***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: INTRODUCTION The contribution of platelet activation to the pathogenesis of sickle cell disease ( SCD ) remains uncertain . We evaluated the safety and efficacy of eptifibatide , a synthetic peptide inhibitor of the αIIbβ3 receptor , in SCD patients during acute painful episodes . MATERIAL S AND METHODS In this single site , double-blind , placebo-controlled trial , eligible patients with SCD admitted for acute painful episodes were r and omized to receive eptifibatide or placebo at a ratio of 2:1 . RESULTS Thirteen patients ( SS - 10 , Sβ(0 ) - 2 , SC - 1 ) were r and omized to receive either eptifibatide  ( N=9 ; 6 females ; median age - 25years ) or placebo ( N=4 ; 3 females ; median age - 31years ) . In the intent-to-treat analysis , there were no major bleeding episodes in either the eptifibatide or placebo arms ( point estimate of difference : 0.00 , 95 % CI ; -0.604 , 0.372 ) . There was one minor bleeding episode in the eptifibatide arm ( point estimate of difference for any bleeding : 0.11 , 95 % CI : -0.502 , 0.494 ) . There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups ( point estimate of difference : 0.11 , 95 % CI : -0.587 , 0.495 ) . There were no differences in the median times to discharge , median times to crisis resolution or the median total opioid use . CONCLUSIONS In this small study , eptifibatide appeared to be safe , but did not improve the times to crisis resolution or hospital discharge . Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD . Clinical trials.gov Identifier : NCT00834899 Background The hallmark of sickle cell disease ( SCD ) is pain from a vaso-occlusive crisis . Although ambulatory pain accounts for most days in pain , pain is also the most common cause of hospitalization and is typically treated with parenteral opioids . The evidence base is lacking for most analgesic practice in SCD , particularly for the optimal opioid dosing for patient-controlled analgesia ( PCA ) , in part because of the challenges of the trial design and conduct for this rare disease . Purpose The purpose of this report is to describe our Network ’s experiences with protocol development , implementation , and analysis , including overall study design , the value of pain assessment s rather than ‘ crisis ’ resolution as trial endpoints , and alternative statistical analysis strategies . Methods The Improving Pain Management and Outcomes with Various Strategies ( IMPROVE ) PCA trial was a multisite inpatient r and omized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network . The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale , and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes . A time-to-event analysis strategy was planned for the primary endpoint . Results Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period , 38 were r and omized and 4 withdrawn . The trial was closed early due to poor accrual , reflecting a substantial number of challenges encountered during trial implementation . Limitations While some of the design issues were unique to SCD or analgesic studies , many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems , particularly in the context of large urban academic medical centers . Lessons learned Complicated clinical organization of many sites likely slowed study initiation . More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance . During the subsequent data analysis , alternative statistical approaches were considered , the results of which should inform future efficacy assessment s and increase future trial recruitment success by allowing substantial reductions in target sample size . Conclusions A complex r and omized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care . A number of design considerations were shown to be feasible in this setting , and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements . While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy , this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials BACKGROUND Protocol -eligible subjects may not be c and i date s for research participation or may decline . To determine factors that affected accrual , we evaluated enrollment in BABY HUG , a multi-center , r and omized , placebo-controlled Phase III trial of hydroxyurea ( HU ) in infants with sickle cell anemia . METHODS An anonymized registry of potential subjects served as the primary source of data . Study coordinators considered all infants less than age 18 months with a hemoglobin FS diagnosis on newborn screening . Data included the number of potentially eligible subjects , whether parents were approached , and reasons for participating or declining . RESULTS Of 1106 potential participants , 28 % were not approached for reasons such as prior poor adherence to clinical care . Interested families expressed willingness to contribute to medical knowledge ( 51 % ) , hope of being r and omized to receive hydroxyurea ( 51 % ) , and desire for closer clinical care ( 51 % ) as reasons for participating . Disease severity or the perception that their child was ill had less impact on willingness to participate ( 16 % ) . Parents who declined cited fear of research ( 19 % ) , transportation problems ( 14 % ) , and the dem and ing nature of the study ( 25 % ) . Ultimately , 234 ( 21 % ) gave informed consent , with little variability of acceptance rates among sites . Importantly , the number of subjects enrolled correlated with the number of families that were approached . Sites that excluded patients based on clinical /psychosocial biases were not more successful in recruiting than those who approached all eligible subjects . CONCLUSION Large , dem and ing clinical trials require an adequate pool of potential participants . Approaching all potentially eligible patients without predetermined biases enhances success in recruitment The  Pediatric Hydroxyurea  Phase 3 Clinical Trial ( BABY HUG ) was a phase 3 multicenter , r and omized , double-blind , placebo-controlled clinical trial of hydroxyurea in infants ( beginning at 9 - 18 months of age ) with sickle cell anemia . An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups . One hundred and ninety-three subjects were r and omized to hydroxyurea ( 20 mg/kg/d ) or placebo ; there were 374 patient-years of on- study observation .  Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain , dactylitis , acute chest syndrome , and hospitalization ; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea . Despite expected mild myelosuppression , hydroxyurea was not associated with an increased risk of bacteremia or serious infection . These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia . This clinical trial is registered with the National Institutes of Health ( NCT00006400 , www . clinical trials.gov ) A r and omized , controlled clinical trial established the efficacy and safety of short‐term use of hydroxyurea in adult sickle cell anemia . To examine the risks and benefits of long‐term hydroxyurea usage , patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea . The purpose of this follow‐up was to search for adverse outcomes and estimate mortality . For each outcome and for mortality , exact 95 % confidence intervals were calculated , or tests were conducted at α = 0.05 level ( P‐value < 0.05 for statistical significance ) . Although the death rate in the overall study cohort was high ( 43.1 % ; 4.4 per 100 person‐years ) , mortality was reduced in individuals with long‐term exposure to hydroxyurea . Survival curves demonstrated a significant reduction in deaths with long‐term exposure . Twenty‐four percent of deaths were due to pulmonary complications ; 87.1 % occurred in patients who never took hydroxyurea or took it for < 5 years . Stroke , organ dysfunction , infection , and malignancy were similar in all groups . Our results , while no longer the product of a r and omized study because of the ethical concerns of withholding an efficacious treatment , suggest that long‐term use of hydroxyurea is safe and might decrease mortality . Am . J. Hematol . 2010 . © 2010 Wiley‐Liss , BACKGROUND Prophylactic transfusion prevents strokes in children with sickle cell anemia who have abnormalities on transcranial Doppler ultrasonographic examination . However , it is not known how long transfusion should be continued in these children . METHODS We studied children with sickle cell disease who had a high risk of stroke on the basis of a transcranial Doppler screening examination and who had received transfusions for 30 months or longer , during which time the Doppler readings became normal . The children were r and omly assigned to continued transfusion or no continued transfusion .  Children with severe stenotic lesions on cerebral magnetic resonance angiography were excluded . The composite primary end point was stroke or reversion to a result on Doppler examination indicative of a high risk of stroke . RESULTS The study was stopped after 79 children of a planned enrollment of 100 underwent r and omization . Among the 41 children in the transfusion-halted group , high-risk Doppler results developed in 14 and stroke in 2 others within a mean ( + /-SD ) of 4.5+/-2.6 months ( range , 2.1 to 10.1 ) of the last transfusion . Neither of these events of the composite end point occurred in the 38 children who continued to receive transfusions . The average of the last two transcranial Doppler results before transfusion was started was the only predictor of the composite end point ( P=0.05 ) . CONCLUSIONS Discontinuation of transfusion for the prevention of stroke in children with sickle cell disease results in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke . ( Clinical Trials.gov number , NCT00006182 . Doppler‐defined pulmonary hypertension ( PH ) in sickle cell disease ( SCD ) is associated with 40 % mortality at 40 months . To assess the effect of bosentan in SCD‐PH , two r and omized , double‐blind , placebo‐controlled , 16‐week studies were initiated . Safety concerns are particularly relevant in SCD due to comorbid conditions . ASSET‐1 and ‐2 enrolled patients with pulmonary arterial hypertension ( PAH ) and pulmonary venous hypertension ( PH ) , respectively .  Haemodynamics and 6‐min walk distance ( 6MWD ) were obtained at baseline and week 16 . The studies were terminated due to slow site initiation and patient enrolment ( n = 26 ) . Bosentan appeared to be well tolerated . Although sample sizes were limited , in ASSET‐1 at baseline , 6MWD correlated with cardiac output ( CO ; P = 0·006 ) with non‐significant inverse correlations between 6MWD and pulmonary vascular resistance ( PVR ; P = 0·07 ) and between 6MWD and right atrial pressure ( P = 0·08 ) . In ASSET‐2 at baseline , there was a non‐significant correlation between 6MWD and CO ( P = 0·06 ) . Due to limited sample sizes , efficacy endpoints were not analysed . However , in both studies , non‐significant increases in CO were observed with bosentan compared to placebo . Similarly , non‐significant decreases in PVR were observed with bosentan . Limited data in SCD‐PH suggest that a low 6MWD predicts a low CO . St and ard‐dose bosentan appears to be well tolerated . Further investigation is warranted . Clinical trials.gov registration numbers NCT00310830 , NCT00313196 , NCT00360087 BACKGROUND In a previous open-label study of hydroxyurea therapy , the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia , with only mild myelotoxicity . By inhibiting sickling , increased levels of fetal hemoglobin might decrease the frequency of painful crises . METHODS In a double-blind , r and omized clinical trial , we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year . The trial was stopped after a mean follow-up of 21 months . RESULTS Among 148 men and 151 women studied at 21 clinics , the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo  ( median , 2.5 vs. 4.5 crises per year , P < 0.001 ) . The median times to the first crisis ( 3.0 vs. 1.5 months , P = 0.01 ) and the second crisis ( 8.8 vs. 4.6 months , P < 0.001 ) were longer with hydroxyurea treatment . Fewer patients assigned to hydroxyurea had chest syndrome ( 25 vs. 51 , P 
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This study , for the first time , quantifies outcomes of sickle cell disease trials and provides support to the belief that barriers exist to successful completion , publication , and dissemination of sickle cell trial results