A Phase 3 Trial of
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            -Glutamine in Sickle Cell Disease

Niihara, Yutaka; Miller, Scott T.; Kanter, Julie; Lanzkron, Sophie; Smith, Wally R.; Hsu, Lewis L.; Gordeuk, Victor R.; Viswanathan, Kusum; Sarnaik, Sharada A.; Osunkwo, Ifeyinwa; Guillaume, Edouard; Sadanandan, Swayam; Sieger, Lance; Lasky, Joseph L.; Panosyan, Eduard H.; Blake, Osbourne A.; New, Tamara; Bellevue, Rita; Tran, Lan; Razon, Rafael; Stark, Charles W.; Neumayr, Lynne; Vichinsky, Elliott

doi:10.1056/nejmoa1715971

Cited by 427 publications

(384 citation statements)

References 23 publications

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“…Furthermore, patient concerns regarding the HU safety profile and the monitoring that is required to determine a well-tolerated, effective dose have led to low prescription rates and poor patient adherence 18,[23][24][25]. The drug was approved in the USA 26 based on results from a phase 3 study that have recently been published 27. The drug was approved in the USA 26 based on results from a phase 3 study that have recently been published 27.…”

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confidence: 99%

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

et al. 2018

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The cell adhesion molecule P‐selectin plays a key role in the pathogenesis of a vaso‐occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double‐blind, placebo‐controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti‐P‐selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2‐4/5‐10), SCD genotype (HbSS/non‐HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event‐free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5‐10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time‐to‐first VOC vs placebo in these subgroups. The rates of treatment‐emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event‐free and delays time‐to‐first VOC.

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confidence: 99%

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

et al. 2018

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“…Three studies assessing the effect of exogenous l ‐glutamine administration in patients with SCD were ultimately retained due to applicability. Study designs included one nonrandomized controlled trial and two randomized controlled trials, each published under the same first author . Table summarizes the efficacy and safety results of each study.…”

Section: Resultsmentioning

confidence: 99%

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

et al. 2019

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l‐glutamine was approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease (SCD) in 2017. A vaso‐occlusive crisis (VOC) occurs in persons with SCD and is associated with acute pain episodes. This systematic review summarizes the evidence for l‐glutamine in the prevention of VOC and associated pain in patients with SCD. Medline, Embase, and International Pharmaceutical Abstracts were searched for records reporting on l‐glutamine use in persons with SCD. Eligibility criteria identified primary reports of investigations conducted in humans who were administered l‐glutamine, reported on outcomes related to VOC or associated pain, published in English, and were available as full text. All relevant efficacy, safety, participant demographic data, and study method characteristics were extracted and documented. Risk‐of‐bias assessments were conducted using the Risk of Bias in Non‐Randomized Studies‐of Interventions (ROBINS‐I) tool and the revised Cochrane risk‐of‐bias tool for randomized studies. Three studies assessing the effect of exogenous l‐glutamine administration in patients with SCD met eligibility criteria: one prospective nonrandomized controlled study and two prospective randomized controlled trials. Rate of VOC and related hospitalizations were reduced in patients receiving l‐glutamine, although some conflicting results were noted between studies. l‐glutamine was generally well tolerated. Limitations of one or more of the eligible studies included small sample size, nonblinding, and study groups that differed at baseline. l‐glutamine has limited high‐quality evidence supporting its use. Although l‐glutamine is FDA approved for the prevention of frequent episodes of VOC pain, only one randomized controlled trial has strong evidence to support this indication. Based on the results of a systematic review, l‐glutamine may be considered for patients unable to receive hydroxyurea or in addition to hydroxyurea for reduction in VOC and associated pain.

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“…L‐glutamine was approved by the FDA in 2017 to reduce the acute complications of SCD on the scientific basis that it might help to restore the redox ratio. However, data from the Phase‐III study of L‐glutamine did not demonstrate any change in the haemolysis laboratory parameters observed between patients who were treated with L‐glutamine and those on placebo (Niihara et al , ), indicating that the benefits from L‐glutamine on VOC were most likely not mediated through its action in sickled erythrocytes. Work is currently on‐going in our laboratory to determine whether the beneficial effects of L‐glutamine in SCD are in restoring the intestinal barrier and reducing intestinal bacteria/bacterial product translocation.…”

Section: Targeting the Intestinal Pathophysiological Changes For Thermentioning

confidence: 99%

Intestinal pathophysiological and microbial changes in sickle cell disease: Potential targets for therapeutic intervention

et al. 2019

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Summary There is a large therapeutic gap in the treatment of sickle cell disease (SCD). Recent studies demonstrated the presence of pathophysiological and microbial changes in the intestine of patients with SCD. The intestinal microbes have also been found to regulate neutrophil ageing and possible basal activation of circulating neutrophils. Both aged and activated neutrophils are pivotal for the pathogenesis of vaso‐occlusive crisis in SCD. In this paper, we will provide an overview of the intestinal pathophysiological and microbial changes in SCD. Based on these changes, we will propose therapeutic approaches that could be investigated for treating SCD.

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

Cited by 427 publications

References 23 publications

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

Intestinal pathophysiological and microbial changes in sickle cell disease: Potential targets for therapeutic intervention

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