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 .).

; for the TCD With Transfusions Changing to Hydroxyurea (TWiTCH) Trial Investigators Chronic transfusions are recommended for children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities ( 200 cm/sec) to help prevent the occurrence of a primary stroke [1]. The goal is usually to maintain the sickle hemoglobin concentration (HbS) <30%; however, this goal is often difficult to achieve in clinical practice. The NHLBI-sponsored trial ''TCD With Transfusions Changing to Hydroxyurea (TWiTCH)'' will compare standard therapy (transfusions) to alternative therapy (hydroxyurea) for the reduction of primary stroke risk in this patient population. Transfusions will be given according to current transfusion practices at participating sites. To determine current academic community standards for primary stroke prophylaxis in children with SCA, 32 clinical sites collected data on 340 children with abnormal TCD velocities receiving chronic transfusions to help prevent primary stroke. The average (mean ± 1 SD) pretransfusion HbS was 34 ± 11% (institutional average 23-48%); the 75th and 90th percentiles were 41 and 50%, respectively. Lower %HbS was associated with higher pretransfusion Hb values and receiving transfusions on time. These data indicate variable current transfusion practices among academic pediatric institutions and in practice, 30% HbS may not be an easily attainable goal in this cohort of children with SCA and abnormal TCD.Children with sickle cell anemia (SCA) compose a high risk group for the development of stroke. If untreated, 11% will experience a clinical stroke by 20 years of age [2]. Adams et al. have shown that children with SCA who are at risk for primary stroke can be identified by measuring time-averaged mean blood flow velocities in the internal carotid or middle cerebral arteries by TCD [3]. Abnormal TCD velocities ( 200 cm/sec) are associated with high risk for stroke and warrant transfusion therapy to reduce the risk of primary stroke. First stroke can be successfully prevented in 90% of children with SCA and abnormal TCD velocities by the use of chronic transfusion therapy, with a goal of keeping HbS concentrations less than 30% [1].TCD with Transfusions Changing to Hydroxyurea (TWiTCH) is an NHLBIsponsored, Phase III, multicenter trial comparing standard therapy (monthly transfusions) to alternative therapy (daily hydroxyurea) to reduce the risk of primary stroke in children with SCA and documented abnormal TCD velocities. Since transfusions compose the standard treatment arm, accurate %HbS values achieved in actual clinical practice were needed for protocol development. The majority of our information about transfusing patients with SCA to prevent stroke comes from secondary stroke prevention, i.e., the use of chronic red blood cell transfusions to prevent a second stroke after a first clinical stroke has occurred. Classically, transfusions are administered at 4-week intervals to maintain HbS at less than 30%. After several years of transfusion therapy, a few centers ...

Background: Missed medical appointments decrease continuity of medical care, waste resources, and may affect health outcomes. We examined the factors associated with missed children’s supervision visits in Eastern Brooklyn, NY, USA. Methods: We surveyed guardians whose children received routine medical care at four pediatric clinics. Participants filled out a questionnaire that queried: demographics, food security, recent relocation, parental support of healthy behaviors, and length of knowing provider. Preexisting disease(s) and missed visits were retrieved from medical records. Regression analyses were used to determine factors that were associated with missing medical appointments. Results: Among 213 families, 33% faced food insecurity and 16.4% reported moving within the past 12 months. Forty percent of children missed at least 1 visit. Food insecurity (adjusted odds ratio [aOR] 2.3, 95% confidence interval [CI 1.0% to 5.2%) and recent relocation (aOR 1.8, 95% CI 1.1-3.4 were associated with missed health supervision visits, whereas greater parental healthy behaviors (aOR 0.5, 95% CI 0.3-0.9) and longer length of knowing provider (aOR 0.8, 95% CI 0.7-1.0) were associated with fewer missed appointments. Conclusion: This study indicates that social inequity may contribute to poor adherence to medical appointments through multiple mechanisms, including food insecurity, lack of social stability, and parental health behaviors. Multidimensional proactive prevention, and reactive tolerance should be considered as opportunities to mitigate the impact of social inequity on health outcomes.

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Background: Sickle cell disease (SCD) is characterized by continuous oxidative stress through various mechanisms contributing to the pathophysiology and clinical course of sickle cell crises (SCC) and organ damage. L-glutamine is a precursor for the synthesis of essential metabolic redox cofactors including Nicotinamide Adenine Dinucleotide (NAD). Early studies have demonstrated that altered erythrocyte NAD redox potential was improved by oral L-glutamine therapy, suggesting that higher L-glutamine utilization in SCD exceeded de novo synthesis and its depletion played a role in oxidative stress. A Phase 2 study of Pharmaceutical Grade L-glutamine (L-glutamine) versus placebo showed promising results on clinical endpoints. In a Phase 3 study with 230 SCD patients, randomized 2:1 to L-glutamine or placebo, the median number of SCCs was 25% lower for L-glutamine than placebo (L-glutamine 3.0 vs. placebo 4.0). An analysis of SCC events showed significant differences between groups (p < 0.01). Categories for pre-specified subgroups for Age, Gender and Hydroxyurea (HU) use were defined in the statistical plan. HU use was also a randomization stratification factor since HU is the only FDA-approved drug for SCD treatment. Examination of the HU subgroup for differences in L-glutamine effect across categories (HU vs. no HU) was appropriate since approximately 66% of patients remained on HU throughout the Phase 3 study. To investigate the subgroup treatment effect size, treatment by subgroup interaction and consistency of the primary endpoint across the categories of the subgroups, an examination was performed following the guidelines for reporting subgroup analysis. Methods: The Negative Binomial Regression (NBR) model was utilized to generate an estimate of treatment effect and treatment by subgroup interactions of the three pre-specified subgroups. SCC events are most accurately described as counts and NBR is specifically intended for modeling count variables, usually for over-dispersed counts as seen in SCD studies. Rates of SCC for each treatment arm in a subgroup (Rate L-glutamine per 48 weeks / Rate placebo per 48 weeks) provide rate ratios, and an estimate of effect size, with 95% confidence intervals. A rate ratio <1.0 favored L-glutamine. Tests for treatment by subgroup interactions were conducted simultaneously. A significant interaction could be seen if the treatment is better than placebo for one category and worse than placebo for the other. Predefined categories for subgroups with corresponding sample sizes were as follows: Age: 5 - 18 years (n = 118) and ≥ 18 years (n = 111); Gender: Females (n = 124) and Males (n = 105). HU use before and during study: Yes (n = 153) and No (n = 76). Data for this Phase 3 subgroup report were obtained from an integrated dataset and the NBR model with treatment, subgroup, region and HU use as main effects and a treatment by subgroup interaction term was run with log (time on study) as an offset. Results: Age Subgroup:Both the 5 - 18 years and the > 18 years groups had a lower rate of SCCs per 48 weeks in the L-glutamine arm relative to placebo. The rate ratio was 0.93 [0.67 - 1.29] for the 5 - 18 years group and 0.64 [0.45 - 0.89] in the > 18 years group. There was no treatment by Age Group interaction (p = 0.118). Gender Subgroup: Both the Female and the Male groups had a lower rate of SCCs per 48 weeks in the L-glutamine treatment arm. The rate ratio was 0.81 [0.59 -1.12] for the Female group and 0.73 [0.51 - 1.05] for the Male group, indicating consistent treatment effects across genders. There was no treatment by Gender interaction (p = 0.683). Hydroxyurea Use Subgroup: Both HU groups had a lower rate of SCCs per 48 weeks in the L-glutamine arm. The treatment effects were consistent across groups, with a rate ratio of 0.78 [0.51 - 1.20] for the group without HU use and 0.77 [0.58 - 1.03] for the group with HU use. There was no treatment by HU use interaction (p = 0.961). See Figure 1 for a graphic example. Conclusion: For the Age and Gender subgroups, both categories in each subgroup benefited from L-glutamine but to varying degrees noted by the difference in rate ratios. For the HU use subgroup, both categories (on HU and not on HU) benefited from L-glutamine similarly. Lack of interactions in all subgroups indicated that regardless of category within a subgroup, treatment effect by Pharmaceutical Grade L-glutamine was beneficial. Figure 1 Hydroxyurea Use Subgroup Analysis Figure 1. Hydroxyurea Use Subgroup Analysis Disclosures Niihara: Emmaus Medical, Inc.: Employment, Equity Ownership. Viswanathan:Novartis: Speakers Bureau. Razon:Emmaus Medical, Inc.: Employment. Tran:Emmaus Medical, Inc.: Employment, Equity Ownership. Stark:Emmaus Medical, Inc.: Employment, Equity Ownership.