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

Tracking Information

• First Submitted Date: August 27, 2015
• First Posted Date: August 31, 2015
• Results First Submitted Date: March 13, 2022
• Results First Posted Date: June 6, 2022
• Last Update Posted Date: June 6, 2022
• Study Start Date: February 2016
• Actual Primary Completion Date: February 21, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 17, 2022)

Total Parenteral Opioid Use in IV Morphine Equivalents [ Time Frame: 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.

Original Primary Outcome Measures (submitted: August 27, 2015)

Total parenteral opioid use [ Time Frame: Post study drug delivery (Up to 8 hours) ]

The total amount of parenteral opioids used by participants measured in mg/kg. The total is calculated after study drug delivery for participants in the emergency department (ED) and during hospital stay.

Current Secondary Outcome Measures (submitted: May 17, 2022)

• Length of Hospital Stay [ Time Frame: Discharge (Up to 8 days) ]
  The total number of hours spent in the hospital from study drug delivery to time of discharge.
• Time to Vaso-occlusive Pain Event (VOE) Resolution in Emergency Department [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Duration of study (Up to 8 days) ]
  The total number of study drug doses given throughout the study period.
• Rate of Acute Chest Syndrome [ Time Frame: 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.
• Rate of Blood Transfusion [ Time Frame: Duration of study (Up to 8 days) ]
  Number of participants requiring a blood transfusion throughout the study period.
• Oxygen Saturation Level [ Time Frame: At time of Emergency Department Admission ]
  Average oxygen saturation level of participants at time of ED arrival
• Oxygen Saturation Level [ Time Frame: At time of hospital admission and at time of Hospital discharge (Up to 8 days) ]
  The difference in oxygen saturation levels from emergency department arrival to hospital discharge.
• Rate of Return Visits to Emergency Department (ED) Within 72 Hours [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Post hospital discharge (within 30 days) ]
  Number of patients readmitted to the hospital within 30 days of discharge.

Original Secondary Outcome Measures (submitted: August 27, 2015)

• Length of hospital stay [ Time Frame: Discharge (Up to 7 days) ]
  The total number of hours spent in the hospital from study drug delivery to time of discharge.
• Time to vaso-occlusive pain event (VOE) resolution in emergency department [ Time Frame: 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 [ Time Frame: Post study drug delivery (Up to 8 hours) ]
  The total number of hours between study drug delivery and no parenteral opioid use, pain relief improved to tolerate oral pain medications, ability to walk, and residual pain low enough to be managed at home.
• Change in Vaso-occlusive pain (VOE) scores [ Time Frame: Baseline, Time of discharge (Up to 7 days) ]
  Pain associated with VOE will be measured on a scale of 0-10 using a visual analog scale (VAS), which consists of a 10-cm horizontal line, with the ends representing the extreme limits of "no-pain" (0) and "worst pain" (10).
• Length of emergency department (ED) stay [ Time Frame: Up to 8 hours ]
  Total hours from time of ED triage to discharge or hospital admission.
• Rate of Emergency Department (ED) discharge [ Time Frame: Post emergency department admission (Up to 8 hours) ]
  Number of participants discharged from ED without a hospital admission.
• Total opioid dose [ Time Frame: Post study drug delivery (Up to 8 hours) ]
  Total opioid dose in mg/kg in the first 8 hours after study drug delivery.
• Total number of study drug doses [ Time Frame: Duration of study (Up to 7 days) ]
  The total number of study drug doses given throughout the study period.
• Rate of acute chest syndrome [ Time Frame: Duration of study (Up to 7 days) ]
  Number of participants diagnosed with acute chest syndrome throughout the study period.
• Rate of blood transfusion [ Time Frame: Duration of study (Up to 7 days) ]
  Number of participants requiring a blood transfusion throughout the study period.
• Oxygen saturation level [ Time Frame: Discharge from emergency department (ED) (Up to 8 hours) ]
  Average oxygen saturation level of participants at time of ED discharge.
• Change in oxygen saturation level [ Time Frame: Hospital admission (Up to 4 hours), Hospital discharge (Up to 7 days) ]
  The difference in oxygen saturation levels from hospital admission to discharge.
• Rate of return visits to emergency department (ED) within 72 hours [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Post hospital discharge (within 30 days) ]
  Number of patients readmitted to the hospital within 30 days of discharge.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Arginine Therapy for Sickle Cell Disease Pain
• Official Title: Phase 2 Randomized Control Trial of Arginine Therapy for Pediatric Sickle Cell Disease Pain
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Sickle Cell Disease
• Vaso-occlusive Pain Episode

Intervention

• Drug: 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.
  Other Name: Arginine
• Drug: L-arginine Loading Dose
  One loading dose of L-arginine will be dispensed intravenously (IV) at 200 mg/kg
  Other Name: Arginine
• Other: Placebo
  Placebo of intravenous (IV) normal saline 1-2 ml/kg three times a day until discharge from the emergency department (ED) or hospital.

Study Arms

• Experimental: 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.
  Intervention: Drug: L-arginine
• Experimental: 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.
  Interventions:

  • Drug: L-arginine
  • Drug: L-arginine Loading Dose
• Placebo Comparator: 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.
  Intervention: Other: Placebo

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 21, 2022): 108
• Original Estimated Enrollment (submitted: August 27, 2015): 114
• Actual Study Completion Date: February 21, 2021
• Actual Primary Completion Date: February 21, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02536170
• Other Study ID Numbers: IRB00076988; FD-R-004814 ( Other Grant/Funding Number: FDA ); 1K24AT009893-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Claudia R. Morris, Emory University
• Original Responsible Party: Claudia Morris, Emory University, Associate Professor
• Current Study Sponsor: Emory University
• Original Study Sponsor: Same as current

Collaborators

• Children's Healthcare of Atlanta
• National Center for Complementary and Integrative Health (NCCIH)

Investigators

• Principal Investigator: Claudia Morris, MD; Emory University

• PRS Account: Emory University
• Verification Date: May 2022