End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.
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ABSTRACT:
SUBMITTER: Farrell AT
PROVIDER: S-EPMC6963248 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.
Farrell Ann T AT Panepinto Julie J Desai Ankit A AA Kassim Adetola A AA Lebensburger Jeffrey J Walters Mark C MC Bauer Daniel E DE Blaylark Rae M RM DiMichele Donna M DM Gladwin Mark T MT Green Nancy S NS Hassell Kathryn K Kato Gregory J GJ Klings Elizabeth S ES Kohn Donald B DB Krishnamurti Lakshmanan L Little Jane J Makani Julie J Malik Punam P McGann Patrick T PT Minniti Caterina C Morris Claudia R CR Odame Isaac I Oneal Patricia Ann PA Setse Rosanna R Sharma Poornima P Shenoy Shalini S
Blood advances 20191201 23
To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-pa ...[more]
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Project description:To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.
| S-EPMC6963237 | biostudies-literature
Project description:Sickle cell disease (SCD) is a group of common, life-threatening disorders caused by a point mutation in the β globin gene. Early diagnosis through newborn and early childhood screening, parental education, and preventive treatments are known to reduce mortality. However, the cost and complexity of conventional diagnostic methods limit the feasibility of early diagnosis for SCD in resource-limited areas worldwide. Although several point-of-care tests are commercially available, most are antibody-based tests, which cannot be used in patients who have recently received a blood transfusion. Here, we describe the development of a rapid, low-cost nucleic acid test that uses real-time fluorescence to detect the point mutation encoding hemoglobin S (HbS) in one round of isothermal recombinase polymerase amplification (RPA). When tested with a set of clinical samples from SCD patients and healthy volunteers, our assay demonstrated 100% sensitivity for both the βA globin and βS globin alleles and 94.7 and 97.1% specificities for the βA globin allele and βS globin allele, respectively (n = 91). Finally, we demonstrate proof-of-concept sample-to-answer genotyping of genomic DNA from capillary blood using an alkaline lysis procedure and direct input of diluted lysate into RPA. The workflow is performed in <30 min at a cost of <$5 USD on a commercially available benchtop fluorimeter and an open-source miniature fluorimeter. This study demonstrates the potential utility of a rapid, sample-to-answer nucleic acid test for SCD that may be implemented near the point of care and could be adapted to other disease-causing point mutations in genomic DNA.
| S-EPMC7992048 | biostudies-literature
Project description:BACKGROUND: The prevalence of Sickle cell disease is extremely high in Democratic Republic of Congo. Despite this high prevalence of the disease, data on renal abnormalities in children are rare. METHOD: The study proposed to assess blood pressure, glomerular function, urea and uric acid levels in 65 steady state Congolese children with homozygous sickle cell disease and 67 normal controls. RESULTS: In Hb-SS group, blood pressure level tended to be lower than Hb-AA groups but there was no statistically significant difference (p>0.05) between the two groups. The absolute values for GFR corrected for BSA were significantly higher in Hb-SS group compared to Hb-AA group (130.5±34.1 ml/min/1.73 m2 vs 113.7±24.5 ml/min/1.73 m2; p = 0.004). Children with Hb-SS were more likely to hyperfiltrate (30.8% of subjects) than children with Hb-AA (6.1% of subjects). Proteinuria was found in 4 (6.2%) children with Hb-SS. Uric acid level was significantly increased in children with Hb-SS compared to corresponding values in control group (4.4±1.3 mg/dl vs 3.5±1.1 mg/dl; p<0.001). Urea level was significantly decreased compared to corresponding values in Hb-AA group (15.3±8.3 mg/dl vs 22.9±10.1 mg/dl; p<0.001). CONCLUSION: Hyperfiltration, low creatinine, lower urea and high uric acid are more common in children with sickle cell disease than in normal controls.
| S-EPMC4014510 | biostudies-other
Project description:Differences in definitions of acute pediatric diarrhea result in variable estimates of morbidity and mortality, treatment coverage, and associations with risk factors and outcomes. We reviewed published literature and guidelines focused on acute pediatric diarrhea in low- and middle-income countries. Clinical guidelines most commonly defined diarrhea in terms of quantity of loose or watery stool with consideration of normal stool patterns, whereas research studies often relied exclusively on a quantitative definition. The most commonly used quantitative definition, ?3 loose or watery stools in a 24-hour period, has been compared to gold standards of caregiver perception and visual inspection of stool, with variable agreement. Age, breast-feeding status, and setting (facility vs household-based) influence the performance of quantitative diarrhea definitions in children. Universal adoption of a set of valid gold standard definitions specifically aligned with various programmatic and research goals will lead to more accurate coverage estimates and better-informed resource prioritization.
| S-EPMC5907861 | biostudies-other
Project description:Acute heart failure syndromes (AHFS) remain a major cause of morbidity and mortality, in part because the development of new therapies for these disorders has been marked by frequent failure and little success. The heterogeneity of current approaches to AHFS drug development, particularly with regard to end points, remains a major potential barrier to progress in the field. End points involving hemodynamic status, biomarkers, symptoms, hospital stay, end organ function, and mortality have all been employed either alone or in combination in recent randomized clinical trials in AHFS. In this review, we will discuss the various end point domains from both a clinical and a statistical perspective, summarize the wide variety of end points used in completed and ongoing AHFS studies, and suggest steps for greater standardization of end points across AHFS trials.
| S-EPMC3961583 | biostudies-other
Project description:BACKGROUND:Stepped-wedge cluster randomized trials (SW-CRTs) are increasingly popular in health-related research in both high- and low-resource settings. There may be specific ethical issues that researchers face when designing and conducting SW-CRTs in low-resource settings. Knowledge of these issues can help to improve the ethical conduct of SW-CRTs in a global health context. METHODS:We performed an ethical analysis of two studies using SW-CRT designs in low-resource settings: the Que Vivan Las Madres study conducted from 2014 to 2017 in Guatemala and the Atmiyata study conducted from 2017 to 2018 in rural parts of India. For both case studies, we identified and evaluated the classification of the study as research or nonresearch and the ethical issues regarding the justification of the design, including the delayed rollout of an intervention that had a promising effect. RESULTS:In our case studies, some minor ethical issues surfaced about the registration and stakeholder pressure on the order of randomization, but both included good justification for the design and delayed rollout. Our analysis did, however, demonstrate that careful consideration of the role of randomization and registration of the trials is important. DISCUSSION:SW-CRTs can provide an opportunity for rigorous evaluation of interventions destined to be rolled out on the basis of limited evidence. Furthermore, in SW-CRTs, the underlying objective is often to provide a robust evaluation of the effectiveness for generalized dissemination, and this makes the SW-CRT no less a research study than any other form of cluster randomized trial. CONCLUSION:The design and conduct of stepped-wedge cluster randomized trials raises at least two ethical issues that need special consideration in both high- and low-resource settings: the justification for using the design, specifically the delayed rollout of the intervention to the control group, and the classification of the study as research or nonresearch. In our case studies, these issues did not seem to raise special ethical scrutiny in low-resource settings. Further ethical evaluation will hopefully result in specific ethical guidelines for the use of SW-CRTs in both high- and low-resource settings to contribute to responsible functioning of these trials and adequate protection of participants.
| S-EPMC6921381 | biostudies-literature
Project description:Sickle cell disease (SCD) is a common, life-threatening genetic disorder that is best managed when diagnosed early by newborn screening. However, SCD is most prevalent in low-resource regions of the world where newborn screening is rare and diagnosis at the point-of-care is challenging. In many such regions, the majority of affected children die, undiagnosed, before the age of 5 years. A rapid and affordable point-of-care test for SCD is needed. The diagnostic accuracy of HemoTypeSC, a point-of-care immunoassay, for SCD was evaluated in individuals who had SCD, hemoglobin C disease, the related carrier (trait) states, or a normal hemoglobin phenotype. Children and adults participated in low-, medium- and high-resource environments (Ghana [n = 383], Martinique [n = 46], and USA [n = 158]). Paired blood specimens were obtained for HemoTypeSC and a reference diagnostic assay. HemoTypeSC testing was performed at the site of blood collection, and the reference test was performed in a laboratory at each site. In 587 participants, across all study sites, HemoTypeSC had an overall sensitivity of 99.5% and specificity of 99.9% across all hemoglobin phenotypes. The test had 100% sensitivity and specificity for sickle cell anemia. Sensitivity and specificity for detection of normal and trait states were >99%. HemoTypeSC is an inexpensive (<$2 per test), accurate, and rapid point-of-care test that can be used in resource-limited regions with a high prevalence of SCD to provide timely diagnosis and support newborn screening programs.
| S-EPMC6298816 | biostudies-literature
Project description:Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality. While new CF disease-modifying agents are currently undergoing clinical trial evaluation, the implementation of such trials in young children is limited by the lack of age-appropriate clinical trial end points. Advances in infant and preschool lung function testing, imaging of the chest and the development of biochemical biomarkers have led to increased possibility of quantifying mild lung disease in young children with CF and objectively monitoring disease progression over the course of an intervention. Despite this, further standardization and development of these techniques is required to provide robust objective measures for clinical trials in this age group.
| S-EPMC5033038 | biostudies-literature
Project description:ImportancePredictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first.ObjectiveTo determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis.Design, setting, and participantsThis study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017.Main outcomes and measuresThe primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test.ResultsOf Track's 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS.Conclusions and relevanceReasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach.
| S-EPMC5710578 | biostudies-literature
Project description:BackgroundMany modern molecular diagnostic assays targeting nucleic acids are typically confined to developed countries or to the national reference laboratories of developing-world countries. The ability to make technologies for the rapid diagnosis of infectious diseases broadly available in a portable, low-cost format would mark a revolutionary step forward in global health. Many molecular assays are also developed based on polymerase chain reactions (PCR), which require thermal cyclers that are relatively heavy (>20 pounds) and need continuous electrical power. The temperature ramping speed of most economical thermal cyclers are relatively slow (2 to 3 °C/s) so a polymerase chain reaction can take 1 to 2 hours. Most of all, these thermal cyclers are still too expensive ($2k to $4k) for low-resource setting uses.Methodology/principal findingsIn this article, we demonstrate the development of a low-cost and rapid water bath based thermal cycler that does not require active temperature control or continuous power supply during PCR. This unit costs $130 to build using commercial off-the-shelf items. The use of two or three vacuum-insulated stainless-steel Thermos food jars containing heated water (for denaturation and annealing/extension steps) and a layer of oil on top of the water allow for significantly stabilized temperatures for PCR to take place. Using an Arduino-based microcontroller, we automate the "archaic" method of hand-transferring PCR tubes between water baths.Conclusions/significanceWe demonstrate that this innovative unit can deliver high speed PCR (17 s per PCR cycle) with the potential to go beyond the 1,522 bp long amplicons tested in this study and can amplify from templates down to at least 20 copies per reaction. The unit also accepts regular PCR tubes and glass capillary tubes. The PCR efficiency of our thermal cycler is not different from other commercial thermal cyclers. When combined with a rapid nucleic acid detection approach, the thermos thermal cycler (TTC) can enable on-site molecular diagnostics in low-resource settings.
| S-EPMC4492969 | biostudies-literature