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A Phase 3 Trial of l-Glutamine in Sickle Cell Disease.

  • 2018-07-19
  • The New England journal of medicine 379(3)
    • Yutaka Niihara
    • Scott T Miller
    • Julie Kanter
    • Sophie Lanzkron
    • Wally R Smith
    • Lewis L Hsu
    • Victor R Gordeuk
    • Kusum Viswanathan
    • Sharada Sarnaik
    • Ifeyinwa Osunkwo
    • Edouard Guillaume
    • Swayam Sadanandan
    • Lance Sieger
    • Joseph L Lasky
    • Eduard H Panosyan
    • Osbourne A Blake
    • Tamara N New
    • Rita Bellevue
    • Lan T Tran
    • Rafael L Razon
    • Charles W Stark
    • Lynne D Neumayr
    • Elliott P Vichinsky

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 230
Population
230 patients (age range, 5 to 58 years; 53.9% female) with sickle cell anemia or sickle β0-thalassemia and a history of two or more pain crises during the previous year
Methods
multicenter, randomized, placebo-controlled, double-blind, phase 3 trial; pharmaceutical-grade l-glutamine (0.3 g per kg per dose) twice daily by mouth vs placebo, 48-week treatment period
Blinding
Double-blind
Duration
48 weeks
Funding
Industry-funded
  • Large Human Trial
  • Highly Cited

Background

Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain.

Methods

In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle β0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period.

Results

A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group.

Conclusions

Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

Research Insights

  • L-Glutamine→Reduced Hospitalization

    Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group.

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    0.3 g per kilogram of body weight per dose twice daily
  • L-Glutamine→Reduced Pain Crises

    The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group.

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    0.3 g per kilogram of body weight per dose twice daily

Adverse Events Reported

  • L-Glutamine→fatigue

    Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group.

    Finding
    Increased risk
    Grade
    mild
  • L-Glutamine→musculoskeletal pain

    Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group.

    Finding
    Increased risk
    Grade
    mild
  • L-Glutamine→nausea

    Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group.

    Finding
    Increased risk
    Grade
    mild
  • L-Glutamine→noncardiac chest pain

    Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group.

    Finding
    Increased risk
    Grade
    mild
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