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L-citrulline Injection in Patients Aged 6-21 Years Old With Sickle Cell Disease Presenting With Vaso-Occlusive Crisis (VOC)

Primary Purpose

Acute Vaso Occlusive Crisis (VOC)

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
L-citrulline
D5 1/2NS
Sponsored by
Asklepion Pharmaceuticals, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Vaso Occlusive Crisis (VOC)

Eligibility Criteria

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

Inclusion Criteria:

  1. Sickle cell disease (all genotypes)
  2. Children, adolescents and young adults between ages 6 to 21 years
  3. In a steady disease state and not in the midst of any acute complication other than VOC due to sickle cell disease at study entry
  4. For female of childbearing potential, a negative urine pregnancy test and using an adequate method of contraception, or denies sexual activity
  5. Subjects or parents or legal guardian of the subject who are willing and able to sign and provide consent and assent (where appropriate for the age of the child).

Exclusion Criteria:

  1. Current pain lasting >3 days
  2. >6 hospital admissions in the prior year
  3. History of opioid dependence/substance abuse
  4. Has been on a clinical trial of a new therapy for sickle cell disease within the last 3 months
  5. Presence of any other complication related to sickle cell disease such as splenic sequestration, hepatic sequestration, stroke, avascular necrosis of the hip/shoulder, acute priapism, renal dysfunction, dactylitis, acute chest syndrome and other major medical conditions or organ dysfunction
  6. Severe anemia (hemoglobin <6 g/dL)
  7. History of red blood cell transfusion within the last 30 days
  8. Systemic steroid therapy within the last 48 hours
  9. Pregnancy or lactation (subjects must have a negative urine pregnancy test)
  10. Serum creatinine levels:

    1. Age 6 to 13 years >0.9 mg/dL
    2. Age 14 to 17 years >1.0 mg/dL
    3. Age >18 years >1.5 mg/dL
  11. Report of fever (>38°C) within last 48 hours
  12. Presence of acute chest syndrome, sepsis, bacterial infection, hemodynamic instability
  13. Subjects with inability to have parental assent given (ages 6 to 17 years) or consent (ages 18 through 21 years).

    Note: Parents or legal guardians can provide consent for subjects who are unable to provide assent (eg, sleepy or preoccupied by their pain).

  14. History of allergic reaction to L-citrulline product
  15. Medications that are known to be contra-indicated with use of L-citrulline
  16. History of diabetes.
  17. Subjects with a baseline prothrombin time International Normalized ratio (INR) >2.0.
  18. Received any blood products within 3 weeks of the screening visit.
  19. Unreliable venous access
  20. The PI considers that the subject will be unable to comply with the study requirements.

Sites / Locations

  • Children's National HospitalRecruiting
  • The University of Mississippi Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Arm 1 (L-citrulline)

Arm 2 (L-citrulline)

Arm 3 (L-citrulline)

Arm 4 (L-citrulline)

Part 2 Arm 1 (L-citrulline)

Part 2 Arm 2 D5 1/2NS

Arm Description

25 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours

50 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours

100 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours

100 mg/kg bolus + 11 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours

Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio. L-citrulline will be administered to the active arm.

Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio.

Outcomes

Primary Outcome Measures

Dose Optimization (Part 1)
During Part 1 of the study four cohorts will be enrolled. Cohorts will be squentially completed. Each cohort has a different dosing schema.
To determine the how the study medication is processed by the body.
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters Peak of drug in the blood will be measured
To determine the how the study medication is processed by the body.
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters Trough of drug in the blood will be measured
To determine the how the study medication is processed by the body.
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters of steady state concentration (Cmax) of drug in the blood will be measured
To determine the how the study medication is processed by the body.
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters of AUC of drug in the blood will be measured
Change in Visual Analogue Scale (VAS) pain score
Please note that scale info should be entered in the outcome measure description field: at least 2-point decrease or 30% change in pain intensity VAS or Faces Pain Scale score RANGE from 0 (No pain) to 100 (Maximum Pain) (for subjects 6 to 7 years old) when compared with baseline value; assessed every 15 minutes
Change from baseline in amount of overall opioid use
Opioid consumption will be recorded from baseline to end of study.
Discharge from ED/hospital within 7 hours
Time spent in the ED/hospital will be collected
Assessment of safety
The rate of reported AE analysis and Lab abnormalities for each cohort

Secondary Outcome Measures

Preliminary assessment of pain change measured
The standard of care Visual Analog Scale (VAS) pain scale will be administered at baseline then every 15 minutes after the start of study
Preliminary assessment of change of opioid use overall
The standard of care will be followed for pain management. the amount of opioids consumed will be collected.
Time to clinical resolution of VOC
Time to clinical resolution of VOC depicted by sustained VAS score; assessed every 15 minutes
Duration or length of hospital stay
Data collected from the ED visit through day 30 follow-up will look at reoccurrence of admission.

Full Information

First Posted
March 18, 2021
Last Updated
August 17, 2023
Sponsor
Asklepion Pharmaceuticals, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04852172
Brief Title
L-citrulline Injection in Patients Aged 6-21 Years Old With Sickle Cell Disease Presenting With Vaso-Occlusive Crisis (VOC)
Official Title
A Phase I/IIA Open-label Dose-Finding Study With Subsequent Double-blind, Placebo-controlled, Randomized Study of L-citrulline in Sickle Cell Disease Presenting to Emergency Department (ED) in Vaso Occlusive Crisis (VOC) in Children, Adolescents and Young Adults (6 to 21 Years)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 29, 2021 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
July 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Asklepion Pharmaceuticals, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine if intravenous L-citrulline can abrogate an active vaso-occlusive crisis in sickle cell disease, resulting in decreased pain, reduction or elimination of opiate usage, and reduction or elimination of hospital admission. The applicant is developing intravenous L-citrulline (Turnobi™) for treatment of sickle cell disease (SCD). The current development program targets treatment of sickle cell-associated vaso-occlusive crisis (VOC) specifically. The aim of Part 1 is to identify the optimum dose regimens for the Part 2 of the trial which is a double-blind, placebo controlled adaptive 'pick-the-winner' design. This study will allow assignment of more subjects to the better treatment arm/s based on emerging data. The study, initially, will evaluate efficacy and tolerability of incremental doses of intravenous (IV) L-citrulline (Turnobi™) in patients with SCD while receiving standard of care therapy for VOC.
Detailed Description
Overall Design: This is a study in children, adolescents, and young adults (6 to 21 years) with SCD presenting to an emergency department (ED) with VOC. Children below age 6 are likely to be recruited in a subsequent phase, once proof of concept is established on optimized dose regimen. Eligible subjects will have documented SCD. Intravenous L citrulline (Turnobi™) or placebo will be administered in addition to standard of care VOC therapy to children, adolescents, and young adults presenting with SCD VOC - defined as painful episode without other apparent causes of pain and without significant organ dysfunction or signs of systemic infection. This is a single center study, conducted in 2 parts: Part 1: This is an open-label, ascending dose part of the study. After obtaining the informed consent/assent, the enrolled subjects will be in the ED for up to 7 hours where L-citrulline will be administered as depicted in the dosing panel below. Each dose will be administered sequentially until 5 subjects per dose cohort are accrued. Dosing panels in Part 1: 25 mg/kg bolus + 9 mg/kg/hr infusion; 50 mg/kg bolus + 9 mg/kg/hr infusion; 100 mg/kg bolus + 9 mg/kg/hr infusion; 100 mg/kg bolus + 11 mg/kg/hr infusion; After each panel of 5 have been dosed, response to a dose is determined by the Principal Investigator (PI) with the internal review committee based primarily on analgesic effects assessed by review of Visual Analogue Scale (VAS) score, opioid dosing, and tolerability. If the dose panel is assessed safe and 3 of 5 subjects in a cohort respond to the treatment, the current dose arm will continue to accrue a total of 10 subjects. If the dose panel is assessed as safe; however, fewer than 3 of the 5 subjects respond, the current dose arm will be stopped, and the subjects will be recruited to the next dosing panel. Two additional panels of 5 to 10 subjects receiving doses outside these ranges may be accrued at the request of the internal review committee if determined necessary to achieve the study's objectives. As long as supported by emerging data, the subjects in these additional panels may receive a lower or higher bolus injection but no greater than 150 mg/kg bolus and/or a lower or higher infusion dose but no greater than 15 mg/kg/hour. Up to 60 subjects may be enrolled in Part 1 of the study with a likely sample size of approximately 40 subjects. Part 1 of the study is intended to select up to 2 effective and tolerated dose regimens for Part 2 of the study. Part 2: The optimal dose regimens (at least1 but probably 2) selected from Part 1 will be analyzed in a randomized, double-blind, placebo-controlled adaptive pick-the-winner design. This will allow assignment of more subjects to the better treatment arm/s based on emerging data. Efficacy will be based primarily on analgesic effect assessed by VAS/opioid dose composite, admission or not, and tolerability based on adverse drug reactions by the internal review committee. A total of 60 subjects will take part in Part 2. Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio. After 30 subjects (10 per treatment arm) have been randomized, an interim analysis will be performed. If the higher dose is providing markedly more pain relief than the lower dose - with no safety issues - then the lower dose will be dropped. Otherwise, if efficacy and safety look similar, the lower dose will be retained, and the higher dose will be dropped. In other words, the most successful active treatment arm will be chosen for further study versus placebo. The internal review committee will be responsible for making this decision. Subsequently, 30 more patients will be randomized in a 1:1 fashion in the remaining 2 study arms (15 patients each). In the unlikely case that the placebo arm demonstrates superior response to both active treatment arms, the interval review committee will recommend discontinuing the study. If after 30 subjects, it is determined by the internal review committee that 1 of the 2 doses is significantly more effective in subjects with particular characteristics, the less effective L-citrulline dose regimen can be dropped for those subjects, eg, if those with more severe VOC only respond to the higher dose but those with less severe VOC respond equally well to either dose, subjects with severe VOC will be adaptively allocated into a separate stratum and randomized only to the higher dose or placebo. All subjects in both Part 1 and Part 2 will receive standard of care for analgesia per SCD pain management protocol consistent with the Children's national ED guidance guided individualized care plan irrespective of treatment with study treatment or placebo. The end of the study is defined as the date of the last visit of the last subject in the study or last scheduled procedure the last subject in the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Vaso Occlusive Crisis (VOC)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Open-label Dose-Finding Study with Subsequent Double-blind, Placebo-controlled, Randomized Study of L-citrulline in Sickle Cell Disease Presenting to Emergency Department (ED) in Vaso Occlusive Crisis (VOC) in Children, Adolescents and Young Adults (6 to 21 years).
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double blind placebo controlled (Part 2)
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1 (L-citrulline)
Arm Type
Active Comparator
Arm Description
25 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
Arm Title
Arm 2 (L-citrulline)
Arm Type
Active Comparator
Arm Description
50 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
Arm Title
Arm 3 (L-citrulline)
Arm Type
Active Comparator
Arm Description
100 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
Arm Title
Arm 4 (L-citrulline)
Arm Type
Active Comparator
Arm Description
100 mg/kg bolus + 11 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
Arm Title
Part 2 Arm 1 (L-citrulline)
Arm Type
Active Comparator
Arm Description
Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio. L-citrulline will be administered to the active arm.
Arm Title
Part 2 Arm 2 D5 1/2NS
Arm Type
Placebo Comparator
Arm Description
Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio.
Intervention Type
Drug
Intervention Name(s)
L-citrulline
Other Intervention Name(s)
L-CIT, CIT
Intervention Description
L-citrulline is a naturally occurring amino acid. It is produced by, and normally present in, the human body.
Intervention Type
Other
Intervention Name(s)
D5 1/2NS
Other Intervention Name(s)
Saline
Intervention Description
Saline
Primary Outcome Measure Information:
Title
Dose Optimization (Part 1)
Description
During Part 1 of the study four cohorts will be enrolled. Cohorts will be squentially completed. Each cohort has a different dosing schema.
Time Frame
Collected from enrollment to end of study over 18 months
Title
To determine the how the study medication is processed by the body.
Description
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters Peak of drug in the blood will be measured
Time Frame
Collected from enrollment to Emergency room Discharge, Approximability 7 Hours
Title
To determine the how the study medication is processed by the body.
Description
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters Trough of drug in the blood will be measured
Time Frame
Collected from enrollment to Emergency room Discharge, Approximability 7 Hours
Title
To determine the how the study medication is processed by the body.
Description
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters of steady state concentration (Cmax) of drug in the blood will be measured
Time Frame
Collected from enrollment to Emergency room Discharge, Approximability 7 Hours
Title
To determine the how the study medication is processed by the body.
Description
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters of AUC of drug in the blood will be measured
Time Frame
Collected from enrollment to Emergency room Discharge, Approximability 7 Hours
Title
Change in Visual Analogue Scale (VAS) pain score
Description
Please note that scale info should be entered in the outcome measure description field: at least 2-point decrease or 30% change in pain intensity VAS or Faces Pain Scale score RANGE from 0 (No pain) to 100 (Maximum Pain) (for subjects 6 to 7 years old) when compared with baseline value; assessed every 15 minutes
Time Frame
Collected from enrollment to end of study over 18 months
Title
Change from baseline in amount of overall opioid use
Description
Opioid consumption will be recorded from baseline to end of study.
Time Frame
Collected from enrollment to end of study over 18 months
Title
Discharge from ED/hospital within 7 hours
Description
Time spent in the ED/hospital will be collected
Time Frame
Collected from enrollment to end of study over 18 months
Title
Assessment of safety
Description
The rate of reported AE analysis and Lab abnormalities for each cohort
Time Frame
Collected from enrollment to end of study over 18 months
Secondary Outcome Measure Information:
Title
Preliminary assessment of pain change measured
Description
The standard of care Visual Analog Scale (VAS) pain scale will be administered at baseline then every 15 minutes after the start of study
Time Frame
Collected from enrollment to end of study (2-Days)
Title
Preliminary assessment of change of opioid use overall
Description
The standard of care will be followed for pain management. the amount of opioids consumed will be collected.
Time Frame
Collected from enrollment to end of study (30 Days)
Title
Time to clinical resolution of VOC
Description
Time to clinical resolution of VOC depicted by sustained VAS score; assessed every 15 minutes
Time Frame
Collected from enrollment to end of study (30 Days)
Title
Duration or length of hospital stay
Description
Data collected from the ED visit through day 30 follow-up will look at reoccurrence of admission.
Time Frame
Collected from enrollment to end of study (30-Days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Sickle cell disease (all genotypes) Children, adolescents and young adults between ages 6 to 21 years In a steady disease state and not in the midst of any acute complication other than VOC due to sickle cell disease at study entry For female of childbearing potential, a negative urine pregnancy test and using an adequate method of contraception, or denies sexual activity Subjects or parents or legal guardian of the subject who are willing and able to sign and provide consent and assent (where appropriate for the age of the child). Exclusion Criteria: Current pain lasting >3 days >6 hospital admissions in the prior year History of opioid dependence/substance abuse Has been on a clinical trial of a new therapy for sickle cell disease within the last 3 months Presence of any other complication related to sickle cell disease such as splenic sequestration, hepatic sequestration, stroke, avascular necrosis of the hip/shoulder, acute priapism, renal dysfunction, dactylitis, acute chest syndrome and other major medical conditions or organ dysfunction Severe anemia (hemoglobin <6 g/dL) History of red blood cell transfusion within the last 30 days Systemic steroid therapy within the last 48 hours Pregnancy or lactation (subjects must have a negative urine pregnancy test) Serum creatinine levels: Age 6 to 13 years >0.9 mg/dL Age 14 to 17 years >1.0 mg/dL Age >18 years >1.5 mg/dL Report of fever (>38°C) within last 48 hours Presence of acute chest syndrome, sepsis, bacterial infection, hemodynamic instability Subjects with inability to have parental assent given (ages 6 to 17 years) or consent (ages 18 through 21 years). Note: Parents or legal guardians can provide consent for subjects who are unable to provide assent (eg, sleepy or preoccupied by their pain). History of allergic reaction to L-citrulline product Medications that are known to be contra-indicated with use of L-citrulline History of diabetes. Subjects with a baseline prothrombin time International Normalized ratio (INR) >2.0. Received any blood products within 3 weeks of the screening visit. Unreliable venous access The PI considers that the subject will be unable to comply with the study requirements.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gurdyal Kalsi, MD, MFPM
Phone
410-736-3750
Email
gurdyal.kalsi@asklepionpharm.com
First Name & Middle Initial & Last Name or Official Title & Degree
Heather Hill
Phone
+1 433.839.5726
Email
heather.hill@asklepionpharm.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gurdyal Kalsi, MD, MFPM
Organizational Affiliation
Asklepion Pharmaceuticals, LLC
Official's Role
Study Director
Facility Information:
Facility Name
Children's National Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Suvankar Majumdar, MD
Email
smajumdar@childrensnational.org
First Name & Middle Initial & Last Name & Degree
Kara Hom
Email
khom@childrensnational.org
Facility Name
The University of Mississippi Medical Center
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew W Maready, MD, FAAP, FACEP
Phone
6019842195
Email
mmaready@umc.edu
First Name & Middle Initial & Last Name & Degree
Stephanie Moore, BSN,RN, NRP
Phone
6014967812
Email
smoore13@umc.edu

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

L-citrulline Injection in Patients Aged 6-21 Years Old With Sickle Cell Disease Presenting With Vaso-Occlusive Crisis (VOC)

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