C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis.

BACKGROUND: Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent ß-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of ß-cell function and metabolic outcomes in new-onset type 1 diabetes. METHODS: 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test. FINDINGS: 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods. INTERPRETATION: Interventions that preserve ß-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials. FUNDING: JDRF and Diabetes UK.

T1dCteGui: A User-Friendly Clinical Trial Enrichment Tool to Optimize T1D Prevention Studies by Leveraging AI/ML Based Synthetic Patient Population.

Whereas islet autoantibodies (AAs) are well-established risk factors for developing type 1 diabetes (T1D), there is a lack of biomarkers endorsed by regulators to enrich clinical trial populations for those at risk of developing T1D. As such, the development of therapies that delay or prevent the onset of T1D remains challenging. To address this drug development need, the Critical Path Institute's T1D Consortium (T1DC) acquired patient-level data from multiple observational studies and used a model-based approach to evaluate the utility of islet AAs as enrichment biomarkers in clinical trials. An accelerated failure time model was developed, discussed in our previous publication, which provided the underlying evidence required to receive a qualification opinion for islet AAs as enrichment biomarkers from the European Medicines Agency (EMA) in March 2022. To further democratize the use of the model for scientists and clinicians, we developed a Clinical Trial Enrichment Graphical User Interface. The interactive tool allows users to specify trial participant characteristics, including the percentage of participants with a specific AA combination. Users can specify ranges for participant baseline age, sex, blood glucose measurement from the 120-minute timepoints of an oral glucose tolerance test, and HbA1c. The tool then applies the model to predict the mean probability of a T1D diagnosis for that trial population and renders the results to the user. To ensure adequate data privacy and to make the tool open-source, a deep learning-based generative model was used to generate a cohort of synthetic subjects that underpins the tool.

Consortium-based approach to receiving an EMA qualification opinion on the use of islet autoantibodies as enrichment biomarkers in type 1 diabetes clinical studies.

The development of medical products that can delay or prevent progression to stage 3 type 1 diabetes faces many challenges. Of note, optimising patient selection for type 1 diabetes prevention clinical trials is hindered by significant patient heterogeneity and a lack of characterisation of the time-varying probability of progression to stage 3 type 1 diabetes in individuals positive for two or more islet autoantibodies. To meet these needs, the Critical Path Institute's Type 1 Diabetes Consortium was launched in 2017 as a pre-competitive public-private partnership between stakeholders from the pharmaceutical industry, patient advocacy groups, philanthropic organisations, clinical researchers, the National Institutes of Health and the Food and Drug Administration. The Type 1 Diabetes Consortium acquired and aggregated data from three longitudinal observational studies, Environmental Determinants of Diabetes in the Young (TEDDY), Diabetes Autoimmunity Study in the Young (DAISY) and TrialNet Pathway to Prevention (TN01), and used analysis subsets of these data to support the model-based qualification of islet autoantibodies as enrichment biomarkers for patient selection in type 1 diabetes prevention trials, including registration studies. The Type 1 Diabetes Consortium has now received a qualification opinion from the European Medicines Agency for the use of these biomarkers, a major success for the field of type 1 diabetes. This endorsement will improve product developers' ability to design clinical trials of agents intended to prevent or delay type 1 diabetes that are reduced in size and/or length, while being adequately powered.

Leveraging Real-World Data for EMA Qualification of a Model-Based Biomarker Tool to Optimize Type-1 Diabetes Prevention Studies.

The development of therapies to prevent or delay the onset of type 1 diabetes (T1D) remains challenging, and there is a lack of qualified biomarkers to identify individuals at risk of developing T1D or to quantify the time-varying risk of conversion to a diagnosis of T1D. To address this drug development need, the T1D Consortium (i) acquired, remapped, integrated, and curated existing patient-level data from relevant observational studies, and (ii) used a model-based approach to evaluate the utility of islet autoantibodies (AAs) against insulin/proinsulin autoantibody, GAD65, IA-2, and ZnT8 as biomarkers to enrich subjects for T1D prevention. The aggregated dataset was used to construct an accelerated failure time model for predicting T1D diagnosis. The model quantifies presence of islet AA permutations as statistically significant predictors of the time-varying probability of conversion to a diagnosis of T1D. Additional sources of variability that greatly improved the accuracy of quantifying the time-varying probability of conversion to a T1D diagnosis included baseline age, sex, blood glucose measurements from the 120-minute timepoints of oral glucose tolerance tests, and hemoglobin A1c. The developed models represented the underlying evidence to qualify islet AAs as enrichment biomarkers through the qualification of novel methodologies for drug development pathway at the European Medicines Agency (EMA). Additionally, the models are intended as the foundation of a fully functioning end-user tool that will allow sponsors to optimize enrichment criteria for clinical trials in T1D prevention studies.

Effective Data Sharing as a Conduit for Advancing Medical Product Development.

INTRODUCTION: Patient-level data sharing has the potential to significantly impact the lives of patients by optimizing and improving the medical product development process. In the product development setting, successful data sharing is defined as data sharing that is actionable and facilitates decision making during the development and review of medical products. This often occurs through the creation of new product development tools or methodologies, such as novel clinical trial design and enrichment strategies, predictive pre-clinical and clinical models, clinical trial simulation tools, biomarkers, and clinical outcomes assessments, and more. METHODS: To be successful, extensive partnerships must be established between all relevant stakeholders, including industry, academia, research institutes and societies, patient-advocacy groups, and governmental agencies, and a neutral third-party convening organization that can provide a pre-competitive space for data sharing to occur. CONCLUSIONS: Data sharing focused on identified regulatory deliverables that improve the medical product development process encounters significant challenges that are not seen with data sharing aimed at advancing clinical decision making and requires the commitment of all stakeholders. Regulatory data sharing challenges and solutions, as well as multiple examples of previous successful data sharing initiatives are presented and discussed in the context of medical product development.

Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report.

On September 27-28, 2018 the Food and Drug Administration (FDA) and the Critical Path Institute's Transplant Therapeutics Consortium convened a public workshop titled "Evidence-Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment." The workshop facilitated cooperative engagement of transplant community stakeholders, including pharmaceutical industry, academic researchers, clinicians, patients, and regulators to discuss methods to advance the development of novel immunosuppressive drugs for use in solid organ transplantation. Day 1 focused on the utility of biomarkers in drug development, with considerations for seeking regulatory endorsement for use in clinical trials. Biomarkers add value to drug development by improving patient selection criteria, safety monitoring, endpoint selection, and more. Regulatory endorsement through the FDA Biomarker Qualification Program encourages the use of biomarkers in drug development by instilling confidence and consistency in biomarker interpretation across trials. Public-private partnerships or consortia allow stakeholders to share expertise, resources, and data in pursuit of biomarker qualification. Biomarkers relevant to pretransplant risk assessment, early posttransplant care, and assessment of immune response, immunosuppressive drug efficacy, and graft function as discussed on day 1 of the workshop are described.

Centruroides sculpturatus envenomation in three adult patients requiring treatment with antivenom.

CONTEXT: Envenomation by Centruroides sculpturatus can manifest with cranial nerve dysfunction and neuromuscular hyperactivity. While these symptoms are most commonly seen in young children, they may also be seen in adults. CASE DETAILS: Three cases of adult patients are presented with grades III & IV scorpion envenomation. They reported symptoms including disconjugate, roving eye movements, and motor involvement. Also reported were hyposmia, difficulty with fine motor movements, and dysgeusia. All were first treated with benzodiazepines with little to no effect. They then received a three vial antivenom bolus with resolution of severe symptoms within 30-60 min. DISCUSSION: Severe Centruroides envenomation can occur in adults as well as children. These three cases demonstrate the usefulness, safety, and effectiveness of antivenom therapy to quickly relieve symptoms in adult patients with grades III & IV envenomations.

Impaired cardiac and peripheral hemodynamic responses to inhaled ß2-agonist in cystic fibrosis.

BACKGROUND: Pulmonary system dysfunction is a hallmark of cystic fibrosis (CF) disease. In addition to impaired cystic fibrosis transmembrane conductance regulator protein, dysfunctional ß2-adrenergic receptors (ß2AR) contribute to low airway function in CF. Recent observations suggest CF may also be associated with impaired cardiac function that is demonstrated by attenuated cardiac output (Q), stroke volume (SV), and cardiac power (CP) at both rest and during exercise. However, ß2AR regulation of cardiac and peripheral vascular tissue, in-vivo, is unknown in CF. We have previously demonstrated that the administration of an inhaled ß-agonist increases SV and Q while also decreasing SVR in healthy individuals. Therefore, we aimed to assess cardiac and peripheral hemodynamic responses to the selective ß2AR agonist albuterol in individuals with CF. METHODS: 18 CF and 30 control (CTL) subjects participated (ages 22 ± 2 versus 27 ± 2 and BSA = 1.7 ± 0.1 versus 1.8 ± 0.0 m(2), both p < 0.05). We assessed the following at baseline and at 30- and 60-minutes following nebulized albuterol (2.5mg diluted in 3.0mL of normal saline) inhalation: 12-lead ECG for HR, manual sphygmomanometry for systolic and diastolic blood pressure (SBP and DBP, respectively), acetylene rebreathe for Q and SV. We calculated MAP = DBP + 1/3(SBP-DBP); systemic vascular resistance (SVR) = (MAP/Q)•80; CP = Q•MAP; stroke work (SW) = SV•MAP; reserve (%change baseline to 30- or 60-minutes). Hemodynamics were indexed to BSA (QI, SVI, SWI, CPI, SVRI). RESULTS: At baseline, CF demonstrated lower SV, SVI, SW, and SWI but higher HR than CTL (p < 0.05); other measures did not differ. At 30-minutes, CF demonstrated higher HR and SVRI, but lower Q, SV, SVI, CP, CPI, SW, and SWI versus CTL (p < 0.05). At 60-minutes, CF demonstrated higher HR, SVR, and SVRI, whereas all cardiac hemodynamics were lower than CTL (p < 0.05). Reserves of CP, SW, and SVR were lower in CF versus CTL at both 30 and 60-minutes (p < 0.05). CONCLUSIONS: Cardiac and peripheral hemodynamic responsiveness to acute ß2AR stimulation via albuterol is attenuated in individuals with CF, suggesting ß2AR located in cardiac and peripheral vascular tissue may be dysfunctional in this population.

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis.

RATIONALE: Despite the demonstrated advantageous systemic changes in response to regular exercise for individuals with cystic fibrosis (CF), exercise is still viewed as an elective rather than a vital component of therapy, and it is likely that these benefits extend to and are partially mediated by exercise-induced changes in ion regulation. OBJECTIVE: We sought to determine if exercise could provide comparable improvements in ion regulation in the CF lung as albuterol, measured using exhaled breath condensate (EBC) collection and nasal potential difference (NPD). METHODS: Fourteen CF (13-42 yrs.) and sixteen healthy (18-42 yrs.) subjects completed a randomized crossover study of albuterol and submaximal exercise. EBC was collected at baseline, 30- and 60-min post-albuterol administration, and at baseline and during three separate 15 min cycling exercise bouts at low, moderate, and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). NPD was performed at 30- and 80-min post albuterol or following moderate and vigorous intensity exercise. RESULTS: CF subjects had lower EBC Cl(-), but no difference in EBC Na(+) at baseline when compared to healthy subjects. EBC Cl(-) increased four-fold with moderate exercise which was similar to that seen 60-min post albuterol administration for CF subjects. Neither exercise nor albuterol altered EBC Na(+). The change in NPD voltage with amiloride (ΔAmil) was greater and there was minimal Cl(-) secretion (ΔTCC) seen at baseline in the CF compared to the healthy subjects. ΔAmil was greater with both albuterol and exercise when compared to baseline within both CF and healthy groups, but there was no significant difference in the ΔTCC response with either treatment. CONCLUSION: Both exercise and albuterol can alter ion regulation increasing Cl(-) secretion to a significant and similar degree in individuals with CF.

Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis.

BACKGROUND: Although exercise is a vital component of the therapy prescribed to individuals with cystic fibrosis (CF), it is not a priority due to a finite amount of treatment time and the view that exercise is not as beneficial as pharmacological treatments by many individuals with CF. We sought to compare the therapeutic benefits of exercise and their prescribed bronchodilator albuterol. METHODS: CF (n = 14) and healthy (n = 16) subjects completed three visits, a baseline screening with VO2 max test and two treatment visits. On the two treatment visits, subjects completed spirometry and diffusing capacity of the lungs for nitric oxide (DLNO) maneuvers either at baseline, 60, and 110 min post-albuterol administration, or at baseline and the midway point of three separate 15 min exercise bouts at low, moderate and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). RESULTS: With moderate exercise the increase in DLNO was double (39 ± 8 vs 15  ± 6% change) and the level of bronchodilation similar (23% change) when compared to 110 min post-albuterol in individuals with CF. During exercise FVC became reduced (-309 ± 66 mL with moderate exercise) and the increase in FEV1 was attenuated (103 ± 39 vs 236 ± 58 mL, exercise vs. albuterol) when compared with the response to albuterol in individuals with CF. Epinephrine (EPI) release increased 39, 72 and 144% change with low, moderate and vigorous intensity exercise respectively for individuals with CF, but this increase was blunted when compared to healthy subjects. CONCLUSION: Our results suggest that moderate intensity exercise is the optimal intensity for individuals with CF, as low intensity exercise increases EPI less than 50% and vigorous intensity exercise is over taxing, such that airflow can be restricted. Although the duration of the beneficial effect is uncertain, exercise can promote greater improvements in gas diffusion and comparable bronchodilation when compared to albuterol.