Background:There remains an unmet medical need for new treatments for patients with sickle cell disease (SCD). Increased oxidant stress plays a major part in the pathophysiology of sickle cell disease. It can lead to disturbance of cell membranes, exposure of adhesion molecules and damage to the contents of the sickle red blood cells (sRBC). Previous work from our laboratory has demonstrated enhancement of nicotinamide adenine dinucleotide (NAD) in sRBC by supplementation with a precursor of NAD, L-glutamine. A multi-center Phase 2 placebo-controlled trial in patients with SCD utilizing oral prescription grade L-glutamine resulted in a trend for a decrease in the incidence of painful crises at 24 weeks and a statistically significant decrease in hospitalization during the same time period in the L-glutamine group without increased adverse events. Based on these results, a large multicenter Phase 3 clinical trial was undertaken to evaluate the efficacy and safety of prescription grade L-glutamine therapy in patients with SCD.

Methods: A randomized (2:1), double-blind, placebo-controlled, parallel-group trial was conducted at 31 sites across the United States. Subjects were stratified by hydroxyurea usage. Eligibility criteria included patients ≥ 5 years of age with documented diagnoses of HbSS or HbS/β0-thalassemia with at least two documented episodes of sickle cell crises (SCC) diagnosed in a medical facility during the 12 months prior to screening. Pregnant women and patients with uncontrolled liver disease or renal insufficiency were excluded. Prescription grade L-glutamine at 0.6 g/kg/day (max 30 g), or placebo, was taken in two divided doses. Daily dose was rounded to the closest 10 g. The study drug was given for 48 weeks, then was tapered to zero over 3 weeks and a final evaluation visit was made 2 weeks after last dose. The primary endpoint was number of SCC; secondary endpoints include rates of hospitalization and adverse events; additional analyses include cumulative hospital days, incidence of acute chest syndrome (ACS) and time to first crises.

Results:A total of 230 patients were enrolled; ages 5-58; 53.9 % female. 152 were assigned to L-glutamine and 78 to placebo; the groups were well balanced for clinical characteristics. The median incidence of SCC was significantly lower in the treatment group compared to the placebo group (3 events vs. 4 respectively; p=0.008); The median incidence of hospitalization was significantly lower in the treatment group compared to placebo group (2 events vs. 3 events respectively; p=0.005); Median cumulative hospital days were significantly lower by 41% in the treatment group (6.5 days) compared to the placebo group (11 days) (p=0.022); 11.9 % of the L-glutamine group and 26.9% of the placebo group were affected by acute chest syndrome (ACS) (p=0.006). The median time to first crisis was 54 days in placebo group and 87 days in treatment group (p=0.010). Adverse events in the treatment arm were similar to those observed in the placebo arm. Statistically significant improvements for the frequency of painful crises and hospitalization persisted with analysis stratified by hydroxurea use, age, and gender.

Conclusion: This Phase 3 study in SCD demonstrated that treatment with prescription grade L-glutamine provided clinical benefit over placebo by reducing the frequency of painful crises and hospitalization. Additional clinical benefit was observed when evaluating ACS, time to first crises and duration of hospital stay. There was no increase in adverse events compared to placebo. Prescription oral L-glutamine is easy to administer and does not require special monitoring.


Niihara:Emmaus Medical Inc: Employment, Equity Ownership. Tran:Emmaus Medical Inc: Employment, Equity Ownership. Razon:Emmaus Medical Inc: Employment. Macan:Emmaus Medical Inc: Employment. Stark:Emmaus Medical Inc: Employment, Equity Ownership. Wun:Emmaus Medical Inc: Consultancy; Pfizer: Steering Committee Other. Adams-Graves:Emmaus Medical Inc: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.

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