Safety and prescribing recommendations for verapamil in newly diagnosed pediatric type 1 diabetes (T1D): The CLVer experience.

Objectives: To report the safety and side effects associated with taking verapamil for beta-cell preservation in children with newly-diagnosed T1D. Research Design and Methods: Eighty-eight participants aged 8.5 to 17.9 years weighing ≥ 30 kg were randomly assigned to verapamil (N = 47) or placebo (N = 41) within 31 days of T1D diagnosis and followed for 12 months from diagnosis, main CLVer study. Drug dosing was weight-based with incremental increases to full dosage. Side effect monitoring included serial measurements of pulse, blood pressure, liver enzymes, and electrocardiograms (ECGs). At study end, participants were enrolled in an observational extension study (CLVerEx), which is ongoing. No study drug is provided during the extension, but participants may use verapamil if prescribed by their diabetes care team. Results: Overall rates of adverse events were low and comparable between verapamil and placebo groups. There was no difference in the frequency of liver function abnormalities. Three CLVer participants reduced or discontinued medication due to asymptomatic ECG changes. One CLVerEx participant (18 years old), treated with placebo during CLVer, who had not had a monitoring ECG, experienced complete AV block with a severe hypotensive episode 6 weeks after reaching his maximum verapamil dose following an inadvertent double dose on the day of the event. Conclusions: The use of verapamil in youth newly-diagnosed with T1D appears generally safe and well tolerated with appropriate monitoring. We strongly recommend monitoring for potential side effects including an ECG at screening and an additional ECG once full dosage is reached.ClinicalTrials.gov number: NCT04233034.

Use of the Community-Derived Open-Source Automated Insulin Delivery Loop System in Type 2 Diabetes.

Background: No published data are available on the use of the community-derived open-source Loop hybrid closed-loop controller ("Loop") by individuals with type 2 diabetes (T2D). Methods: Through social media postings, we invited individuals with T2D currently using the Loop system to join an observational study. Thirteen responded of whom seven were eligible for the study, were using the Loop algorithm, and provided data. Results: Mean (±standard deviation) age was 61 ± 13 years, and mean body mass index was 31 ± 5 kg/m2. All but one participant were using noninsulin glucose-lowering medications. Self-reported mean hemoglobin A1c decreased from 7.3% ± 1.1% before starting Loop to 6.0% ± 0.5% on Loop. Time in range 70-180 mg/dL increased from 84% to 93%. The amount of time in hypoglycemia was extremely low before and with Loop (time <54 mg/dL was 0.04% ± 0.06% vs. 0.09% ± 0.07%, respectively). No severe hypoglycemia or diabetic ketoacidosis events were reported while using Loop. Conclusion: These data, though limited, suggest that the Loop system is likely to be effective when used by individuals with T2D and should be evaluated in large-scale studies. Clinical Trial Registration numbers: NCT05951569.

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. Objective: To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Interventions: Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. Main Outcomes and Measures: The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Results: Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. Conclusions and Relevance: In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main Outcomes and Measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and Relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Real-World, Patient-Reported and Clinic Data from Individuals with Type 1 Diabetes Using the MiniMed 670G Hybrid Closed-Loop System.

Background: The purpose of this study was to collect 1 year of real-world data from individuals with type 1 diabetes (T1D) initiating the Medtronic 670G hybrid closed-loop insulin delivery system as part of usual care. We sought to expand current knowledge to understand how use of the system impacts patient-reported outcomes, in addition to clinical outcomes, for children and adults with T1D. Methods: Questionnaires were completed by the participant (and/or parent) before initiation of the 670G system (baseline) and at 6 weeks, 6 months, and 12 months from enrollment. Clinical data were obtained at routine clinical visits. Results: Of 132 participants who initiated Auto Mode, 80 completed the 12-month questionnaires while persisting with the system. Nearly all reported receiving adequate training on the 670G. Participant and parent-reported fear of hypoglycemia decreased by 6 and 11 points, respectively, from baseline to 12 months. More than half reported issues with sleep interruption at night due to alarms and 40% did not like frequent exits from Auto Mode. For the subset who had complete continuous glucose monitor data (n = 27), mean percent time in target range (70-180 mg/dL) was 66% at baseline, and 74% and 68% at 6 and 12 months, respectively. Conclusions: With this study, we have captured real-time feedback from patients with T1D who initiated the 670G system and continued to use it over 12 months regarding their experience with the system. This has helped to illuminate both benefits and burdens associated with the first commercially available hybrid closed-loop system.

BMI, physical activity, and breast cancer subtype in white, black, and Sea Island breast cancer survivors.

Higher BMI, lower rates of physical activity (PA), and hormone receptor-negative breast cancer (BC) subtype are associated with poorer BC treatment outcomes. We evaluated the prevalence of high BMI, low PA level, and BC subtype among survivors with white/European American (EA) and African American (AA) ancestry, as well as a distinct subset of AAs with Sea Island/Gullah ancestry (SI). We used the South Carolina Central Cancer Registry to identify 137 (42 EAs, 66 AAs, and 29 SIs) women diagnosed with BC and who were within 6-21 months of diagnosis. We employed linear and logistic regression to investigate associations between BMI, PA, and age at diagnosis by racial/ethnic group. Most participants (82%) were overweight/obese (P=0.46). BMI was highest in younger AAs (P=0.02). CDC PA guidelines (≥150min/week) were met by only 28% of participants. The frequency of estrogen receptor (ER)-negative BC subtype was lower in EAs and SIs than in AAs (P<0.05). This is the first study to identify differences in obesity and PA rates, and BC subtype in EAs, AAs, and SIs. BMI was higher, PA rates were lower, and frequency of ER-negative BC was higher in AAs as compared to EAs and SIs. This study highlights the need to promote lifestyle interventions among BC survivors, with the goal of reducing the likelihood of a BC recurrence. Integrating dietary and PA interventions into ongoing survivorship care is essential. Future research could evaluate potential differential immune responses linked to the frequency of triple negative BC in AAs.

Diffusion Tensor Imaging Connectomics Reveals Preoperative Neural Connectivity Changes in Children with Postsurgical Posterior Fossa Syndrome.

BACKGROUND AND PURPOSE: Posterior fossa syndrome (PFS), characterized by loss of language and other neurological impairments within the immediate postoperative period, occurs in approximately 25% of children who undergo surgical resection of posterior fossa tumors. Diffusion tensor imaging connectomics offer promise for elucidation of pathway-level disruption in neural connectivity of patients with this disorder. We aim to determine differences in pre- and postoperative connectomics between children with PFS and children with mild or no language deficit after surgery. METHODS: Pre- and postoperative diffusion tensor imaging connectomics were applied and compared among patients with PFS, mild deficits, and intact language. RESULTS: A total of 35 patients were included in the study. Twenty-three patients with preoperative data and 24 patients with postoperative data were included in the analysis. Mean ages: PFS-8.5 years, mild-3.1 years, intact language-9.4 years (P = .02). Diagnoses included medulloblastoma (44.1%), pilocytic astrocytoma (28.6%), ependymoma (8.6%), other (11.4%), and unknown (8.6%). Five (21.7%) patients had PFS, 4 (17.4%) had mild deficits, and 14 (60.9%) had intact language. The assortativity coefficient was significantly higher in patients with PFS when compared to patients with mild deficits (P = .023). In the connectometry analyses, decreased connectivity was found involving the corpus callosum, right corticothalamic pathway, and right corticostriatal pathway in patients with PFS when compared to patients with intact language. CONCLUSIONS: Our findings revealed significant differences in preoperative neural connectivity involving the corticothalamic and other pathways among children who did, versus who did not, develop PFS postoperatively. Diffusion tensor imaging connectomics offers a unique opportunity to study the effect of the posterior fossa tumors on cerebello-cerebral networks and provide new insights into the mechanism of the structural plasticity/reorganization after surgery.

Worldwide Organization of Neurocritical Care: Results from the PRINCE Study Part 1.

INTRODUCTION: Neurocritical care focuses on the care of critically ill patients with an acute neurologic disorder and has grown significantly in the past few years. However, there is a lack of data that describe the scope of practice of neurointensivists and epidemiological data on the types of patients and treatments used in neurocritical care units worldwide. To address these issues, we designed a multicenter, international, point-prevalence, cross-sectional, prospective, observational, non-interventional study in the setting of neurocritical care (PRINCE Study). METHODS: In this manuscript, we analyzed data from the initial phase of the study that included registration, hospital, and intensive care unit (ICU) organizations. We present here descriptive statistics to summarize data from the registration case report form. We performed the Kruskal-Wallis test followed by the Dunn procedure to test for differences in practices among world regions. RESULTS: We analyzed information submitted by 257 participating sites from 47 countries. The majority of those sites, 119 (46.3%), were in North America, 44 (17.2%) in Europe, 34 (13.3%) in Asia, 9 (3.5%) in the Middle East, 34 (13.3%) in Latin America, and 14 (5.5%) in Oceania. Most ICUs are from academic institutions (73.4%) located in large urban centers (44% > 1 million inhabitants). We found significant differences in hospital and ICU organization, resource allocation, and use of patient management protocols. The highest nursing/patient ratio was in Oceania (100% 1:1). Dedicated Advanced Practiced Providers are mostly present in North America (73.7%) and are uncommon in Oceania (7.7%) and the Middle East (0%). The presence of dedicated respiratory therapist is common in North America (85%), Middle East (85%), and Latin America (84%) but less common in Europe (26%) and Oceania (7.7%). The presence of dedicated pharmacist is highest in North America (89%) and Oceania (85%) and least common in Latin America (38%). The majority of respondents reported having a dedicated neuro-ICU (67% overall; highest in North America: 82%; and lowest in Oceania: 14%). CONCLUSION: The PRINCE Study results suggest that there is significant variability in the delivery of neurocritical care. The study also shows it is feasible to undertake international collaborations to gather global data about the practice of neurocritical care.

Global Survey of Outcomes of Neurocritical Care Patients: Analysis of the PRINCE Study Part 2.

BACKGROUND: Neurocritical care is devoted to the care of critically ill patients with acute neurological or neurosurgical emergencies. There is limited information regarding epidemiological data, disease characteristics, variability of clinical care, and in-hospital mortality of neurocritically ill patients worldwide. We addressed these issues in the Point PRevalence In Neurocritical CarE (PRINCE) study, a prospective, cross-sectional, observational study. METHODS: We recruited patients from various intensive care units (ICUs) admitted on a pre-specified date, and the investigators recorded specific clinical care activities they performed on the subjects during their first 7 days of admission or discharge (whichever came first) from their ICUs and at hospital discharge. In this manuscript, we analyzed the final data set of the study that included patient admission characteristics, disease type and severity, ICU resources, ICU and hospital length of stay, and in-hospital mortality. We present descriptive statistics to summarize data from the case report form. We tested differences between geographically grouped data using parametric and nonparametric testing as appropriate. We used a multivariable logistic regression model to evaluate factors associated with in-hospital mortality. RESULTS: We analyzed data from 1545 patients admitted to 147 participating sites from 31 countries of which most were from North America (69%, N = 1063). Globally, there was variability in patient characteristics, admission diagnosis, ICU treatment team and resource allocation, and in-hospital mortality. Seventy-three percent of the participating centers were academic, and the most common admitting diagnosis was subarachnoid hemorrhage (13%). The majority of patients were male (59%), a half of whom had at least two comorbidities, and median Glasgow Coma Scale (GCS) of 13. Factors associated with in-hospital mortality included age (OR 1.03; 95% CI, 1.02 to 1.04); lower GCS (OR 1.20; 95% CI, 1.14 to 1.16 for every point reduction in GCS); pupillary reactivity (OR 1.8; 95% CI, 1.09 to 3.23 for bilateral unreactive pupils); admission source (emergency room versus direct admission [OR 2.2; 95% CI, 1.3 to 3.75]; admission from a general ward versus direct admission [OR 5.85; 95% CI, 2.75 to 12.45; and admission from another ICU versus direct admission [OR 3.34; 95% CI, 1.27 to 8.8]); and the absence of a dedicated neurocritical care unit (NCCU) (OR 1.7; 95% CI, 1.04 to 2.47). CONCLUSION: PRINCE is the first study to evaluate care patterns of neurocritical patients worldwide. The data suggest that there is a wide variability in clinical care resources and patient characteristics. Neurological severity of illness and the absence of a dedicated NCCU are independent predictors of in-patient mortality.

Serum-Associated Antibiotic Tolerance in Pediatric Clinical Isolates of Pseudomonas aeruginosa.

BACKGROUND: When grown in human serum, laboratory isolates of Pseudomonas aeruginosa exhibit tolerance to antibiotics at inhibitory concentrations. This phenomenon, known as serum-associated antibiotic tolerance (SAT), could lead to clinical treatment failure of pseudomonal infections. Our purpose in this study was to determine the prevalence and clinical impact of SAT in Pseudomonas isolates in hospitalized children. METHODS: The SAT phenotype was assessed in patients aged <18 years admitted with respiratory or blood cultures positive for P. aeruginosa. The SAT phenotype was a priori defined as a ≥2-log increase in colony-forming units when grown in human serum compared with Luria-Bertani medium in the presence of minocycline or tobramycin. RESULTS: SAT was detected in 29 (64%) patients. Fourteen patients each (34%) had cystic fibrosis (CF) and tracheostomies. Patient demographics and comorbidities did not differ by SAT status. Among CF patients, SAT was associated with longer duration of intravenous antibiotics (10 days vs 5 days; P < .01). CONCLUSIONS: This study establishes that SAT exists in P. aeruginosa from human serum and may be a novel factor that contributes to differences in clinical outcomes. Future research should investigate the mechanisms that contribute to SAT in order to identify novel targets for adjunctive antimicrobial therapies.

Alcohol and Tobacco Use in an Ethnically Diverse Sample of Breast Cancer Patients, Including Sea Island African Americans: Implications for Survivorship.

Background/Objective: Data suggest that modifiable risk factors such as alcohol and tobacco use may increase the risk of breast cancer (BC) recurrence and reduce survival. Female BC mortality in South Carolina is 40% higher among African Americans (AAs) than European Americans (EAs). Given this substantial racial disparity, using a cross-sectional survey design we examined alcohol and tobacco use in an ethnically diverse statewide study of women with recently diagnosed invasive breast cancer. This included a unique South Carolina AA subpopulation, the Sea Islanders (SI), culturally isolated and with the lowest European American genetic admixture of any AA group. Methods: Participants (42 EAs, 66 non-SI AAs, 29 SIs), diagnosed between August 2011 and December 2012, were identified through the South Carolina Central Cancer Registry and interviewed by telephone within 21 months of diagnosis. Self-reported educational status, alcohol consumption and tobacco use were obtained using elements of the Behavior and Risk Factor Surveillance System questionnaire. Results: Alcohol: EAs were approximately twice as likely to consume alcohol (40%) and to be moderate drinkers (29%) than either AA group (consumers: 24% of non-SI AAs, 21% of SIs; moderate drinkers 15 and 10% respectively). Users tended to be younger, significantly among EAs and non-SI AAs, but not SIs, and to have attained more education. Heavy drinking was rare (≤1%) and binge drinking uncommon (≤10%) with no differences by race/ethnicity. Among both AA subgroups but not EAs, alcohol users were six to nine times more likely to have late stage disease (Regional or Distant), statistically significant but with wide confidence intervals. Tobacco: Current cigarette smoking (daily or occasional) was reported by 14% of EAs, 14% of non-SI AAs and 7% of SIs. Smoking was inversely associated with educational attainment. Use of both alcohol and cigarettes was reported by 3-6% of cases. Conclusions: Prevalences of alcohol and cigarette use were similar to those in the general population, with alcohol consumption more common among EAs. Up to half of cases used alcohol and/or tobacco. Given the risks from alcohol for disease recurrence, and implications of smoking for various health outcomes, these utilization rates are of concern.

Determining the Joint Effect of Obesity and Diabetes on All-Cause Mortality and Cardiovascular-Related Mortality following an Ischemic Stroke.

Although obesity and diabetes mellitus, or diabetes, are independently associated with mortality-related events (e.g., all-cause mortality and cardiovascular-related mortality) following an ischemic stroke, little is known about the joint effect of obesity and diabetes on mortality-related events following an ischemic stroke. The aim of this study is to evaluate the joint effect of obesity and diabetes on mortality-related events in subjects with a recent ischemic stroke. Data from the multicenter Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial was analyzed for this study. The joint effect of obesity and diabetes on mortality-related events was estimated via Cox proportional hazards regression models. No difference in the hazard of all-cause mortality following an ischemic stroke was observed between obese subjects with diabetes and underweight/normal-weight subjects without diabetes. In contrast, obese subjects with diabetes had an increased hazard of cardiovascular-related mortality following an ischemic stroke compared with underweight/normal-weight subjects without diabetes. Additionally, there was evidence of an attributable proportion due to interaction as well as evidence of a highly statistically significant interaction on the multiplicative scale for cardiovascular-related mortality. In this clinical trial cohort of ischemic stroke survivors, obesity and diabetes synergistically interacted to increase the hazard of cardiovascular-related mortality.

Determining the joint effect of obesity and diabetes on functional disability at 3-months and on all-cause mortality at 1-year following an ischemic stroke.

BACKGROUND: Obesity and diabetes mellitus, or diabetes, are independently associated with post-ischemic stroke outcomes (e.g., functional disability and all-cause mortality). Although obesity and diabetes are also associated with post-ischemic stroke outcomes, the joint effect of obesity and diabetes on these post-ischemic stroke outcomes has not been explored previously. The purpose of the current study was to explore whether the effect of obesity on post-ischemic stroke outcomes differed by diabetes status in a cohort of acute ischemic stroke subjects with at least a moderate stroke severity. METHODS: Data from the Interventional Management of Stroke (IMS) III clinical trial was analyzed for this post-hoc analysis. A total of 656 subjects were enrolled in IMS III and were followed for one year. The joint effects of obesity and diabetes on functional disability at 3-months and all-cause mortality at 1-year were examined. RESULTS: Of 645 subjects with complete obesity and diabetes information, few were obese (25.74%) or had diabetes (22.64%). Obese subjects with diabetes and non-obese subjects without diabetes had similar odds of functional disability at 3-months following an ischemic stroke (adjusted common odds ratio, 1.038, 95% CI: 0.631, 1.706). For all-cause mortality at 1-year following an ischemic stroke, obese subjects with diabetes had a similar hazard compared with non-obese subjects without diabetes (adjusted hazard ratio, 1.005, 95% CI: 0.559, 1.808). There was insufficient evidence to declare a joint effect between obesity and diabetes on either the multiplicative scale or the additive scale for both outcomes. CONCLUSIONS: In this post-hoc analysis of data from the IMS III clinical trial of acute ischemic stroke patients with at least a moderate stroke severity, there was not sufficient evidence to determine that the effect of obesity differed by diabetes status on post-ischemic stroke outcomes. Additionally, there was not sufficient evidence to determine that either factor was independently associated with all-cause mortality. Future studies could differentiate between metabolically healthy and metabolically unhealthy patients within BMI categories to determine if the effect of obesity on post-stroke outcomes differs by diabetes status.

Early tracheostomy in ventilated stroke patients: Study protocol of the international multicentre randomized trial SETPOINT2 (Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial 2).

BACKGROUND: Tracheostomy is a common procedure in long-term ventilated critical care patients and frequently necessary in those with severe stroke. The optimal timing for tracheostomy is still unknown, and it is controversial whether early tracheostomy impacts upon functional outcome. METHOD: The Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial 2 (SETPOINT2) is a multicentre, prospective, randomized, open-blinded endpoint (PROBE-design) trial. Patients with acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage who are so severely affected that two weeks of ventilation are presumed necessary based on a prediction score are eligible. It is intended to enroll 190 patients per group (n = 380). Patients are randomized to either percutaneous tracheostomy within the first five days after intubation or to ongoing orotracheal intubation with consecutive weaning and extubation and, if the latter failed, to percutaneous tracheostomy from day 10 after intubation. The primary endpoint is functional outcome defined by the modified Rankin Scale (mRS, 0-4 (favorable) vs. 5 + 6 (unfavorable)) after six months; secondary endpoints are mortality and cause of mortality during intensive care unit-stay and within six months from admission, intensive care unit-length of stay, duration of sedation, duration of ventilation and weaning, timing and reasons for withdrawal of life support measures, relevant intracranial pressure rises before and after tracheostomy. CONCLUSION: The necessity and optimal timing of tracheostomy in ventilated stroke patients need to be identified. SETPOINT2 should clarify whether benefits in functional outcome can be achieved by early tracheostomy in these patients.