Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices).

In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe.

Comparable effects of inhaled fluticasone propionate and budesonide on the HPA-axis in adult asthmatic patients.

This randomized, double-blind, double-dummy, multicentre cross-over study compared the effects on the hypothalamic-pituitary-adrenal (HPA) axis of fluticasone propionate (750 microg twice daily given via the Diskus) and budesonide (800 microg twice daily given via the Turbuhaler). Two treatment periods of 2 weeks each were preceded by a 2-week run-in period and separated by a 2-week washout period. During run-in and washout, patients received beclomethasone dipropionate (BDP) or budesonide at a constant dose of 1500-1600 microg day(-1). Sixty patients aged 18-75 years with moderate to severe asthma not fully controlled by treatment with 1500-1600 microg day(-1) budesonide or BDP entered run-in and 45 completed the study. HPA axis suppression was assessed by morning serum cortisol (area under the curve from 08.00 to 10.30 hours) and 12-h nocturnal urinary cortisol excretion, measured at the end of run-in (baseline 1), at the end of washout (baseline 2), and at the end of each treatment period. Neither budesonide nor fluticasone produced significant suppression of either parameter compared to baselines. Only a few patients had serum-cortisol and urinary cortisol values below the normal range, before and after treatment. This shows that the patients did not have adrenal suppression before entering the study. The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0.99 (95% CI 0.92-1.06), indicating equivalent effects on the HPA axis. This result was achieved after having omitted two patients' results, due to their very sensitive reaction to budesonide, but not to fluticasone. Two exacerbations of acute asthma occurred during budesonide treatment and none during fluticasone treatment. Both treatments were well tolerated. In conclusion, budesonide 1600 microg day(-1) via Turbuhaler and fluticasone propionate 1500 microg day(-1) via Diskus had no clinical effects on the HPA axis in patients with moderate to severe asthma.

Ranitidine effervescent and famotidine wafer in the relief of episodic symptoms of gastro-oesophageal reflux disease.

BACKGROUND: The aim of this study was to measure the efficacy of 150-mg ranitidine effervescent tablets compared with 20-mg famotidine wafers in the management of patients presenting to primary care physicians with episodic symptoms of gastro-oesophageal reflux disease (GORD). METHODS: The study was of a multicentre, open, randomized, parallel-group design in which 32 Norwegian general practitioners participated. After a pre-treatment demographic and symptom assessment, eligible patients were allocated to either ranitidine effervescent tablet or famotidine wafer. Patients were then provided with the study medication, a stopwatch, and a 2-week symptom diary card. Efficacy was primarily determined by the time to adequate symptom relief for the first symptom episode. RESULTS: In total, 377 patients were recruited to the study; 187 patients received ranitidine effervescent, and 190 received famotidine wafer. More than 50% of the patients had daily GORD symptoms before recruitment. Median time to adequate symptom relief was 15 min in the ranitidine group and 18.5 min in the famotidine group (P = 0.005). Adequate symptom relief within 60 min was reported by 165 (92%) ranitidine patients and 156 (84%) famotidine patients (P = 0.02). The number of non-responders after 60 min was twice as great in the famotidine group: 30 (16%) versus 15 (8%). A greater proportion of patients in the famotidine group liked taking the wafer formulation: 173 (94%) versus 126 (70%) (P = 0.001). CONCLUSION: There was a statistically significant difference in favour of 150-mg ranitidine effervescent tablets in terms of time to adequate symptom relief and the proportion of patients who achieved adequate symptom relief for the first episode. A greater proportion of patients in the famotidine group liked the type of formulation than in the ranitidine group.

Delayed CT of the kidneys after iopentol (Imagopaque 350) injection in patients with normal renal function. An assessment of the gradual decrease in opacification over 32 h after injection.

The elimination of the non-ionic contrast medium iopentol (Imagopaque, Nycomed Imaging AS, Oslo, Norway) from the kidneys was investigated in adult patients with normal renal function referred for cerebral computed tomography (CT). Twenty-four patients were included in the study. Each patient was given one intravenous injection of 50 ml iopentol 350 mg I/ml. CT scans of the kidneys were taken before, immediately after, 8 h after and 32 h after the injection of contrast medium. To assess the rate of iopentol disappearance, calculations were made for the cortex, medulla and aorta, based on changes from the baseline (pre-contrast) measurements, in Hounsfield units (HU). The median estimated time for disappearance was 28 h from the cortex, 32 h from the medulla and 8 h from the aorta. Thus, a small retention of contrast medium can usually be seen after normalization of aortic HU values.

Image quality and safety after iodixanol in intravenous urography; a comparison with iohexol.

A double-blind, randomized phase III study compared intravenous urography in 100 adult patients receiving iodixanol 320 mgI ml-1 (Visipaque) with 99 patients receiving iohexol 350 mgI ml-1 (Omnipaque). The aim of the study was to investigate differences in image quality between a non-ionic dimeric contrast medium (CM) and a non-ionic monomer at 40 ml per patient and 60-100 ml per patient volume levels. There were no statistically significant differences between iodixanol and iohexol with respect to overall diagnostic information, which was found to be optimal in 86% and 79%, respectively. Immediately after the injection, the renal border was better delineated with iohexol than with iodixanol (p = 0.0001). Marked papillary blush occurred more often in the iodixanol group (16%) than in the iohexol group (0%), as did visualization of the collecting ducts (24% vs 5%) (p = 0.001). The incidence of adverse events was similar and low for both contrast media. In patients who received the higher doses of CM (60-100 ml), the frequency of discomfort was significantly lower after iodixanol than after iohexol (p = 0.006). We conclude that, in intravenous urography, iodixanol provides at least as good image quality as does iohexol. Iodixanol may cause less discomfort than iohexol, in particular when larger volumes of CM are injected.

Angiography with nonionic X-ray contrast media in severe chronic renal failure: renal function and contrast retention.

The effects of contrast media on renal function and the cortical retention of contrast media after abdominal angiography were investigated. Sixteen nondiabetic patients with predialytic chronic renal failure received either the nonionic dimeric contrast medium iodixanol or the monomeric contrast medium iohexol in a double-blind randomized study. All patients were well hydrated before, during and after angiography. Mean 99mTc-DTPA clearance was 14.0 ml/min/1.73 m2 in the iodixanol group, and 9.3 ml/min/1.73 m2 in the iohexol group at baseline. No statistically significant changes were seen after angiography. Serum creatinine increased significantly 48 and 72 h after angiography in both groups, and then normalized. Creatinine clearance was reduced only in the iohexol group, at 72-96 h. The urinary excretion of renal enzymes and of total protein did not change significantly. No patients developed oliguria or required dialysis during the 7-day observation period. Increased attenuation in the renal cortex, measured by computed tomography and probably reflecting intracellular retention of contrast medium, peaked at 24 h, and was observed in both groups during the follow-up period. Thus, although transient and minor changes in glomerular filtration rate were noted, both iodixanol and iohexol were safe for use in angiography in nondiabetic patients with severe chronic failure when the patients were well hydrated.

Determination of glomerular filtration rate with Visipaque in patients with severely reduced renal function.

Iodixanol (Visipaque, Nycomed Imaging AS, Oslo, Norway), and isotonic, dimeric and non-ionic contrast medium (CM), and iohexol (Omnipaque, Nycomed Imaging AS, Oslo, Norway), a low-osmolar, monomeric and non-ionic contrast medium, were used as glomerular filtration rate (GFR) markers in patients with severely impaired renal function. Different methods for determining GFR were compared. A total of 16 patients with s-creatinine > 400 mumol/l were enrolled in the study; 8 in each CM group. Serum-iodine was measured, and plasma CM clearance was determined using the Bröchner-Mortensen method, the single-sample method and conventional method. The ratios between the results obtained from the conventional method and each of the two other methods were calculated. These data were plotted against the mean of the pairs compared, and the upper and lower limits of agreement were calculated as the mean ratio +/- 2SD. The comparison showed a high degree of agreement between methods, and the two simpler methods seem to be good alternatives to the conventional method, which gave good estimates of GFR (vs that determined by means of renal 125I-iothalamate clearance) when 24-h blood samples were included. However, slight overestimations of GFR, due to extrarenal excretion of the CM, were observed. In summary, serum clearance of iodixanol, as determined by the Bröchner-Mortensen method or single-sample method seems to be a simple and accurate marker for GFR in patients with severely reduced renal function. The findings obtained with iodixanol were similar to those obtained with iohexol.

A blinded comparison of fluticasone propionate with budesonide via powder devices in adult patients with moderate-to-severe asthma: a clinical evaluation.

In Vitro and in vivo data have demonstrated that there are detectable differences between inhaled corticosteroids commonly used to treat asthma. However, controversy still remains as to whether these differences translate into clinical benefits. This 12-week, international, randomized, doubleblind, parallel-group study was undertaken to compare the efficacy and safety of fluticasone propionate (FP) 800 mug daily, administered as a powder via the Diskhaler((R)), and budesonide (BUD) 1600 mug daily, administered using the Turbuhaler((R)), in adult patients with moderate-tosevere asthma. A total of 518 patients participated in the study, 256 of whom received FP and 262 BUD. Assessment of mean morning peak expiratory flow (PEF) over the 12-week treatment period revealed a statistically significant difference in efficacy between FP 800 mug daily and BUD 1600 mug daily in favour of FP (p = 0.003), with an overall improvement of 20.9 l/min with FP compared with 12.4 l/min on BUD. Statistically significant differences in favour of FP were seen over the 12 weeks for mean evening PEF (p = 0.04), diurnal PEF variation (p = 0.03) and percentage predicted PEF (p = 0.003), as well as forced expiratory volume (p = 0.008), forced vital capacity (p = 0.02) and PEF (p = 0.005) measured at clinic visits. The median percentage of symptom-free nights increased over the 12-week study period in both treatment groups, with similar changes seen for the median percentage of days with symptom score < 2, rescue medication use and exacerbations of asthma. The incidence of adverse events was found to be comparable in the two treatment groups. The geometric mean ratios of serum cortisol levels were found to be 1.03 for FP, indicating no mean hypothalamic-pituitary-adrenal axis suppression from baseline, and 0.93 for BUD (p = 0.0002 compared with FP). In summary, FP 800 mug daily showed a greater efficacy/safety ratio in the treatment of moderate-to-severe asthma than BUD 1600 mug daily.

A comparison of iodixanol with iopamidol in aorto-femoral angiography.

This double-blind, randomized, parallel group clinical investigation in 140 consecutive patients undergoing aorto-femoral arteriography was carried out to compare iodixanol (Visipaque) 270 mgI ml-1 with iopamidol (Iopamiro) 300 mgI ml-1. The aims of the study were to compare adverse events and discomfort, clinical chemistry parameters in blood, haemodynamics and diagnostic information of the angiograms in the two groups. The main parameter for statistical analysis was the visual analogue scale (VAS) score for overall discomfort experienced by the patients during the examination. 134 patients, 69 and 65 receiving iodixanol and iopamidol, respectively, were examined according to the protocol and included in the evaluation. The two groups of patients were judged to be comparative. Statistically significant milder discomfort was felt with iodixanol than with iopamidol (p = 0.0001); mean VAS values 16 mm and 51 mm, respectively. Pain was reported far less frequently after iodixanol than after iopamidol (7.4% versus 50.8%) whereas sensation of warmth was less intense after iodixanol than after iopamidol. Four patients in the iodixanol group and two in the iopamidol group reported transient, non-serious adverse events. The difference was not statistically significant (p = 0.68). Systolic blood pressure was affected to a slightly greater degree after injection of iopamidol than after injection of iodixanol. Measurements of diastolic blood pressure, as well as clinical chemistry parameters in blood, revealed no changes of clinical importance, and all arteriograms performed were of diagnostic value. The conclusion is that iodixanol 270 mgI ml-1 is as efficacious as iopamidol 300 mgI ml-1, but produces less discomfort during arteriography. As such, iodixanol is a good alternative to iopamidol in aorto-femoral angiography.

Elimination of the non-ionic X-ray contrast media iodixanol and iohexol in patients with severely impaired renal function.

Iodixanol (Visipaque) and iohexol (Omnipaque) are dimeric and monomeric, respectively, non-ionic X-ray contrast media (CM), with well-characterized pharmacokinetics in healthy volunteers. This study was undertaken to study the pharmacokinetics of the contrast media in patients with severely impaired renal function. A total of 16 patients referred for preoperative abdominal angiography were randomized to form two groups of eight patients, receiving either iodixanol 320 mgI ml-1 or iohexol 350 mgI ml-1. Urine and faeces were sampled before the examination and collected quantitatively for five days afterwards, and blood samples were drawn frequently. The concentrations of iodine and contrast medium in urine and in serum, and the amount of iodine in faeces were determined. Mean baseline creatinine clearance was 13.6 and 9.9 ml min-1 1.73 m-2 in the iodixanol and iohexol groups, respectively. Patients in the iodixanol group received on average 0.34 gI per kg bodyweight (bw) and those in the iohexol group 0.39 gI per kg bw. The semilogarithmic plots of serum concentration of CM vs. time indicated elimination according to a two-compartment model. The mean elimination half-life was 23.0 h for iodixanol and 27.2 h for iohexol, and the mean apparent volume of distribution was similar for the two CM, ranging from 0.20 to 0.30 1 per kg bw. Mean plasma clearance of iodixanol was 10.4 ml min-1 1.73 m-2 and 6.9 ml min-1 1.73 m-2 for iohexol, whereas the mean renal clearances were 8.7 and 6.1 ml min-1 1.73 m-2, respectively. Mean faecal recovery was 8.2% for iodixanol and 6.1% for iohexol, and the respective figures for that in urine were 76.1 and 74.8%. Renal clearance of radiolabelled iothalamate, a marker of glomerular filtration rate (GFR), measured simultaneously, indicated that both CM were eliminated by the kidneys by glomerular filtration only. Thus, both media are suitable as GFR markers.

Urinary excretion of retinol-binding protein in healthy children and adolescents.

Retinol-binding protein (RBP) is a marker of tubular reabsorption in the kidneys. The aim of our study was to investigate urinary RBP excretion in healthy children to obtain reference values related to age and pubertal stage. Overnight samples from 143 subjects (73 girls, 70 boys) aged 10-18 years were investigated. RBP was quantified by a solid-phase sandwich enzyme immunoassay. Both the RBP excretion rate and the RBP/creatinine ratio (RBP/Cr) showed a skewed distribution. The medians and the 5th-95th percentiles were 38 ng/min (15-127) and 9 micrograms/mmol (4-23), respectively. The RBP excretion rate and RBP/Cr ratio were similar in both sexes, and linear multiple regression analysis showed no association with age or pubertal stage, although a weak relationship (r = 0.27) was found between RBP excretion rate and age in boys and RBP/Cr ratio and age (r = -0.28) in girls by simple correlation analysis. The correlation between RBP excretion rate and RBP/Cr ratio was 0.76; the RBP excretion rate and RBP/Cr ratio measured on 2 consecutive days, showed a correlation coefficient of 0.84 and 0.88, respectively. We conclude that overnight RBP excretion in children over 10 years shows a low day-to-day variation and, in practical terms, is independent of age, gender and pubertal stage.

Comparison of sequential and fixed-sample designs in a controlled clinical trial with laparoscopic versus conventional cholecystectomy.

BACKGROUND: The aim of this study was to compare a fixed-sample and a sequential design with regard to study duration, sample size, and medical results in a real-life situation. METHODS: A randomized study comparing laparoscopic and conventional cholecystectomy was carried out with a fixed-sample design, parallel with a sequential design. The main variable was duration of postoperative convalescence. RESULTS: In the fixed-sample trial the necessary number of patients was calculated to be 72. The sequential trial was conclusive after inclusion of 24 patients and reduced the duration of the study from 43 to 18 weeks. Additionally, the sequential trial reached the same conclusions as the fixed-sample trial in all the observed variables except for one. CONCLUSION: The present study indicates that sequential design should be used more frequently in clinical trials, to involve the smallest possible number of patients necessary to reach a conclusion.

Urinary albumin excretion rate and puberty in non-diabetic children and adolescents.

Slightly elevated urinary albumin excretion rate (microalbuminuria) is a marker of early diabetic nephropathy, but it is unclear if the established definition of microalbuminuria (20-200 micrograms/min) is correct for children and adolescents. We investigated the albumin excretion rate, albumin/creatinine ratio and urinary albumin concentration in 150 healthy schoolchildren and adolescents to (a) obtain a reference value for albumin excretion rate, (b) relate albumin excretion to pubertal stages and (c) evaluate albumin/creatinine ratio and morning albumin concentration as screening methods for elevated albumin excretion rate. Albumin concentration was measured by immunoturbidimetry in timed overnight urine samples. The albumin excretion showed a skewed distribution (geometric mean 3.2 micrograms/min, 95 percentile 15.1 micrograms/min). In girls, a peak in the albumin excretion rate was found at the pubertal stage 4 (Tanner) and in boys at stage 5. Albumin/creatinine ratio of 2.5 mg/mmol as a screening level for elevated albumin excretion (15 micrograms/min) showed a high positive (0.88) and negative (0.99) predictive value.

Laparoscopic and open cholecystectomy. A prospective, randomized study.

OBJECTIVE: To compare laparoscopic with open cholecystectomy. DESIGN: Prospective random control trial. SETTING: Central Hospital of Akershus, Nordbyhagen, Norway. SUBJECTS: 74 consecutive patients due to undergo elective cholecystecomy between October 1990 and June 1991. INTERVENTIONS: Two patients were excluded from randomisation, and two were withdrawn after randomisation. The remaining 70 were randomly allocated to open or laparoscopic cholecystectomy (n = 35 in each group). MAIN OUTCOME MEASURES: Duration of operation and postoperative stay in hospital, amount of postoperative pain, incidence of complications, and duration of convalescence and sick leave. RESULTS: Laparoscopic cholecystectomy took twice as long as open (median [range] 100 [52-180] minutes compared with 50 [15-115], p < 0.01), but patients stayed in hospital half the time (2 [1-9] days compared with 4 [2-22], p < 0.01); required less opiate analgesia (4 [0-20] doses compared with 6 [0-13], p = 0.02; took less sick leave (11 [4-267] days (n = 18) compared with 34 [20-48] (n = 22), p < 0.01); and spent less time in convalescence (8 [3-40] days (n = 17) compared with 49 [10-247] (n = 12), p < 0.01). There were six complications in the laparoscopy group and seven in the open cholecystectomy group. CONCLUSION: Because of the significant differences between laparoscopic and open cholecystectomy we have now adopted the laparoscopic method as our standard, but we think that we can improve our results further by refining our operative techniques and giving our patients more information.

[Physical activity habits among adults in Nord-Trøndelag]. / Mosjonsvaner hos voksne i Nord-Trøndelag.

This article describes the physical activity of 61,732 adults in the Norwegian county of Nord-Trøndelag. We collected information about physical activity by questionnaire during the Nord-Trøndelag Health Survey in 1984-86. Non-attendents are systematically analyzed and discussed. The article also deals with problems of defining physical activity. The frequency of physical activity gives a different measure of physical activity than does intensity and duration. 15% of the women and 14% of the men were totally inactive. If we consider physical activity at a level high enough to have a preventive effect as regards development of disease, for example, we found that 65% did not practise physical activity often enough or with sufficient intensity or duration. The groups of men aged 70-79 years and women aged 60-69 years contained the persons who practised physical activity most often, while the 20-29 age group contained those who practised physical activity with greatest intensity and for the longest time. We used age, sex, education, residential municipality and physically strenuous work as variables explaining inactivity and high activity. All the variables made a significant contribution to the logistic regression, but gave a better persons characterization of highly active than of inactive persons.

Perfusion in vivo of the porcine placenta. Fixation for EM.

A method for vascular perfusion in vivo, especially for EM fixation, was developed with the porcine placenta. The effect of fixation at varying parameters was studied. Nine multiparous Danish Landrace sows ranging in gestation from 33 to 112 days and in body weight from 160 to 257 kg were used. After general and local anaesthesia laparotomy was undertaken on the left flank and the uterine horn was perfused through a. uterina with buffered glutaraldehyde. Local perfusion through a. umbilicalis was undertaken in one case, and installation of concentrated glutaraldehyde into the allantoic cavity was performed in five cases. Perfusion-fixed and fresh tissue samples were fixed in OsO4 and processed for electron microscopy. The osmolarity of the buffer was varied between 470 and 660 mOsm. At high tonicity cytoplasm was well preserved but the intercellular spaces of the uterine epithelium was dilated. At about 575 mOsm the preservation was still good and the spaces were occluded. At lower tonicity damage occurred in the cytoplasm. The trophoblast was generally better preserved than the uterine epithelium. A rapid perfusion flow was beneficial for fixation.