Search

Aims: This study aimed to explore the effect of discontinuation of long-term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study., Materials and Methods: An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re-examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin-creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow-up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium., Results: No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI -12, 55; p = 0.28) nor the placebo (5%; 95% CI -13, 26; p = 0.63) group at follow-up. No difference in UACR between the groups was observed at follow-up (relative difference in geometric mean: 11%, 95% CI -26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05)., Conclusions: UACR did not change after discontinuation of long-term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys., (© 2024 John Wiley & Sons Ltd.)

Background & Aims: Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown., Methods: In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 μg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 μg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy)., Results: Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12])., Conclusions: Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment., Clinical Trial Registration: NCT00932971., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial., Methods and Results: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m 2 , and BMI < 27 kg/m 2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively., Conclusion: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m 2 , BMI < 27 kg/m 2 , or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d., (© 2023. The Author(s).)

Background & Aims: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient-reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta., Methods: Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF-36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG-IFNa-2a)-based treatment in the HIDIT-II trial. HIDIT-II was a randomized prospective trial exploring PEG-IFNa-2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available., Results: Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG-IFNa-2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV-RNA clearance was not associated with relevant changes in physical or social SF-36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co-treatment had no influence on QOL., Conclusions: Overall, our findings suggest that PEG-IFNa-2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF-36 questionnaires. Of note, several patients may benefit from PEG-IFNa-2a-based therapies with off-treatment improvements in quality of life., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Aims: Baseline diabetic retinopathy (DR) and risk of development of microalbuminuria, kidney function decline, and cardiovascular events (CVEs) in type 2 diabetes., Methods: Post-hoc analysis of the PRIORITY study including 1758 persons with type 2 diabetes and normoalbuminuria followed for a median of 2.5 (IQR: 2.0-3.0) years. DR diagnosis included non-proliferative and proliferative abnormalities, macular oedema, or prior laser treatment. Cox models were fitted to investigate baseline DR presence with development of persistent microalbuminuria (urinary albumin-creatinine ratio > 30 mg/g); chronic kidney disease (CKD) G3 (eGFR <60 ml/min/1.73m 2 ); and CVE. Models were adjusted for relevant risk factors., Results: At baseline, 304 (17.3 %) had DR. Compared to persons without DR, they were older (mean ± SD: 62.7 ± 7.7 vs 61.4 ± 8.3 years, p = 0.019), had longer diabetes duration (17.9 ± 8.4 vs. 10.6 ± 7.0 years, p < 0.001), and higher HbA 1c (62 ± 13 vs. 56 ± 12 mmol/mol, p < 0.001). The adjusted hazard ratios of DR at baseline for development of microalbuminuria (n = 197), CKD (n = 166), and CVE (n = 64) were: 1.50 (95%CI: 1.07, 2.11), 0.87 (95%CI: 0.56, 1.34), and 2.61 (95%CI: 1.44, 4.72), compared to without DR., Conclusions: Presence of DR in normoalbuminuric type 2 diabetes was associated with an increased risk of developing microalbuminuria and CVE, but not with kidney function decline., Competing Interests: Declaration of competing interest NT is a full-time employee of Novo Nordisk A/S. TWH has equity in Novo Nordisk A/S. ML has received research support from Boehringer Ingelheim, Bayer and Merck Sharp & Dohme, and lecture fees from AstraZeneca, Bayer and Boehringer Ingelheim. All fees are given to Holbaek hospital. FP has served as a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Mundipharma, MSD, Novartis, Amgen and has received research grants to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. AO has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, Astrazeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma and is Director of the Catedra Mundipharma-UAM of diabetic kidney disease and the Catedra Astrazeneca-UAM of chronic kidney disease and electrolytes. HM is the cofounder and co-owner of Mosaiques Diagnostics GmbH. JS and PZ are employees of Mosaiques Diagnostics GmbH. MF-M has received speaker fees or support for medical meetings and research grants from AstraZeneca and Novo Nordisk and speaking fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Novartis, Baxter, and Sanofi-Aventis. IR has received honoraria for lectures of AstraZenec, Bayer, Boehringer Ingelheim, and Mundipharma. PR has received research support and personal fees from AstraZeneca, Bayer and Novo Nordisk, and personal fees from Astellas Pharma Inc., Bayer, Boehringer Ingelheim, Eli Lilly and Company, Gilead, Merck, Merck Sharp & Dohme, Mundipharma, Sanofi, and Vifor Pharma. All fees are given to Steno Diabetes Center Copenhagen. All other authors declare no competing interests that could be perceived as affecting the impartiality of the reported results., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker., Methods: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country., Findings: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1-3 in 445 (44%) participants, 4-5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05-2·92) unadjusted and 1·67 (1·34-2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60-2·01) when unadjusted and 1·63 (1·41-1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6-77·1%) for mortality (threshold 0·47) and 67·4% (64·4-70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5-95% percentile interval 0·730-1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04)., Interpretation: The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1-4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs., Funding: German Federal Ministry of Health., Competing Interests: Declaration of interests HM is the co-founder and co-owner of Mosaiques-Diagnostiques (Hannover, Germany). JS and JR are employees of Mosaiques-Diagnostics. HDR received consulting fees and honoraria for presentations from Alexion, AstraZeneca, and Bristol-Myers-Squibb. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period., Experimental Design: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse., Results: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage ( P = 0.02) and para-aortic lymph node involvement ( P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor ( R = 0.39, P < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS ( P < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection., Conclusions: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer. See related commentary by Wentzensen and Clarke, p. 5733 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD&#95;MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD&#95;MS17 classification factor above 0.1 to receive either prednisolone (2-2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66-4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.

Background: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www.raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A "metagene" of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]., Methods: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA)., Findings: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pβ-Cat552), ranked highest for good prognosis, while pβ-Cat675 was associated with worse prognosis., Interpretation: These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pβ-Cat552 and pβ-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis., Funding: European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer., Competing Interests: Declaration of Interests All authors report no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The standard therapy for patients suffering from sensorineural hearing loss is cochlear implantation. The insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in a loss of residual hearing. Studies have suggested that a particular combination of the antioxidants vitamins A, C and E as well as the vasodilator magnesium (together: ACEMg) may protect the residual hearing., Methods: The potential protective effect of ACEMg on residual hearing preservation in cochlear implant (CI) patients was investigated in a single-centre, randomized, placebo-controlled, double-blind phase II clinical trial. CI candidates with some residual hearing in low frequencies receiving MED-EL implants of different FLEX electrode array lengths were treated with ACEMg tablets or placebo respectively 2 days preoperatively and up to 3 months postoperatively. The study objective was to demonstrate that ACEMg is more efficacious than placebo in preserving residual hearing during cochlear implantation by comparing the hearing loss (change in hearing thresholds at 500 Hz from baseline) 3 months after the first fitting between the two treatment groups and to investigate the treatments' safety., Results: Fifty-one patients were included in the study, which had to be terminated before the recruitment goal was reached because of IMP-resupply mismanagement of one partner. In the intention-to-treat population, 25 patients were treated with ACEMg and 24 patients with placebo. The mean hearing loss at 500 Hz was (± 15.84) 30.21 dB (placebo) or (± 17.56) 26.00 dB (ACEMg) 3 months after the initial fitting. Adjusting the postoperative hearing loss for the baseline residual hearing, planned electrode length and surgeon results in 8.01 dB reduced hearing loss in ACEMg-treated patients compared to placebo-treated ones. The safety analysis revealed that ACEMg was generally well-tolerated with adverse event frequencies below the placebo level., Conclusion: This is the first clinical trial investigating a drug effect on residual hearing in CI patients. These first-in-man data may suggest that a perioperative oral administration of ACEMg is safe and may provide protection of residual hearing in CI patients., Trial Registration: EU Clinical Trial Register No. 2012-005002-22 . Registered on 6 December 2013., Funding: European Commission FP7-HEALTH-2012-INNOVATION-2.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone., Methods: In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed., Findings: Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0-3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80-3·42; p<0·0001, after adjustment for baseline variables of age, sex, HbA 1c , systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1·73 m 2 ) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3·50; 95% CI 2·50-4·90, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5·15, 95% CI 3·41-7·76; p<0·0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0·81, 95% CI 0·49-1·34; p=0·41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5·5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug., Interpretation: In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2·5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients., Funding: European Union Seventh Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and "research infrastructures" for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe., Methods: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action., Results: Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know-how and documents. Since harmonization was mainly a bottom-up approach up until now, the extent and topics dealt with are diverse and there is only little cross-networking and cross-country exchange so far., Conclusions: Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country., Competing Interests: The authors affirm that they have no conflicts of interest to disclose. This survey was conducted with no external funding or specific internal funding and was done within the usual employment contracts., (© 2020 The Authors. Learning Health Systems published by Wiley Periodicals, Inc. on behalf of the University of Michigan.)