A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Effects on In Vivo Markers of Platelet Activation and of Coagulation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1049-1049
Author(s):  
Joseph A. Jakubowski ◽  
Chunmei Zhou ◽  
David S. Small ◽  
Kenneth J. Winters ◽  
D. Richard Lachno ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Research Funding ◽  
Blood Platelet ◽  
Cell Disease ◽  
Employment Equity ◽  
Equity Ownership ◽  
Adp Receptor

Abstract Abstract 1049 Introduction: Evidence suggests that platelets are activated in sickle cell disease (SCD) and this appears to increase further during painful crises caused by vascular occlusions from sickled red blood cells. Antiplatelet therapy may be useful in reducing the frequency and severity of acute pain episodes and reducing the risk of thrombotic complications. Prasugrel, an ADP receptor antagonist, irreversibly inhibits the P2Y12 ADP receptor, blocking ADP-stimulated platelet activation and aggregation and reducing downstream procoagulant activities. Here we present the first evaluation of prasugrel's effects on markers of in vivo platelet activation and of coagulation in subjects with SCD. Methods: Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Markers of platelet activation and coagulation included whole-blood platelet-monocyte and -neutrophil aggregates, and whole blood platelet-associated P-selectin and platelet CD40L, all measured by flow cytometry and presented as percent (%) of marker positive cells. Plasma soluble (s) P-selectin, CD40L, and plasma prothrombin fragment 1.2 (F1.2) were evaluated by ELISA. Results: Results from the biomarkers are presented in the table. Prior to prasugrel administration (baseline), subjects with SCD had significantly higher levels of the following biomarkers compared to healthy subjects: Platelet-monocyte aggregates, platelet-neutrophil aggregates, platelet CD40L, and plasma F1.2. In addition, subjects with SCD had numerically higher values of sCD40L, as well as platelet-associated and sP-selectin. Prasugrel treatment resulted in numerical decreases in levels of all biomarkers (with the exception of platelet-associated CD40L for control subjects), most notably in SCD subjects with elevated baseline levels. Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs. Conclusion: In this study, compared to healthy controls, baseline elevation of several platelet-activation and coagulation markers among adult subjects with SCD is consistent with that seen in previous studies of both children and adults with SCD. The decrease in platelet activation biomarkers following 12 days of prasugrel treatment in subjects with SCD suggests prasugrel interrupts SCD-related platelet activation in vivo and raises the possibility that prasugrel may modulate the frequency and/or severity of painful crises associated with SCD. These data support additional studies of the safety and efficacy of prasugrel in the treatment of vascular complications associated with SCD. Disclosures: Jakubowski: Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding; GLSynthesis: Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Compnay: Employment, Equity Ownership.

Biomarkers of Hemostatic Activation in a Randomized, Double-Blind, Phase 2 Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2127-2127
Author(s):  
Ted Wun ◽  
Charles L. Knupp ◽  
Lillian E. McMahon ◽  
John J. Strouse ◽  
Chunmei Zhou ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Research Funding ◽  
Study Drug ◽  
Phase 2 ◽  
Cell Disease ◽  
Employment Equity ◽  
Double Blind ◽  
Equity Ownership

Abstract Abstract 2127 Introduction: Activation of the hemostatic cascade and platelet activation in particular, has been implicated in the pathogenesis of sickle cell disease (SCD). Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndromes undergoing percutaneous coronary revascularization. We evaluated serial biomarkers of hemostatic activation from a trial of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo ratio. Study drug, prasugrel 5 mg or placebo, was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Samples for biomarkers were collected prior to initiation of study drug, on day 10 ± 2, and on day 30 ± 3. Multi-color fluorescent activated cell sorting and monoclonal antibodies were used to determine platelet P-selectin expression, platelet-monocyte aggregates (PMA), and platelet-neutrophil aggregates (PNA) using previously published protocols. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays. Statistical comparison between prasugrel and placebo was performed using a mixed model with treatment, baseline measurement, genotype of SCD, visit and the interaction between visit and treatment as fixed effects and subjects as a random effect. Results: Forty-one patients were randomized to prasugrel 5 mg and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients in the prasugrel and 9 in the placebo arm were on hydroxyurea prior to study drug. Results are shown in the Figure. Compared to placebo, platelet P-selectin (unstimulated), sP-selectin, and sCD40L all achieved or approached significantly lower values in the prasugrel group on day 10 and 30, as did ADP-stimulated platelet P-selectin values (data not shown). TXB2 was significantly lower on day 10 but not on day 30 (Fig. 1), as were PMA/PNA unstimulated, and PMA/PNA in response to ADP ex vivo. F1.2 levels were not different between the groups at either day 10 or 30 (data not shown). Conclusions: As would be predicted by the mechanism of action, prasugrel resulted in decreased cellular and soluble biomarkers of platelet activation. There was no effect on coagulation as assessed by F1.2, a marker of thrombin generation. Clinical results reported elsewhere suggest a decrease in pain rate. Prasugrel 5 mg po daily clearly decreases markers of platelet activation in adult SCD patients. These biomarkers can be incorporated in future studies of prasugrel in SCD to correlate with clinical outcomes. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Knupp:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. McMahon:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Strouse:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 847-847 ◽  
Author(s):  
Ted Wun ◽  
Denis Soulieres ◽  
Lakshmanan Krishnamurti ◽  
Abdullah Kutlar ◽  
Kenneth Ataga ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Study Drug ◽  
Medical Attention ◽  
Phase 2 ◽  
Cell Disease ◽  
Employment Equity ◽  
Double Blind ◽  
Equity Ownership

Abstract Abstract 847FN2 Introduction: Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5 mg daily prasugrel, the dose was to be escalated to 7.5 mg. Results: Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). Conclusions: Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

scholarly journals Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 990-990
Author(s):  
John F Tisdale ◽  
Francis J. Pierciey ◽  
Rammurti Kamble ◽  
Julie Kanter ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Abstract Background Patients with severe sickle cell disease (SCD) may benefit from β-globin gene transfer into autologous hematopoietic stem cells (HSC). Successful HBB gene transfer requires vector-mediated transduction of primitive HSCs. Steady-state bone marrow (BM) is the default HSC source in patients with SCD. Normal human BM contains up to 30% CD34+CD19+ pro-B cells and other lineage-committed cell types (CD34dim) that will not contribute to improved long-term erythropoiesis via gene therapy; these cells mobilize at low rates. CD34+ cell yields from BM harvest (BMH) are typically lower than those after mobilization and peripheral blood (PB) apheresis; multiple rounds of BMH may be required to obtain adequate cell doses for autologous gene therapy (GT) protocols. As G-CSF can cause life-threatening SCD complications and is contraindicated, plerixafor, a CXCR4 receptor antagonist, may accomplish HSC mobilization without the neutrophil or endothelial activation that elicit vaso-occlusion. We modified the protocol for the HGB-206 phase 1 study of LentiGlobin GT in severe SCD (NCT02140554) to assess HSC mobilization with plerixafor alone, followed by apheresis and transduction of mobilized cells. We also characterized BM-derived and plerixafor-mobilized HSC populations from patients with SCD. Methods HGB-206 is a phase 1 study of LentiGlobin Drug Product (DP), which contains autologous HSCs transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector, in patients with severe SCD (defined as a history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of &gt;2.5 m/s). Patients in group B receive 240 µg/kg plerixafor followed 4-6 hours later by apheresis, processing ~3 total blood volumes to collect backup HSCs. If &lt; 1.5 x 106 CD34+ cells are collected, patients undergo a second day of apheresis. Cells collected in excess of those required for backup in case of graft failure are transduced with BB305 lentiviral vector for exploratory analyses. Group B patients then proceed to BMH to obtain cells for clinical DP manufacture. Group C will receive DP manufactured from mobilized PB. Mass cytometry (CyTOF) was used to analyze ex vivo cultured CD34+ cells with over 35 cell surface markers. Results To date, 3 patients have undergone plerixafor mobilization. Patients had a transient 1.5- to 3-fold increase in peak white blood cell and absolute neutrophil levels after plerixafor. Peak absolute CD34+ cell counts in PB were 170, 58, and 160 x 106 CD34+ cells/liter. A total of 15.3, 5.6, and 9.0 x 106 CD34+ cells/kg were collected in a single day of apheresis, and no subsequent apheresis or mobilization was required. In the same study, a mean of 5.0 (range 0.3-10.8) x 106 CD34+ cells/kg were collected per BMH (N=21). The mobilization and apheresis procedures had an acceptable toxicity profile. No dose-limiting toxicities were observed after plerixafor dosing. One patient had a single VOC approximately 48 hours after receiving plerixafor; this patient also experienced VOCs of similar severity after BMH. In contrast, after 21 BMHs in 9 patients, 18 ≥ grade 3 AEs were reported in 6 patients, primarily pain. Ex vivo cultured CD34+ cells isolated from BMH consisted of an average of 41.0% (17.3%-50.7%) CD34dim cells, with 16%-50% of the CD34dim cells expressing lymphoid markers. In contrast, ex vivo cultured CD34+ cells isolated from plerixafor mobilized PB contained an average of 8.2% (1.5-19.5%) CD34dim cells. Similar drug product vector copy numbers were obtained after research-scale transduction of CD34+ cells from marrow and PB from the same patient. Conclusion Initial results suggest that obtaining adequate doses of CD34+ cells from plerixafor-mobilized PB of patients with SCD may be safe and feasible, without the life-threatening complications associated with G-CSF, and with fewer, less invasive procedures compared with BMH. PB-derived CD34+ cells may contain lower proportions of lineage-committed CD34+ cells than BM-derived cells from patients with SCD. Cells collected by BMH and PB mobilization/apheresis appear to have an equivalent transduction efficiency. Together these results indicate that it may be possible to use plerixafor-only mobilization in clinical studies of autologous HSC GT in SCD. Results of mobilization, apheresis, and DP manufacturing at clinical scale for additional patients will be available for presentation. Disclosures Pierciey: bluebird bio: Employment. Kanter: American Society of Hematology (Sickle Cell Disease Guideline Panel): Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MUSC: Other: The site PI for sponsored research conducted at MUSC who receives funds from: Novartis, bluebird bio, GBT, Sancillo, Apopharma, Pfizer; NHLBI (sickle cell disease research advisory committee): Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancillo: Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; GBT: Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kwiatkowski: Novartis: Research Funding; Bluebird Bio: Research Funding; Apopharma: Research Funding; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria. Thompson: Novartis: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta: Research Funding; Celgene: Consultancy, Research Funding. Shestopalov: bluebird bio: Employment, Equity Ownership. Bonner: bluebird bio: Employment, Equity Ownership. Joseney-Antoine: bluebird bio: Employment, Equity Ownership. Asmal: bluebird bio: Employment, Equity Ownership. Walters: bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; Sangamo Therapeutics: Consultancy; AllCells, Inc: Other: Medical Director.

scholarly journals Edx-17: A Novel, Safe and Efficacious Treatment for Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1357-1357
Author(s):  
Robert H. Broyles ◽  
Sunil K. Joshi ◽  
Carol D. Curtis ◽  
Austin C. Roth ◽  
Patrick A. Floyd ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Erythroid Precursor ◽  
Gamma Globin ◽  
Equity Ownership

Abstract Gene regulation of developmental hemoglobin switching holds the potential for therapeutic relief from all symptoms associated with Sickle Cell Disease (SCD). Reactivation of fetal gamma-globin expression (HbF) can replace mutant betaS-globin (HbS) to produce functional hemoglobin tetramers and eliminate the hemoglobin polymerization that is characteristic of sickled red blood cells. We have discovered a protein that regulates this developmental switch, and have identified a compound that stimulates expression of this protein. EdX-17 promotes expression of the anti-stress factor ferritin heavy chain (FtH), which enters the nucleus of erythroid precursor cells and activates expression of fetal gamma-globin, producing HbF (PNAS 98:9145-50, 2001; Blood 108:790a, 2006). Mononuclear cells were isolated from SCD patient blood and matured in vitro to the advanced erythroblast stage using a 28-day, 2-phase culture system (Methods in Molecular Biology 482:127-40, 2009; Blood 119:6296-306, 2012). Treatment with EdX-17 for 24h resulted in a dose-responsive induction of gamma-globin gene expression and a concomitant dose-responsive increase in HbF was observed after 28 days in culture. These studies demonstrate that EdX-17 doses in the picomolar range are sufficient to significantly enhance HbF. Furthermore, EdX-17 treatment reconstitutes fetal hemoglobin (HbF) in transgenic betaYAC mice to levels above 25-30% - the range thought to be sufficient to ameliorate symptoms of SCD – with no detectable ill effects. In fact, mice treated with EdX-17 tend to have shinier coats, are more alert and stronger than age-matched, untreated mice. Development of this novel therapeutic is expected to ameliorate SCD symptoms, decrease pain and morbidity, increase life-span, greatly improve patient quality of life, and significantly reduce treatment costs. Supported in part by The Sickle Cell Cure Foundation, Inc., the Bill & Melinda Gates Foundation, and EpimedX, LLC. Disclosures Broyles: EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Curtis:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Roth:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Belegu:EpimedX, LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Impact on Ex Vivo Platelet Reactivity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1053-1053
Author(s):  
Joseph A. Jakubowski ◽  
Chunmei Zhou ◽  
David S. Small ◽  
Kenneth J. Winters ◽  
D. Richard Lachno ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Platelet Reactivity ◽  
Healthy Controls ◽  
Subject Group ◽  
Population Differences ◽  
Cell Disease ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 1053 Introduction: There is evidence of increased platelet reactivity in subjects with sickle cell disease (SCD). This could contribute to vaso-occlusive complications that characterize the disease; thus, antiplatelet therapy may be useful in the management of SCD. Prasugrel, a novel thienopyridine P2Y12 ADP receptor antagonist, is an effective inhibitor of ADP-mediated platelet activation and aggregation, but it has not been evaluated in SCD. The present study examined 1) the utility of various platelet assays used to assess platelet reactivity in blood from subjects with SCD; and 2) the impact of prasugrel on platelet reactivity in subjects with SCD compared to healthy controls. Methods: Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Platelet reactivity to ADP at baseline and after 12 days of prasugrel treatment was assessed by 1) maximum platelet aggregation (MPA) to 5mM ADP using light transmission aggregometry (LTA); 2) area under the aggregation curve (AU.min) to 6.5 mM ADP using impedance aggregometry (IA); 3) P2Y12 reactivity units (PRU) by VerifyNow P2Y12 (VN); and 4) platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Baseline population differences and the within-group changes from baseline were analyzed using t-tests. The population differences for change from baseline were analyzed using an analysis of covariance model, with dose, subject group, and dose-by-subject group interaction as fixed effects, and baseline measurement as the covariate. Results: All data are shown as mean±SD. At baseline and prior to initiation of prasugrel, subjects with SCD showed increased platelet reactivity vs. healthy controls, as evidenced by VN (PRU: 407.9±39.6 vs. 322.5±74.2, p=0.003) and IA (AU.min: 106.4±27.9 vs. 76.5±13.2, p=0.002). However, there was no difference between subjects with SCD and healthy controls in baseline platelet reactivity with LTA (MPA: 73.1±14.4% vs. 80.4±23.2%, p=0.376). Baseline PRI by VASP was significantly lower in subjects with SCD than in healthy controls (PRI: 59.4±23.3% vs. 78.9±10.0%, p=0.018) (Figure). After 12 days of treatment with prasugrel, all measures of platelet reactivity were significantly reduced compared with baseline in both SCD subjects and healthy controls (p< 0.05 for each assay); absolute change from baseline were as follows: LTA (−33.4 vs. −49.9), IA (−63.2 vs. −49.5), VN (−197.4 vs. −212.0), and VASP (−46.0 vs. −49.9; all SCD vs. control respectively, Figure). Changes from baseline in subjects with SCD compared to changes from baseline in healthy controls were not statistically significant after adjusting for baseline. Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs. Conclusion: At baseline, compared with healthy controls, subjects with SCD had increased platelet aggregation to ADP in whole blood by two independent assays (VN and IA), but similar aggregation in platelet-rich plasma (LTA). These results may be influenced by the lower hematocrit and higher platelet count in subjects with SCD. At baseline, subjects with SCD had more variable VASP PRI values resulting in reduced mean PRI. It remains to be determined whether this is a reflection of altered ADP and/or PGE1 signaling in certain individuals with SCD. Prasugrel administration significantly attenuated ADP-stimulated platelet reactivity in SCD subjects as measured by LTA, IA, VN, and VASP. The extent of prasugrel inhibition of platelet function in SCD was similar to that observed in prasugrel-treated healthy controls as measured by all 4 assays. The present results demonstrate that prasugrel inhibits platelet function in subjects with SCD, and that this inhibition can be monitored by a variety of assays. These results provide the basis for future studies evaluating prasugrel for the treatment of vascular complications associated with SCD. p value: change from baseline; error bars: arithmetic mean±SD for combined dose data Disclosures: Jakubowski: Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; GLSynthesis: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Company: Employment, Equity Ownership.

scholarly journals Chronic Kidney Disease Is Under-Screened in SCD and Mild Albuminuria Is Associated with a Drop in Hemoglobin: A Report from the Grndad Sickle Cell Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2284-2284
Author(s):  
Elizabeth Williams ◽  
Elizabeth Brown ◽  
Deepa Manwani ◽  
Payal Desai ◽  
Joshua J. Field ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Sickle Cell Disease ◽  
Kidney Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

The Globin Research Network for Data and Discovery (GRNDaD) is a combined effort, from 6 US clinical sites (Baltimore, Cleveland, Columbus OH, Milwaukee, Oakland, and The Bronx) that care for people with sickle cell disease (SCD), to improve care through shared data collection and review and quality improvement. Using a single IRB-Reliant protocol, we have assembled harmonized baseline and annual data on 758 adults with sickle cell disease (41.7% male and 58.3% female, mean age 35.5), collected on a REDCap server housed at Johns Hopkins. For this study, we reviewed adherence to the 2014 NHLBI Guidelines on the management of SCD -- which recommends annual screening for chronic kidney disease (CKD) by testing for albuminuria or proteinuria in anyone over the age of 10 with sickle cell disease. To evaluate whether subjects had an annual visit in any given year we used the recording of a well visit hemoglobin. Of the 758 adults in the study 411 had at least one year of follow up data marked as completed. Among these 411 adults there were 826 distinct observations. Of these 826 observations, 137 observations among 85 subjects did not have any hemoglobin lab drawn, suggesting that they did not have a well outpatient visit during that year. Amongst the observation years, where a well hemoglobin was performed, yearly screening for albuminuria occurred in 37.4% (258/689) of annual observations. There was an association between having screening for CKD and site of care (p<.0001), with some sites having adhered to guidelines in 34.2% of observation years and others having adhered 75.9% of years. There was no association between adherence and genotype or sex. Albuminuria was associated with a clinical phenotype. A multi-variable linear mixed effects model controlling for age and gender with a randomly varying intercept based on the subject, excluding chronically transfused subjects, and stratified by sickle cell anemia (HbSS or HbSB0, SCA) or variant genotypes was used. There was a significant association in those with SCA between the presence of albuminuria between 30 and 300, level (A2) and hemoglobin. Hemoglobin levels were, on average, 0.79 g/dL lower in those with albuminuria between 30-300 when compared to those with no albuminuria (A1, P=0.005). For those with SCA and albuminuria greater than 300 (A3), the sample size was small (n=28) and hemoglobin levels were 0.61 g/dl lower compared to those without albuminuria but this was not statistically significant (p=0.12). For those with variant compound heterozygous SCD and A2 albuminuria, hemoglobin levels were not statistically significantly different from those without albuminuria. However, high-grade albuminuria (A3) was associated with hemoglobin levels which were, on average, 1.86 g/dL lower than those in group A1 (P=0.004). Interestingly, the association between reduced hemoglobin and albuminuria was seen in both variant and SCA genotypes in the context of a preserved creatinine (<1.0 mg/dL). Using a multisite registry we demonstrate the need to develop strategies to assist providers and patients with adherence to guideline based recommendations for routine screening for chronic kidney disease in adults with SCD. The early association of albuminuria with worsening anemia, even in the absence of elevated creatinine levels, suggests an added urgency to screening. The causality of the association remains unclear but emphasizes the need for longitudinally followed cohorts that might help us understand the relationship between anemia and the development of CKD. Figure Disclosures Manwani: Novartis: Consultancy; Pfizer: Consultancy; GBT: Consultancy, Research Funding. Desai:Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Neumayr:La Jolla Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Bayer: Consultancy; CTD Holdings: Consultancy; CDC: Research Funding; Celgene: Research Funding; Imara: Research Funding; NHLBI: Research Funding; Sangamo: Research Funding; HRSA: Research Funding; GBT: Research Funding; Emmaus: Consultancy; Apopharma: Consultancy; Sancillo: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Silarus: Research Funding; Terumo: Research Funding; PCORI: Research Funding; Doris Duke Foundation: Research Funding; Seattle Children's Research Grants: Research Funding. Clay:Novartis: Speakers Bureau. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Global Blood Therapeutics: Employment, Equity Ownership. Lanzkron:PCORI: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

Platelet Activation and Inhibition in Sickle Cell Disease (PAINS) Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5147-5147
Author(s):  
Andrew L. Frelinger ◽  
Joseph A. Jakubowski ◽  
Julie K. Brooks ◽  
Sabrina L. Zayas ◽  
Michelle A. Berny-Lang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Healthy Subjects ◽  
Research Funding ◽  
Cell Disease ◽  
Activation Markers ◽  
Circulating Levels

Abstract Abstract 5147 Platelet activation/aggregation in sickle cell disease (SCD) may promote tissue ischemia, suggesting antiplatelet therapy may be useful. However, assessing platelet function and the effect of antiplatelet therapy in blood from SCD patients may be confounded by hemolysis with release of ADP. Here we evaluate levels of platelet activation markers in SCD adolescents vs. normal controls and compare, by multiple methods, the effect of in vitro blockade of the platelet ADP receptor P2Y12 by prasugrel's active metabolite, R-138727. Platelet activation markers in blood from SCD adolescents (n=15) and healthy adults (n=10), and the effect of R-138727 (0. 1 – 10 μM) added in vitro, were evaluated with and without ADP stimulation. Circulating levels of platelet-monocyte and platelet-neutrophil aggregates were significantly higher (p <0. 01) in SCD patients than in healthy controls. R-138727, in a concentration-dependent manner, inhibited platelet function in both SCD patients and healthy subjects as judged by ADP-stimulated light transmission aggregation, VerifyNow P2Y12 assay, multiple electrode aggregometry, and flow cytometric analysis of platelet vasodilator-stimulated phosphoprotein, activated GPIIb-IIIa and P-selectin. The R-138727 IC50s for each assay were not significantly different in SCD vs. healthy subjects. In summary: 1) The high circulating levels of platelet-monocyte and platelet-neutrophil aggregates demonstrate in vivo platelet activation in SCD and may be useful as markers of the in vivo pharmacodynamic efficacy of antiplatelet therapy in SCD. 2) The similar in vitro R-138727 IC50s in SCD and healthy subjects suggest that the prasugrel dose-dependence for platelet inhibition in SCD patients will be similar to that previously observed in healthy subjects. Disclosures: Frelinger: Eli Lilly: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; GLSynthesis: Research Funding. Jakubowski:Eli Lilly: Employment. Heeney:Novartis: Consultancy, Research Funding; Eli Lilly and Company: Research Funding; Pfizer: Consultancy. Michelson:Eli Lilly: Data monitoring committee and idependent external monitor of clinical trials, Research Funding; Takeda: Research Funding; Oxygen Biotherapeutics: Research Funding; Alexion: Research Funding; Omthera: Research Funding.

Mitophagy Induction Is a Potential Therapeutic Approach for Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 267-267
Author(s):  
Ramasamy Jagadeeswaran ◽  
Benjamin Alejandro Vazquez ◽  
Vinzon Ibanez ◽  
Maria A Ruiz ◽  
Robert E Molokie ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Approach ◽  
Research Funding ◽  
Single Point Mutation ◽  
Cell Disease ◽  
Blood Disorder ◽  
In Vivo Treatment

Abstract Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide. A single point mutation of the sixth amino acid of β-globin causes glutamic acid to be replaced by valine, rendering the hemoglobin susceptible to polymerization when deoxygenated. SCD patients suffer from the wide variety of disease manifestations including chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. In addition to the HbS polymerization-mediated rigid and fragile sickle-shaped red blood cell (RBC) formation, an excessive formation of intracellular reactive oxygen species (ROS) occurs in SCD red blood cells, which accelerates their hemolysis. This causes the release of ROS, free extracellular hemoglobin, hemin, and inflammatory cytokines that trigger disease progression. We analyzed levels of ROS in SCD patient RBCs and observed a higher fraction of intracellular ROS positive RBC in SCD (HbSS) compared to control (HbAA) RBC of adults [Control (HbAA): 7.1%± 1.4 %, n=11; SCD (HbSS): 25.3 % ± 4.3%, n=9; p<0.0004]. We also made the novel observation that mature RBCs from SCD patients abnormally contain mitochondria as evidenced by flow cytometry analysis of blood samples of 36 SCD patients and 14 normal human control subjects.[Control (HbAA):0.4 % ± 0.04%, n=14; SCD (HbSS): 7.8%± 0.9%, n=30; p<0.0001]. Further subset analysis from SCD patients with HbSC showed mitochondrial retention in their mature RBCs [HbSC: 2.2%± 0.6%,n=6 p<0.01], however to a lesser degree than patients with HbSS. Transmission electron microscopy confirmed the presence of mitochondria in mature RBC of patients with SCD. ROS analysis between mitochondria positive vs. negative fractions showed that mitochondria-positive (TMRM+) RBC fractions have higher levels of ROS compared to mitochondria-negative (TMRM-) RBC fractions. This data strongly suggests that retained mitochondria significantly contribute to the production of ROS in SCD RBCs. Similar to humans, a higher fraction of RBCs of SCD mice (B6;129-Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow/J) retain mitochondria compared to control mice RBC [Control (HbAA): 0.29% ± 0.18%; SCD (HbSS): 16.68%± 1.9%, p<0.0001]. While investigating RN-1, a lysine specific demethylase-1 (LSD-1) inhibitor, as a HbF inducing agent, we observed that SCD mice treated with RN-1 showed a reduction in the fraction of RBCs which retain mitochondria. Therefore, we investigated mitophagy-inducing drugs as a possible useful therapeutic approach for SCD by administering mitophagy-inducing agent Sirolimus. SCD mice treated with RN-1 (5mg), or Sirolimus (5mg) had a significant decrease in the fraction of mitochondria containing RBCs (RN1: 4.96± 1.0%, p<0.0005; Sirolimus: 6.4% ± 1.8%, p<0.002). We observed a reduction of ROS in mature RBCs coupled with decreased mitochondrial retention in RBCs after in vivo treatment with RN1 or Sirolimus as measured by co-staining of TMRM, APC-conjugated CD71antibody, and CM-H2DCFDA. We also observed a significant improvement in RBC survival after the in vivo treatment with Sirolimus or RN-1. RBC survival was measured by flow cytometry and calculated biotin positive circulating RBCs after 2 days of in vivo labeling [SCD treated with vehicle control: 40 %± 2.6%; SCD treated with RN1 (2.5mg): 69.9 ± 2.6%, p<0.004; Sirolimus (5mg): 67.5% ± 6.1%, p<0.04]. Based on this data, mitophagy-inducing drugs have the potential to be a novel therapeutic approach for the treatment of SCD patients. Disclosures Jagadeeswaran: Acetylon: Research Funding. DeSimone:EpiDestiny: Consultancy, Other: patents around decitabine and tetrahydrouridine. Lavelle:Acetylon: Research Funding. Rivers:Acetylon: Research Funding.

scholarly journals Central Venous Access Device (CVAD) Use and Complications in Sickle Cell Disease Patients from Medicaid and Commercially-Insured U.S. Populations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2057-2057
Author(s):  
Nancy Maserejian ◽  
Cortney Hayflinger ◽  
Susan Eaton ◽  
Catherine Madigan ◽  
William E. Hobbs
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Central Venous Access ◽  
Venous Access ◽  
Treatment Burden ◽  
Cell Disease ◽  
Central Venous ◽  
Employment Equity ◽  
Equity Ownership ◽  
The Mean

Abstract Central venous access devices (CVADs), such as tunneled central venous catheters (tCVADs) and peripherally inserted central catheters (PICCs), help provide essential care for some patients with sickle cell disease (SCD). CVADs facilitate administration of multiple intravenous (IV) medications and blood products, as well as blood draws for laboratory analysis. Understanding CVAD use and complications is particularly relevant for SCD patients because of their high risk of having insufficient peripheral IV access. Prior studies describing CVAD use and complications in SCD patients were limited by small sample sizes, typically including 15-20 SCD patients in a single treatment center. The resulting estimates for CVAD use and complications in SCD patients vary widely, are insufficient for development of evidence-based guidelines, and may not be representative of the treatment burden in the broader SCD population. The purpose of this study was to describe the frequency of CVAD use and CVAD-associated complications among SCD patients in a large US population sample. We used data from two large U.S. insurance claims databases from Truven Health MarketScan® Research to examine both Medicaid-insured and commercially-insured SCD patients. From January 2009 through December 2013, these databases encompassed over 14 million Medicaid-insured and over 116 million commercially-insured patients. SCD patients were defined as patients with at least two International Classification of Disease-9 (ICD-9) diagnosis codes for SCD (282.41-42, 282.6x) on separate dates in excess of sickle cell trait codes, or one ICD-9 code for an inpatient (emergency department or hospitalization) visit with sickle cell crisis. CVAD insertions were identified using relevant procedure codes for tCVADs or PICCs. We conducted two sets of analyses for each database: (1) per patient among those with at least one CVAD insertion, and (2) per CVAD insertion. We conducted descriptive analyses on the frequency of CVAD-related procedures (e.g., repair, replacement, removal of obstructive material, repositioning), complications, and infections, thromboses, or phlebitis. A total 17,119 Medicaid-insured SCD patients and 21,342 commercially-insured SCD patients were observed for an average of 3-4 years, during which 1,945 (11.4%) and 1,316 (6.2%) patients, respectively, had at least one CVAD insertion. Most SCD patients (80%) were aged >18 y at time of first CVAD insertion; 18% of adult Medicaid SCD patients had at least one CVAD inserted. The mean number of CVAD insertions per patient was 3.1 (Medicaid) and 2.4 (commercially-insured). In the per CVAD analysis, complication claims were frequent, including infection (31-37%), thrombosis (4-5%), and phlebitis/thrombophlebitis (12-15%). The mean time to removal of CVADs (duration) was 31-34 days (PICC lines) and 102 days (tCVADs). In the per patient analysis, 54.3% had infection claims, 24.3% had thrombosis claims, and 10.2% had phlebitis/thrombophlebitis claims in Medicaid (see Table and Figure; additional results to be provided, also stratified by age). Both tCVADs and PICCs were commonly used in SCD patients, particularly adults, with high occurrence of infection, thrombosis and phlebitis/thrombophlebitis, as well as repeated CVAD insertions. Determinants of CVAD use and complications warrant further investigation to inform practice standards. These findings from a large observational study indicate that device-related risks of administering IV treatments are limitations of IV treatment options and may add to SCD treatment burden. Table 1. Medicaid-Insured Commercially-Insured Any CVAD (Overall) PICC Only tCVAD Only Both PICC and tCVAD Any CVAD (Overall) PICC Only tCVAD Only Both PICC and tCVAD N (%) 1,945 681 (35.0%) 893 (45.9%) 371 (19.1%) 1,316 450 (34.2%) 664 (50.5%) 202 (15.3%) Age, mean (sd) y 30.0 (16.3) 34.2 (14.9) 26.9 (17.5) 30.1 (13.6) 32.6 (17.1) 34.1 (15.8) 31.3 (18.3) 33.2 (15.9) CVAD insertions per patient, mean (sd) 3.1 (3.9) 3.1 (3.9) 1.8 (1.3) 6.2 (5.8) 2.4 (2.3) 2.5 (2.6) 1.6 (1.0) 4.5 (2.9) CVAD insertions total 6,107 3,651 2,456 n/a 3,082 1,636 1,446 n/a Duration per CVAD, median days 44 31 102 n/a 53 34 102 n/a CVAD complications, % patients with CVAD Complication, general 28.8% 13.2% 31.8% 50.1% 22.3% 9.1% 25.9% 39.6% Removal of obstructive material 11.2% 3.8% 15.3% 14.6% 9.0% 2.4% 11.4% 15.3% Replacement 8.3% 3.7% 10.2% 12.4% 6.5% 3.8% 6.5% 12.9% Figure 1. Figure 1. Disclosures Maserejian: Biogen: Employment, Equity Ownership. Hayflinger:Biogen: Consultancy, Employment. Eaton:Biogen: Employment, Equity Ownership. Madigan:Biogen: Employment, Equity Ownership. Hobbs:Biogen: Employment, Equity Ownership.

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

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 685-685
Author(s):  
Yutaka Niihara ◽  
Rafael Razon ◽  
Suvankar Majumdar ◽  
Brian Claggett ◽  
Onyinye C. Onyekwere ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Treatment Effect ◽  
Recurrent Events ◽  
Recurrent Event ◽  
Cell Disease ◽  
Employment Equity ◽  
Phase 3 ◽  
Hazard Ratios ◽  
Equity Ownership

Abstract 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. EndariTM (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. Disclosures Niihara: Emmaus Medical, Inc: Employment, Equity Ownership. Razon: Emmaus Medical, Inc: Employment. Wood: Emmaus Medical, Inc: Employment, Equity Ownership. Singh: Emmaus Medical, Inc: Employment. Tran: Emmaus Medical, Inc: Employment, Equity Ownership. Stark: Emmaus Medical, Inc: Employment, Equity Ownership.

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