Dataset Information

Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME).

ABSTRACT: Objective:VOLUME is a randomized, open-label, post-approval pragmatic trial aiming to evaluate long-term pulmonary and cardiovascular safety of Exubera® (EXU; insulin human [rDNA origin] Inhalation Powder) in routine clinical practice. The primary study objective is to compare risk of persistent decline in forced expiratory volume in 1?second (FEV1) among patients treated with and without EXU. Research design and methods:Patients eligible to take EXU per approved local label were randomized to EXU or routine care and followed per usual care, with scheduled FEV1 tests at baseline, 6 months, and yearly.Randomization halted in October 2007 after Pfizer announced it would stop marketing EXU due to low sales. EXU patients were subsequently transitioned to usual care and all patients were followed for 6 additional months. Results:Although there was insufficient power to evaluate the primary endpoint (37% of the planned 5,300 were randomized), the study provided important descriptive information.Per the primary endpoint definition, more EXU group patients (n?=?8) experienced a persistent decline in FEV1 (n?=?0 in usual care). Using a broader, clinically relevant pre-specified supplementary definition of persistent decline, similar numbers were observed in the EXU (n?=?27) and usual care (n?=?24) groups. Slightly more pulmonary and allergic serious adverse event composite endpoints were seen in the EXU group. There were no consistent treatment group differences in the cardiovascular composite endpoint, all-cause mortality, or glycemic control. Conclusions:Clinically important declines in lung function that persisted more than 60 days were uncommon and of similar frequency in Exubera and usual care. Clinicaltrialsgov:NCT00359801.

SUBMITTER: Gatto NM

PROVIDER: S-EPMC7251384 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME).

Gatto Nicolle M NM Bracken Michael B MB Kolitsopoulos Francesca F Duggan William T WT Koch Gary G GG Wise Robert A RA Jackson Neville C NC

Contemporary clinical trials communications 20190813

<h4>Objective</h4>VOLUME is a randomized, open-label, post-approval pragmatic trial aiming to evaluate long-term pulmonary and cardiovascular safety of Exubera® (EXU; insulin human [rDNA origin] Inhalation Powder) in routine clinical practice. The primary study objective is to compare risk of persistent decline in forced expiratory volume in 1 second (FEV<sub>1</sub>) among patients treated with and without EXU.<h4>Research design and methods</h4>Patients eligible to take EXU per approved local ...[more]

PMID: 32478195

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Project description:BackgroundSolitary pulmonary nodule (SPN) is a common finding in routine clinical practice when performing chest imaging tests. The vast majority of these nodules are benign, and only a small proportion are malignant. The application of predictive models of nodule malignancy in routine clinical practice would help to achieve better diagnostic management of SPN. The present systematic review was carried out with the purpose of critically assessing studies aimed at developing predictive models of solitary pulmonary nodule (SPN) malignancy from SPN incidentally detected in routine clinical practice.MethodsWe performed a search of available scientific literature until October 2020 in Pubmed, SCOPUS and Cochrane Central databases. The inclusion criteria were observational studies carried out in low-risk population from 35 years old onwards aimed at constructing predictive models of malignancy of pulmonary solitary nodule detected incidentally in routine clinical practice. Studies had to be published in peer-reviewed journals, either in Spanish, Portuguese or English. Exclusion criteria were non-human studies, or predictive models based in high-risk populations, or models based on computational approaches. Exclusion criteria were non-human studies, or predictive models based in high-risk populations, or models based on computational approaches (such as radiomics). We used The Transparent Reporting of a multivariable Prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement, to describe the type of predictive model included in each study, and The Prediction model Risk Of Bias ASsessment Tool (PROBAST) to evaluate the quality of the selected articles.ResultsA total of 186 references were retrieved, and after applying the exclusion/inclusion criteria, 15 articles remained for the final review. All studies analysed clinical and radiological variables. The most frequent independent predictors of SPN malignancy were, in order of frequency, age, diameter, spiculated edge, calcification and smoking history. Variables such as race, SPN growth rate, emphysema, fibrosis, apical scarring and exposure to asbestos, uranium and radon were not analysed by the majority of the studies. All studies were classified as high risk of bias due to inadequate study designs, selection bias, insufficient population follow-up and lack of external validation, compromising their applicability for clinical practice.ConclusionsThe studies included have been shown to have methodological weaknesses compromising the clinical applicability of the evaluated SPN malignancy predictive models and their potential influence on clinical decision-making for the SPN diagnostic management.Systematic review registrationPROSPERO CRD42020161559.

Project description:The increasing number of studies demonstrates the high potency of the intrathecal (IT) route for the delivery of biopharmaceuticals to the central nervous system (CNS). Our earlier data exhibited that both the infused volume and the infusion rate can regulate the initial disposition of the administered solute within the cerebrospinal fluid (CSF). This disposition is one of key factors in defining the subsequent transport of the solute to its intended target. On the other hand, fast additions of large volumes of liquid to the CSF inevitably raise the CSF pressure [a.k.a. intracranial pressure (ICP)], which may in turn lead to adverse reactions if the physiologically delimited threshold is exceeded. While long-term biological effects of elevated ICP (hydrocephalus) are known, the safety thresholds pertaining to short-term ICP elevations caused by IT administrations have not yet been characterized. This study aimed to investigate the dynamics of ICP in rats and non-human primates (NHPs) with respect to IT infusion rates and volumes. The safety regimes were estimated and analyzed across species to facilitate the development of translational large-volume IT therapies. The data revealed that the addition of a liquid to the CSF raised the ICP in a rate and volume-dependent manner. At low infusion rates (<0.12 ml/min in rats and <2 ml/min in NHPs), NHPs and rats displayed similar tolerance patterns. Specifically, safe accommodations of such added volumes were mainly facilitated by the accelerated pressure-dependent CSF drainage into the blood, with I stabilizing at different levels below the safety threshold of 28 ± 4 mm Hg in rats and 50 ± 5 mm Hg in NHPs. These ICPs were safely tolerated for extended durations (of at least 2-25 min). High infusion rates (including boluses) caused uncompensated exponential ICP elevations rapidly exceeding the safety thresholds. Their tolerance was species-dependent and was facilitated by the compensatory role of the varied components of craniospinal compliance while not excluding the possibility of other contributing factors. In conclusion, large volumes of liquids can safely be delivered via IT routes provided that ICP is monitored as a safety factor and cross-species physiological differences are accounted for.

Dataset Information

Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME).

Publications

Pulmonary and cardiovascular safety of inhaled insulin in routine practice: The Exubera Large Simple Trial (VOLUME).

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