22%)	8
Hyperglycemia †	0/36 (0.00%)	0	1/36 (2.78%)	1	2/36 (5.56%)	2
Decreased Platelet count †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
Decreased Bicarbonate †	1/36 (2.78%)	1	0/36 (0.00%)	0	0/36 (0.00%)	0
Cardiac disorders
Acute Chest Syndrome after randomization †	4/36 (11.11%)	4	3/36 (8.33%)	3	1/36 (2.78%)	1
Acute Chest Syndrome †	4/36 (11.11%)	4	4/36 (11.11%)	4	2/36 (5.56%)	2
Hypertension †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
Gastrointestinal disorders
Anorexia †	10/36 (27.78%)	10	8/36 (22.22%)	8	6/36 (16.67%)	6
Abdominal Pain †	9/36 (25.00%)	9	9/36 (25.00%)	9	9/36 (25.00%)	9
Diarrhea †	3/36 (8.33%)	3	4/36 (11.11%)	4	1/36 (2.78%)	1
Gastritis †	0/36 (0.00%)	0	1/36 (2.78%)	1	1/36 (2.78%)	1
Nausea †	15/36 (41.67%)	15	17/36 (47.22%)	17	13/36 (36.11%)	13
Vomiting †	9/36 (25.00%)	9	11/36 (30.56%)	12	8/36 (22.22%)	8
Vomiting after randomization †	8/36 (22.22%)	8	5/36 (13.89%)	5	5/36 (13.89%)	5
General disorders
Chills †	6/36 (16.67%)	6	5/36 (13.89%)	5	5/36 (13.89%)	5
Fever †	7/36 (19.44%)	7	10/36 (27.78%)	10	6/36 (16.67%)	6
Emergency Department visit after Discharge †	0/36 (0.00%)	0	1/36 (2.78%)	2	0/36 (0.00%)	0
Musculoskeletal and connective tissue disorders
Leg/ Neck/ Hip Pain †	0/36 (0.00%)	0	2/36 (5.56%)	3	1/36 (2.78%)	1
Nervous system disorders
Headache †	14/36 (38.89%)	16	10/36 (27.78%)	10	9/36 (25.00%)	9
Headache after randomization †	7/36 (19.44%)	7	4/36 (11.11%)	4	5/36 (13.89%)	5
Lethargy †	0/36 (0.00%)	0	1/36 (2.78%)	1	0/36 (0.00%)	0
Renal and urinary disorders
Urinary Tract Infection †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
Respiratory, thoracic and mediastinal disorders
Cough †	10/36 (27.78%)	10	6/36 (16.67%)	6	10/36 (27.78%)	10
Oxygen administered †	1/36 (2.78%)	1	0/36 (0.00%)	0	1/36 (2.78%)	1
Wheezing †	2/36 (5.56%)	2	1/36 (2.78%)	1	5/36 (13.89%)	5
Skin and subcutaneous tissue disorders
Lip Swelling †	0/36 (0.00%)	0	1/36 (2.78%)	1	0/36 (0.00%)	0
Skin Rash †	0/36 (0.00%)	0	1/36 (2.78%)	2	0/36 (0.00%)	0
Vascular disorders
Hematoma †	0/36 (0.00%)	0	0/36 (0.00%)	0	1/36 (2.78%)	1
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Claudia Morris
• Organization: Emory University
• Phone: 404-727-5500
• EMail: claudia.r.morris@emory.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Reyes LZ, Figueroa J, Leake D, Khemani K, Kumari P, Bakshi N, Lane PA, Dampier C, Morris CR. Safety of intravenous arginine therapy in children with sickle cell disease hospitalized for vaso-occlusive pain: A randomized placebo-controlled trial in progress. Am J Hematol. 2022 Jan 1;97(1):E21-E24. doi: 10.1002/ajh.26396. Epub 2021 Nov 12. No abstract available.

Morris CR, Brown LAS, Reynolds M, Dampier CD, Lane PA, Watt A, Kumari P, Harris F, Manoranjithan S, Mendis RD, Figueroa J, Shiva S. Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain. Blood. 2020 Sep 17;136(12):1402-1406. doi: 10.1182/blood.2019003672.

• Responsible Party: Claudia R. Morris, Emory University
• ClinicalTrials.gov Identifier: NCT02536170
• Other Study ID Numbers: IRB00076988; FD-R-004814 ( Other Grant/Funding Number: FDA ); 1K24AT009893-01 ( U.S. NIH Grant/Contract )
• First Submitted: August 27, 2015
• First Posted: August 31, 2015
• Results First Submitted: March 13, 2022
• Results First Posted: June 6, 2022
• Last Update Posted: June 6, 2022