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AIM/HYPOTHESIS: The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. METHODS: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. RESULTS: A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. CONCLUSIONS/INTERPRETATION: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. FUNDING: This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. REGISTRATION: This systematic review is registered in PROSPERO (CRD42019120083).

In a clinical trial with a survival outcome, an interim analysis is often performed to allow for early stopping for efficacy. If the interim analysis is early in the trial, one might conclude that a new treatment is more effective (compared to e.g.\ a placebo) and stop the trial, whereas the survival curves in the trial arms are not mature for the research question under investigation, for example because the curves are still close to 1 at that time. This means that the decision is based on a small percentage of the events in the long run only; possibly the events of the more frail patients in the trial who may not be representative for the whole group of patients. It may not be sensible to conclude effectiveness based on so little information. Criteria to determine the moment the interim analysis will be performed, should be chosen with care, and include the maturity of the data at the time of the interim analysis. Here, the expected survival rates at the interim analysis play a role. In this paper we will derive the asymptotic distribution of the Kaplan-Meier curves at the (random) moment the interim analysis will be performed for a one and two arm clinical trial. Based on this distribution, an interval in which the Kaplan Meier curves will fall into (with probability 95\%) is derived and could be used to plan the moment of the interim analysis in the design stage of the trial, so before the trial starts., Comment: 21 pages, 2 figures, 3 tables

Aim/hypothesis: The physiological counterregulatory response to hypoglycaemia is reportedly hierarchically organized, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To more accurately compare thresholds for activation of these responses between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. Methods: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using methods for interval censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% confidence interval of the mean baseline measurement or euglycaemic control clamp. Results: A total of 63 articles were included. Compared to non-diabetic controls, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 (3.2-4.2) vs. 3.4 (2.8-3.9 mmol/l), noradrenaline (3.2 (3.2-3.7) vs. 3.0 (2.8-3.1) mmol/l), cortisol (3.5 (3.2-4.2) mmol/l vs. 2.8 (2.8-3.4) mmol/l), and growth hormone (3.8 (3.3-3.8) vs. 3.2 (3.0-3.3) mmol/l) all occurred at lower glucose levels in people with than in those without diabetes (all p ≤ 0.01). Similarly, although both autonomic (3.4 (3.4-3.4) vs. 3.0 (2.8-3.4) mmol/l) and neuroglycopenic (3.4 (2.8-∞ vs. 3.0 (3.0-3.1) mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. Conclusions/interpretation: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia.

Additional file 1: Estimated effects of ICPT as compared to CAU for completers (ICPT N = 38, CAU N = 21)

Supplemental material, 180914_WEBAPPENDIX_Sample_size_for_cRCT_stepped_wedge_trials_with_more_than_2_levels for Sample size calculation for stepped-wedge cluster-randomized trials with more than two levels of clustering by Steven Teerenstra, Monica Taljaard, Anja Haenen, Anita Huis, Femke Atsma, Laura Rodwell and Marlies Hulscher in Clinical Trials

Item does not contain fulltext AIMS: The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. METHODS: The study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes - i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole - were retrieved from the Dutch Medicines Regulatory Authority. RESULTS: In most studies, the intrasubject variability in total and peak drug exposure was comparable for the brand-name [in the range 0.01-0.24 for area under the concentration-time curve (AUCt ) and 0.02-0.29 for peak plasma concentration (Cmax ) on a log scale] and generic (0.01-0.23 for AUCt and 0.08-0.33 for Cmax ) drugs, and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUCt and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction could be considered negligible (-0.069 to 0.047 for AUCt and -0.091 to 0.02 for Cmax ). CONCLUSION: In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name to a generic drug is comparable with that seen following repeated administration of the brand-name drug in the patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation-dependent variation in exposure is observed upon switching. Thus, our data support that, for the medicines that were included in the present investigation, from a clinical pharmacological perspective, the benefit-risk balance of a generic drug is comparable with that of the brand-name drug.

Mean scores and standard deviation of the outcome domains per group at baseline (T0), halfway (T1) and post treatment (T2) (DOCX 29 kb)

Regression coefficient table- Regression coefficients for the maximum likelihood model and the models built in accordance with the three winning strategies. (DOCX 15Â kb)

Data summary table- A summary of the predictor information in the four DVT data sets. (DOCX 15Â kb)

Calibration plots- Calibration plots of models developed in the Full Oudega data using the winning strategies, assessed in the Toll validation data. (DOCX 188Â kb)

Pubmed Search strategy. (DOCX 16 kb)

Calibration plots- Calibration plots of models developed in the Full Oudega data using the winning strategies, assessed in the Toll validation data. (DOCX 188Â kb)

Regression coefficient table- Regression coefficients for the maximum likelihood model and the models built in accordance with the three winning strategies. (DOCX 15Â kb)

SPIRIT checklist. (DOC 122 kb)

SPIRIT checklist. (DOC 122 kb)