Participants and recruitment; inclusion criteria

This study is designed as an open-label multicentre randomised controlled trial with two parallel groups including a total of 372 female patients (n=186 with rt-CGM, n=186 with SMBG) with a recent diagnosis of GDM. Diagnosis of GDM (ie, diabetes first diagnosed in the second and third trimester and not clearly type 1 or type 2 diabetes20) is made in accordance with the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria after 24+0 weeks of gestation by a 2 hours 75 g OGTT.21 The study will be conducted at five academic hospitals in Austria, Switzerland, Sweden and Germany. All pregnant women (aged between 18 and 55 years) will be consecutively recruited after diagnosis of GDM between 24+0 and 31+6 weeks of gestation among women visiting the pregnancy outpatient departments (Division of Obstetrics and feto-maternal Medicine, Medical University of Vienna, Austria; Division of Obstetrics, University Hospital Basel, Switzerland; Department of Obstetrics, Charité‐Universitätsmedizin Berlin, Germany) or the diabetes outpatient departments (Division of Endocrinology and Metabolic Diseases at the Heinrich Heine University, Düsseldorf, Germany; Department of Medicine, University Hospital, Örebro, Sweden).

Exclusion criteria

Overt diabetes (ie, pregestationally known type 1 or type 2 diabetes or fasting plasma glucose during the OGTT ≥126 mg/dL (7.0 mmol/L) or HbA1c≥6.5% (44 mmol/L) or 2 hours post-load OGTT levels ≥200 mg/dL (11.1 mmol/L) assessed before 24+0 weeks of gestation, whereby results need to be confirmed by repeated testing in the absence of unequivocal hyperglycaemia according to the American Diabetes Association (ADA) standards20), history of bariatric surgery or other surgeries that induce malabsorption, long-term use (>2 weeks) of systemic steroids prior to enrolment, multiple pregnancy, patients already using glucose lowering medications (metformin or insulin) before study entry, fetal growth restriction due to placental dysfunction at study entry, inpatient psychiatric treatment up to 1 year before enrolment, participation in this study in previous pregnancy.

Study visits during pregnancy

A flow diagram of the study visits is provided in figure 1. A broad risk evaluation will be performed in participating women at the initial contact (V1) including: evaluation of maternal age, parity, history of GDM in previous pregnancies, detailed family history, ethnicity, preconceptional diseases, obstetric history. Height (stadiometer measured to the nearest centimetre) and actual weight (calibrated scales, light indoor clothing) will be additionally assessed. Moreover, an evaluation of preconceptional weight (self-reported) and body mass index (BMI) as well as measurement of blood pressure will be performed. All patients receive medical advice for nutrition (isocaloric diet containing 40%–50% carbohydrates, 20% proteins and 30%–35% fat, divided into three meals and three snacks) and regular physical exercising for 30 min per day following international recommendations. In addition, participants are advised on capillary blood glucose measurement (fasting as well as 1 hour after starting each meal) at the initial visit (V1). Randomisation will be done after a run-in period of 6–8 days when patients get used to SMBG (V2). The third visit (V3) will be scheduled 8–10 days after V2 and further follow-up visits every 2 weeks (ie, 12–16 days after each visit). HbA1c and glycosylated fibronectin will be assessed at V2 as well as at the first visit between 36+0 and 38+6 weeks of gestation (12 mL, non-fasting state) (V4). Detailed fetal ultrasound examinations, a detailed examination of dietary intake as well as a blinded CGM (control group only) will be performed at V2 and V4. Body weight change and use of glucose lowering medications (amount of insulin units) will be examined at every visit. At every follow-up visit, glucose measurements (SMBG or rt-CGM) and routine ultrasound examinations (fetal biometry and umbilical artery doppler) will be evaluated by the medical staff and all patients will be treated according to the standard of care for patients with GDM. This includes lifestyle modification and insulin therapy if recommended thresholds are exceeded. Both groups will be treated to be in the target range between 65 and 140 mg/dL (3.6 to 7.8 mmol/L) with at least 8 hours fasting glucose levels equal or below 95 mg/dL (5.3 mmol/L) and 1 hour postprandial glucose measurements equal or below 140 mg/dL (7.8 mmol/L) in accordance with the CONCEPTT study16 and the ADA recommendations,22 respectively. Intermediate acting neutral protamine Hagedorn (NPH) insulin is started in the evening if ≥2 measurements of fasting glucose are equal or above 95 mg/dL (5.3 mmol/L) in a period of 1 week and rapid acting insulin analogues (Aspart or Lispro) if ≥2 measurements of 1 hour postprandial glucose (either after breakfast, lunch or dinner) are equal or above 140 mg/dL (7.8 mmol/L) in a period of 1 week. NPH is started with 6–10 IU and increased by 4 IU (or in case of higher doses, ie, >25 IU by 20%) and rapid acting insulin (bolus insulin) is started with 2–4 IU and increased by 2–4 IU if thresholds are not achieved within 3 days. Long-acting insulin analogues such as glargine (U100/U300) or detemir can be used as an alternative to NPH. Patients are trained on insulin management and titration according to their glucose levels. Metformin can be used according to local practice guidelines (recommended in Sweden but not in Austria, Germany or Switzerland as first-line pharmacological intervention).

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Figure 1

Patient flow diagram. CGM, continuous glucose monitoring; FSCTT, fetal subcutanous tissue thickness; FFQ, food frequency questionnaire; GDM, gestational diabetes mellitus; IPAQ, international physical activity questionnaire; PPAQ, pregnancy physical activity questionnaire; RT-CGM, real-time CGM; SF-36, short form 36; SMBG, self-monitored bloodglucose.

Study visits postpartum

Cord blood will be sampled and stored (at −80°C) immediately after delivery (VPP0). A postpartum examination will be scheduled within 48 hours after delivery (VPP1) for assessment of neonatal parameters and maternal HbA1c and glycosylated fibronectin (12 mL, non-fasting state), as well as between 8 and 16 weeks after delivery (VPP2) in all patients for a detailed re-examination of glucose homeostasis postpartum (including lifestyle and dietary pattern as well as HbA1c, glycosylated fibronectin as well as a blinded CGM for 10 days and an OGTT to assess the presence of prediabetic conditions after pregnancy with GDM). The postpartum OGTT is further used to provide estimates of insulin sensitivity, β-cell function and hepatic insulin extraction, the major physiological components of impaired glucose tolerance.

Randomisation

Participants will be randomised to either treatment (rt-CGM augmented glucose monitoring) or control group (routine care SMBG) in a 1:1 ratio. The minimisation method23 with a 0.85 assignment probability will be used to minimise the imbalance between the groups according to week of gestation at study entry, that is, at V1 (three strata: 24+0 to 25+6, 26+0 to 27+6, 28+0 to 29+6, 30+0 to 31+6), previous pregnancy with GDM (two strata: yes or no) and preconceptional overweight/obesity status with three strata: (1) normal weight (ie, BMI below 25.0 kg/m²); (2) overweight (BMI 25.0–29.9 kg/m²); (3) obesity (BMI equal or above 30.0 kg/m²). Randomisation will be performed at the second study visit (V2) by using a randomisation software provided by the Medical University of Vienna.

Intervention

Patients randomised to the intervention group will be equipped with a rt-CGM sensor (Dexcom G6 sensor, a small flexible device that records interstitial glucose levels every 5 min) at V2. The sensor will be inserted into the subcutaneous tissue of the anterior abdominal wall (if this location is not tolerated by the pregnant patients, the upper buttock or posterior upper arm may be used instead). Additionally, patients will be advised to record capillary blood glucose values if glucose alerts or readings do not match with symptoms or expectations. Participants will be educated on how to exchange the sensor (has to be exchanged every ten days) and will be equipped with a real-time CGM monitor and instructed in its use. The monitor provides the user with information about current glucose levels and notifies the patient before her upper or lower glucose threshold are reached and when glucose levels change rapidly. All patients in the intervention group will be specially trained in the use of the system. As an alternative to the real-time monitor, the patients’ smartphone with an anonymised access to the CLARITY mobile app can be used (for details, see the Intervention: device description section).

Intervention: device description

The Dexcom G6 intended use is for the management of diabetes in persons aged 2 years and older. The Dexcom G6 System is intended to replace fingerstick blood glucose testing for diabetes treatment decisions. Interpretation of the Dexcom G6 System results should be based on the glucose trends and several sequential readings over time. The Dexcom G6 System also aids in the detection of episodes of hyperglycaemia and hypoglycaemia, facilitating both acute and long-term therapy adjustments. The Dexcom G6 System can be used alone or in conjunction with digitally connected medical devices for the purpose of managing diabetes.

The system consists of a sensor, transmitter, receiver and mobile app. The sensor is a small, flexible wire inserted into subcutaneous tissue where it converts glucose into electrical current. The sensor incorporates an interferent layer that minimises the effect of potential electroactive interferents, such as acetaminophen, by preventing it from reaching the sensor wire surface. The benefit of this interferent layer in blocking the effects of acetaminophen prevents falsely high glucose readings. Thus, users may ingest acetaminophen while wearing the G6 CGM system. The transmitter, which is connected to the sensor and worn on the body, samples the electrical current produced by the sensor and converts the measurement into a glucose reading using an onboard algorithm. The receiver and/or the app displays the glucose reading along with a rate of change arrow and a trend graph. Additionally, the receiver and/or app issues alarms and alerts to notify the patient of glucose level changes and other important system conditions. Also, alarms will be provided if the receiver detects loss of connection to the sensor. The app provides the additional capability to share data with ‘followers’ using the Dexcom Share service. The receiver can be put into a blinded mode using CLARITY software. In this mode, users are unable to see the CGM data or receive CGM alerts.

CGM Ancillary Devices Dexcom CLARITY is an accessory for users of the Dexcom CGM system. It is a software programme that allows the transfer of glucose data from the CGM system to Dexcom remote servers for data management to allow the use of the CGM data by the user and study clinicians. Target ranges of 65 to 140 mg/dL (3.6 to 7.8 mmol/L) will be set and the patients will be introduced in the use of alarm settings. Both participants and study sites will use CLARITY to transfer glucose data between user and study site, whether CGM is used in blinded or real-time mode. A CLARITY mobile app can be used for a retrospective review of glucose data on the smart device and can also be set up to allow receipt of push notifications of CGM data facilitating weekly data review. For all patients (intervention and control group), an anonymised CLARITY account will be created by using a sequential study number which is allocated at randomisation (sex will be female and birth date for each account will be set to 1 January 1990 for all accounts). CLARITY also provides metrics to check for patient compliance.

Intervention: study proceedings

• For participants who have a supported phone, the G6 CGM app will be installed on participant’s smartphone.

• An anonymised CLARITY mobile account will be set up and linked to the research site.

• Participants will use CGM data for their diabetes management.

• A high alert threshold will be set at 140 mg/dL (7.8 mmol/L). Low alert threshold and urgent low soon alerts will be turned off. If participants require insulin, the low alert will be turned on and the threshold set at 65 mg/dL (3.6 mmol/L). In addition, the urgent low alert (55 mg/dL (3.1 mmol/L)), the urgent low soon alert (when glucose levels are falling fast and will be below 55 mg/dL (3.1 mmol/L) in less than 20 min) as well as alerts for rise and fall rate (3 mg/dL (0.17 mmol/L)) in addition to alerts for signal loss and no readings for more than 20 min will be enabled.

• Participants with applicable smartphones may have CLARITY push notifications on the CLARITY mobile app about weekly time in range comparison enabled during the study.

• For app users, the ‘Share and Follow’ functionality will be discussed and encouraged (ie, the study participants are able to invite followers to review their glucose levels).

• For participants using the receiver only, the receiver will be downloaded into the CLARITY clinic account at each visit.

• For participants using real-time CGM data summary will be downloaded for documentation at V3 and V4 (between 36+0 and 38+6) as well as after delivery (VPP1).

• The research team will review the CGM in CLARITY to inform lifestyle and therapy recommendations.

• The Dexcom G6 system does not require calibration during the study period.

Control group

The participants of the control group will perform self-monitored blood glucose testing with a study-provided blood glucose metre, including testing supplies. They will perform capillary blood glucose monitoring as routinely used for patients with GDM, that is, at least four capillary blood glucose values daily including measurements in a fasting state as well as 1 hour after starting each meal by using a routinely available blood glucose measurement device. The study participants will keep a logbook of their glucose values, which will be reviewed by clinicians from the study team at each visit and used for lifestyle and dietary recommendations as is routinely done in clinical practice. From V2 to V3 as well as once for ten days between gestational week 36+0 and 38+6, the control group receive blinded CGM; neither patients nor the treating medical staff will have access to the data recorded by the CGM sensor at this point in time. Instead, patients will control blood glucose levels based on SMBG, as is the routine procedure in current GDM treatment. Otherwise, the control group will receive the same study assessments as the intervention group. The blinded CGM will be removed and returned to Dexcom after the 10 days wear period after CGM data are uploaded to CLARITY by an unblinded investigator who must not communicate about the results with patients or medical staff.

Each participant of the control group will be assigned a study blood glucose metre to measure and store their blood glucose values during the study. Therefore, the Contour Next One system will be used. The metre has CE Mark clearance and is commercially available in Europe. Participants will receive an ample supply of metre test materials based on quantities routinely used. A commercially available desktop software (Diabass Pro) used in conjunction with Contour Next One system glucose metre for blood glucose monitoring will be used for downloading the metre data by the sites at V3 and V4 after checking that dates and times are correct.

Blood glucose metres used by the control group will be assessed to establish frequency of testing (overall and per week) as well as percentage of days with less than four measurements per day.

Analyses of CGM data

Rt-CGM data allow a detailed examination of the percentage of time in which glucose levels are in target range (time in target) (65–140 mg/dL (3.6–7.8 mmol/L)), hyperglycaemic episodes (glucose ≥140 mg/dL (7.8 mmol/L)) as well as mild (<65 mg/dL (3.6 mmol/L)), moderate (≤54 mg/dL (3.0 mmol/L)) or severe hypoglycaemic episodes (requiring third party assistance) and their duration. To this purpose, several indices of the glucose control quality will be calculated, such as Glycaemic Risk Assessment Diabetes Equation some indices of hypoglycaemia and hyperglycaemia, such as the High Blood Glucose Index (HBGI) and Low Blood Glucose Index, and indices assessing the risk associated to both low and high glycaemic values, such as Index of Glycaemic Control and Average Daily Risk Range. Glycaemic variability will also be assessed, which can be quantified by SD of the CGM data, or by more sophisticated indices, such as Mean Amplitude Glucose Excursions, Continuous Overlapping Net Glycaemic Action, Lability Index,24 25 as well as further indices that we developed internally, such as the Shape Index.26 These will be compared between real-time CGM users and controls (ie, from data obtained during the blinded CGM wear).

Assessment of dietary patterns

Dietary patterns will be assessed in all patients at V1, VPP1 and VPP2 via a published and validated Food Frequency Questionnaire (FFQ) proposed by the German Robert Koch Institute.27 It was also previously used for the German DEGS project (Studie zur Gesundheit Erwachsener in Deutschland) (www.degs-studie.de). Information from the FFQ will be analysed quantitatively or summarised by eating scores proposed in the literature (such as the Healthy Eating Index 2010 or Alternate Healthy Eating Index 2010) reflecting diet quality based on actual guidelines.28 29 In addition, all patients will be advised to conduct a nutritional protocol (7 days) from V2 to V3 as well as once at V4 (between 36+0 and 38+6 weeks of gestation). In a subgroup (only study site Vienna), dietary intake will also be assessed by performing 24 hours recalls by trained interviewers at V2, V4 and post partum (VPP2): one face-to-face interview (approx. 1 hour) and the others as telephone interviews (approx. 30 min) during which data are entered simultaneously in GloboDiet. GloboDiet is a computerised programme which was developed by the International Agency for Cancer Research within the framework of the European Prospective Investigation into Cancer and Nutrition Study for the conduction of harmonised and standardised 24 hours recalls.30 This open-ended software was used in numerous previous studies and was validated within the European Food Consumption Validation project.31–33 In brief, GloboDiet is an interview-based dietary assessment instrument that allows obtaining a very detailed description and quantification of foods, recipes and supplements consumed in the course of the preceding day and thus standardising data within and between countries. Probing questions and entering consumed foods in chronological order support the respondent’s memory. The standardised structure prescribes—on the food group level—possibilities of description and quantification of food items to choose from. Quantification of consumed foods is supported by the GloboDiet picture book that comprises coloured photographs of foods in different portion sizes, photographs of familiar household measures and schematic displays of forms (eg, bread, cake). The software provides an automatic coding of food items and recipe ingredients as well as a rough calculation of nutrient intake meant for quality control of the interview. GloboDiet is characterised by the obtained standardisation of dietary data within Europe, a large number of available foods and recipes, and a very detailed description of consumed foods. Currently, GloboDiet is one of the few dietary instruments providing comparable nutritional data within Europe. After finalisation of the interviews, GloboDiet will be linked to the local nutrition database—the Bundeslebenmittelschlüssel (BLS) enhanced by the Austrian Nutrition Table (Österreichische Nährwerttabelle, ÖNWT), containing typical Austrian foods and recipes—allowing analyses on food ingredients level and to conduct precise energy and risk assessment.

Assessment of physical activity

Physical activity will be assessed at V1, VPP1 and VPP2 via the International Physical Activity Questionnaire (IPAQ, long form). The IPAQ represents a well-accepted, validated instrument for monitoring population levels of physical activity in different settings and countries.34 It will be analysed via published guidelines for data processing and analysis at the IPAQ homepage Guidelines for data processing and analysis of the IPAQ35: in short, collected data will be summarised as median metabolic equivalent of task minutes per week, representing a continuous score for walking, moderate intensity activities, vigorous intensity activities and total activities, as recommended. In addition, the Pregnancy Physical Activity Questionnaire will be performed to capture information on physical activity participation and sedentary behaviour during pregnancy.36

Assessment of maternal intramyocellular and intrahepatocellular lipids

Intramyocellular (IMCL), and intrahepatocellular lipid contents (HCL) will be measured by using proton magnetic resonance spectroscopy (¹H MRS) in a subgroup of 40 patients (20 rt-CGM, 20 SMBG) at V3 and after delivery (VPP2) according to previously described methods.37–39 The participants will be studied in supine position within a 3.0 Tesla whole-body magnet (Siemens or Philips). MRS is a non-invasive technique to evaluate tissue-specific metabolism and was shown to be safe and well tolerated by pregnant women in previous studies.40 41 Patients will be positioned with a left pelvic tilt to avoid pressure on the inferior vena cava according to other studies in pregnancy.41 For IMCL measurements, the calf muscle (right leg) will be positioned in a quadrature bird cage ¹H volume coil. A circular ¹H surface coil will be positioned over the liver for HCL measurement.

Fetal biometry

Parameters of fetal anthropometry as determined by ultrasound as well as neonatal data including length, weight, gestational age at delivery will be included in the final analysis. A detailed fetal ultrasound examination will be performed at V2 and repeated at V4 (between 36+0 to 38+6 weeks of gestation) to assess fetal growth parameters including head circumference, biparietal diameter and abdominal circumference and abdominal fat thickness, femur length (measured and expressed as standardised gestational age related fetal growth percentiles42), amnion fluid index as well as size and location of the placenta and fetal subcutaneous tissue thickness. Moreover, fetal growth symmetry will be assessed by fetal head to abdomen circumference ratio and fetal doppler measurements (mainly umbilical artery and middle cerebral artery43 and ductus venosus). Furthermore, fetal hepatic size (all hepatic diameters, such as area and volume) and umbilical venous volume flow and an echocardiography of the fetus will be performed in a subgroup (only study site Vienna).

Obstetric outcome

Obstetric outcome (caesarean section, birth injury, preterm birth before 37 completed weeks of gestation) stillbirth, small for gestational age (birth weight <10 th pctl), LGA infant (birth weight >90 th pctl), shoulder dystocia, admitted to neonatal intensive care unit umbilical cord blood pH, Apgar score) will be recorded immediately after delivery. Length of hospital stay for mothers and offspring as well the duration of high-level neonatal care, respiratory distress, fetal hyperbilirubinaemia and neonatal death ≤28 days will be further assessed. Calculations of age-adjusted and sex-adjusted percentiles will be performed by using international anthropometric standards according to those used in the CONCEPTT study.44 Neonatal hypoglycaemia is defined as local blood glucose ≤31 mg/dL (1.7 mmol/L) in the first 24 hours after delivery and ≤45 mg/dL (2.5 mmol/L) after the first 24 hours after delivery or treatment with glucose infusion according to the Hyperglycemia and Adverse Pregnancy Outcome study.3 Additional anthropometric measures of the offspring include head, shoulder and abdominal circumference, length, upper and lower arm and leg circumference and skinfold measurements (suprailiac and subscapular, triceps, quadriceps) in accordance with previous studies.45–47 Thereby, skinfold measurements will be performed by using a validated instrument (Harpenden Skinfold Caliper) within 48 hours after delivery (VPP1).

Assessment of cord blood

17 mL umbilical cord blood (1×8 mL serum and 1×9 mL EDTA) will be taken immediately after delivery to examine cord-blood glucose, insulin and C-peptide.

Postpartum OGTT

The OGTT will be performed at VPP2 (ie, 8–16 weeks after delivery): after collecting blood samples for measurements of glucose (2 mL blood), insulin and C-peptide (3 mL blood) in the fasting state (at least 8 hours), participating women will receive a standardised 300 mL 75 g glucose. Further blood samples of glucose, insulin and C-peptide measurements will be taken at 30, 60, 90 and 120 min after intake of glucose. Insulin sensitivity during the OGTT will be assessed by the oral glucose insulin sensitivity index according to Mari et al48; this quantifies dynamic glucose clearance per unit change of insulin. The more recently developed PREDIM index will be used in addition.49 The new index provides excellent prediction of clamp-derived insulin sensitivity from OGTT or meal data. As an approximation for hepatic insulin resistance, the homeostasis model assessment of insulin resistance will be used. Insulin secretion will be calculated by using the C-peptide deconvolution method.50 β-cell function parameters, such as pancreatic glucose sensitivity and rate sensitivity, and potentiation of insulin secretion, will be computed by mathematical modelling.50

Assessment of HRQoL and patients’ preferences

HRQoL will be elicited using the SF-36 and the EQ-5D-5L.51 It can be expected that adherence to lifestyle and dietary recommendations are associated with individual risk preferences. Hence, risk and time preferences will be elicited based on a lottery approach.52 53 Participants will be asked to choose between two hypothetical lotteries that differ in expected outcomes which enables us to derive an individual classification of the risk type, that is, risk-averse, risk-neutral or risk-loving individuals. Quality of life as well as risk and time preferences will be assessed at V1, VPP1 and VPP2. Obstetrical patient’s satisfaction will be additionally assessed at VPP1 by using the Wijma score.54

Patient and public involvement

Patients and public were not involved in the study design and will not be involved in the study conduct, recruitment and dissemination.

Health economic evaluation

For the evaluation of a complex intervention, a health economic evaluation is recommended as well.55 56 In this study, a CEA and a CUA will be conducted from the perspective of the health insurance. The effect measure employed in the CEA will be the primary outcome of the main trial, that is, avoided cases of LGA newborns. Even if the effect parameter of the intervention group will not be superior to the control group, a health economic evaluation will be performed to inform about efficiency since costs might be lower in the intervention group.57 Due to the short intervention period quality-adjusted life weeks (QALWs) will be used in the CUA. QALWs will be calculated based on either the EQ-5D-5L or the SF-6D58 that derives preference-based scores from the SF-36. To receive utilities, quality of life will be evaluated by country-specific population-based preferences separately for each country involved in the trial. Similarly, intervention costs as well as healthcare costs (direct costs) will be calculated separately for each country using local prices and adjusted for local purchasing power parity. Healthcare use will be assessed by a validated instrument that is adapted to the requirements of the study.59 Healthcare use will comprise resource use dedicated to the mother but not the child, for example, clinical visits, outpatient contacts, contacts with therapists and medication. Intervention associated costs are costs of devices, software, test strips and costs due to education and training of study participants. Since the evaluation covers only the observation period alongside the trial, costs and effects will not be discounted. Comparing the outcomes and costs of the intervention group with the outcomes and costs of the control group yields the incremental cost-effectiveness ratio (ICER: additional cost per additional LGA newborn avoided) and the cost–utility ratio (ICUR: additional costs per additional QALW gained).

Reporting of adverse events, data and safety monitoring

Any (serious) adverse events (AE/SAE) are recorded by the investigator using the specific AE/SAE sheet of the clinical report form. All SAE are reported to the responsible ethics committee within an appropriate time frame.

Data safety and accuracy as well as patient safety will be monitored by local data and safety monitoring committees for clinical trials (eg, the KKS—competence centre for clinical trials—in Austria).

Sample size and statistical analysis

Ethics and dissemination

This study received ethical approval from the main ethic committee in Vienna (1863/2018). Ethics approval will be obtained by the local institutional review boards in Basel, Berlin, Dusseldorf and Orebro. It was registered under www.ClinicalTrials.gov (NCT03981328). Data will be presented at international conferences and published in peer-reviewed journals.