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

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ClinicalTrials.gov Identifier: NCT02447874
Recruitment Status : Enrolling by invitation
First Posted : May 19, 2015
Last Update Posted : November 5, 2018
Sponsor:
Collaborators:
Children's Healthcare of Atlanta
National Center for Complementary and Integrative Health (NCCIH)
Information provided by (Responsible Party):
Claudia Morris, Emory University

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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Drug: Arginine Drug: Arginine (Loading) Drug: Arginine (Continuous) Phase 1 Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Arginine Therapy for the Treatment of Vaso-Occlusive Events in Children With Severe Sickle Cell Disease
Study Start Date : May 2015
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : July 2019


Arm Intervention/treatment
Experimental: Standard dose
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
Drug: Arginine

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
Other Name: Arginine Hydrochloride Injection, R-Gene® 10

Experimental: Loading dose + standard dose
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
Drug: Arginine

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
Other Name: Arginine Hydrochloride Injection, R-Gene® 10

Drug: Arginine (Loading)
Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 200 mg/kg once
Other Name: Arginine Hydrochloride Injection, R-Gene® 10

Experimental: Loading dose + continuous infusion
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
Drug: Arginine (Loading)
Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 200 mg/kg once
Other Name: Arginine Hydrochloride Injection, R-Gene® 10

Drug: Arginine (Continuous)
Arginine will be dispensed intravenously (in the vein) as a continuous IV infusion of 300 mg/kg/24hr
Other Name: Arginine Hydrochloride Injection, R-Gene® 10




Primary Outcome Measures :
  1. Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time [ Time Frame: Day 1 through study completion, an average of up to 7 days ]
    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.

  2. Change in nitric oxide metabolites [ Time Frame: Baseline, day 1 through study completion, an average of up to 7 days ]
    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 :
  1. Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine [ Time Frame: Day 1 ]
    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])

  2. Maximum observed plasma concentration of arginine [ Time Frame: Day 1 ]
    Maximum measured concentration of the arginine in plasma

  3. Apparent clearance of arginine [ Time Frame: Day 1 ]
    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.

  4. Terminal elimination half-life (t1/2) for arginine [ Time Frame: Day 1 ]
    Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the plasma.

  5. Change in red blood cell (RBC) arginine [ Time Frame: Baseline, day 1 through study completion, an average of up to 7 days ]
    Change in rbc arginine will be calculated as rbc arginine at the end of arginine administration minus rbc arginine at baseline.

  6. Daily urine arginine [ Time Frame: From Day 1 until study completion, an average of up to 7 days ]
    Total amount of arginine excreted in urine daily

  7. Global arginine bioavailability (GABR) [ Time Frame: From enrollment through study completion, an average of up to 7 days ]
    GABR represents a measure of endothelial function. GABR will be calculated by arginine divided by the sum of ornithine plus citrulline [arginine/(ornithine+citrulline)].

  8. Change in asymmetric dimethylarginine (ADMA) levels [ Time Frame: Baseline, day 1 and through study completion, an average of up to 7 days ]
    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.

  9. Modeling nitric oxide (NOx) level versus plasma arginine level [ Time Frame: From enrollment through study completion, an average of up to 7 days ]
  10. Biomarkers of hemolysis [ Time Frame: From enrollment through study completion, an average of up to 7 days ]
    Biomarkers of hemolysis (lactate dehydrogenase, hemoglobin, reticulocytes, arginase, indirect bilirubin) represent intravascular hemolysis and nitric oxide bioavailability.

  11. Erythrocyte glutathione levels [ Time Frame: From enrollment through study completion, an average of up to 7 days ]
    Erythrocyte glutathione is a biomarker for oxidative stress. It will be measured by using liquid chromatography.

  12. Level of cytokines [ Time Frame: From enrollment through study completion, an average of up to 7 days ]
    Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.



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Ages Eligible for Study:   7 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02447874


Locations
United States, Georgia
Children's Healthcare fo Atlanta at Hughes Spalding
Atlanta, Georgia, United States, 30303
Children's Healthcare of Atlanta at Egleston
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Children's Healthcare of Atlanta
National Center for Complementary and Integrative Health (NCCIH)
Investigators
Principal Investigator: Claudia Morris, MD Emory University

Responsible Party: Claudia Morris, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT02447874     History of Changes
Other Study ID Numbers: IRB00077736
1K24AT009893-01 ( U.S. NIH Grant/Contract )
First Posted: May 19, 2015    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn