Initial Experience with the IMPROVE Trial-a Phase III Analgesic Trial for Hospitalized Sickle Cell Painful Episodes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2667-2667 ◽  
Author(s):  
Carlton Dampier ◽  
Wally R. Smith ◽  
Carrie Wager ◽  
Margaret Bell ◽  
James R. Eckman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Effects ◽  
Sample Size ◽  
Sickle Cell ◽  
Average Length ◽  
Small Sample ◽  
Phase Iii ◽  
Constant Infusion ◽  
Acute Chest Syndrome ◽  
Opioid Administration

Abstract Abstract 2667 Background: Acute pain is the leading cause of hospitalization in both children and adults with sickle cell disease (SCD). Opioid analgesics are used for pain relief, but are associated with significant adverse effects that are bothersome to patients and may predispose to serious sickle-related pulmonary events. Evidence is limited for the most effective opioid administration strategy that maximizes analgesia and minimizes adverse effects. Patient Controlled Analgesia (PCA) has the potential advantage to allow a patient to optimize pain control without dependence on healthcare providers for administration. PCA generally consists of an opioid given by constant infusion with additional demand doses as needed; the proper dosing for each is largely unknown, particularly at high opioid doses. The SCDCRN conducted a multi-center phase III clinical trial comparing two alternative opioid PCA dosing strategies (HDLI-higher demand dose with low constant infusion or LDHI- lower demand dose and higher constant infusion). The required sample size for the trial was 278 subjects. Patients and Methods: SCD patients ≥ age 10 years hospitalized for significant pain (baseline pain VAS ≥ 4.5/10) who had received < 12 hours of previous analgesic therapy and provided informed consent were eligible; patients with renal/hepatic dysfunction, who received large amounts of oral opioids prior to admission, or who had evidence of acute chest syndrome were excluded. Investigators used standardized opioid dosing tables for morphine or hydromorphone, and for participants weighing ±50 kg. Opioid-related symptoms were assessed with a validated daily questionnaire; multimodal assessments of pain, physical function, and sleep were conducted by an assessor blinded to treatment assignment/dose level; because of safety concerns, individuals responsible for making dosing decisions were not blinded. The assigned PCA strategy was continued until patients were transitioned to oral analgesics. An intention to treat analysis was planned for the time to a significant (2.5 cm) improvement in average daily 10 cm pain VAS. Secondary endpoints included total opioid usage and frequency of opioid-related symptoms. Results: From January 1, 2010 to June 8, 2010, a total of 1050 patients age ≥ 10 years were hospitalized for pain; 216 were ineligible, 796 were missed for logistic/staffing issues at sites, and 38 subjects completed randomization prior to trial closure (due to inadequate time to complete enrollment prior to Network termination in March 2011). Average age of enrolled subjects was 23.9 ± 12.2 years (range 10–52 years), and 53% were female. The HDLI arm had 50% morphine and 40% pediatric subjects (10-17 years); the LDHI arm had 44% morphine and 50% pediatric subjects. Four subjects were withdrawn (1 parent permission withdrawal, 2 inadvertent withdrawals by PI, 1 ineligible). Baseline VAS was high (mean 7.5 cm HDLI, and 7.7 cm LDHI). A reduction in pain intensity during PCA treatment was observed in both treatment arms (mean difference from baseline ± SEM: 2.7 ±1.5 cm HDLI vs 2.8 ±2.0 cm LDHI; time to significant improvement 22.0 ±3.0 hours HDLI vs 22.1 ±3.8 hours LDHI), with 75% of the HDLI subjects and 79% of the LHDI experiencing a significant improvement in pain. Average length of hospitalization was 143.7 ±94.2 hours HDLI vs 102.4 ±42.6 hours LDHI. The reliability or significance of any similarities or differences noted in this descriptive analysis is limited by the small sample size. Opioid utilization in the two treatment arms is currently being analyzed. Opioid-related symptoms were well managed and similar in both treatment arms (mean daily opioid symptom severity score (1-4): 0.9 ± 0.6 HDLI vs 0.8 ± 0.6 LDHI). Four episodes of serious hypoxia, likely relate to exacerbation of pulmonary hypertension, developed in adult subjects during the study (2 HDLI, 2 LDHI). Conclusions: The premature closure of the study limits potential conclusions regarding safety and efficacy, or superiority of either treatment regimen. The data gathered will help resolve potential design issues related to the complexity of running an inpatient opiod PCA trial and help guide modification of subject selection and enrollment, optimization of opioid dosing and monitoring, and endpoint assessments. Given the clinical priority of adequate pain management and the challenges of opioid PCA therapy, completion of this trial is imperative. Supported by NHLBI. Disclosures: Dampier: Anthera Pharmaceuticals Inc:; Glycomimetics Inc:. Telen: GlycoMimetics: Consultancy, clinical trial sponsorship.

Changes In Cell-Derived Plasma Microparticles During The Acute Chest Syndrome In Children With Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2239-2239 ◽  
Author(s):  
Christopher M McKinney ◽  
Marguerite R Kelher ◽  
Christopher C Silliman
Keyword(s):  
Sickle Cell Disease ◽  
Sample Size ◽  
Sickle Cell ◽  
Systemic Inflammation ◽  
Small Sample ◽  
Acute Chest Syndrome ◽  
Separate Analysis ◽  
Cell Disease ◽  
Larger Sample

Abstract Introduction Microparticles (MP) are small (less than 1 µm), membrane-derived extracellular vesicles produced following cellular activation or apoptosis. They have been implicated as causative in a wide variety of pro-inflammatory diseases. Sickle cell disease is a hemoglobinopathy characterized by chronic hemolysis and systemic inflammation which can be complicated by vaso-occlusive pain crises (VOC) or the acute chest syndrome (ACS). Increasingly there is evidence that microparticles may play an important role in the pathophysiology of sickle cell disease. We hypothesize that plasma microparticles are elevated during ACS compared to VOC and baseline (resting). Methods Whole blood was obtained under an approved consent from the Colorado Multiple Institution Review Board at the University of Colorado Denver, from three subjects with homozygous sickle cell disease (ages 4-18) at three distinct time points: baseline (resting) at routine clinic visits and upon hospitalization for VOC and ACS. The samples underwent differential centrifugation: plasma was isolated (5,000xg for 7 min at RT) and then cell free supernatant was separated (12,500xg for 6 min at 4°C). MPs were isolated by centrifugation at 17,000xg for 60 minutes at 4°C, and the MP pellet was resuspended in an equal volume of 1.25% human serum albumin. The samples were incubated with CD41 (PE)-, CD45 (PerCP-Cy5)-, and CD235 (FITC)-antibodies that are specific for MPs derived from platelets, leukocytes, and erythrocytes, respectively, and analyzed by flow cytometry. Statistics were performed using ANOVA with post-hoc Newman-Keuls test. Results The amount of leukocyte-derived MP (WBC) measured during ACS was significantly higher (almost two-fold) than levels measured during baseline (resting) (p < 0.05), but not VOC. The erythrocyte (RBC) MP levels were also significantly elevated during ACS, compared to resting and VOC (p<0.05). There is a trend toward higher platelet (Plt) MP levels during ACS compared to both baseline and VOC, however this does not reach statistical significance likely due to the small sample size (n=3) (Fig. 1). In a separate analysis, the MPs from two patients admitted for VOC with evolution to ACS during the same hospitalization exhibited a three-fold increase in WBC MP levels during VOC that preceded their progression to ACS by 24-72 hours. Discussion Microparticles may play a significant role in the pathophysiology of ACS in sickle cell disease. Leukocyte-derived MPs are elevated in ACS at higher levels than baseline. This likely reflects the important role of white blood cells (WBCs) in systemic inflammation and the importance of WBC-endothelial interactions in ACS. While platelet- and erythrocyte-derived MPs may be involved in ACS, a larger sample size will be needed to detect this effect. In addition, while hospitalized, two patients who had a similar magnitude increase in WBC MPs during VOC eventually progressed to ACS; thus, serial MP measurements could potentially serve as a biomarker to identify patients at risk for imminent development of ACS. Further prospective studies with larger sample sizes will be needed for validation. Future directions of study should also evaluate the role of endothelial-derived MPs and the role of ICAM-1. Disclosures: No relevant conflicts of interest to declare.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

Risk Factors for Intracranial Hemorrhage in Children with Sickle Cell Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1657-1657
Author(s):  
John J. Strouse ◽  
Michael R. DeBaun ◽  
James F. Casella
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Ischemic Stroke ◽  
Steady State ◽  
Sickle Cell ◽  
Intracranial Hemorrhage ◽  
Sickle Cell Anemia ◽  
Small Sample ◽  
Acute Chest Syndrome ◽  
Corticosteroid Administration

Background: Intracranial hemorrhage (ICH) is an uncommon, but devastating, complication of sickle cell disease (SCD) with mortality from 30 to 65%. Most reported cases are in adults; little is known about children. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and hypertransfusion. Methods: Retrospective case-control study designed to characterize and evaluate risk factors for ICH among children with SCD age < 19 years hospitalized at Johns Hopkins Children’s Center from January 1979 to March 2004. Cases had SCD and ICH (intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic subdural and epidural hemorrhages were excluded). Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing the Division of Pediatric Hematology’s records. ACS was defined as a new pulmonary infiltrate and two of the following: chest or rib pain, dyspnea, fever, tachypnea, grunting, nasal flaring, or retractions. Blood pressure was adjusted for age, sex, and hemoglobin genotype. Results: We identified 7 cases (mean age=11.2 years, range 2 to 16 years) and 9 controls (mean age 6.2 years, range 2 to 8 years). As expected, cases were significantly older than controls (p<0.01). All cases and controls had sickle cell anemia. Cases presented with impaired mental status (5/7), bradycardia (5/7), headache (4/7), and emesis (3/7). They often had multiple sites of hemorrhage (5/7) and died during the initial hospitalization (4/7). Five had IPH involving the frontal, parietal, and/or temporal lobes (2 of the patients with IPH also had SAH, 1 had IVH and 1 had both SAH and IVH). Two additional patients had SAH (one also with IVH). Most cases and controls had elevated systolic blood pressure at the time of stroke (4/7 cases, 8/9 controls). Cases had lower steady-state hemoglobin (mean±SE 7.1±0.3 g/dl vs. 7.7±0.4 g/dl), lower steady-state blood pressures (systolic 104±9 vs. 117±5 mm Hg, diastolic 50±5 vs. 61±5 mm Hg) and higher steady-state leukocyte counts (16,590±2823/ul vs. 13,851±2184/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration was increased 2.8 g/dl (39.9%) from steady-state at the time of stroke in cases and was unchanged in controls (p=0.08). Other events in the two weeks before ICH associated with increased odds of ICH included transfusion (simple in 5 cases, erythrocytapheresis in 1), ACS (3 cases), and corticosteroid administration (high-dose dexamethasone for ACS in 2, stress doses for possible adrenal insufficiency in 1). Conclusions: In this group of children with SCD, ICH was associated with antecedent events including transfusion and possibly corticosteroids. Mortality was similar to that of adults with SCD and ICH. Limitations of this study include the small sample size and the retrospective design. The contribution of antecedent events to ICH in children with SCD deserves further evaluation. Odds Ratios of Intracranial Hemorrhage For Events in the Last 14 Days Event Odds Ratio (95% CI) P-value Transfusion 48 (1.8-2469) <0.01 ACS 6 (0.3-33) 0.26 Corticosteroids ∞ (1.3- ∞) 0.06

Determinants of Inter-Procedure Interval in Patients with Sickle Cell Anemia Enrolled a Chronic Red Blood Cell Exchange Program

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4284-4284
Author(s):  
Alecia C. Nero ◽  
Theresa Nguyen Kinard ◽  
Beverley Adams-Huet ◽  
Karen Matevosyan ◽  
Ravindra Sarode
Keyword(s):  
Blood Cell ◽  
Multiple Regression ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Red Blood Cell ◽  
Small Sample ◽  
Blood Type ◽  
Acute Chest Syndrome ◽  
Intractable Pain ◽  
Post Procedure

Abstract Background: Sickle cell anemia (SCA) is a genetically inherited disorder that can lead to severe sequelae in any organ system. The most clinically devastating complications, e.g. stroke, are managed with chronic red blood cell (RBC) transfusions as curing the underlying SCA is often not an option. Chronic RBC exchange (RBCx), is an effective alternative to simple transfusions and often performed every 4-5 weeks. Isovolemic Hemodilution-Red Blood Cell Exchange (IHD-RBCx) is a modified RBCx method used at UT Southwestern Medical Center (UTSW) and increases the time interval between transfusions, i.e. inter-procedure interval (IPI), up to 9 weeks while maintaining the desired hemoglobin S targets at safe levels. This minimizes the overall lifetime procedures and blood exposures. The standard operating procedure for IHD-RBCx is published (Matevosyan et al, 2012). However, we observed IPI variability between patients in this chronic IHD-RBCx program. We sought to analyze hematologic characteristics in a cohort of adult SCA patients that may be associated with this noted variability. Methods: This IRB approved cross-sectional study evaluated medical and blood bank records of adult patients with SCA, i.e. hemoglobin SS or Sβ0 thalassemia genotypes, undergoing chronic IHD-RBCx at UTSW adult hospital sites between January 1, 2012 and December 31, 2013. Excluded participants were those with autoimmune disease, non-compliance with IHD-RBCx leading to delays > 7 days, or use of hydroxyurea or steroids within four months of the study period. Patients with < 5 exchanges were excluded as several procedures are needed to determine baseline IPIs. The primary indication for IHD-RBCx was secondary stroke prevention. Three subjects had alternative indications (i.e. recurrent severe acute chest syndrome that failed hydroxyurea therapy, intractable pain and severe anemia ineligible for iron chelation due to end-stage renal disease). Median values during the 2 year study were determined for the IPI, laboratory, and RBC properties for use in subsequent analyses. Correlation and multiple regression analyses were performed to determine variables predictive of IPI. Results: Twenty-four SCA patients in this chronic IHD-RBCx transfusion program met inclusion criteria of which 14 (58.3%) were female with age range 18-41 years. Three subjects had incomplete data. The median number of packed RBC (pRBC) units per IHD-RBCx was 8 (range: 6-11 units). The median volume per unit of pRBCs was 304.5 mL (range: 298.8-326.5 mL) with average age of the pRBCs 5.8 days ± 0.7 days. The median IPI was 55.8 days (range: 36.0-65.5 days). The strongest correlation with IPI was the change from the mid to post-procedure hemoglobin and hematocrit values, r=0.56, p=0.005 and r=0.57, p=0.003, respectively. Participants with documented direct antiglobulin test positivity (n=7), compared to those who remained negative (n=16), had 4.9 days increased IPI. This difference was not statistically significant, p=0.19. ABO differences in blood type also did not show statistical significant differences. However, A+ subjects had a 58 day interval compared to 51, 52, 53 days for B+, O+, O- respectively (Figure). In multiple regression models, log blood urea nitrogen (BUN) and post-procedure white blood cell count (WBC) were found to be independent predictors of IPI, beta=-11.3, p=0.04 and -2.1, p=0.03 respectively, with adjusted R2=0.31. Conclusions: Chronic IHD-RBCx effectively treats severe SCA complications. Discontinuing transfusions lead to repeat stroke events or the recurrence of disease manifestations making chronic transfusion programs an indefinite therapy. Outside of the expected correlation between the IPI and hemoglobin/hematocrit, WBC and BUN were found to have negative associations with IPIs. The decrease in WBCs is likely due to the direct clearing effect by the operating system. The association between BUN and IPI may imply relationship with renal function. Interestingly, association with creatinine was not statistically significant. The study is limited by the small sample size. Future studies of similar cohorts should prospectively evaluate target mechanisms which may lead to interventions that can minimize lifetime blood exposures given the growing demands for continued RBCx in severe SCA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Implementation of a Pediatric Observation Unit for Children with Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4838-4838
Author(s):  
Sophia Sharifali ◽  
Lashon Sturgis ◽  
Cindy Neunert ◽  
Natalie Lane ◽  
Robert Gibson ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sample Size ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Acute Chest Syndrome ◽  
Care Hospital ◽  
Cell Disease ◽  
Observation Unit ◽  
Exclusion Criteria ◽  
Direct Admission

Abstract Acute vaso-occlusive crisis (VOC), the most common manifestation of Sickle Cell Disease (SCD), is the number one cause for visits to the Emergency Department (ED). Pediatric patients differ from adult patients with SCD due to variations in opioid tolerance and age-specific complications. Many pediatric patients can be sent home after evaluation and treatment in an ED, however, others will need hospitalization for further pain management as well as continued evaluation. Observation Units (OUs), ED-associated units for evaluation and protocol management of short-term conditions (<24 hours), have successfully provided more rapid care while still maintaining quality. At our institution, using an OU-based protocol, we have demonstrated improved care with decreased resource utilization in an adult population with SCD experiencing VOC. However, there is limited data for the use of OU in pediatric patients with VOC. Our objective was to determine the feasibility of a pediatric OU for the evaluation and treatment of patients with uncomplicated VOC. A retrospective, descriptive chart review study was conducted on all pediatric patients (<18 years) with SCD between July 1, 2012 to June 30, 2013. The study was conducted in an academic pediatric tertiary care hospital (annual volume 27k/year). A medical record search was conducted using ICD-9 codes and SCD related DRG codes. The cohort was then limited to patients who received care in the academic ED or were transferred from another hospital for direct admission (DA). The cohort was limited to visits with pain related to VOC. Patients with a complication other than VOC were excluded as well as patients admitted to the intensive care unit. Cohort data as well as exclusion criteria are in table 1. Visits that were admitted to the floor (either as a direct admission or admitted from the ED) with a length of stay (LOS) less than 48 hours were included in the analysis. Patients were grouped into categories based on LOS: < 24 hours, <36 hours, and <48 hours Though the OU will only manage up to 24 hours, categories of LOS longer than 24 hours were included in order to capture elements that may lengthen a patients stay such as waiting time, time until disposition and discharge. Table 1. Sample Size and Exclusion Criteria # of Patients treated for Sickle Cell Between 7/1/2012 - 6/30,2012 197 patients Limiting to patients seen in ED or having a DA 119 patients Limiting to confirmed diagnosis of SCD (multiple genotypes) = 6 113 patients Limiting to reason of visit to a pain complaint = 6 107 patients Limiting to reason of pain to VOC = 3 104 patients Limited or no data in EMR (left prior to treatment) = 3 101 patients Exclusion of patients with visits only for complications of SCD* = 21 80 patients Final Sample Size for analysis 80 patients *Complications include acute chest syndrome, sepsis, splenic sequestration, fever, infiltrates, and infection 80 patients had 160 visits for uncomplicated VOC from 7/1/2012 - 6/30/2012. Of the 160 visits, the patient was admitted53.8% (86) of the time. Of the 86 visits resulting in admission, 30 (34.9%) were DA and 56 (65.1%) were admitted from the academic ED. LOS of the admission by DA or from the academic ED is in table 2. Table 2. LOS for Admissions DA to Floor 30 total visits LOS < 24 Hours 5 (16.6%) visits LOS < 36 Hours 10 (33.3%) visits LOS < 48 Hours 17 (56.7%) visits ED to Floor 56 total visits LOS < 24 Hours 4 (7.1%) visits LOS < 36 Hours 10 (17.9%) visits LOS < 48 Hours 21 (37.5%) visits OU's are ideal for the evaluation and management of patients requiring more than a few hours of ED treatment but less than 24 hours of hospital therapy. Our study shows that there is a large number of patients with SCD and VOC are admitted (53.8%). Based on our study, 44% of admissions have a LOS less than 48 hours. We believe that 48 hours is a reasonable cutoff for consideration of OU care as disposition decisions on the floor occur at 12-hour and sometimes 24-hour intervals leading to an increase in LOS beyond the actual treatment time. All patients, including DA patients, should be eligible for OU treatment if they meet inclusion criteria. This is evidenced by the finding that the LOS is shorter for DA patients (56.7%) versus admissions from the academic ED (37.5%). Overall, pediatric SCD patients would benefit from the presence of a pediatric OU by potentially decreasing the rate of inpatient admissions. An observation unit should therefore be strongly considered in centers with large volume SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial

2015 ◽  
Vol 90 (12) ◽  
pp. 1099-1105 ◽  
Author(s):  
Jane S. Hankins ◽  
Mary Beth McCarville ◽  
Angela Rankine-Mullings ◽  
Marvin E. Reid ◽  
Clarisse L.C. Lobo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Transcranial Doppler ◽  
Phase Iii

Use of a dual-layer amniotic membrane in the treatment of diabetic foot ulcers: an observational study

2020 ◽  
Vol 29 (Sup9) ◽  
pp. S8-S12
Author(s):  
Isabella Sledge ◽  
David Maislin ◽  
Dave Bernarducci ◽  
Robert Snyder ◽  
Thomas E Serena
Keyword(s):  
Clinical Trial ◽  
Sample Size ◽  
Primary Endpoint ◽  
Amniotic Membrane ◽  
Diabetic Foot ◽  
Standard Of Care ◽  
Small Sample ◽  
Foot Ulcers ◽  
Diabetic Foot Ulcers ◽  
Complete Closure

Background: Despite advances in the treatment, fewer than half of diabetic foot ulcers (DFUs) heal in 12 weeks and 85% of non-traumatic amputations follow the development of a DFU. The search for treatment options continues. Placental-derived products have shown promise in the treatment of DFUs. This study investigates Artacent (Tides Medical, US), a unique amniotic patch containing two layers of amnion and its potential to increase growth factor delivery. Method: This observational analysis included patients with DFUs with documented failure to heal by >50% after the protocol-defined run-in period (either two or four weeks) of standard of care (SOC), and who had been randomised in a larger clinical trial that had been discontinued earlier for logistical reasons. Patients were randomised to either weekly or biweekly application of the dual-layer amniotic membrane (DLAM) plus SOC and were included in per-protocol effectiveness analyses. Descriptive statistics were chosen for this analysis. Primary endpoint was complete closure at 12 weeks. Results: A total of 26 patients were included in the analysis. Examination of baseline patient characteristics revealed that the ulcers were larger than in most DFU clinical trials (4.65±4.89cm2). For the primary endpoint, 17/26 (65%, 95% CI: 44–83%) of the combined treatment arms achieved complete closure. The small sample size precluded a meaningful comparison of healing between weekly and biweekly DLAM applications. Conclusion: The observations taken from the discontinued clinical trial suggest that the DLAM promotes healing of DFUs. The healing rates are similar to those in other placental-based tissue studies. In addition, the relatively larger size of the ulcers suggests that the DLAM may be effective in ulcers that are more resistant to standard of care. In the future, a revised clinical trial with a greater sample size is planned.

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.

Barriers to Deferoxamine Adherence for Adults with Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3760-3760 ◽  
Author(s):  
Marsha Treadwell ◽  
Jennifer Sung ◽  
Eileen Murray ◽  
Robert Hagar ◽  
Kimberly Major ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Sickle Cell Disease ◽  
Adverse Effects ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Clinical Care ◽  
Cell Disease ◽  
Transfusion Therapy

Abstract Background: The barriers to adherence with chelation therapy for chronically transfused and iron overloaded patients with sickle cell disease (SCD) have been described only anecdotally. Objectives: To describe barriers to home deferoxamine (DFO) administration adherence among adults with SCD. It was hypothesized that barriers would include limited patient education on the importance of chelation and perceived aversiveness of the regimen. Methods: Medical records were reviewed for 189 adult patients seen at a comprehensive sickle cell center. Patients with transfusion induced hemosiderosis, defined as a serum ferritin ≥ 1500 ng/ml, were administered a four item interview asking if iron overload had ever been discussed with them; if they had been informed they were iron over loaded; if chelation therapy had been offered; and if not currently home chelating, why not. Patients not interviewed were deceased (3); unavailable (10); or declined (3). A study coordinator who did not provide clinical care conducted the interviews. Results: 54 of the 189 patients (29%) had a history of intermittent or chronic transfusion, or pheresis. 45 of these patients were iron overloaded. 29 of these patients agreed to complete the interview; 22 (76%) were female. Average age was 41.5 years (range 22.4 – 58.4 years) and average serum ferritin was 4240.8 (range 1547 – 9420). 23 of the 29 patients (79%) reported that their physician or nurse had discussed iron overload and chelation with them. 16 of these (55%) reported that they were currently receiving home DFO therapy. Reasons given for not administering home DFO included: Reason Number (%) “Don’t want to stick self” 3 (23) No longer being transfused or being exchanged 3 (23) Awaiting clinical trial for oral chelator 2 (15) Home situation too complex 2 (15) Don’t want to (no further explanation) 2 (15) Too many adverse effects 1 (8) Discussion: Life threatening levels of iron overload were observed in intermittently transfused adult sickle cell patients. Contrary to expectations, iron overload and its treatment had been discussed with most patients. However, just over half were currently chelating at home. Toxicity of DFO and misunderstanding that iron overload is no longer a problem if chronic transfusion therapy stops are the most common reasons for non-compliance. Repeated patient counseling are essential in order to prevent progressive iron toxicity in sickle cell disease. Reason Number (%) “Don’t want to stick self” 3 (23) No longer being transfused or being exchanged 3 (23) Awaiting clinical trial for oral chelator 2 (15) Home situation too complex 2 (15) Don’t want to (no further explanation) 2 (15) Too many adverse effects 1 (8)

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