Arginine Therapy for Sickle Cell Disease Pain

Overview

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.

Full Title of Study: “Phase 2 Randomized Control Trial of Arginine Therapy for Pediatric Sickle Cell Disease Pain”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: February 21, 2021

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

  • 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.
  • Drug: L-arginine Loading Dose
    • One loading dose of L-arginine will be dispensed intravenously (IV) at 200 mg/kg
  • 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.

Arms, Groups and Cohorts

  • 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.
  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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.

Secondary Measures

  • 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 3 Years

Maximum Age: 21 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Emory University
  • Collaborator
    • Children’s Healthcare of Atlanta
  • Provider of Information About this Clinical Study
    • Principal Investigator: Claudia R. Morris, Professor – Emory University
  • Overall Official(s)
    • Claudia Morris, MD, Principal Investigator, Emory University

References

Bakshi N, Liu Z, Gillespie S, Keesari R, Leake D, Khemani K, Kumari P, Rees CA, Dampier C, Morris CR. Patient-reported outcomes in children with sickle cell disease at presentation for an acute pain episode. Blood Adv. 2023 Sep 12;7(17):5103-5107. doi: 10.1182/bloodadvances.2021006794. No abstract available.

Citations Reporting on Results

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.

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