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New PID-algorithm for automated glucose clamps

Introduction

The euglycemic, hyperinsulinemic glucose clamp is the gold standard for the determination of pharmacokinetic and pharmacodynamic (PK/PD) effects of new anti-diabetic drugs, in particular insulins. In a typical glucose clamp experiment, a drug-induced decline in blood glucose (BG) concentrations is prevented by infusing glucose at a variable rate, so that BG is "clamped" at a pre-determined target level.

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Topics: Clinical Trials in Diabetes, About Profil, Diabetes Technology

Posted by Dr. Carsten Benesch on Aug 21, 2019 5:19:00 PM
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The new European Medical Device Regulation (MDR)

Introduction

The actual Medical Device Directive (MDD) 93/42/EEC [1]and the Active Implantable Medical Device Directive (AIMDD) 90/385/ECC [2]are the basic directives for all kinds of medical devices in Europe. These directives are mandatory for all member states and have to be put into national legislation by the national parliaments within a given time limit. It is not allowed to reduce or change the requirements of the directive but the parliaments can implement additional requirements like the German “Medizinprodukteberater” (consultant for medical devices) in §31 of the German medical device law. 

 

In contrast to the Medical Device Directive the Medical Device Regulation (MDR) [3]comes directly from the European Commission in Brussels without any approval by the national parliaments and has to be applied as European, supranational law within a given time limit. Additional national requirements resolved by the national parliaments are possible.

One of the reasons for the new MDR was the PIP-scandal: One manufacturer used the cheaper industrial silicon for breast implants instead of the ultra-pure medical silicon. Once this scandal had been made known publicly the Commission decided to tighten up the directive to prevent this kind of criminal process.

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Topics: Clinical Trial Methods

Posted by Dr. Carsten Benesch on Aug 2, 2018 5:12:00 PM
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Advanced precision of Continuous Whole Blood Glucose concentration measurements

Continuous Glucose Concentration Measurement

A continuous glucose monitor (CGM) is a sensor that automatically determines the blood glucose concentration at regular intervals (quasi continuous). Typical intervals range from 1 to 15 minutes which equals 60 to 4 glucose values per minute. The blood glucose can be measured directly in the veins (invasive sensors or intra venous (iv)-sensors) or in other body compartments like subcutaneous tissue, tear fluid, saliva (minimal invasive sensors). The most common and commercial available CGMs measure the interstitial glucose concentration and convert the obtained interstitial glucose values to blood glucose values by a suitable calibration.

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Topics: The Science behind Diabetes, Clinical Trials in Diabetes

Posted by Dr. Carsten Benesch on Jan 23, 2018 5:17:00 PM
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Minimal Blood Loss with Automated Glucose Clamps: A new configuration of ClampArt

Glucose Clamps

The euglycemic, hyperinsulinemic glucose clamp is the gold standard for the determination of pharmacokinetic and pharmacodynamic (PK/PD) effects of (new) anti-diabetic drugs, in particular insulins. In a typical glucose clamp experiment, a drug-induced decline in blood glucose (BG) concentrations is prevented by infusing glucose at a variable rate, so that BG is "clamped" at a pre-determined target level (TL).

Glucose clamps can be done either manually or in an automated fashion. In manual clamps the investigator performs BG measurements and manually adjusts glucose infusion rates (GIR) every 3–10 minutes, whereas in automated clamps, a device measures BG continuously and adapts GIR every minute according to an implemented algorithm. While modern devices such as ClampArt® have improved the quality of continuous BG-measurements and the accuracy of glucose delivery, they still need a relatively high amount of blood (about 2 ml/hour) for their continuous BG measurements. This blood loss is a major challenge in particular for studies with ultra-long acting basal insulins requiring multiple clamps with duration of up to 48 hours post-dosing in one individual.

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Topics: The Science behind Diabetes, Clinical Trials in Diabetes, About Profil

Posted by Dr. Carsten Benesch on Oct 4, 2017 4:52:00 PM
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Error Grid Analysis

The performance of blood glucose (BG) meter can be described by analytical accuracy or clinical accuracy. Analytical accuracy describes the difference between BG values from BG meter being evaluated and BG values obtained with a reference method. A typical tool for analytical accuracy is linear regression and typical measures include the coefficient of correlation (precision and bias) and percentage deviations. These measures are unsuitable to describe clinical accuracy as they cannot identify important outliers and the clinical consequence of treatment decisions based on BG meters with percentage deviations strongly depends on the BG level. While analytical accuracy is a quantitative method, clinical accuracy is a qualitative method for describing BG meter accuracy. Results of treatment decisions were judged based on differences between the BG meter values and the true BG value. The widely accepted tool for clinical accuracy is the error grid analysis.

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Topics: Clinical Trials in Diabetes, About Profil

Posted by Dr. Carsten Benesch on Jul 27, 2017 5:05:00 PM
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A different design of Glucose Clamps: Fixed Rate of Blood Glucose Change rather than Fixed Blood Glucose Levels

Glucose Clamps

The euglycemic, hyperinsulinemic glucose clamp is the gold standard for the determination of pharmacokinetic and pharmacodynamic (PK/PD) effects of (new) anti-diabetic drugs, in particular insulins. In a typical glucose clamp experiment, a drug-induced decline in blood glucose (BG) concentrations is prevented by infusing glucose with a variable glucose infusion rates (GIR) to keep blood glucose concentrations (BG) as closely as possible to a pre-defined target level.

Thus, the glucose clamp is designed as a closed-loop system where BG is measured frequently and the changes in BG and deviation of BG from the target level are the major factors for determining glucose infusion rates.

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Topics: Clinical Trials in Diabetes, About Profil

Posted by Dr. Carsten Benesch on Jun 13, 2017 4:27:00 PM
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Improved Algorithm for Automated Glucose Clamps

What is Glucose Clamping

The glucose clamp is a method for the determination of pharmacokinetic and pharmacodynamic (PK/PD) effects of anti-diabetic drugs (e.g. insulin) where the blood glucose (BG) concentration lowering effect is antagonized by variable glucose infusion rates (GIRs). Any device used for automated glucose clamps consists of a glucose sensor and a glucose infusion pump as well as an appropriate algorithm that calculates the amount of glucose solution that has to be infused to keep the blood glucose level at a pre-defined target level. In contrast to manual techniques automated glucose clamps (e.g. using the Biostator) offer the advantage of a bias-free assessment of the pharmacodynamic properties of blood-glucose lowering agents and a minute-by-minute adaptation of glucose infusion rates thereby keeping blood glucose concentrations very close to the clamp target level. However, the Biostator algorithm leads to pronounced oscillations of both BG and GIR requiring mathematical smoothing procedures for the determination of time-related parameters. As ClampArt, our novel automated clamp device, offers the option to modify the clamp algorithm we compared the unmodified Biostator algorithm (UBA) and a potentially improved clamp algorithm (ICA) regarding GIR/BG oscillations and clamp quality.

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Topics: Clinical Trials in Diabetes, About Profil

Posted by Dr. Carsten Benesch on Jan 10, 2017 5:30:00 PM
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Improved Automated Glucose Clamps with ClampArt

Glucose Clamps

The pharmacokinetic/pharmacodynamic (PK/PD) effects of anti-diabetic drugs are usually characterized in glucose clamp experiments where variable glucose infusion rates (GIR) keep blood glucose concentrations (BG) as closely as possible to a pre-defined target level. The metabolic effect of the investigated anti-diabetic drug is then characterized by the time course of the GIR. For a high glucose clamp quality low BG- und GIR-variability are desirable. In automated glucose clamps the GIR is usually calculated every minute by an implemented algorithm such as the Biostator algorithm published in 1982. This algorithm is crucial for good clamp quality and an improved algorithms leads directly to improved clamp quality.

For ClampArt, our CE-marked state-of-the-art glucose clamp device, we optimized the implemented algorithm to reduce the oscillations of both BG and GIR.

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Topics: About Profil

Posted by Dr. Carsten Benesch on Aug 11, 2015 2:00:00 PM
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Great Progress in Development of an Artificial Pancreas

The EU-funded AP@home Project

The aim of this project was the development of a wearable artificial pancreas that automatically regulates insulin delivery, enabling patients with diabetes to live a close to normal life. The EU-funded AP@home project has developed a prototype to reduce treatment burden in daily life in patients with diabetes. The next step is to develop this prototype system into a product. The AP@home project was funded through the 7th Framework Programme. It started in 2010 and has just come to an end. Universities and companies in Germany, UK, the Netherlands, France, Austria, Italy and Switzerland participated in the project (www.apathome.eu).

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Posted by Dr. Carsten Benesch on Jul 9, 2015 1:14:00 PM
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