There are good reasons to perform a randomized controlled trial (RCT) even in early phases of clinical development. However, the low sample sizes in those settings lead to high variability of the treatment effect estimate. The variability could be reduced by adding external control data if available. For the common setting of suitable subject-level control group data only available from one external (clinical trial or real-world) data source, we evaluate different analysis options for estimating the treatment effect via hazard ratios. The impact of the external control data is usually guided by the level of similarity with the current RCT data. Such level of similarity can be determined via outcome and/or baseline covariate data comparisons. We provide an overview over existing methods, propose a novel option for a combined assessment of outcome and baseline data, and compare a selected set of approaches in a simulation study under varying assumptions regarding observable and unobservable confounder distributions using a time-to-event model. Our various simulation scenarios also reflect the differences between external clinical trial and real-world data. Data combinations via simple outcome-based borrowing or simple propensity score weighting with baseline covariate data are not recommended. Analysis options which conflate outcome and baseline covariate data perform best in our simulation study.

BackgroundGlobally, diabetes mellitus (DM) and peripheral artery disease (PAD) have an increasing incidence and a high prevalence and are both associated with high morbidity and complication rates, e.g., as chronic non-healing peripheral ulcers. Impaired macro- and microcirculation and peripheral neuropathy lead to an increased risk of foot ulcers and infections. These complications are difficult to treat, have a high risk of becoming chronic and often lead to lower limb amputation. The aim of this planned study was to investigate the potential effects of acupuncture on improving microcirculation in patients with Diabetic Foot Syndrome (DFS) and PAD.Materials and methodsIn 18 patients with chronic non-healing peripheral ulcers and diagnosed DM or PAD, data on 8 microcirculatory parameters were collected simultaneously on intact skin close to the wound margin. Microcirculation was assessed using an O2C device combining laser Doppler shift and white light spectroscopy (LEA Medizintechnik GmbH, Giessen, Germany). Unilateral and bilateral acupuncture was performed on the connecting line between acupuncture points Stomach 14 and Stomach 15.ResultsAfter unilateral acupuncture (ipsilateral to the wound side), a statistically significant improvement in 7 out of 8 microcirculatory parameters was demonstrated compared to baseline measurements before acupuncture. After bilateral acupuncture, there was an additional improvement and statistical significance in all parameters in both DFS and PAD patients.DiscussionThese results show an improvement in the microcirculation and peripheral blood flow at the edges of the wound. As impaired micro- and macrocirculation is considered to be a critical prognostic factor for the healing of a peripheral lesion, the intervention could have a positive impact on the healing of (chronic) peripheral wounds.

Understanding of the processes associated with socialization into collaborative work plays an important role in interprofessional education and collaborative practice. In order to evaluate changes in socialization toward interprofessional collaborative practice a measure is needed that captures professional beliefs, attitudes and behaviors of individuals in learning activities and in workplace practice. This article presents the translation and psychometric properties of the German Version of the Interprofessional Socialization and Valuing Scale (ISVS-21). Following translation from English to German, data of the German version of the questionnaire (ISVS-21-D) was collected in six different interprofessional education and practice settings amongst undergraduate students and health professionals. In total, 494 responses were analyzed. Results showed high reliability with Cronbach's alpha .90. Although not all fit indices are in the desired range, results give preliminary indication of the underlying single factor of the ISVS-21-D and suggest that the German version of the ISVS-21-D is a reliable instrument that can be used to measure interprofessional socialization in German health professionals and health care students as well as within other disciplines.

Zusammenfassung Hintergrund: Im Rahmen des Forschungsprojektes „Ganzheitliches Versorgungsprogramm für ältere Patienten zur Stärkung von spirituellen Bedürfnissen, sozialer Aktivität und Selbstfürsorge in der hausärztlichen Versorgung (HoPES3)“ wird die Implementierung von Spiritual Care in allgemeinärztlichen Praxen untersucht. Forschungsfragen : Wie reagieren kranke ältere Menschen auf das Angebot einer spirituellen Anamnese? Was sind hinderliche Faktoren für spirituelle Gespräche in Hausarztpraxen? Methode : Ärzte und Ärztinnen aus 24 Praxen boten 164 ihrer Patienten und Patientinnen eine spirituelle Anamnese an. Mit 29 der Patienten bzw. Patientinnen wurden bis zu sechs Monate später qualitative leitfadengestützte Interviews geführt. Die Interviews wurden mittels Reflexive Thematic Analysis (RTA) ausgewertet. Ergebnisse : Insgesamt hatten von den 29 befragten Patienten/Patientinnen nur elf das vollständige Anamnesegespräch geführt, die Mehrheit hatte das Gespräch abgelehnt. Als Gründe werden angegeben: Vorbehalte gegenüber religiösen Institutionen, Einschätzung der Thematik als „zu persönlich“ und ein Bedürfnis nach Selbstwirksamkeit. Die Beziehung zum Arzt oder der Ärztin wird mehrheitlich positiv geschildert, gleichzeitig wird ein allgemeines Bedürfnis nach einem Austausch auf Augenhöhe deutlich. Diskussion : In den Reaktionen der Patienten/Patientinnen kann die Wirkung einer Machtasymmetrie in der Arzt-Patienten-Beziehung beobachtet werden, verstärkt durch das strukturelle Setting der Praxis sowie durch Parallelen des Gesundheitssystems mit religiösen Systemen, die bei der spirituellen Anamnese zum Tragen kommen können. Schlussfolgerung : Bei Weiterbildungen im Feld Spiritual Care sollte die Sensibilität für das Thema Machtasymmetrien gestärkt werden.

Background Shared decision-making (SDM), which increases the patient’s well-being, adherence, and success of treatment, is becoming increasingly important in medicine and especially in oncology. To empower patients to participate more actively in consultations with their physicians decision aids have been developed. In non-curative settings, such as the treatment of advanced lung cancer, decisions differ substantially from the curative setting, as uncertain gains in terms of survival outcomes and quality of life have to be weighed against the severe side effects of treatment regimens. There is still a lack of tools developed and implemented for such specific settings in cancer therapy that support shared decision-making. The aim of our study is to evaluate the effectiveness of the HELP decision aid. Methods The HELP-study is designed as a randomized, controlled, open monocenter trial with two parallel groups. The intervention consists of the use of the HELP decision aid brochure, accompanied by a decision coaching session. The primary endpoint is clarity of personal attitude as operationalized by the Decisional Conflict Scale (DCS) after the decision coaching. Randomization will be performed as stratified block randomization according to the characteristic of preferred decision-making at baseline with a 1:1 allocation. The participants in the control group get usual care, i.e., the doctor-patient conversation takes place without preliminary coaching and deliberation about their preferences and goals. Discussion Developing decision aids (DA) for (lung) cancer patients with limited prognosis should empower patients to address these aspects and include information about “Best Supportive Care” as a treatment option. Using and implementing the decision aid HELP can not only give patients the possibility to include their personal wishes and values in the decision-making process, but also raise the awareness of shared decision-making itself among these patients and their physicians. Trial registration German Clinical Trial Register DRKS00028023. Registered on 8 February 2022.

To understand if GPs’ spiritual competence, their personal spirituality and attitude towards enquiring about spirituality in practice interrelate, we conducted a cross-sectional survey of 30 German GPs regarding issues of SC. We found correlations between GPs’ personal spirituality, their spiritual competence and their attitudes towards SC. The ability to perceive spiritual needs of patients was the competence most strongly related to GPs’ attitude towards SC. The competence with the strongest correlation to personal spirituality was Self-awareness and Proactive opening. No correlation was found between affiliation to a spiritual community and GPs’ attitude towards SC. The results show that GPs’ personal spirituality and spiritual competence are indeed related to addressing spirituality with their patients. To foster SC, training programmes should raise awareness for one’s personal spirituality and encourage one to reflect on spiritual competence.

Purpose: The APROVE study is a prospective one-arm phase-2 study investigating the safety and treatment tolerability of postoperative proton beam therapy in women with uterine cervical or endometrial cancer. In this analysis, we report the primary study endpoint of safety and treatment tolerability as well as toxicity rates and progression-free survival (PFS).Methods and Materials: 25 patients were treated with postoperative proton beam therapy with a total dose of 45 to 50.4 Gy (RBE) in 5 to 6 x 1.8 Gy (RBE) fractions weekly using active raster-scanning intensity modulated proton beam therapy (IMPT). Sequential or simultaneous platinum-based chemotherapy was administered if indicated. The primary endpoint was defined as the lack of any acute >= grade 3 gastrointestinal (GI) or urogenital (GU) toxicity according to the Common Terminology Criteria for Adverse Events v 4.0 or premature treatment abortion. Secondary endpoints were clinical symptoms and toxicity, quality of life, and PFS.Results: All patients completed IMPT according to the protocol, with a median treatment duration of 43 days (range, 33 to 51 days). No patient developed gastrointestinal or genitourinary toxicity >= grade 3, and the treatment tolerability rate was 100%. Therefore, the null hypothesis H0: Tolerability Rate <= 80% could be rejected in favor of the alternative hypothesis H1: Tolerability rate >80% using an exact binomial test with a one-sided significance level of alpha = 10% (one-sided P value P = .0059). The median follow-up time after the end of IMPT was 25.1 months (range, 20.2 to 50.3 months). 18 of 25 (75%) patients completed the study follow-up of 24 months. 7 patients had progressive disease. Kaplan-Meier-estimated mean PFS was 39.9 months (95% confidence interval: 33.37 to 46.5 months).Conclusions: Postoperative IMPT is a safe treatment option for cervical and endometrial cancer patients, with only low-grade acute and late toxicities. Larger randomized trials are necessary to further assess the potential of IMPT and improve patient selection.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/)

Abstract Background Non-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment. Methods/ design In this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy. Discussion Preclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response. Trial registration Clinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019–002192-33 . Registered 24 October 2019,

Abstract Introduction The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms. Methods 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading. Results Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years. Conclusion Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue. Trial registration: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017).

Background About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3 -ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. Methods In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m 2 bidaily day one to day three, mitoxantrone 10mg/m 2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α =0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. Conclusion Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3 -ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. Ethics and dissemination Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial registration ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Objectives: After a successful Marketing Authorization Application for clinical trials with time-to-event endpoints, the degree of the added benefit from new treatments remains unknown and needs to be assessed. Unfortunately, until now no clear definition for added benefit determination of a treatment exists. Nevertheless, European authorities / societies have developed 2 "additional benefit assessment" methods, which have up to now not been compared: the European Society for Medical Oncology (ESMO) developed a dual rule considering relative and absolute benefit. The German Institute for Quality and Efficiency in Health Care (IQWiG) developed a method using upper 95% hazard ratio confidence interval. Methods: We evaluate and compare both methods in an extensive simulation study including different censoring rates, failure time distributions, and treatment effects for sample size calculation. The methods' performance is assessed via Receiver Operating Characteristic curves, Spearman correlation, and percentage of achieved maximal scores. Results: The results show that IQWiG's method has in many situations a lower maximal scoring proportion than ESMO's rule, that is, up to 28.5% versus 94.7%. Various failure time distributions lead to strongly changed maximal scoring percentages for ESMO. High positive correlation between the methods is present for moderate treatment effects. Conclusions: IQWiG's method is usually more conservative than ESMO's. ESMO's rule tends to be more susceptible for various failure time distributions. Using the lower confidence interval limit seems to be a better solution resulting in a higher true-positive rate without increasing the false-positive rate. Thus, IQWiG's method might need to be adapted accordingly to achieve a better overall classification.

Background Recently, the combination of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab with first-line chemotherapy has demonstrated to improve outcome for patients with advanced small cell lung cancer (SCLC), leading to approval of this regimen. At the same time, accumulating (pre-)clinical data suggest synergisms of radiotherapy and immunotherapy via the radiation-mediated induction of anti-tumor immunogenicity. Combining the recent findings, the TREASURE trial aims at further enhancing response to upfront chemo-immunotherapy by the addition of thoracic radiotherapy (TRT). Methods/design The TREASURE trial is a randomized, multicenter, phase II clinical trial ( ClinicalTrials.gov identifier, NCT04462276). One hundred four patients suffering from extensive disease (ED) SCLC, with any response to the standard of care induction chemo-immunotherapy will be randomized to receive atezolizumab maintenance therapy with or without TRT. The primary endpoint of this study is overall survival (OS). Secondary endpoints include further measures of efficacy, safety, and the collection of biomarker samples. A safety interim analysis will take place after n = 23 patients receiving TRT have been observed for three months after the end of TRT. Discussion This trial will investigate whether treatment efficacy can be improved by adding TRT to atezolizumab maintenance therapy in ED SCLC patients with any response after chemo-immunotherapy. Safety and feasibility of such a regimen will be evaluated, and biomaterials for a translational research project will be collected. Together, the results of this trial will deepen our comprehension of how checkpoint inhibition and radiotherapy interact and contribute to the evolving landscape of SCLC therapy. Trial registration Clinicaltrials.gov identifier: NCT04462276 (Date of initial registration: 8th July 2020), https://clinicaltrials.gov/ct2/show/NCT04462276 Eudra-CT Number: 2019-003916-29 (Date of initial registration: 30th March 2020), https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003916-29/DE

Background: The "Holistic Care Program for Elderly Patients to Integrate Spiritual Needs, Social Activity and Self-Care into Disease Management in Primary Care" (HoPES3) examines the implementation of a spiritual history (SH) as part of a multifaceted intervention in German general practices. While the effectiveness of the interventions was evaluated in a cluster-randomized trial, this article investigates the patients' views concerning the acceptability of the SH and its effects. Methods: A mixed-methods study was conducted in which 133 patients of the intervention group filled in a standardized questionnaire after the intervention. Later, 29 of these patients took part in qualitative semi-standardized interviews. Results: According to the survey, 63% (n = 77) of patients found the SH helpful. In the interviews, however, many indicated that they either kept the conversation brief or declined the offer to talk about spirituality. Contents of longer conversations referred to difficult life events, personal sources of strength, and experiences with religious institutions. Many patients who had a longer conversation about spirituality reported that their relationship with their general practitioner (GP) had improved. Almost all patients recommended integrating a personal conversation of this kind into primary care. Conclusions: The SH seems to be a possible 'door opener' for a trusting doctor-patient relationship, which can then be built upon.

Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE ) in hospitalized patients with severe COVID-19 ( n = 134) within four risk groups ((1) cancer ( n = 56); (2) immunosuppression ( n = 16); (3) laboratory-based risk factors ( n = 36); and (4) advanced age ( n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer ( P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response.

In a basket trial, a new treatment is tested in different subgroups, called the baskets. In oncology, the baskets usually comprise patients with different primary tumor sites but a common biomarker. Most basket trials are uncontrolled phase II trials and investigate a binary endpoint such as tumor response. To combine the data of baskets that show a similar response to the treatment, many basket trial designs use Bayesian borrowing methods. This increases the power compared to a basketwise analysis. However, it can lead to posterior probabilities that are not monotonically increasing in the number of responses. We show that, as a consequence, two types of counterintuitive decisions can arise-one that occurs within a single trial and one that occurs when the results are compared between different trials. We propose two monotonicity conditions for the inference in basket trials. Using a design recently proposed by Fujikawa and colleagues, we investigate the case of a single-stage basket trial with equal sample sizes in all baskets and show that, as the number of baskets increases, these conditions are violated for a wide range of different borrowing strengths. We show that in the investigated scenarios pruning baskets can help to ensure that the monotonicity conditions hold and investigate how this affects type I error rate and power.

Background: Therapy options are limited for COVID-19 patients with hematological disease, cancer, immunosuppression or advanced age. Even though no benefit was observed for convalescent plasma in unselected patients with COVID-19, retrospective data suggest that it could be effective in patients unable to mount a sufficient immune response upon SARS-CoV-2 infection. Plasma from vaccinated donors has not been systematically assessed for COVID-19 treatment. Aims: We conducted a randomized clinical trial to address plasma efficacy in patients at high risk for an adverse outcome. Methods: COVID-19 patients with confirmed SARS-CoV-2 infections and oxygen saturation <=94% were randomized (NCT05200754). Patients received convalescent or vaccinated SARS-CoV-2 plasma in two bags (238 - 337 ml plasma each) from different donors on day 1 and 2 (PLASMA) or standard of care (CONTROL). Randomization was stratified according to four clinical patient groups, hematological/solid cancer (group-1), treatment or disease associated immunosuppression (group 2), high risk disease by standard parameters (group-3) or age >=75 years (group-4). Mechanically ventilated patients were not eligible. Plasma was obtained from donors with high level neutralizing activity (titer >=1:80) either after SARS-CoV-2 infection (convalescent) or after vaccination with at least two doses of mRNA vaccines (vaccinated). Crossover for the control group was allowed at day 10. The primary endpoint was time to improvement as two points on a seven-point ordinal scale or live discharge from the hospital (IMPROVEMENT) with prespecified analyses of subgroups (Janssen M, et al. Trials 2020 Oct 6;21(1):828). Results: A total of 133 patients were randomized with 68 receiving PLASMA with a median age of 68 years (range 36-95) or CONTROL (n=65, of which n=10 (15.4%) crossed over at day 10) with a median age of 70 years (range 38-90). The distribution of the four predefined groups was group-1, n=53; group-2, n=18; group-3, n=35; and group-4, n=27. The intention to treat analysis revealed a non-significant shorter time to IMPROVEMENT for patients in PLASMA (median 12.5 days, 95%-CI [10; 16]) compared to patients in CONTROL (median 18 days, 95%-CI [11; 28]), hazard ratio 1.24, 95% confidence interval [0.83; 1.85], p=0.29). Overall, 27 patients died (PLASMA, n=12; CONTROL, n=15; p=0.80). Predefined subgroup analysis revealed a clinically significant benefit in patients with hematological malignancies, other cancers or immunosuppression (group-1, group-2, n=71). With a median time to improvement of 13 days (95%-CI [9; 19]) for PLASMA and 32 days (95%-CI [17; 57]) for CONTROL(HR 2.03, 95%-CI [1.17; 3.6], p=0.01). A sensitivity analysis revealed that IMPROVEMENT appeared to be seen even earlier with vaccinated (median 10 days, 95%-CI [8; 14]) compared to convalescent SARS-CoV-2 plasma (median 13 days, 95%-CI [6; 38]) and CONTROL. Within group-1 and group-2, six patients in PLASMA (18.2%) and 10 in CONTROL (28.6%) died. No significant differences in improvement were observed in group-3 and group-4 with a HR of 0.72 (95%-CI [0.41; 1.28], p=0.26). Within group-3 and group-4, six patients in PLASMA (18.8%) and five in CONTROL (16.7%) died. No previously unknown side effects of plasma therapy emerged within the trial. Image:Summary/Conclusion: Plasma from convalescent and particularly vaccinated donors improved outcome of COVID-19 patients with an underlying hematological disease /cancer or other reasons of impaired immune response. Plasma did not improve outcome in immune-competent patients with other risk factors and/or older age.