How to avoid concerns with the interpretation of two primary endpoints if significant superiority in one is sufficient for formal proof of efficacy.

Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an established standard, is demonstrated. Traditionally one primary endpoint is specified, but various diseases exist where treatment success needs to be based on the assessment of two primary endpoints. With co-primary endpoints, both need to be "significant" as a prerequisite to claim study success. Here, no adjustment of the study-wise type-1-error is needed, but sample size is often increased to maintain the pre-defined power. Studies that use an at-least-one concept have been proposed where study success is claimed if superiority for at least one of the endpoints is demonstrated. This is sometimes also called the dual primary endpoint concept, and an appropriate adjustment of the study-wise type-1-error is required. This concept is not covered in the European Guideline on multiplicity because study success can be claimed if one endpoint shows significant superiority, despite a possible deterioration in the other. In line with Röhmel's strategy, we discuss an alternative approach including non-inferiority hypotheses testing that avoids obvious contradictions to proper decision-making. This approach leads back to the co-primary endpoint assessment, and has the advantage that minimum requirements for endpoints can be modeled flexibly for several practical needs. Our simulations show that, if planning assumptions are correct, the proposed additional requirements improve interpretation with only a limited impact on power, that is, on sample size.

Using a Further Planning MRI after Neoadjuvant Androgen Deprivation Therapy Significantly Reduces the Radiation Exposure of Organs at Risk in External Beam Radiotherapy of Prostate Cancer.

Radiotherapy for prostate cancer is often preceded by neoadjuvant androgen deprivation therapy (ADT), which leads to a reduction in the size of the prostate. This study examines whether it is relevant for treatment planning to acquire a second planning magnetic resonance imaging (MRI) after ADT (=MRI 2) or whether it can be planned without disadvantage based on an MRI acquired before starting ADT (=MRI 1). The imaging data for the radiotherapy treatment planning of 17 patients with prostate cancer who received two planning MRIs (before and after neoadjuvant ADT) were analyzed as follows: detailed comparable radiation plans were created separately, each based on the planning CT scan and either MRI 1 or MRI 2. After ADT for an average of 17.2 weeks, the prostate was reduced in size by an average of 24%. By using MRI 2 for treatment planning, the V60Gy of the rectum could be significantly relieved by an average of 15% with the same coverage of the target volume, and the V70Gy by as much as 33% (compared to using MRI 1 alone). Using a second MRI for treatment planning after neoadjuvant ADT in prostate cancer leads to a significant relief for the organs at risk, especially in the high dose range, with the same irradiation of the target volume, and should therefore be carried out regularly. Waiting for the prostate to shrink after a few months of ADT contributes to relief for the organs at risk and to lowering the toxicity. However, the use of reduced target volumes requires an image-guided application, and the oncological outcome needs to be verified in further studies.

Reduced humoral but stable cellular SARS-CoV-2-specific immunity in liver transplant recipients in the first year after COVID-19.

Mortality due to COVID-19 is not increased in immunosuppressed individuals after liver transplantation (OLT) compared to individuals without immunosuppression. Data on long-term protective immunity against SARS-CoV-2 in immunosuppressed convalescents, is limited. We prospectively measured immune responses against SARS-CoV-2 by quantifying antibodies against 4 different antigens (spike protein 1 and 2, receptor binding domain, nucleocapsid) and T cell responses by IFN-γ ELISPOT against 4 antigens (membrane, nucleocapsid, spike protein 1 and 2) in 24 OLT convalescents with immunosuppressive therapy longitudinally in the first year after COVID-19 including a booster vaccination in comparison to a matched cohort of non-immunosuppressed convalescents (non-IS-Con). Pre-pandemic OLT samples were retrieved from our prospective OLT biorepository (n = 16). No relevant T cell reactivity or immunoglobulin G (IgG) against SARS-CoV-2 were detectable in pre-pandemic samples of OLT recipients despite reactivity against endemic corona-viruses. OLT convalescents had a lower prevalence of IgG against nucleocapsid (54% vs. 90%) but not against spike protein domains (98-100% vs. 100%) after vaccination in the second half-year after COVID-19 compared to non-IS-Con. Also, concentrations of anti-nucleocapsid IgG were lower in OLT convalescents than in non-IS-Con. Concentration of IgG against spike protein domains was significantly increased by a booster vaccination in OLT convalescents. But concentration of IgG against two of three spike protein domains remains slightly lower compared to non-IS-Con finally. However, none of these differences was mirrored by the cellular immunity against SARS-CoV-2 that remained stable during the first year after COVID-19 and was not further stimulated by a corona vaccination in OLT convalescents. In conclusion, despite lower concentrations of anti-SARS-CoV-2 IgG in OLT convalescents anti-SARS-CoV-2 cellular immunity was as robust as in non-IS-Con.

Validity and reliability of the German multidimensional fatigue inventory in spinal muscular atrophy.

OBJECTIVE: Fatigue is a common and burdensome symptom of spinal muscular atrophy. Given its complex interactions, different dimensions of fatigue need to be investigated. The Multidimensional Fatigue Inventory is a widely used instrument that captures five distinct dimensions. The aim of this study was to investigate the validity and reliability of the German Multidimensional Fatigue Inventory in spinal muscular atrophy and to evaluate the presence of clinically relevant fatigue. METHODS: One hundred and forty adult spinal muscular atrophy patients completed the Multidimensional Fatigue Inventory in a nationwide, multicenter, cross-sectional study. Structural validity was explored using principal component analysis. Cronbach's α was calculated to evaluate internal consistency. Convergent validity was assessed by correlation with a Visual Analog Scale for fatigue and the EuroQol-Five Dimension-Five Level Scale as a measure of quality of life. RESULTS: The original five-component model of the questionnaire constituted an acceptable fit. Internal consistency and convergent validity of general, physical, mental fatigue, and reduced activity were good. We observed a floor effect for mental fatigue. While physical fatigue exceeded the cutoff for clinically relevant fatigue, all dimensions but reduced motivation correlated negatively with quality of life. Age, depression, and ≥4 copies of the survival motor neuron 2 gene were associated with higher general/physical fatigue; unemployed participants reported higher scores for reduced activity/motivation. INTERPRETATION: The Multidimensional Fatigue Inventory is a valid and reliable instrument to assess different dimensions of fatigue in spinal muscular atrophy. Fatigue is a relevant problem in spinal muscular atrophy and its assessment should be incorporated into standard care.