Pharmacokinetics and Safety of Endari (L-glutamine) in Sickle Cell Disease Patients

A Phase 4, Open-Label, Single-Center Study to Assess Pharmacokinetic Characteristics and Safety of Endari in Patients With Sickle Cell Disease

L-glutamine has been approved in the US to reduce the acute complications of sickle cell disease (SCD) in adult and pediatric patients 5 years of age and older. The purpose of this single-center, open-label, phase 4 study is to evaluate the pharmacokinetic characteristics and safety of L-glutamine in patients with SCD.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Pharmacokinetics
• Intervention / Treatment: Drug: L-glutamine

Detailed Description

Sickle cell disease (SCD) is associated with a mutation in the β-hemoglobin gene that results in abnormal polymerization of hemoglobin. Polymerization of hemoglobin causes the red blood cell to sickle, leading to a cascade of events which cause acute complications for SCD patients.

L-glutamine has been approved in the US to reduce the acute complications of sickle cell disease (SCD) in adult and pediatric patients 5 years of age and older.

The purpose of this single-center, open-label, phase 4 study is to evaluate the pharmacokinetic characteristics and safety of L-glutamine in patients with SCD.

8 SCD patients and 4 healthy volunteers will receive weight-based dosing of L-glutamine for 3 weeks. Doses will be changed weekly: 0.1 g/kg administered twice daily during week 1, 0.3 g/kg administered twice daily during week 2, and 0.6 g/kg administered once daily during week 3.

The primary objective is to evaluate the pharmacokinetic characteristics of L-glutamine in SCD patients compared with healthy volunteers.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 5 years of age and older at Screening.
2. Has documented diagnosis of SCD with known genotype (HbSS, HbSβ0 and HbSC).
3. Written informed consent provided by patient or the patient's legally authorized representative.
4. Non-pregnant females of childbearing age must agree to avoid pregnancy during the study and to practice a recognized form of birth control during the course of the study (e.g., barrier, birth control pills, or abstinence).

Inclusion Criteria for Healthy Volunteers:

1. No known hematologic illness.
2. No known renal impairment.
3. 18 Years of age or older at screening.
4. Written informed consent provided by patient or the patient's legally authorized representative.
5. African American and Hispanic participants preferred.

Exclusion Criteria:

1. Recent significant medical condition that required hospitalization (other than sickle cell crisis) within 2 months prior to starting L-glutamine therapy.
2. History of chronic kidney disease Stage 4 (glomerular filtration rate [GFR]=15-29) or Stage 5 (GFR<15 mL/min/1.73 m2).
3. History of chronic liver disease Child Pugh class C (10-15 points).
4. Received any blood products 3 months prior to starting L-glutamine therapy.
5. Currently pregnant or lactating or planning to conceive during the study period.
6. Currently taking or has taken any form of glutamine supplement within 30 days prior to starting L-glutamine therapy.
7. Has been treated with an investigational medication/treatment within 30 days prior to starting L-glutamine therapy.
8. Is currently enrolled in an investigational drug or device study and/or has participated in such a study within 30 days prior to starting L-glutamine therapy.
9. Factors that would, in the judgment of the investigator, make it difficult for the patient to comply with study requirements.
10. Patient is currently being treated with crizanlizumab or voxelotor.

Exclusion Criteria for Healthy Volunteers:

1. Known allergies to L-glutamine.
2. Informed consent document was not completed and signed.
3. Currently pregnant or lactating or planning to conceive during the study period.
4. Known hematologic illness, renal or hepatic impairment.
5. Received any blood products within 3 months of starting L-glutamine therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: L-glutamine; Pharmacokinetic characteristics of L-glutamine	Drug: L-glutamine; Pharmacokinetic study; Other Names: Endari

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under Curve (AUC) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients	PK (AUC)	Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose)
Maximum Plasma Concentration (Cmax) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients	PK (Cmax)	Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose)
Half-life (t1/2) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients	PK (t1/2)	Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose)
Time to Peak Concentration (Tmax) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients	PK (Tmax)	Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glutamate levels	Plasma and serum glutamate levels.	Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
Effect of Food on L-glutamine Area Under Curve (AUC)	Food effect on AUC.	Week 1 Day 1, Week 2 Day 1, Week 4 Day 1.
Effect of Food on L-glutamine Maximum Plasma Concentration (Cmax)	Food effect on Cmax.	Week 1 Day 1, Week 2 Day 1, Week 4 Day 1.
L-glutamine Dose Effect on Area Under Curve (AUC)	Dose effect on AUC.	Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
L-glutamine Dose Effect on Maximum Plasma Concentration (Cmax)	Dose effect on Cmax.	Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
L-glutamine Interpatient Variability of Area Under Curve (AUC)	Interpatient variability of AUC.	Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
L-glutamine Interpatient Variability of Maximum Plasma Concentration (Cmax)	Interpatient variability of Cmax.	Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
Ammonia levels	Basal whole blood ammonia levels.	Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.

Collaborators and Investigators

• Sponsor: Emmaus Medical, Inc.
• Investigators: Study Chair: Yutaka Niihara, MD, Emmaus Medical, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 4, 2021
• Primary Completion (ACTUAL): June 30, 2021
• Study Completion (ACTUAL): June 30, 2021

Study Registration Dates

• First Submitted: December 18, 2020
• First Submitted That Met QC Criteria: December 22, 2020
• First Posted (ACTUAL): December 24, 2020

Study Record Updates

• Last Update Posted (ACTUAL): August 2, 2022
• Last Update Submitted That Met QC Criteria: July 29, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: pharmacokinetics; Sickle cell disease; L-glutamine
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: EM-PK-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No