Dasiglucagon: A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia Results of Phase 3 Randomized Double-Blind Clinical Trial.
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ABSTRACT:
SUBMITTER: Pieber TR
PROVIDER: S-EPMC8247529 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDasiglucagon, a next-generation, ready-to-use aqueous glucagon analog formulation, has been developed to treat severe hypoglycemia in individuals with diabetes.ObjectiveThe aim of this trial was to evaluate the safety and efficacy of dasiglucagon in pediatric individuals with type 1 diabetes (T1DM). Participants were children and adolescents (6-17 years) with T1DM.MethodsIn this randomized double-blind trial, 42 participants were randomly allocated (2:1:1) to a single subcutaneous (SC) injection of dasiglucagon (0.6 mg), placebo, or reconstituted glucagon (GlucaGen; dosed per label) during insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery (first PG increase ≥20 mg/dL after treatment initiation without rescue intravenous glucose). The primary comparison was dasiglucagon vs. placebo; glucagon acted as a reference.ResultsThe median time (95% confidence interval) to PG recovery following SC injection was 10 min (8-12) for dasiglucagon vs. 30 min (20 to -) for placebo (P < .001); the median time for glucagon was 10 min (8-12), which did not include the time taken to reconstitute the lyophilized powder. PG recovery was achieved in all participants in the dasiglucagon and glucagon groups within 20 min of dosing compared to 2 out of 11 patients (18%) with placebo. The most frequent adverse events were nausea and vomiting, as expected with glucagon treatment.ConclusionsConsistent with adult phase 3 trials, dasiglucagon rapidly and effectively restored PG levels following insulin-induced hypoglycemia in children and adolescents with T1DM, with an overall safety profile similar to glucagon.
| S-EPMC8361970 | biostudies-literature
Project description:BACKGROUND:Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. METHODS:Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 ?g glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. RESULTS:Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. CONCLUSION:A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. CLINICAL TRIALS REGISTRATION:NCT03255629.
| S-EPMC7174034 | biostudies-literature
Project description:For more than half a century glucagon has been used as a critical care medicine in the treatment of life-threatening hypoglycemia. It is commercially supplied as a lyophilized powder intended to be solubilized in dilute aqueous hydrochloric acid immediately prior to administration. We have envisioned a "ready-to-use" glucagon as a drug of more immediate and likely use. Through a series of iterative changes in the native sequence we have identified glucagon analogs of appreciably enhanced aqueous solubility at physiological pH, and of chemical stability suitable for routine medicinal use. The superior biophysical properties were achieved in part through adjustment of the isoelectric point by use of a C-terminal Asp-Glu dipeptide. The native glutamines at positions 3, 20 and 24 as well as the methionine at 27 were substituted with amino acids of enhanced chemical stability, as directed by a full alanine scan of the native hormone. Of utmost additional importance was the dramatically enhanced stability of the peptide when Ser16 was substituted with alpha,aminoisobutyric acid (Aib), a substitution that stabilizes peptide secondary structure. The collective set of changes yield glucagon analogs of comparable in vitro and in vivo biological character to native hormone but with biophysical properties much more suitable for clinical use.
| S-EPMC3986664 | biostudies-literature
Project description:BACKGROUND:Severe hypoglycemic events (SHEs) in patients with diabetes are associated with substantial health care costs in the United States (US). Injectable glucagon (IG) is currently available for treatment of severe hypoglycemia but is associated with frequent handling errors. Nasal glucagon (NG) is a novel, easier-to-use treatment that is more often administered successfully. The economic impact of this usability advantage was explored in cost-offset and budget impact analyses for the US setting. METHODS:A health economic model was developed to estimate mean costs per SHE for which treatment was attempted using NG or IG, which differed only in the probability of treatment success, based on a published usability study. The budget impact of NG was projected over 2 years for patients with type 1 diabetes (T1D) and type 2 diabetes treated with basal-bolus insulin (T2D-BB). Epidemiologic and cost data were sourced from the literature and/or fee schedules. RESULTS:Mean costs were $992 lower if NG was used compared with IG per SHE for which a user attempted treatment. NG was estimated to reduce SHE-related spending by $1.1?million and $230?000 over 2 years in 10?000 patients each with T1D and T2D-BB, respectively. Reduced spending resulted from reduced professional emergency services utilization as successful treatment was more likely with NG. CONCLUSIONS:The usability advantage of NG over IG was projected to reduce SHE-related treatment costs in the US setting. NG has the potential to improve hypoglycemia emergency care and reduce SHE-related treatment costs.
| S-EPMC6955465 | biostudies-literature
Project description:Molecular technologies have allowed laboratories to detect and establish the profiles of human cancers by identifying a variety of somatic variants. In order to improve personalized patient care, we have established a next-generation sequencing (NGS) test to screen for somatic variants in primary or advanced cancers. In this study, we describe the laboratory quality management program for NGS testing, and also provide an overview of the somatic variants identified in over 1000 patient samples as well as their implications in clinical practice.Over the past one-and-a-half years, our laboratory received a total of 1028 formalin-fixed, paraffin-embedded (FFPE) tumor tissues, which consisted of non-small-cell lung carcinomas (NSCLCs), colon adenocarcinomas, glioma/glioblastomas, melanomas, breast carcinomas, and other tumor types. During this time period, we implemented a series of quality control (QC) checks that included (1) pre-DNA extraction, (2) DNA quantification, (3) DNA quality, (4) library quantification, (5) post-emulsification PCR, and (6) post-sequencing metrics. At least 10 ng of genomic DNA (gDNA) were used to prepare barcoded libraries using the AmpliSeq CHPv2. Samples were multiplexed and sequenced on Ion Torrent 318 chips using the Ion PGM System. Variants were identified using the Variant Caller Plugin, and annotation and functional predictions were performed using the Golden Helix SVS.A total of 1005 samples passed QC1-3, and following additional library preparation QC checkpoints, 877 samples were sequenced. Samples were classified into two categories: wild-type (127) and positive for somatic variants (750). Somatic variants were classified into clinically actionable (60%) and non-actionable (40%).The use of NGS in routine clinical laboratory practice allowed for the detection of tumor profiles that are essential for the selection of targeted therapies and identification of applicable clinical trials, contributing to the improvement of personalized patient care in oncology.
| S-EPMC5506542 | biostudies-other
Project description:During severe hypoglycemic episodes, people with diabetes depend on others to help with treatment. We compared needle-free nasal glucagon and commercially available injectable glucagon for ease of use by caregivers of people with diabetes and by others in treating simulated episodes of severe hypoglycemia.Sixteen instructed caregivers and 15 noninstructed acquaintances administered nasal and injectable glucagon to manikins, simulating unconscious people with diabetes during severe hypoglycemia episodes.With nasal glucagon, 15 caregivers (94%) and 14 acquaintances (93%) administered a full dose (mean time 0.27 and 0.44?min, respectively). One caregiver and one acquaintance did not administer nasal glucagon because they did not fully depress the plunger on the device. Two caregivers deliberately administered both insulin and nasal glucagon, believing that insulin would also help the patient. With injectable glucagon, eight caregivers (50%) injected glucagon (mean time 1.89?min), but only two (13%) administered the full dose. Three acquaintances (20%) injected a partial dose of injectable glucagon (mean time 2.40?min); none gave a full dose. Errors included injecting diluent only, bending the needle, and injecting with an empty syringe. Two caregivers and one acquaintance injected insulin because they confused insulin with injectable glucagon.More than 90% of participants delivered full doses of nasal glucagon, while 13% and 0% of caregivers and acquaintances delivered full doses of injectable glucagon, indicating that nasal glucagon is easier for nonmedically trained people to administer. Thus, nasal glucagon has the potential to substantially improve treatment for patients experiencing a life-threatening episode of severe hypoglycemia.
| S-EPMC5563859 | biostudies-other
Project description:Thousands of mutations across >50 genes have been implicated in inherited cardiomyopathies. However, options for sequencing this rapidly evolving gene set are limited because many sequencing services and off-the-shelf kits suffer from slow turnaround, inefficient capture of genomic DNA, and high cost. Furthermore, customization of these assays to cover emerging targets that suit individual needs is often expensive and time consuming.We sought to develop a custom high throughput, clinical-grade next-generation sequencing assay for detecting cardiac disease gene mutations with improved accuracy, flexibility, turnaround, and cost.We used double-stranded probes (complementary long padlock probes), an inexpensive and customizable capture technology, to efficiently capture and amplify the entire coding region and flanking intronic and regulatory sequences of 88 genes and 40 microRNAs associated with inherited cardiomyopathies, congenital heart disease, and cardiac development. Multiplexing 11 samples per sequencing run resulted in a mean base pair coverage of 420, of which 97% had >20× coverage and >99% were concordant with known heterozygous single nucleotide polymorphisms. The assay correctly detected germline variants in 24 individuals and revealed several polymorphic regions in miR-499. Total run time was 3 days at an approximate cost of $100 per sample.Accurate, high-throughput detection of mutations across numerous cardiac genes is achievable with complementary long padlock probe technology. Moreover, this format allows facile insertion of additional probes as more cardiomyopathy and congenital heart disease genes are discovered, giving researchers a powerful new tool for DNA mutation detection and discovery.
| S-EPMC4568077 | biostudies-literature
Project description:Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types.One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts.Three hundred forty-six frozen samples were procured in total. WES was performed on 113 samples and RNA-Seq on 72 samples. Successful cell strain, tumor organoid, and/or patient-derived xenograft development was achieved in four samples, including an inoperable pediatric glioma. WES data were used to assess clonal evolution and molecular heterogeneity of tumors in individual patients. Mutational profiles of primary tumors and metastases yielded candidate mediators of metastatic spread and organotropism including CUL9 and PIGM in metastatic ependymoma and ANKRD52 in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates.A next-generation sequencing-based autopsy program in conjunction with a pre-mortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.
| S-EPMC5761727 | biostudies-other
Project description:Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.
| S-EPMC7381310 | biostudies-literature
Project description:Hypoglycemia, the state of abnormally low blood glucose level, is an acute complication of insulin and sulfonylurea therapy in diabetes management. Frequent insulin dosing and boluses during daily diabetes care leads to an increased risk of dangerously low glucose levels, which can cause behavioral and cognitive disturbance, seizure, coma, and even death. This study reports an insulin-responsive glucagon delivery method based on a microneedle (MN)-array patch for the prevention of hypoglycemia. The controlled release of glucagon is achieved in response to elevated insulin concentration by taking advantage of the specific interaction between insulin aptamer and target insulin. Integrating a painless MN-array patch, it is demonstrated that this insulin-triggered glucagon delivery device is able to prevent hypoglycemia following a high-dose insulin injection in a chemically induced type 1 diabetic mouse model.
| S-EPMC5769873 | biostudies-literature