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[FG] Steiger Jürg & Koller Michael

Projects & Collaborations

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Immediate and pre-emptive therapies for SARS CoV-2 positive and negative patients with high risk for Covid-19 pneumonia: Immunocompromised Collaborative Host Swiss Cohorts Based Trial Platform Initiative

Research Project  | 2 Project Members

Endorsed public health measures have confined the SARS-CoV-2 pandemic in Western Europe but leave due to very low herd immunity a high proportion of the population at risk of infection. In a not unlikely second epidemic routine and repetitive PCR testing is essential for at risk populations for complicated SARS-CoV-2 for infection protection and monitoring. It is less clear, whether preventive treatment in individuals with Covid-19 infection with mild symptoms or in those uninfected but at high risk of complicated SARS-CoV-2 infection may offer additional protection against complicated SARS-CoV-2 infection. Methods We will set up a trial platform which will be implemented and nested into the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study to investigate during a new epidemic the comparative effectiveness of immediate and preventive therapy with emerging antivirals against SARS-CoV-2. Patients in these cohorts with mild SARS-CoV-2 infection with no pneumonia and SARS-CoV-2 negative patients at risk for complicated infection due to age, HIV (<350-500 CD4 cells/µl), solid organ transplantation or with risk factors for COVID-19 pneumonia who consent to participate in the trial will be randomised to candidate antivirals. The primary composite endpoint is CT-confirmed pneumonia, hospitalization or death from any cause. Need for immediate hospitalization for any reason is an exclusion criteria. Based on accumulating evidence of ongoing and published trials of antiviral drugs against SARS-CoV-2 infection, patients will be randomized in the presence of one active drug to drug A versus control, in the presence of two drugs to drug A or B or control. Interim analyses are planned to adaptively randomize patients to the most effective comparator arm (intervention duration 18 months). Arms may be suspended for ineffectiveness and new arms may be added to the trial as novel therapies emerge. Interventional drugs will be selected by expert panels from both cohorts with provision of external up-to date evidence from meta-analytical reports. Relevance The project intends to establish a trial platform that is nested into existing cohort infrastructure to investigate the comparative effectiveness of early and preemptive upcoming antiviral therapies to prevent complications from SARS-CoV-2 in two very vulnerable patient populations. The chosen innovative trial designs allows for rapid trial implementation in case of a second epidemic and in the absence of an effective vaccine. The trial platform can be easily extended to involve further Swiss (or international) cohorts and will serve as an ideal instrument for potential future pandemics.

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Swiss Transplant Cohort Study PSIG

Research Project  | 10 Project Members

The Swiss Transplant Cohort Study (STCS) is a prospective open multicentre cohort study of all solid organ transplant (SOT) recipients in Switzerland. The project was initiated in 2007 and started to actively enrol patients in May 2008. The project has been funded, among others, by the SNSF as the core funding agency and currently stays in its 4th funding period. The STCS has evolved into the key tool of transplantation outcome research in Switzerland and has gained rapid international recognition due to the high granularity of data and systematic sampling, resulting in a remarkable scientific output. The key strength that made the STCS a prominent research platform is that the leading national experts from various disciplines collaborate under one roof. Over the last years, the number of scientific projects conducted within the STCS network was continuously increasing, with the 100th project approved by the STCS Scientific committee in 2016. Currently, 41 publications appeared in peer-reviewed scientific journals. Transplant infectious diseases continued to be one of the key areas of interest with a particular track record of critical issues in CMV infections. New areas have emerged, such as airway microbiome assessments in lung transplant recipients, T-cell response studies of BK virus infections in renal transplant recipients or genetic host factors of various infectious diseases phenotypes. Since 2012, the STCS collects antibiotic drug resistance data and first results are expected in 2017. Also recently, the genetic dataset has been enlarged to 3000 patients with genome-wide data and 10 published genetic studies of various phenotypes. The Psychosocial Interest Group (PISG) presented novel studies on body weight evolution, the influence of drug adherence and on workability after renal transplantation. Multiple national and international partners collaborate with the STCS for knowledge- and data exchange, resulting in high-ranked publications. A new level will be achieved with the inter-cohort collaboration with the Danish Persimune cohort and the creation of a metacohort with a common research portfolio. The backbone of the STCS is the unique data structure that allows reflecting every transplant type and the monitoring of even more complicated follow-up scenarios. The data involves clinical -, organ-specific -, laboratory -, psychosocial and behavioural -, genetic and infectious disease contents prospectively collected on a long-term schedule. In parallel, bio-banking of plasma, cell and DNA samples takes place at 0 - 6 - 12 months. Moreover, the STCS is legally mandated to keep a limited-registry of non-consenting patients. By the end of 2016, the STCS centres enrolled 4023 patients with 4187 transplantations, and a total of 4392 transplanted organs. During a maximum follow-up of nearly 9 years, 545 patients died (13.5%) and only 42 patients were lost to follow-up (1%). 93% of all Swiss transplant recipients provided written informed consent to the full STCS datasets, and 99% of consenting patients contributed to the STCS bio-bank. The STCS publishes comprehensive reports for the public and key federal institutions, such as the Federal Office of Public Health, UniMedSuisse and the Swiss Highly Specialized Medicine Board. In 2017, clinical transplant experts conducted in-depth reviews of all datasets and defined the necessary adaptations for the next upgrade (STCS generation 3). Furthermore the genetic working group was created to coordinate funding of extended genotyping and regulate the further use of genetic data. By May 2017, 76 persons were working for the STCS corresponding to 23.8 full-time equivalents being financed by SNF, third party, and own funds. For the next funding period, the STCS will face a number of significant challenges. Patients will be involved more closely to specify their needs and integrate their priorities. In addition to the two randomized trials ongoing and in preparation, additional trials are planned to improve the management of infectious complications post-transplant. The immunological datasets need an update to enable high-quality immunological studies. The current data model will expend towards an interoperability platform to link hospital routine care- and lab data from the centres using the standards proposed by the Swiss Personalized Health Network (SPHN). Conclusion: At the end of four SNF funding periods, the STCS represents a transplant cohort with a patient volume largely above 4000, that experiences large international recognition and that serves a broad variety of clinical, translational, interventional, psychosocial, and health services research. The presented approach to expand the data model towards a data and interoperability platform will prepare the STCS to enter the personalized health area.

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NEOZYTOLYSE BEI DER BEHANDLUNG DER RENALEN ANÄMIE MIT ERYTHROPOESE STIMULIERENDEN AGENZIEN (ESA)

Research Project  | 1 Project Members

Die Behandlung der renalen Anämie mit rekombinantem Erythropoetin und seinen Derivaten (Erythropoe-se stimulierende Agenzien, ESA) ist eine gut etablierte Therapie. Bis zur Einführung von Methoxy-PEG-Epo-beta (CERA, Mircera®) lag die Halbwertszeit der verfügbaren Präparate bei intravenöser Anwendung bei 7 bis 24 Stunden. Applikationsintervalle von 4 Wochen sind mit diesen ESAs schwierig[1], während sie bei CERA problemlos möglich sind, obwohl auch dessen Halbwertszeit (5.6 Tage) im Vergleich zum Do-sisintervall (28 Tage) vergleichsweise kurz ist[2]. Die Gründe warum lange Applikationsintervalle bei kür-zer wirksamen ESA grundsätzlich schwierig, bei einzelnen Patienten aber möglich sind, sind unklar. Seit über 10 Jahren ist ein physiologischer Vorgang bekannt, bei dem es unter Absinken der endogenen Erythropoetinspiegel zu einer aktiven Reduktion der Anzahl von Erythrozyten kommt[3]. Dieser Vorgang wird als Neozytolyse bezeichnet. Betroffen von diesem Abbau scheinen vorwiegend junge Formen von Erythrozyten mit einem Lebensalter von unter zehn Tagen zu sein. Auf Grund der Beschränkung der Neo-zytolyse auf junge Formen von Erythrozyten sind die Effekte der Neozytolyse in Retikulozyten und E-rythrozyten die noch positiv für CD36 sind, zu erwarten. Durch die Zufuhr geringer Mengen rekombinanten Erythropoetins kann die Neozytolyse unterbunden werden. Es wird vermutet, dass die Neozytolyse auch bei der Behandlung der renalen Anämie hämodialysierter Patienten eine Rolle spielt da bei der Gabe von kurzwirksamen ESA die Serumwerte schnell stark absinken[4]. Bei einer Halbwertszeit des CERA von 5,6 Tagen könnten die vorliegenden Serumspiegel nach zwei Halbwertszeiten noch hoch genug sein um die neu produzierten Erythrozyten effektiv vor der Neozytolyse zu schützen. Ziel der Studie Durch die Messung von Retikulozyten und Erythrozyten positiv für CD36 in kurzen Intervallen (bei jeder Dialyse) und die Bestimmung des Alters dieser Retikulozyten soll das Vorliegen der Neozytolyse unter Anwendung von kürzer wirksamen ESA im Vergleich zu CERA untersucht werden. Arbeitshypothese ist, dass die lange Halbwertszeit von CERA, welche bei intravenöser Applikation 134 Stunden beträgt, das Auftreten der Neozytolyse unterbindet. Des weiteren soll die Auswirkung von Neozytolyse auf den Eisenstoffwechsel geklärt werden. Da es möglich ist, dass die residuelle Erythropoetinsekretion der Patienten eine wesentliche Rolle spielt, wird bei der Patientenauswahl darauf geachtet, dass die Extreme der basalen Epo-Sekretion gleichmässig vertreten sind. Design der Studie Bei dieser Studie handelt sich um eine single center open label und cross over Studie an Patienten wel-che an der Hämodialyse behandelt werden. Eingeschlossen werden 16 Patienten. Das Design ist in Ab-bildung 1 ersichtlich.

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Development and validation of a coronary risk prediction model for ageing European and US American individuals: a collaborative project of the Rotterdam and Cardiovascular Health Studies

Research Project  | 1 Project Members

We aim to develop and validate prognostic models for the prediction of coronary heart disease (CHD) events in individuals of advanced age. The rational of the project is that exisiting risk prediction models for CHD are based on the data of younger popultations (e.g. Framingham or PROCAM models) and that generalizability of these models to elderly subjects is poor. Preventive regimens for risk factor modification (e.g. statins) are currently extended to the ageing population. Initiation of such treatment should, in line with younger subjects, be based on risk stratification which is appropriate for the population of elderly subjects. Within a network of international collaboration, I have access to the data of two large population-based observational cardiovascular cohort studies of elderly subjects, the Rotterdam study (RS) and the US Cardiovascular Health Study (CHS). Based on the data of the RS, we will develop gender-specific CHD risk prediction models. In a second step, we will validate the RS-model within the data of the CHS. I.e. predicted 10-year risk of CHD resulting from the RS model will be compared to the observed risks of the CHS data. Good performance and therefore validity of the models is indicated in the case of close agreement between predicted risk based on the development set and observed risk in the validation set. The authorities of the RS and the CHS, as well as the ethic committee of Basel (EKBB) have approved this study. Valid coronary risk prediction in the elderly is of urgent need due to the expansion of (potentially expensive) coronary risk prevention strategies to elderly people.

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Swiss transplant cohort study (STCS)

Research Project  | 2 Project Members

Transplantation medicine has evolved from an experimental approach to a life saving standard treatment option for many patients. Each year, 400 solid organ (kidney, heart, lung, liver, pancreas and Langerhans islets) and 100 allogenic stem cell transplants are performed in six Swiss transplant centers (Basel, Bern, Geneva, Lausanne, Zurich and St. Gall). Following transplantation, life long pharmacological immunosuppression is required to control rejection. These treatments favor the development of infections and malignancies, which together with uncontrolled rejections are responsible for the majority of deaths. In order to coordinate and promote research in the field of transplantation including psychosocial aspects all Swiss transplant centers have agreed to establish a Swiss Transplant Cohort Study (STCS) financed by the Swiss National Research Foundation. This interfacultary and interdisciplinary effort will create the first nation-wide transplantation cohort in which all types of transplanted organs are included. It will allow studies aiming at improving patient survival and quality of life. Data interrelated to infectious problems, immunosuppression, graft function, psychosocial aspects and patient survival, as well as patient specimens will be collected prospectively in a longitudinal manner at specific time points. The design of the STCS is in accordance with the new transplantation law, where other requirements such as quality assurance are foreseen. All hospitals with transplant centers further financially support the STCS. Since fall 2006, transplant experts from all six Swiss transplant centers have collaborated to establish the various datasets of the STCS. Thanks to the common effort all the different datasets for each organ are presently finalized. The possibility of coexisting transplants performed at various time points, double transplants and retransplants in a single patient introduces a high degree of complexity in the STCS and requires a sophisticated information flow. Specialists in epidemiology, informatic technology and transplantation medicine are presently elaborating the codebooks and various formularies of the future web based information capture system. So far the milestones initially planned have been respected and it is planned to include the first patients in January 2008.