Clinical trial NCT04684381: Pharmacokinetics and Safety of Endari (L-glutamine) in Sickle Cell Disease Patients
Official title: A Phase 4, Open-Label, Single-Center Study to Assess Pharmacokinetic Characteristics and Safety of Endari in Patients With Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Sickle Cell Disease
Pharmacokinetics
Keywords: Sickle cell disease
pharmacokinetics
L-glutamine
Lead sponsor: Emmaus Medical, Inc.
Sponsor class: INDUSTRY
First posted: 2020-12-24
Enrollment: 13
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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 outcomes:
measure: Glutamate levels
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
measure: Effect of Food on L-glutamine Area Under Curve (AUC)
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 4 Day 1.
measure: Effect of Food on L-glutamine Maximum Plasma Concentration (Cmax)
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 4 Day 1.
measure: L-glutamine Dose Effect on Area Under Curve (AUC)
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
measure: L-glutamine Dose Effect on Maximum Plasma Concentration (Cmax)
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
measure: L-glutamine Interpatient Variability of Area Under Curve (AUC)
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
measure: L-glutamine Interpatient Variability of Maximum Plasma Concentration (Cmax)
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
measure: Ammonia levels
timeFrame: Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1.
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
Study officials:
affiliation: Emmaus Medical, Inc.
name: Yutaka Niihara, MD
role: STUDY_CHAIR
References: