Phase 3 Study of L-Glutamine in Sickle Cell Disease: Analyses of Time to First and Second Crisis and Average Cumulative Recurrent Events

Background

A Phase 3, double-blind, randomized, placebo-controlled trial of L-glutamine in 230 patients (ages 5-58) over 48 weeks was conducted at 31 centers in the United States. Twice daily oral administration of L-glutamine or placebo was based on body weight approximating 0.3 g/kg/dose. The primary endpoint was the number of sickle cell crises (SCCs) during 48 weeks of follow-up. The treatment effect measured was the difference of two median numbers of SCCs between two arms by week 48. The SCCs required treatment with I.V. narcotics/ketorolac at an emergency department or during hospitalization in patients with a history of ≥ 2 crisis from the previous year. Splenic sequestration, acute chest syndrome and priapism were also considered to be SCCs. Patients stabilized on hydroxyurea (HU) treatment for at least 3 months prior to study screening (66% in both arms of the study) remained on HU for the duration of the study. The primary analysis via a Cochran-Mantel-Haenszel (CMH) test statistic showed a highly significant treatment effect (p=0.005). There was a median of 3 crises for the L-glutamine treatment arm and 4 for the placebo arm (25% difference). There were no concerning adverse events from the treatment compared with the placebo arm. In this abstract, we reported the results from additional analyses of times to first and second crisis as well as cumulative recurrent events, which further demonstrated the clinically meaningful treatment effect of L-glutamine.

Methods

The Kaplan-Meier estimates are constructed with the data from the times to the first and second SCC for both arms. The corresponding estimates of the hazard ratios with confidence intervals and p-values are obtained to evaluate the relative merit of two groups. The 50% quartile (median) of the curve and the 95% confidence interval were reported by treatment. Furthermore, recurrent event time analysis was also performed using the Andersen-Gill procedure as well as the robust method by Lin, Wei, Yang and Ying to estimate the intensity rates.

Results

L-glutamine therapy significantly prolonged the time to first and the time to second SCCs. The median time to first crisis was delayed by 30 days (84 days vs. placebo 54 days; p=0.0152) and the median time to second crisis was delayed by 79 days (212 days vs. placebo 133 days; p=0.0260). Hazard ratios for the time to first and second crisis were similar (0.69 and 0.68 respectively), suggesting an approximately 30% hazard reduction from the treatment (Figures 1 and 2). Both cumulative recurrent event analyses models for SCCs yielded an intensity rate ratio of 0.75 with 95% confidence intervals based on the Andersen-Gill of (0.62, 0.90) and Lin, Wei, Yang and Ying of (0.55, 1.01), respectively (Figure 3). This suggested that the average cumulative crisis count was reduced by approximately 25% over the entire 48-week period. Cumulative event curve separation was clear by day 30 of treatment and was maintained over the 48-week study period.

Conclusion

The results of the primary endpoint using time to event analytical methods substantiated the original CMH test result that L-glutamine treatment provided clinical benefit in reducing crises, and other acute complications of sickle cell disease, in patients 5 years of age and older irrespective of hydroxyurea use. Endari^TM (L-glutamine oral powder) is now FDA-approved to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older.

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