Urine Concentrating Ability in Infants with Sickle Cell Anemia: Baseline Data from the BABY HUG Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1413-1413
Author(s):  
Scott T. Miller ◽  
Winfred C. Wang ◽  
Rathi V. Iyer ◽  
Sohail R Rana ◽  
Peter A. Lane ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Study Drug ◽  
Organ Damage ◽  
Phase Iii ◽  
Urine Specimen ◽  
Double Blind ◽  
Young Infants ◽  
Paired Serum Sample ◽  
Urine Concentrating Ability

Abstract A urine concentrating defect is quite common in sickle cell anemia (SCA), has its onset in early childhood, and may be reversible (with transfusion) until age 10 years. BABY HUG is an NHLBI-NICHD sponsored double-blind, placebo-controlled Phase III Clinical Trial (NCT00006400) designed to assess efficacy of hydroxyurea in preventing organ damage in young children with SCA (Hb SS or SβO thalassemia); primary endpoints are spleen function and glomerular filtration rate (GFR). Two hundred thirty-three infants, recruited without regard to disease severity, underwent eligibility screening. To assess urine concentrating ability as a secondary endpoint, parents were instructed to collect and save timed urine specimens from subjects after 4 to 10 hours of fluid deprivation (NPO) overnight for osmolality (OSM) determination. More prolonged deprivation was avoided due to safety concerns. A paired serum sample for OSM, urea nitrogen (BUN), and creatinine was obtained the next morning. All specimens were analyzed in a central laboratory. The analyses included 184 infants with a urine specimen and a reported period of fluid deprivation of at least four hours; 178 had concurrent sera. Mean age was 13.0±2.7 mo (range 7.5 – 17.9 mo) and mean duration of fluid deprivation was 7.4±2.4 hr (4–13 hr). Mean serum OSM was 286±6 mOsm/kg H2O and independent of age, height, weight, or duration NPO. Urine OSM (mean 410±152, median 433, range 58–794 mOsm/kg H2O) was significantly greater than serum osmolality (p<0.0001) and correlated with duration NPO (p=0.001). One hundred forty-two infants (77.2%) concentrated urine (urine OSM > [mean serum OSM + 1 SD]); twenty-two (12.0%) had urine/serum OSM ratio > 2 and 54 (29.4%) had urine OSM > 500 mOsm/L. In addition, five infants (2.7%) were isosthenuric (urine OSM within mean serum OSM ± 1 SD) and 37 (20.1%) hyposthenuric (> 1 SD below mean serum OSM) despite instructions to withhold fluid. Urine OSM was associated with increasing 99mTc-DTPA GFR (p=0.024) and BUN (p<0.0001), but not with serum OSM, age, height, weight or serum creatinine. We conclude that even with a variable, often limited, fluid deprivation challenge, 75 percent of young infants with SCD were able to concentrate urine. We anticipate that at the end of each infant’s two-year study drug treatment period parents will be more successful in achieving the recommended fluid deprivation and urine collection and that differences in concentrating ability between those taking hydroxyurea and those taking placebo will be discernable.

Evaluation of Splenic Function in Infants with Sickle Cell Anemia in the BABY HUG Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3587-3587
Author(s):  
Zora R. Rogers ◽  
Renee R. Rees ◽  
Winfred C. Wang ◽  
Daner Li ◽  
Rathi V. Iyer ◽  
...  
Keyword(s):  
Young Children ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Geometric Mean ◽  
Organ Damage ◽  
Phase Iii ◽  
Qualitative Assessment ◽  
Splenic Function ◽  
Clinical Complications ◽  
Normal Mean

Abstract Organ damage in children with sickle cell anemia [SCA] begins with the spleen. Hydroxyurea [HU] decreases clinical complications and mortality in severely affected adults with SCA, and has proven hematologic benefits in children. To critically assess the efficacy of HU in preventing chronic organ damage, the Pediatric Hydroxyurea Phase III Clinical Trial [BABY HUG], an NHLBI sponsored double-blinded placebo-controlled multi-center trial, was initiated. One objective of the Feasibility and Safety Pilot is to evaluate novel strategies for assessment of splenic function in young children with SCA. To date 23 subjects (13 male; median age 12.9 mos, range 10.3–17.6 mos) have been recruited without regard to disease severity. Pretreatment spleen function determined by Tc-99m sulfur colloid liver-spleen [LS] scan was compared to pocked erythrocyte [PIT] counts and flow cytometric quantitation of Howell-Jolly Bodies [HJB]. Results were correlated with total [Hgb] and % fetal [HbF] hemoglobin, white blood cell [WBC] and platelet [PLT] counts. Splenic uptake of Tc-99m was qualitatively graded as normal, decreased, or absent by two nuclear medicine physicians. Of 17 LS scans reviewed 3 had normal (mean age 12.2 mos) and 14 decreased (mean age 14.6 mos) spleen function. LS scans were also imaged quantitatively by determining the geometric mean total counts over the spleen. Although there was a trend for qualitative LS scan results to discriminate splenic function among patients (p=.08), quantitative spleen counts demonstrated a stronger relationship between lower uptake and reduced splenic function. A logarithmic transformation was applied to each measure (except age) to improve linearity with other variables and stabilize the variance of the transformed data. PIT counts (p<.0001) and WBC counts (p=.023) were significantly linearly associated with age. Age was inversely related to Hgb (p=.005) and %HbF (p=.009), but not associated with PLT (p=.54) or HJB (p=.38). Quantitative spleen counts were related inversely to age (p<.01), PIT counts (p=.02), and WBC (p=.026); linearly to %HbF (p=.0003) and Hgb (p=.04); and had no relationship with HJB (p=.39) or PLT (p=.68). In multivariate analysis with age and PIT counts, the decline in spleen counts had the strongest association with %HbF (p=.006). A PIT count of 3.5%, which classically divides normal from decreased spleen function, separated spleen counts into significantly different groups (p<.001). No similar relationship existed for HbF 25% (p=.059), Hgb 8 g/dl (p=.15), or HJB 300/million rbc (p=.28). These preliminary data indicate that the decline of splenic function with age in young children with SCA can be effectively assessed by multiple techniques in a multi-center study. Compared to the traditional qualitative assessment, quantitative evaluation of the LS scan will allow more informative gradation of the decline in splenic function for the BABY HUG study. Surrogate measures such as PIT counts and %HbF are associated with LS scan results, and may prove to be informative non-invasive markers predictive of splenic function.

Pharmacokinetics of Hydroxyurea in Young Children with Sickle Cell Anemia: A Report from the BABY HUG Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3184-3184 ◽  
Author(s):  
Zora R. Rogers ◽  
Bruce Thompson ◽  
Russell E. Ware ◽  
Winfred C. Wang ◽  
Rathi V. Iyer ◽  
...  
Keyword(s):  
Young Children ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Limit Of Detection ◽  
Pilot Trial ◽  
Phase Iii ◽  
Response To Treatment ◽  
Capsule Formulation ◽  
Double Blind ◽  
Age Related

Abstract There is a paucity of pharmacokinetic (PK) data about hydroxyurea (HU) in persons with sickle cell anemia (SCA) and none in very young children. HU clearance is predominantly renal. The kidney may be damaged during infancy in SCA, but the first abnormality is usually hyperfiltration which may lead to enhanced HU clearance. Following a 15 mg/kg oral dose of commercially available HU capsules, PKs in 7 adults with SCA and normal renal function have been reported to be a mean±SD half-life (T1/2) of 3.14±0.9 hrs, a maximal concentration (Cmax) of 28.32±11.0 ug/mL, and an area under the curve (AUC) of 81.66±15.5 ug•hr/mL. The Phase II Study of HU in adults concluded that initial 2 hour clearance of HU was not associated with either the maximum tolerated dose or fetal hemoglobin response to treatment. However, the AUC did predict HU toxicity and, in another study, the need for dose adjustment in adults with SCA and renal insufficiency. BABY HUG is an NHLBI-NICHD sponsored Pediatric Phase III Clinical Trial designed to critically assess the efficacy of a novel liquid HU preparation in preventing organ damage in young children with SCA. Forty-five African-American infants, 12 to 18 months (mo) of age (mean 14.7 mo) were recruited without regard to disease severity to the just completed randomized, double-blind, placebo-controlled BABY HUG Feasibility and Safety Pilot Trial. First dose PKs were obtained 0, 1, 2, and 4 hours after oral administration of 20 mg/kg of HU in 22 consecutive patients (mean age 14.5 mo), coincident with measurement of glomerular filtration rate (GFR) by nuclear medicine DTPA clearance. An additional PK sample was obtained between 4 and 8 hours in 15 of the 22 (68%). Samples were frozen at −70°C, shipped, and assayed by high resolution gas chromatography with mass spectrometric detection (limit of detection 0.5 ug/mL). The T1/2 (2.36±0.99 hrs), Cmax (19.81±5.8 ug/mL; 0.26±0.8 uM/L), and AUC (68.82±11.5 ug•hr/mL) were somewhat lower in BABY HUG patients than in the small group of adults with SCA from the literature. There were no apparent relationships between PKs and baseline GFR measured by DTPA or calculated from the Schwartz equation. Younger patients ≤15 mo (n=15) had a trend toward a shorter T1/2 (2.1 vs 2.8 hours; p=0.118) and a lower predicted measurable HU concentration at 8 hours (1.2 vs 2.1 ug/mL; p=0.056) than those 16–18 mo (n=7). There were no age related differences in AUC (67.4 vs 71.8 ug•hr/mL; p=0.421) or Cmax (20.5 vs 18.2 ug/mL; p=0.409). PKs of this novel liquid preparation of HU in young children with SCA may be different than that of adults with the standard capsule formulation. The BABY HUG Trial will continue to refine the PK model by additional evaluations including samples from patients as young as 9 mo of age, the new lower age of eligibility for the open study currently accruing patients.

TCD in Infants: A Report from the BABY HUG Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 952-952 ◽  
Author(s):  
Robert J. Adams ◽  
Julio Barredo ◽  
Duane R. Bonds ◽  
Clark Brown ◽  
James Casella ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Maximum Flow ◽  
Organ Damage ◽  
Sample Volume ◽  
Phase Iii ◽  
Mean Velocity ◽  
Increased Risk ◽  
The Mean ◽  
The Right

Abstract Transcranial Doppler (TCD) is useful in children with sickle cell anemia (SCA) to detect increased risk of stroke. The use of TCD in infants less than 2 years of age is less well established, but has previously been shown to be feasible. As a secondary endpoint in the BABY HUG Trial, TCD is expected to provide useful information on the possible effects of hydroxyurea (HU) in babies with SCA. BABY HUG is an NHLBI-NICHD sponsored phase III clinical trial to compare hydroxyurea to placebo to ascertain effectiveness in preventing end organ damage of the spleen and kidney. Eligible subjects underwent a baseline TCD using the Nicolet Companion (EME) 2-MHz pulsed Doppler. All infants were 8–18 months of age at enrollment, had no history of stroke and were not receiving chronic blood transfusions. Blood flow velocities were recorded using the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol with the exception of reducing the standard sample volume to 4 mm. No sedation was used. The time averaged maximum mean was measured to determine the highest velocity on either side to categorize the study as normal (all recordings &lt;170 cm/sec), conditional (170–199cm/sec) or abnormal (≥200 cm/sec). Recordings of the middle cerebral artery (MCA) and internal carotid artery (ICA) bifurcation defined an adequate TCD. TCD was not required for study entry but subjects with an abnormal exam were not eligible for randomization and treatment. TCD exams were read by blinded reviewers at the Medical College of Georgia. TCD results were transmitted to Clinical Trials & Surveys Corporation (C-TASC) for statistical analysis. As of June 24, 2005, 70 TCD exams had been attempted. Two exams were unsuccessful (no data) because of the children’s irritability and 1 was interpreted as inadequate. Of the remaining 67 TCD exams, 66 were normal and one baby had a high conditional TCD (190 cm/sec). No subjects were found ineligible for the study due to TCD results. The mean velocity of the left MCA was 117 cm/sec ±22.9 and that of the right MCA was 114 cm/sec ±24.9. Regression analyses were performed to examine the relationship of maximum flow velocity (VMAX) to age and total hemoglobin (Hb). VMAX was inversely correlated to Hb (left p=&lt;0.0001, right=&lt;0.0014) and directly associated with age (left p=&lt;.0005, right p=&lt;0.0022). When the mean MCA velocity was regressed against age and Hb, both age (p=0.0285) and Hb (p=.0024) were significant. Adequate baseline TCD evaluation was obtained on 67 out of 70 babies. As expected, baseline TCD velocities varied inversely with the degree of anemia and directly with age; all but one was normal by childhood sickle cell disease standards. These studies provide valuable normative data for infants with SCA, and for further assessment of the effect of HU on TCD in infants with SCA as the study progresses.

Influence of Hemoglobin Level on Clinical Findings In Infants with Sickle Cell Anemia: Data From BABY HUG

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1631-1631 ◽  
Author(s):  
Jeffrey D. Lebensburger ◽  
Scott T Miller ◽  
Thomas H. Howard ◽  
James F. Casella ◽  
R. Clark Brown ◽  
...  
Keyword(s):  
Platelet Count ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Organ Damage ◽  
Hemoglobin Level ◽  
Phase Iii ◽  
Acute Chest Syndrome ◽  
Severe Anemia ◽  
Laboratory Findings ◽  
Baseline Hemoglobin

Abstract Abstract 1631 Introduction: Infants with sickle cell anemia (SCA) are at risk for organ damage and clinical events. Risk may vary depending on steady state hemoglobin level. BABY HUG (ClinicalTrials.org, NCT00006400), a NHLBI-NICHD supported phase III randomized placebo-controlled trial, examined the ability of hydroxyurea (HU) to reduce end organ damage to the kidneys and spleen and attenuate other complications of SCA in infants. In this secondary study, we investigated whether placebo-treated subgroups defined by extremes of baseline hemoglobin level differed from one another in frequency of sickle cell-related complications and other laboratory findings, and then compared these data to the entire group of infants treated with HU. Methods: BABY HUG subjects randomized at ages 9 – 18 mo were treated with hydroxyurea (20 mg/kg/d) (N=96) or with placebo (N=97) for 2 years. Those randomized to placebo were classified according to their age-adjusted baseline hemoglobin level and subgroups in the lowest (n=24) and highest (n=24) quartiles compared. (Demarcating Hb values were: age 9 to <12 mo, <8.0 vs. >10.2gm/dL; age12 – 18 mo, <8.1 vs. >9.9gm/dL.) Results: BABY HUG primary endpoints of spleen (splenic uptake of 99mTc sulfur colloid on liver-spleen scan) and kidney (GFR by DTPA clearance) function did not differ in placebo group subjects who were in the lowest and highest quartile hemoglobin levels. However, those in the lowest hemoglobin quartile had a higher incidence of acute chest syndrome (ACS) than those in the highest quartile (0.31 vs. 0.02 events/person-year, RR 14.4, p=0.01) and this difference was significantly attenuated by HU (0.05 events/person-year). The relative risk for developing a pain crisis did not differ between the two placebo subgroups (2.2 vs. 2.1 events/person-year), but HU significantly reduced pain frequency compared to either subgroup (0.94 events/person-year, p<0.001). Subjects in the lowest hemoglobin quartile had higher baseline mean TCD velocities than those in the highest quartile (126.2 vs. 112.4 cm/sec, p=0.008). These differences persisted over the two-year period of study, with exit values of 164.9 and 139.6 cm/sec, respectively (p=0.003). By comparison mean TCD velocity in the HU-treated group was 124.5 cm/sec at baseline and 145.6 at exit. Results of neurocognitive testing were not statistically different between groups; however, a trend toward a lower performance developmental index (PDI, p=0.07), but not a lower mental development index (MDI, p=0.15), was observed in subjects with the lowest hemoglobin levels. Subjects in the lowest quartile also had a higher mean WBC (18.0 vs. 11.4 × 109/L, p<0.001), absolute neutrophil count (5.3 vs. 3.6 × 109/L, p=0.001), and platelet count (416 vs. 315 × 109/L, p=0.0001) compared to those with the highest hemoglobin. The laboratory findings of patients receiving HU also were significantly lower than those of subjects in the lowest hemoglobin group and similar to those in the highest hemoglobin group. Conclusions: Severe anemia in very young patients with SCA was associated with elevated WBC and platelet counts and higher TCD velocities. Interestingly, severe anemia also was associated with increased frequency of ACS, in contrast to the association of ACS with higher hemoglobin levels in older patients. Future studies will need to confirm this relationship and clarify to what extent associated findings (e.g., hyposplenia, elevated WBC or platelet count) contribute to this susceptibility. Severe anemia in young SCA patients is a negative prognostic factor that is significantly impacted by early hydroxyurea therapy. Disclosures: Off Label Use: Hydroxyurea is not approved by FDA for infants with sickle cell disease. Miller:NIH/NHLBI; Emmaus Med Inc, Novartis Pharmaceutical; St Jude Childrens Hospital: Research Funding.

Phase 1 Clinical Trial Of The Candidate Anti-Sickling Agent Aes-103 In Adults With Sickle Cell Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1009-1009 ◽  
Author(s):  
Gregory J. Kato ◽  
Marlene Peters Lawrence ◽  
Laurel G. Mendelsohn ◽  
Rehan Saiyed ◽  
Xunde Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Study Drug ◽  
Adult Patients ◽  
Laboratory Evaluation ◽  
Controlled Study ◽  
Double Blind ◽  
Hydroxyurea Treatment ◽  
Oral Doses

Abstract Background Aes-103 (5-hydroxymethylfurfural, 5-HMF) is a putative anti-sickling agent that has undergone pre-clinical testing for potential treatment for sickle cell disease. It is an organic compound derived from dehydration of certain sugars, found commonly in small amounts in foods such as coffee and prunes. It binds to alpha subunits of hemoglobin and increases its oxygen affinity. At millimolar levels, it inhibits hypoxia-induced sickling in vitro and protects sickle cell mice against hypoxia-induced death. We investigated the safety, tolerability and pharmacokinetics of single oral doses of Aes-103 in a double-blind, placebo controlled, dose-escalation trial in adult patients with sickle cell anemia on hydroxyurea treatment and not on hydroxyurea treatment. Methods Adult patients with sickle cell anemia consented to an IRB-approved FDA investigational New Drug protocol at the NIH Clinical Center. After laboratory evaluation to screen for acceptable clinical status, they were hospitalized for three nights to receive oral dosing of Aes-103 or placebo (5:1 ratio of treatments) in a double-blind design, and vital signs, toxicity monitoring lab results and any adverse events were reviewed by a protocol safety committee, which approved escalation to the next higher dose of study drug. The patients were eligible to be hospitalized again at least one week later for a second, higher dose or placebo. After fasting, patients received oral doses of Aes-103 dissolved in orange juice. Doses were 300, 1000, 2000 or 4000 mg. A subgroup that took 4000 mg after fasting also took 4000 mg after a prescribed high fat meal during a second hospitalization and 1000 mg every 6 hours for four doses without fasting during a third hospitalization. Results Eighteen patients in steady state participated in the trial. The study drug was well tolerated at all doses tested. During the first 24 hours after dosing, a total of 11 adverse events (9 mild, 2 moderate, and zero severe) occurred distributed across a variety of categories in 6 of 15 patients on the Aes-103 arm, compared to 1 mild adverse event in 1 of 3 patients on the placebo arm. An additional 18 adverse events were temporally unrelated to Aes-103, 10 of which involved pain that appeared to be background sickle cell-related pain unrelated to dosing of study drug, seen also in 1 of the 3 placebo adverse events. No severe adverse events occurred in temporal relationship to the study drug. Pharmacokinetic and pharmacodynamic data are currently under analysis, and will be complete at the time of abstract presentation. Conclusions Aes-103 was safely tolerated without severe or recurrently observed complications over a 13-fold range of oral doses. A phase 2 randomized controlled study of Aes-103 or placebo is planned with daily dosing for twenty-eight days in patients with sickle cell anemia. Disclosures: Stern: AesRx, LLC: Equity Ownership.

scholarly journals A double blind, placebo controlled randomized evaluation of the efficacy of a Polyherbal Preparation (FaradinR) in treating sickle cell anaemia in Nigerian children

2021 ◽  
Vol 9 (3) ◽  
pp. 254-263
Author(s):  
D.G. Gbadero ◽  
T.A. Olutogun ◽  
K.J. Olufemi-Aworinde ◽  
L.P. Oluwadare ◽  
A.T. Abolarin ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
White Cell Count ◽  
Randomized Study ◽  
Organ Damage ◽  
Exclusion Criterion ◽  
Double Blind ◽  
Hemoglobin F ◽  
Transfusion Requirements ◽  
Alternative Medications

Introduction: The goal of management of sickle cell anaemia (SCA), for many years, has been to manage acute intermittent crises and  slow down chronic end organ damage. In the past few decades, with increasing understanding of its pathophysiology, compounds primarily preventive in action are being investigated and used. Faradin® (a poly-herbal traditional supplement mixture) has been used aspreventive measure against painful episodes by SCA patients as an over the counter medication and anecdotal evidence suggests that it reduced the frequency and severity of painful crises as well as transfusion requirements. Alternative medications that are both affordable and available should be considered viable alternatives provided safety and efficacy are assured because of the high disease burden in Nigeria.Methods: This was a double controlled randomized study was carried out on twenty children. Each enrolled patient was randomized into either the herbal mixture or placebo after permission to participate in the study was obtain from the parents/guardian for children below 15 years or from both parents/guardian and the patients where the latter are older than 15 years. The main exclusion criterion was prior use or exposure to Faradin. Primary end points were pain alteration, death during study and blood transfusion frequency. Secondary endpoints were hemoglobin levels, neutrophil count, platelet count, hemoglobin F and A2 levels, serum bilirubin, nitric oxide  concentration, drug toxicity and severe complications of sickle cell anemia reported during the study.Results: There was no severe adverse event, deaths or transfusion recorded in the two groups throughout the duration of the study. Mean hematocrit was increased in the Faradin group and reticulocyte count was increased by 12 %. Faradin reduced the total white cell count to half its baseline level and increased hemoglobin F levels by 10%. Weight and appetite were reported to increased and engenders a generalfeeling of wellbeing.Conclusion: Faradin appears to be an efficacious, nontoxic, available and affordable remedy for treating SCA patients in our setting.

scholarly journals Angiotensin receptor signaling in sickle cell anemia has a reno-protective effect on urine concentrating ability but results in sickle glomerulopathy

2018 ◽  
Vol 93 (7) ◽  
pp. E177-E181 ◽  
Author(s):  
Swarnava Roy ◽  
Parul Rai ◽  
Marthe-Sandrine Eiymo Mwa Mpollo ◽  
Kyung-Hee Chang ◽  
Tilat Rizvi ◽  
...  
Keyword(s):  
Protective Effect ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Receptor Signaling ◽  
Angiotensin Receptor ◽  
Urine Concentrating Ability

A phase III, randomized, double-blind, multicenter, active control study of fosnetupitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving cisplatin-based highly emetogenic chemotherapy (HEC): CONSOLE.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 12099-12099
Author(s):  
Yoshimasa Shiraishi ◽  
Akito Hata ◽  
Naoki Inui ◽  
Morihito Okada ◽  
Masahiro Morise ◽  
...  
Keyword(s):  
Study Drug ◽  
Incidence Rates ◽  
Emetogenic Chemotherapy ◽  
Nausea And Vomiting ◽  
Phase Iii ◽  
Highly Emetogenic Chemotherapy ◽  
Double Blind ◽  
Secondary Endpoints ◽  
To Receive ◽  
Age Category

12099 Background: Fosnetupitant (FN) is a phosphorylated pro-drug of netupitant that has high binding affinity for the neurokinin-1 (NK-1) receptor and a long half-life of 70 h. This phase 3 study is the first head-to-head study to compare two NK-1 receptor antagonists, FN and fosaprepitant (FA), in combination with palonosetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (JapicCTI-194611). Methods: Patients scheduled to receive cisplatin (≥70 mg/m2) -based chemotherapy were randomly assigned 1:1 to receive FN 235 mg or FA 150 mg, in combination with palonosetron 0.75 mg and dexamethasone (9.9 mg on day 1, 6.6 mg on days 2-4). The stratification factors were sex, age category (<55 vs. ≥55 years), and site. The primary endpoint was the complete response (CR; no emetic events and no rescue medication) rate, stratified by sex and age category, during the overall phase (0-120 h) to show the non-inferiority (margin, -10%) of FN to FA. The secondary endpoints were: CR rate, complete protection rate, total control rate, no nausea rate, no emetic events rate in each period [i.e., acute (0-24 h), delayed (24-120 h), overall, 0-168 h and 120-168 h], time to treatment failure, and safety, including injection site reactions (ISRs). Assessment of efficacy was continued until 168 h after the initiation of cisplatin. Some eligible patients were evaluated for safety and efficacy of FN for up to four cycles. Results: Between February 2019 and March 2020, total 795 patients were enrolled in the study. The study drug was administered to 785 patients (n=392 in FN vs. n=393 in FA), and all of them were evaluated for efficacy and safety. Baseline characteristics were generally balanced between the two groups. The adjusted overall CR rate was 75.2% in FN vs. 71.0% in FA [MH common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), thus demonstrating non-inferiority of FN to FA. Regarding the other secondary endpoints of efficacy until 168 h, FN was favorable against FA, especially the CR rate during 0-168 h (73.2% in FN vs. 66.9% in FA) (Table). The incidence rates of treatment-related adverse events were 22.2% in FN vs. 25.4% in FA, whereas those of ISRs with any cause or with treatment-related were 11.0% or 0.3% in FN vs 20.6% or 3.6% in FA, respectively ( p<0.001). Conclusions: FN demonstrated non-inferiority to FA, with a favorable safety profile and lower risk for ISRs. For the period beyond 120 h after initiation of chemotherapy, FN may have the potential to improve the prevention of “beyond delayed” CINV. Clinical trial information: JapicCTI-194611. [Table: see text]

Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial

2020 ◽  
Vol 38 (3) ◽  
pp. 193-202 ◽  
Author(s):  
Richard S. Finn ◽  
Baek-Yeol Ryoo ◽  
Philippe Merle ◽  
Masatoshi Kudo ◽  
Mohamed Bouattour ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Interim Analysis ◽  
Statistical Significance ◽  
Study Drug ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Double Blind ◽  
Previously Treated

PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.

scholarly journals First report of reversal of organ dysfunction in sickle cell anemia by the use of hydroxyurea: splenic regeneration

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 1951-1953 ◽  
Author(s):  
S Claster ◽  
E Vichinsky
Keyword(s):  
Immune System ◽  
Organ Dysfunction ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Germinal Centers ◽  
Quadrant Pain ◽  
Significant Impairment ◽  
Splenic Regeneration

Much of the morbidity associated with sickle cell anemia (SCA) is due to ongoing infarction resulting in organ dysfunction. Because the spleen is often the first organ damaged in this illness, there is a significant impairment of the immune system in these patients. Hydroxyurea (HU) has been shown to increase fetal hemoglobin (HbF) and decrease painful episodes in patients with this disease. It is unclear whether HU can prevent organ damage. We treated two SCA patients with HU for several years and found evidence of reversal of previously documented splenic dysfunction. Patient no. 1 was treated for 30 months with an increase in HbF to 30%. HU was stopped because of cytopenia. She developed left upper quadrant pain. A splenectomy was performed due to the possibility of splenic abscesses. A pathologic review found no evidence of infection and an enlarged spleen that showed active germinal centers. Patient no. 2 was treated for 24 months with HU before developing splenomegaly. His HbF levels were 25% to 30%, his pit counts averaged 2%, and his liver spleen scans showed uptake. These two cases show that chronic HU therapy may reverse splenic dysfunction in certain patients and suggest that this drug may have efficacy beyond the elimination of pain in SCA.

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