search
Back to results

Arginine Therapy for the Treatment of Pain in Children With Sickle Cell Disease (R34 pK/PD)

Primary Purpose

Sickle Cell Disease

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Arginine
Arginine (Loading)
Arginine (Continuous)
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

7 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Established diagnosis of sickle cell disease--Hemoglobin SS (Hb-SS) or Sβᴼ-thalassemia
  • 7-21 years of age
  • Weight >= 25kg (55lbs)
  • Pain requiring medical care in an acute care setting (emergency department (ED), hospital ward, day hospital, clinic) requiring parenteral opioids, not attributable to non-sickle cell causes.

Exclusion Criteria:

  • Decision to discharge home from acute care setting.
  • Diagnosis of sickle cell disease with any of the following types: hemoglobin SC disease (HbSC), hemoglobin beta thalassemia (Hb-Beta Thal), hemoglobin SD disease (HbSD), hemoglobin SE disease (HbSE), hemoglobin SO disease (HbSO), hemoglobin AS carrier (Hb AS)
  • Hemoglobin less than 5 gm/dL
  • Immediate Red cell transfusion anticipated
  • Hepatic dysfunction: serum glutamic pyruvic transaminase (SGPT) > 3X upper value
  • Renal dysfunction: Creatinine >1.0 or 2 x baseline
  • Mental status or neurological changes
  • Acute stroke or clinical concern for stroke
  • Pregnancy
  • Allergy to arginine
  • Previous hospitalization < 7 days
  • Previous randomization in this arginine pK study (patient consented and screened failed before receiving study drug or placebo remains eligible for future participation)
  • Use of inhaled nitric oxide, sildenafil or arginine within the last month

Sites / Locations

  • Children's Healthcare fo Atlanta at Hughes SpaldingRecruiting
  • Children's Healthcare of Atlanta at EglestonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Standard dose

Loading dose + standard dose

Loading dose + continuous infusion

Arm Description

Subjects with sickle cell disease (SCD) and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first

Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first

Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive a continuous intravenous (IV) infusion of 300 mg/kg/24hr for 7 days or until discharged from the hospital, whichever occurs first

Outcomes

Primary Outcome Measures

Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time
Total time plasma arginine levels are maintained above the half-saturating concentration (Km) of cationic amino acid transporter protein-1 (CAT-1), which is 150 µM (normal range of extracellular plasma arginine concentration). pK samples will be collected at 6 time-points within 8 hours: prior to arginine treatment (time 0), and at 60, 90, 120 minutes, 4 and 8 hours after the initiation of arginine therapy, and then every 24 hours up to 7 days.
Change in nitric oxide metabolites
The formation of NO metabolites will be measured by determination of its stable end products in serum; nitrite (NO2-) and nitrate (NO3-). Change in nitric oxide metabolites will be calculated as the difference in metabolites from the time prior to arginine treatment (baseline) to the end of the intervention period.

Secondary Outcome Measures

Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine
AUC is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body. AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc])
Maximum observed plasma concentration of arginine
Maximum measured concentration of the arginine in plasma
Apparent clearance of arginine
The clearance of a drug measures the rate at which the drug is removed from the body after the dose. Clearance of arginine after intravenous administration on day 1.
Terminal elimination half-life (t1/2) for arginine
Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the plasma.
Change in red blood cell (RBC) arginine
Change in rbc arginine will be calculated as rbc arginine at the end of arginine administration minus rbc arginine at baseline.
Daily urine arginine
Total amount of arginine excreted in urine daily
Global arginine bioavailability (GABR)
GABR represents a measure of endothelial function. GABR will be calculated by arginine divided by the sum of ornithine plus citrulline [arginine/(ornithine+citrulline)].
Change in asymmetric dimethylarginine (ADMA) levels
ADMA is is a metabolic by-product of continual protein modification processes and interferes with L-arginine in the production of nitric oxide. Change in ADMA levels will be calculated as ADMA levels at the end of arginine administration minus ADMA levels at baseline.
Modeling nitric oxide (NOx) level versus plasma arginine level
Biomarkers of hemolysis
Biomarkers of hemolysis (lactate dehydrogenase, hemoglobin, reticulocytes, arginase, indirect bilirubin) represent intravascular hemolysis and nitric oxide bioavailability.
Erythrocyte glutathione levels
Erythrocyte glutathione is a biomarker for oxidative stress. It will be measured by using liquid chromatography.
Level of cytokines
Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.

Full Information

First Posted
May 15, 2015
Last Updated
June 2, 2023
Sponsor
Emory University
Collaborators
Children's Healthcare of Atlanta, National Center for Complementary and Integrative Health (NCCIH)
search

1. Study Identification

Unique Protocol Identification Number
NCT02447874
Brief Title
Arginine Therapy for the Treatment of Pain in Children With Sickle Cell Disease
Acronym
R34 pK/PD
Official Title
Arginine Therapy for the Treatment of Vaso-Occlusive Events in Children With Severe Sickle Cell Disease
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 2015 (undefined)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
July 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
Children's Healthcare of Atlanta, National Center for Complementary and Integrative Health (NCCIH)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine whether giving extra arginine to patients with sickle cell disease seeking treatment for vaso-occlusive painful events (VOE) will decrease pain scores, decrease need for pain medications or decrease length of hospital stay or emergency department visit.
Detailed Description
Arginine is a simple amino acid that is found in many foods and is part of the proteins in a human's body. Patients with sickle cell disease have low levels of the amino acid arginine and these low levels may be related to pain episodes. Increasing levels of arginine in the blood may lower pain and/or lower the amount of pain medication (like morphine) that is needed to treated them. It may also decrease the amount of time spent in the hospital.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard dose
Arm Type
Experimental
Arm Description
Subjects with sickle cell disease (SCD) and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first
Arm Title
Loading dose + standard dose
Arm Type
Experimental
Arm Description
Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first
Arm Title
Loading dose + continuous infusion
Arm Type
Experimental
Arm Description
Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive a continuous intravenous (IV) infusion of 300 mg/kg/24hr for 7 days or until discharged from the hospital, whichever occurs first
Intervention Type
Drug
Intervention Name(s)
Arginine
Other Intervention Name(s)
Arginine Hydrochloride Injection, R-Gene® 10
Intervention Description
Arginine will be dispensed intravenously (in the vein) in the standard dose of arginine as 100 mg/kg three times a day for seven days or until discharge. Loading dose: 200 mg/kg once Continuous IV: 300 mg/kg/24 hours
Intervention Type
Drug
Intervention Name(s)
Arginine (Loading)
Other Intervention Name(s)
Arginine Hydrochloride Injection, R-Gene® 10
Intervention Description
Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 200 mg/kg once
Intervention Type
Drug
Intervention Name(s)
Arginine (Continuous)
Other Intervention Name(s)
Arginine Hydrochloride Injection, R-Gene® 10
Intervention Description
Arginine will be dispensed intravenously (in the vein) as a continuous IV infusion of 300 mg/kg/24hr
Primary Outcome Measure Information:
Title
Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time
Description
Total time plasma arginine levels are maintained above the half-saturating concentration (Km) of cationic amino acid transporter protein-1 (CAT-1), which is 150 µM (normal range of extracellular plasma arginine concentration). pK samples will be collected at 6 time-points within 8 hours: prior to arginine treatment (time 0), and at 60, 90, 120 minutes, 4 and 8 hours after the initiation of arginine therapy, and then every 24 hours up to 7 days.
Time Frame
Day 1 through study completion, an average of up to 7 days
Title
Change in nitric oxide metabolites
Description
The formation of NO metabolites will be measured by determination of its stable end products in serum; nitrite (NO2-) and nitrate (NO3-). Change in nitric oxide metabolites will be calculated as the difference in metabolites from the time prior to arginine treatment (baseline) to the end of the intervention period.
Time Frame
Baseline, day 1 through study completion, an average of up to 7 days
Secondary Outcome Measure Information:
Title
Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine
Description
AUC is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body. AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc])
Time Frame
Day 1
Title
Maximum observed plasma concentration of arginine
Description
Maximum measured concentration of the arginine in plasma
Time Frame
Day 1
Title
Apparent clearance of arginine
Description
The clearance of a drug measures the rate at which the drug is removed from the body after the dose. Clearance of arginine after intravenous administration on day 1.
Time Frame
Day 1
Title
Terminal elimination half-life (t1/2) for arginine
Description
Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the plasma.
Time Frame
Day 1
Title
Change in red blood cell (RBC) arginine
Description
Change in rbc arginine will be calculated as rbc arginine at the end of arginine administration minus rbc arginine at baseline.
Time Frame
Baseline, day 1 through study completion, an average of up to 7 days
Title
Daily urine arginine
Description
Total amount of arginine excreted in urine daily
Time Frame
From Day 1 until study completion, an average of up to 7 days
Title
Global arginine bioavailability (GABR)
Description
GABR represents a measure of endothelial function. GABR will be calculated by arginine divided by the sum of ornithine plus citrulline [arginine/(ornithine+citrulline)].
Time Frame
From enrollment through study completion, an average of up to 7 days
Title
Change in asymmetric dimethylarginine (ADMA) levels
Description
ADMA is is a metabolic by-product of continual protein modification processes and interferes with L-arginine in the production of nitric oxide. Change in ADMA levels will be calculated as ADMA levels at the end of arginine administration minus ADMA levels at baseline.
Time Frame
Baseline, day 1 and through study completion, an average of up to 7 days
Title
Modeling nitric oxide (NOx) level versus plasma arginine level
Time Frame
From enrollment through study completion, an average of up to 7 days
Title
Biomarkers of hemolysis
Description
Biomarkers of hemolysis (lactate dehydrogenase, hemoglobin, reticulocytes, arginase, indirect bilirubin) represent intravascular hemolysis and nitric oxide bioavailability.
Time Frame
From enrollment through study completion, an average of up to 7 days
Title
Erythrocyte glutathione levels
Description
Erythrocyte glutathione is a biomarker for oxidative stress. It will be measured by using liquid chromatography.
Time Frame
From enrollment through study completion, an average of up to 7 days
Title
Level of cytokines
Description
Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.
Time Frame
From enrollment through study completion, an average of up to 7 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Established diagnosis of sickle cell disease--Hemoglobin SS (Hb-SS) or Sβᴼ-thalassemia 7-21 years of age Weight >= 25kg (55lbs) Pain requiring medical care in an acute care setting (emergency department (ED), hospital ward, day hospital, clinic) requiring parenteral opioids, not attributable to non-sickle cell causes. Exclusion Criteria: Decision to discharge home from acute care setting. Diagnosis of sickle cell disease with any of the following types: hemoglobin SC disease (HbSC), hemoglobin beta thalassemia (Hb-Beta Thal), hemoglobin SD disease (HbSD), hemoglobin SE disease (HbSE), hemoglobin SO disease (HbSO), hemoglobin AS carrier (Hb AS) Hemoglobin less than 5 gm/dL Immediate Red cell transfusion anticipated Hepatic dysfunction: serum glutamic pyruvic transaminase (SGPT) > 3X upper value Renal dysfunction: Creatinine >1.0 or 2 x baseline Mental status or neurological changes Acute stroke or clinical concern for stroke Pregnancy Allergy to arginine Previous hospitalization < 7 days Previous randomization in this arginine pK study (patient consented and screened failed before receiving study drug or placebo remains eligible for future participation) Use of inhaled nitric oxide, sildenafil or arginine within the last month
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Reshika Mendis, MBBS
Phone
404-785-4525
Email
Reshika.mendis@choa.org
First Name & Middle Initial & Last Name or Official Title & Degree
Claudia Morris, MD
Phone
404 727-5500
Email
claudia.r.morris@emory.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claudia Morris, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Healthcare fo Atlanta at Hughes Spalding
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30303
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arnetria Dancy
Phone
404-778-1873
Email
arnetria.dancy@emory.edu
Facility Name
Children's Healthcare of Atlanta at Egleston
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arnetria Dancy
Phone
404-778-1873
Email
arnetria.dancy@emory.edu

12. IPD Sharing Statement

Citations:
PubMed Identifier
32384147
Citation
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.
Results Reference
result

Learn more about this trial

Arginine Therapy for the Treatment of Pain in Children With Sickle Cell Disease

We'll reach out to this number within 24 hrs