Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use.

Treatment of vaso-occlusive crises (VOC) or events in sickle cell disease (SCD) remains limited to symptom relief with opioids. Animal models support the effectiveness of the pan-selectin inhibitor GMI-1070 in reducing selectin-mediated cell adhesion and abrogating VOC. We studied GMI-1070 in a prospective multicenter, randomized, placebo-controlled, double-blind, phase 2 study of 76 SCD patients with VOC. Study drug (GMI-1070 or placebo) was given every 12 hours for up to 15 doses. Other treatment was per institutional standard of care. All subjects reached the composite primary end point of resolution of VOC. Although time to reach the composite primary end point was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P = .19 for both) were observed in the active treatment group vs the placebo group. As a secondary end point, GMI-1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P = .010). These results support a phase 3 study of GMI-1070 (now rivipansel) for SCD VOC. This trial was registered at www.clinicaltrials.gov as #NCT01119833.

Tapered oral dexamethasone for the acute chest syndrome of sickle cell disease.

Tapered oral dexamethasone for acute chest syndrome (ACS) in sickle cell anaemia was studied using a novel ACS assessment tool and investigational biomarkers. Twelve participants were randomized (mean age 17·3 years) before early study termination. Dexamethasone decreased duration of hospitalization for ACS by 20·8 h compared to placebo (P = 0·024). Rebound pain occurred in both groups (3 dexamethasone versus 1 placebo). Overall, dexamethasone decreased the leucocyte activation biomarker, sL-selectin; however, participants with rebound pain had higher sL-selectin within 24 h of treatment (dexamethasone or placebo). This ACS assessment tool was feasibly applied, and sL-selectin is a promising biomarker of ACS therapy.

Health-related quality of life in adults with sickle cell disease (SCD): a report from the comprehensive sickle cell centers clinical trial consortium.

Adults with Sickle Cell Disease (SCD) experience multiple disease-related complications, but few studies have examined relationships between these events and health-related quality of life (HRQOL). We determined the number and type of previous or co-occurring SCD-related complications and their reported HRQOL in a cohort of 1,046 adults from the Comprehensive Sickle Cell Centers (CSCC). Participants had a median age of 28.0 years (48% male, 73% SS or Sß° thalassemia) and had experienced several SCD-related complications (mean 3.8 ± 2.0), which were influenced by age, gender, and hemoglobinopathy type (P < 0.0001). In multivariate models, increasing age reduced all SF-36 scales scores (P < 0.05) except mental health, while female gender additionally diminished physical function and vitality scale scores (P < 0.01). Of possible complications, only vaso-occlusive crisis, asthma, or avascular necrosis diminished SF-36 scale scores. Chronic antidepressants usage predominantly diminished scores on bodily pain, vitality, social functioning, emotional role, and mental health scales, whereas chronic opioid usage diminished all scale scores (P < 0.01). Our study documents substantial impairment of HRQOL in adults with SCD that was influenced by only a few of many possible medical complications. It suggests that more effective treatments of persistent pain and depression would provide the largest HRQOL benefit.

Health-related quality of life in children with sickle cell disease: a report from the Comprehensive Sickle Cell Centers Clinical Trial Consortium.

BACKGROUND: Pediatric health-related quality of life (HRQOL) questionnaires have been validated in children with sickle cell disease (SCD), but small sample sizes in these studies have limited clinical comparisons. We used the baseline clinical data from the Collaborative Data (C-Data) Project of the Comprehensive Sickle Cell Centers (CSCC) Clinical Trial Consortium to perform a detailed, descriptive study of HRQOL using the PedsQL version 4.0 generic core and fatigue scales. METHODS: Retrospective clinical data were obtained via medical record abstraction. Staff-administered health history, psychosocial, and health behavior interviews were completed by a parent or guardian. PedsQL forms were completed separately by the child and a parent/guardian. RESULTS: The study enrolled 1,772 subjects (53% boys) with a mean age of 9.6 years (SD 4.7). SS or Sbeta(0) thalassemia occurred in 68% and 32% had SC or Sbeta(+) thalassemia. The occurrences of pain, priapism, avascular necrosis of hips/shoulders (AVN), or asthma were the most common complications/conditions reported. Multiple regression models controlling for hemoglobinopathies, gender, and age suggested that parent reports of physical functioning and sleep/rest fatigue declined in response to pain or AVN, while school functioning scales declined in response to pain or asthma. Sickle pain, and to a lesser extent asthma, negatively influenced child reports on almost all functioning and fatigue scales. CONCLUSIONS: While longitudinal studies will be necessary to determine sensitivity to change, the current study suggests the potential utility of several PedsQL HRQOL scales as patient-reported outcome measures for observational or interventional treatment studies of children and adolescents with SCD.

Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia.

BACKGROUND: Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease. METHODS: We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions. RESULTS: The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied. CONCLUSIONS: GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM), leukocyte activation (MAC-1, LFA-1, PM aggregates) and the coagulation cascade (tissue factor, thrombin-antithrombin complexes). Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT00911495.

Local linear discriminant analysis (LLDA) for group and region of interest (ROI)-based fMRI analysis.

A post-processing method for group discriminant analysis of fMRI is proposed. It assumes that the fMRI data have been pre-processed and analyzed so that each voxel is given a statistic specifying task-related activation(s), and that individually specific regions of interest (ROIs) have been drawn for each subject. The method then utilizes Local Linear Discriminant Analysis (LLDA) to jointly optimize the individually-specific and group linear combinations of ROIs that maximally discriminates between groups (or between tasks, if using the same subjects). LLDA tries to linearly transform each subject's voxel-based activation statistics within ROIs to a common vector space of ROI combinations, enabling the relative similarity of different subjects' activation to be assessed. We applied the method to data recorded from 10 normal subjects during a motor task expected to activate both cortical and subcortical structures. The proposed method detected activation in multiple cortical and subcortical structures that were not present when the data were analyzed by warping the data to a common space. We suggest that the method be applied to group fMRI data when warping to a common space may be ill-advised, such as examining activation in small subcortical structures susceptible to mis-registration, or examining older or neurological patient populations.