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Prasan Kumar Panda,1 Budha O Singh,1 Bikram Moirangthem,1 Yogesh Arvind Bahurupi,2 Sarama Saha,3 Girraj Saini,4 Minakshi Dhar,1 Mukesh Bairwa,1 Venkatesh Srinivasa Pai,1 Ankit Agarwal,5 Girish Sindhwani,6 Shailendra Handu,7 Ravi Kant8 1Department of Medicine (Infectious Disease Division), All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 2Department of Community and Family Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 3Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 4Department of Nursing, All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 5Department of Critical Care Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 6Department of Pulmonary Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 7Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Rishikesh, India; 8Department of General Surgery, All India Institute of Medical Sciences (AIIMS), Rishikesh, IndiaCorrespondence: Prasan Kumar PandaDepartment of Medicine (Infectious Disease Division), All India Institute of Medical Sciences (AIIMS), Sixth Floor, College Block, Rishikesh, 249203, IndiaTel +91 9868999488Email motherprasanna@rediffmail.comPurpose: Definitive antiviral treatment is not available for COVID-19 infection, with the exception of remdesivir, which still evokes many doubts. Various monotherapy or combination therapies with antivirals or other agents have been tried. The present study aims to evaluate the therapeutic potential of hydroxychloroquine and lopinavir–ritonavir in combination with ribavirin in mild–severe COVID-19.Patients and Methods: A single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of combination antiviral therapies. Enrolled patients in the severe category were randomized into three groups: (A) standard treatment, (B) hydroxychloroquine+ribavirin+standard treatment, or (C) lopinavir+ritonavir+ribavirin+standard treatment; while the non-severe category comprised two groups: (A) standard treatment or (B) hydroxychloroquine+ribavirin. Combination antivirals were given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report.Results: In total, 111 patients were randomized: 24, 23, and 24 in severe categories A, B, and C, respectively, and 20 in each of the non-severe groups. Two patients receiving ribavirin experienced drug induced liver injury, and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups, respectively, showed symptomatic recovery, compared to 93.3% and 86.7% in A and B groups, respectively, in the non-severe category at 72 hours (P> 0.05).Conclusion: Though the results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19 due to very small sized trial, clinically hydroxychloroquine+ribavirin therapy is showing better recovery by 7.4% than standard therapy in the former category. However, results do indicate the benefit of standard therapy in the non-severe category by 6.6%. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.Keywords: coronavirus disease 2019, interventional trial, hydroxychloroquine, lopinavir/ritonavir combination, ribavirin

Background Since the outbreak of coronavirus disease 2019 (COVID-19), many researchers in China have performed related clinical research. However, systematic reviews of the registered clinical trials are still lacking. Therefore, we conducted a systematic review of clinical trials for COVID-19 to summarize their characteristics. Methods This study is based on the PRISMA recommendations in the Cochrane handbook. The Chinese Clinical Registration Center and the ClinicalTrials.gov databases were searched to identify registered clinical trials related to COVID-19. The retrieval inception date was February 9, 2020. Two researchers independently selected the literature based on the inclusion and exclusion criteria, extracted data, and evaluated the risk of bias. Results A total of 75 registered clinical trials (63 interventional studies and 12 observational studies) for COVID-19 were identified. The majority of clinical trials were sponsored by Chinese hospitals. Only 11 trials have begun to recruit patients, and none of the registered clinical trials have been completed; 34 trials were early clinical exploratory trials or in the pre-experiment stage, 13 trials were phase III, and four trials were phase IV. The intervention methods included traditional Chinese medicine in 26 trials, Western medicine in 30 trials, and integrated traditional Chinese medicine and Western medicine in 19 trials. The subjects were primarily non-critical adult patients (≥ 18 years old). The median sample size of the trials was 100 (IQR: 60–200), and the median length of the trial periods was 179 d (IQR: 94–366 d). The main outcomes were clinical observation and examinations. Overall, the methodological quality of both the interventional trials and observational studies was low. Conclusions Intensive clinical trials on the treatment of COVID-19 using traditional Chinese medicine and Western medicine are ongoing or will be performed in China. However, based on the uncertain methodological quality, small sample size, and long trial duration, we will not be able to obtain reliable, high-quality clinical evidence regarding the treatment of COVID-19 in the near future. Improving the quality of study design, prioritizing promising drugs, and using different designs and statistical methods are worth advocating and recommending for clinical trials of COVID-19 in the future.

Preclinical data have shown that rilmenidine can regulate autophagy in models of Huntington’s disease (HD), providing a potential route to alter the disease course in patients. Consequently, a 2-year open-label study examining the tolerability and feasibility of rilmenidine in mild-moderate HD was undertaken. 18 non-demented patients with mild to moderate HD took daily doses of 1 mg Rilmenidine for 6 months and 2 mg for a further 18 months followed by a 3-month washout period. The primary outcome was the number of withdrawals and serious adverse events. Secondary outcomes included safety parameters and changes in disease-specific variables, such as motor, cognitive and functional performance, structural MRI and serum metabolomic analysis. 12 patients completed the study; reasons for withdrawal included problems tolerating study procedures (MRI, and venepuncture), depression requiring hospital admission and logistical reasons. Three serious adverse events were recorded, including hospitalisation for depression, but none were thought to be drug-related. Changes in secondary outcomes were analysed as the annual rate of change in the study group. The overall change was comparable to changes seen in recent large observational studies in HD patients, though direct statistical comparisons to these studies were not made. Chronic oral administration of rilmenidine is feasible and well-tolerated and future, larger, placebo-controlled, studies in HD are warranted. Trial registration: EudraCT number 2009-018119-14. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8647-0) contains supplementary material, which is available to authorized users.

OBJECTIVES We sought to systematically evaluate the external validity of a contemporary randomized controlled stent trial (BIOSCIENCE). METHODS Baseline characteristics and clinical outcomes of patients enrolled into the BIOSCIENCE trial at Bern University Hospital (n = 1216) were compared to those of patients included in the CARDIOBASE Bern PCI Registry at the same institution (n = 1045). The primary study endpoint was the rate of target lesion failure (TLF), defined as a composite of cardiac death, target vessel-myocardial infarction (MI) or target lesion revascularization (TLR), at 1 year. RESULTS Women were underrepresented in the RCT compared to the registry (25 vs. 29.4 %, p = 0.020). Non-participants were older compared to study participants (69.2 ± 12.4 vs. 67.0 ± 11.6, p

Background In addition to their effects on bone health, high doses of cholecalciferol may have beneficial non-classic effects including the reduction of incidence of type 2 diabetes mellitus, cardiovascular disease, and cancer. These pleiotropic effects have been documented in observational and experimental studies or in small intervention trials. Vitamin D insufficiency is a frequent finding in renal transplant recipients (RTRs), and this population is at risk of the previously cited complications. Methods/design The VITALE study is a prospective, multicentre, double-blind, randomized, controlled trial with two parallel groups that will include a total of 640 RTRs. RTRs with vitamin D insufficiency, defined as circulating 25-hydroxyvitamin D levels of less than 30 ng/ml (or 75 nmol/l), will be randomized between 12 and 48 months after transplantation to blinded groups to receive vitamin D3 (cholecalciferol) either at high or low dose (respectively, 100,000 UI or 12,000 UI every 2 weeks for 2 months then monthly for 22 months) with a follow-up of 2 years. The primary objective of the study is to evaluate the benefit/risk ratio of high-dose versus low-dose cholecalciferol on a composite endpoint consisting of de novo diabetes mellitus; major cardiovascular events; de novo cancer; and patient death. Secondary endpoints will include blood pressure (BP) control; echocardiography findings; the incidences of infection and acute rejection episodes; renal allograft function using estimated glomerular filtration rate; proteinuria; graft survival; bone mineral density; the incidence of fractures; and biological relevant parameters of mineral metabolism. Discussion We previously reported that the intensive cholecalciferol treatment (100 000 IU every 2 weeks for 2 months) was safe in RTR. Using a pharmacokinetic approach, we showed that cholecalciferol 100,000 IU monthly should maintain serum 25-hydroxyvitamin D at above 30 ng/ml but below 80 ng/ml after renal transplantation. Taken together, these results are reassuring regarding the safety of the cholecalciferol doses that will be used in the VITALE study. Analysis of data collected during the VITALE study will demonstrate whether high or low-dose cholecalciferol is beneficial in RTRs with vitamin D insufficiency. Trial registration ClinicalTrials.gov Identifier: NCT01431430. Electronic supplementary material The online version of this article (doi:10.1186/1745-6215-15-430) contains supplementary material, which is available to authorized users.

Der wissenschaftliche Nachweis der Überlegenheit einer Biomarker-gesteuerten Risiko-stratifizierung oder gar Therapieentscheidung, die letztendlich zur Verbesserung des Patientenmanagements beitragen sollen, umfasst mehrere Forschungsschritte. Drei spezifische Arbeitsschritte bilden dabei die Basis der klinischen Biomarkerforschung. 1\. Erste Observationsstudien zur Beschreibung des Zusammenhangs zwischen Biomarker und Überlebenswahrscheinlichkeit, 2\. die Untersuchung der spezifischen Charakteristika des Biomarkers im Vergleich zu anderen Biomarkern und 3\. erste Interventionsstudien, die den Vorteil eines Biomarker-gesteuerten Ansatzes letztendlich erst belegen können. Die vorliegende Arbeit beruht auf insgesamt sechs Publikationen welche jeweils einzelne dieser Schritte umfassen. Die darin enthaltenen statistischen Fragestellungen können wie folgt zusammengefasst werden: in Schritt (1) wurde ein U-förmiger Zusammenhang zwischen Messwert und Überlebensprognose mit Hilfe einer Spline-Transformation in einem allgemeinen Regressionsmodell modelliert. In Schritt (2) wurde zum einen der Nachweis des Mehrwertes eines Biomarkers gegenüber bereits vorhandenen klinischen Variablen über eingebettete Regressionsmodelle und den „Net Reclassification Index“ geführt, die Kurz- und Langzeitprognose beschrieben, und schließlich der Nachweis eines Mehrwertes von seriellen Biomarkermessungen gegenüber der Messung zu Studienbeginn geführt. Zu Schritt (3) wurde Design und Planung einer Interventionsstudie aufgestellt, welche das Ziel hat, einen Vorteil der Biomarker-gesteuerten Therapieentscheidung zu belegen. Das Ziel der Arbeit ist es, geeignete statistische Methoden für die komplexen Aufgabenstellungen zu erarbeiten bzw. anzuwenden und die Ergebnisse entsprechend darzustellen. Zur Anwendung kamen dabei dem State of the Art entsprechende Methoden der Biostatistik. Für die Auswertung von seriellen Biomarkern wurden bereits bestehende Methoden weiterentwickelt. Die gezeigten klinischen Ergebnisse, insbesondere für Mid-regionales pro-Adrenomedullin und Procalcitonin, sind von hoher klinischer und kommerzieller Relevanz und wesentliche Meilensteine auf dem Weg zur klinischen Anwendung. Beide Biomarker werden von Thermo Fisher Scientific vertrieben., Scientific proof of the superiority of a biomarker-guided risk stratification or even treatment decisions that will ultimately contribute to the improvement of patient management includes several research steps. Three specific stages are the basis for clinical biomarker research. 1\. First observational studies describing the association between biomarkers and survival, 2\. studies of specific characteristics of the biomarker in comparison to other biomarkers, and 3\. first intervention studies that may ultimately prove the advantage of a biomarker-driven approach. The presented thesis is based on six publications, which cover individual stages. The specific statistical problems may be summarized as follows: in stage (1) a U-shaped relationship between biomarker and survival prognosis using spline transformation was modelled in a general regression model. Stage (2) demonstrated independence and added value of a biomarker compared to existing clinical variables using nested regression models and the net reclassification index, evaluated short- versus long-term survival prediction, and showed added value of serial biomarker measurements on top of a single measurement at baseline. Finally, (3) covered the design and planning of an interventional study to demonstrate superiority of a biomarker-guided therapy decision. The aim of this thesis was to develop and/or apply appropriate statistical methods and to present the results accordingly. State of the art methods in biostatistics were applied. For the evaluation of serial biomarkers, existing methods have been extended. The clinical results shown in the publications, particularly for mid-regional pro- adrenomedullin and procalcitonin, are of great clinical and commercial relevance and represent major milestones on the path to clinical application and acceptance. Thermo Fisher Scientific sells both biomarkers.

To evaluate in an interventional trial on knee osteoarthritis (OA) the level and change of two serum biomarkers and their correlation with imaging parameters. The previously reported interventional OA study (ClinicalTrials.gov: NCT00536302) identified a positive effect of collagen hydrolysate (CH) on cartilage morphology in patients with knee OA using delayed gadolinium enhanced magnetic resonance imaging (dGEMRIC). It was the objective in this research project to evaluate in an interventional clinical trial on knee OA the level and change of two serum biomarkers and their correlation with imaging parameters. In blood samples of study participants, we determined the concentration of procollagen type II N-terminal propeptide (PIIANP) and aggrecan chondroitin sulfate 846 epitope (CS846) at baseline (BL) and at the follow-up (FU) visits at 24 and 48 weeks. We measured the level and change of biomarker concentrations in both study groups, and the correlation of those changes with changes in dGEMRIC. For the biomarker PIIANP, we observed a significantly greater increase in the CH group (29.9% vs. 1.2% at week 24, P = 0.001). For CS846, the mean concentration was lower among the CH treated participants at 24 weeks (78% vs. 96%, P = 0.045). Consistent correlations of changes in biomarkers PIIANP and CS846 with changes of the dGEMRIC score could not be observed. In this study, different changes per treatment group, CH and placebo were seen for dGEMRIC and PIIANP BL to 24 weeks FU, but only weak correlations between changes in dGEMRIC and biochemical markers.

Background: Given the increasing prevalence of youth overweight and obesity in the last decade, prevention as become an international public health priority.Objective: The aim of The PRALIMAP (PRomotion de l'ALIMentation et de l'Activité Physique) trial was to evaluate the 2-year effectiveness of three strategies - « Education », « Screening » et « Environment »- aimed at preventing overweight and obesity among adolescents in high school setting on body size and nutritional knowledge and behaviours. Method: PRALIMAP was a school-based randomized controlled trial beginning in 24 state-run high schools (clusters) in Lorraine (north-eastern France). Each study high school was assigned to receive or not, over a 2-year period (grades 10 and 11), each of the three prevention strategies according to a 2x2x2 factorial school randomization. The prevention strategies were: ?education? (development of nutritional knowledge and skills), "environment" (creation of favourable environment by improving availability of dietary items with a good nutritional quality and physical activity), and "screening" (detection of overweight and obesity and, if necessary, adapted care management). The follow-up consisted of three visits: at the entry of grade 10(T0), grade 11(T1) and grade 12(T2). Body mass index (BMI), BMI z-score and prevalence of overweight and obesity were the main outcomes measures. Secondary outcomes measures were nutritional knowledge and behaviours. Comparisons of changes (T2-T0) of outcomes measures between each strategy schools and their control were carried out using a three-level hierarchical mixed model. A process evaluation allowed estimating an intervention dose really received by adolescents. Results: The 2-year change of anthropometric outcomes was more favourable in the 12 screening high schools as compared with the no-screening ones: a lower increase in BMI (+0,6 vs +0,7, p=0,0303), a greater decrease in BMI z-score (-0,9 vs -0,5, p=0,0173) and a greater decrease in overweight / obesity prevalence (-2,3% vs -0,6%, p=0,0386). The education strategy resulted in improved nutritional behaviours: a greater increase in achievement of starchy food guidelines (3,6% vs -0.7%, p=0.0357) and physical activity practice (+0,02 vs -0,10, p=0,0047). The environment strategy resulted in improved nutritional attitudes: a lower decrease in achievement of number of weekly meals guidelines (-4.5% vs -8.5%, p=0.0101) and greater increase in nutritional knowledge (+1,9 point vs +1,0 point, p=0.0094). Some differences in activity implementation and participation were highlighted and can explain some of the results observed. Conclusions: The screening strategy is an effective way to prevent, at two years, overweight and obesity among adolescents in a high school setting. Nutritional education added to the curriculum is not effective in the short term on body size. The school nutritional environment modification is slightly associated with improved nutritional knowledge and behaviours, Contexte : Etant donné la forte progression de la prévalence du surpoids et de l'obésité à l'adolescence ces dernières décennies, la prévention est devenue une priorité de santé publique internationale. Objectif : L'essai PRALIMAP (PRomotion de l'ALIMentation et de l'Activité Physique) évalue l'impact de trois stratégies de prévention du surpoids et de l'obésité - « Education », « Environnement », « Dépistage » - chez les adolescents en milieu scolaire, sur la corpulence, les connaissances, attitudes et comportements des adolescents vis-à-vis de la nutrition (alimentation et activité physique). Méthode : Les trois stratégies ont été affectées à 24 lycées de la région Lorraine (Nord-est de la France) sur 2 années (en classe de seconde et de première) par randomisation en grappe (=lycée), selon un plan factoriel 2x2x2. La stratégie Éducation consistait en des cours et des travaux de groupe sur la nutrition et une fête nutritionnelle annuelle. La stratégie Environnement consistait à améliorer l'offre nutritionnelle des lycées et organiser une fête nutritionnelle annuelle. La stratégie Dépistage consistait en un repérage des adolescents en surpoids ou obèses suivi d'une prise en charge adaptée collective. Les données ont été recueillies à 3 reprises : à l'entrée en classe de seconde (T0), de première (T1) et de terminale (T2). L'indice de masse corporelle (IMC), son z-score et la proportion d'adolescents en surpoids ou obèses étaient les critères de jugement principaux. Les critères de jugement secondaires étaient les connaissances et comportements nutritionnels. Les différences d'évolution T0-T2 des critères de jugement entre les 12 lycées ayant bénéficié d'une stratégie et les 12 lycées témoins de cette stratégie a été analysée à l'aide de modèles mixtes. Une évaluation du processus a permis d'estimer la dose réelle d'intervention de chaque stratégie dans chacun des lycées. Résultats : La stratégie Dépistage a entrainé une amélioration de la corpulence : augmentation moins importante de l'IMC avec la stratégie Dépistage (+0,6 vs +0,7, p=0,0303), diminution plus importante du z-score de l'IMC (-0,9 vs -0,5, p=0,0173) et de la prévalence du surpoids et de l'obésité (-2,3% vs -0,6%, p=0,0386). La stratégie Education a entrainé une amélioration de certains comportements nutritionnels : augmentation plus importante de la proportion d'adolescent suivant la recommandation nutritionnelle sur les féculents (3,6% vs -0,7%, p=0,0357) et du nombre d'activités physiques pratiquées (+0,02 vs -0,10, p=0,0047). La stratégie Environnement a amélioré les comportements et les connaissances nutritionnels : diminution moins importante de la proportion d'adolescents suivant la recommandation nutritionnelle sur le nombre de repas hebdomadaire (-4,5% vs -8,5%, p=0,0101) et amélioration plus importante du score de connaissances nutritionnelles (+1,9 point vs +1,0 point, p=0,0094). Des différences dans la réalisation des activités et la participation ont été mises en évidence suite à l'estimation de la dose d'intervention et peuvent expliquer certains résultats observés. Conclusion : Une stratégie de dépistage structurée en milieu scolaire apparaît bénéfique sur la réduction du surpoids et de l'obésité. L'addition d'activités d'éducation nutritionnelles dans le cursus n'induit pas d'effets sur la corpulence à court terme. La modification de l'environnement nutritionnel scolaire semble avoir un effet sur les indicateurs intermédiaires de connaissances et comportements nutritionnels