Abstract Objective Cervical cancer and its precursor lesions are treatable if detected early; however, screening participation for high-risk human papillomavirus infections (hr-HPV) remains low. In 2021, Germany recorded 4,544 new cervical cancer cases and 2,071 related deaths. The HaSCo study evaluates the feasibility of HPV self-testing to improve screening participation. This sub-study evaluates performance and acceptability of three self-testing tools. Methods This prospective, randomized sub-study examined Evalyn-Brush, FLOQSwabs, and first-void urine Colli-Pee among women aged 30—65 in Hannover, Germany. Addresses from the residents´ registration office were randomized into seven age groups and an 80/20 city–region distribution. A total of 19,995 women were assigned to opt-in (request a self-test) or opt-out (receive a test directly). Participation was requested from women without regular screening in the past two years. Results 1,860 samples were returned (9.3%). Colli-Pee (10.4%) and FLOQSwabs (10.1%) had similar return rates, while Evalyn showed significantly lower rates (7.4%). Screening frequency didn´t significantly affect return rates (p = 0.1825), although FLOQSwabs showed higher return rates among underscreened women. Invalid sample rates were low, highest for FLOQSwabs (1.67%). A total of 145 samples tested positive for hr-HPV (7.9%). Evalyn collected highest DNA content (p < 0.0001). Colli-Pee was most preferred, and 66.7% of participants favored self-testing. Conclusion HPV self-tests were highly accepted and effective for collecting sufficient DNA material. Direct provision of user-friendly self-tests may support screening participation, particularly among underscreened women. All three devices performed strongly and appear suitable for integration into cervical cancer screening programs.

Conditional marketing authorisation (CMA) is a path to early market access of new medicines addressing an unmet medical need in the European Union (EU), and similar concepts exist in other regulatory regions. For justifying a CMA, the benefit-risk ratio has to be positive, and the applicant must be able to provide comprehensive data post-authorisation for converting the CMA to a full marketing authorisation (MA). A recent proposal is to plan a single randomised clinical trial with interim analyses and base the decision for CMA and full MA on an intermediate and a final primary endpoint. To control the study-wise type-1-error (T1E), the dual primary endpoint concept, essentially a Bonferroni-split of the study-wise T1E between the intermediate and final endpoints, has been proposed. We argue that the resulting statistical definition of formal study success is not in line with clinical assessment of the overall trial outcome. Consistent with the European Medicines Agency (EMA) guideline on multiplicity issues in clinical trials, the intermediate and final endpoints should be co-primary, and we propose that each is assessed with a standard group sequential design. We illustrate our proposal using an oncology phase III trial with complete remission (CR) as the intermediate and overall survival (OS) as the final primary endpoint. Based on the example, we demonstrate that our proposal is a valid and flexible alternative with minimal to no impact on costs in terms of sample size or timing of the interim analysis intended for applying for a CMA but it improves the interpretation of the overall trial outcome.

AIMS:Digitoxin reduced the composite of death or worsening heart failure in DIGIT-HF, but whether these benefits translate into economic value remains unknown. We assessed its cost-effectiveness as add-on therapy for heart failure with reduced ejection fraction (HFrEF) across all 27 European Union Member States (EU-27) and the United States (US). METHODS:We developed a DIGIT-HF-informed, multi-jurisdictional three-state Markov cost-utility model projecting 10-year and lifetime outcomes. Clinical risks and intention-to-treat effects were held constant; hospitalization costs, EQ-5D-5L utilities, digitoxin costs, discounting, and willingness-to-pay (WTP) thresholds varied by jurisdiction. Uncertainty was assessed using 10 000 probabilistic simulations. RESULTS:Across the EU-27, digitoxin was cost-effective at 10 years, with incremental costs of -€338 to +€25 per patient, incremental quality-adjusted life-years (QALYs) of 0.188-0.231, and a maximum incremental cost-effectiveness ratio (ICER) of €120/QALY. Over lifetime, corresponding ranges were -€79 to +€72, 0.373-0.453 QALYs, and a maximum ICER of €174/QALY. At €50 000/QALY, cost-effectiveness probability was 92%. Digitoxin was cost-saving in 24 of 27 Member States at 10 years and 10 of 27 over lifetime. In the USA, it was cost-saving (lifetime savings US$405 per patient; 0.43 QALYs; 93.4% probability of cost-effectiveness). CONCLUSION:Digitoxin generated clinically meaningful health benefits at negligible incremental cost and remained cost-effective across every evaluated EU-27 healthcare system and the USA. Economic value emerged earliest within the first decade and in higher-cost hospital systems, while lifetime analysis captured larger cumulative gains in quality-adjusted survival.

DIGIT-HF is a multicentre, randomized, double-blind, placebo-controlled trial designed to investigate the effect of digitoxin versus placebo on the composite primary endpoint of time to all-cause death and hospital admission for worsening heart failure (HFH) (whichever occurs first) in patients with heart failure (HF) and reduced ejection fraction (HFrEF).1 The DIGIT-HF trial is conducted in compliance with the German Drug Law (AMG), the German Good Clinical Practice (GCP) ordinance, ICH GCP guidelines, and other applicable ethical and regulatory requirements. The DIGIT-HF trial is registered at EudraCT (2013-005326-38). Since recruitment of the first patient in May 2015, seven key protocol amendments have been implemented to specify and clarify its content, particularly to improve the recruitment to reach the required number of primary endpoint events (Figure 1; for details see online supplementary Table S1). Due to the lower than expected recruitment rate, a blinded sample size/trial duration re-estimation was conducted 40 months after beginning of recruitment. It was estimated that the study duration needed to be extended to observe the required number of 734 primary endpoint events. Consequently, the required number of patients was reduced from 2190 to 1653. Following successful application for continued funding, the trial conduct was extended until the end of 2024 with an increased number of recruitment sites. The main challenge of the trial was the lower than expected recruitment, which was probably due to the initial overestimation of the number of patients to be recruited per trial site, although the observed pooled event rate for the primary endpoint was similar as assumed in the sample size calculation. Therefore, the number of trial sites was increased from initially 40 to finally 65. This included extension of the trial to motivated investigators in Austria and Serbia.2 In addition, several competing clinical trials recruiting HFrEF populations funded by pharmaceutical companies (e.g. DAPA-HF, EMPEROR-Reduced)3, 4 started during the DIGIT-HF trial period, which probably impaired recruitment into DIGIT-HF as well. The COVID-19 pandemic also affected recruitment because screening/baseline visits intended to be performed in presence could not be scheduled. Furthermore, trial extension to Serbia was strongly delayed by COVID-19 pandemic just after solving all regulatory issues (e.g. digitoxin is not available and approved in Serbia) mandatory for starting the trial at 10 study sites in Serbia, which significantly affected final recruitment numbers. Overall, the COVID-19 pandemic did affect the study conduct by for example, changing the in-person visits to telephone visits, which may have significantly impaired collection of events, in particular HFH events. To explore potential impact of COVID-19 on the study results, COVID-related data (e.g. respiratory infections, vaccinations) have been collected and will be analysed. Further COVID-related supplementary analyses may be conducted, for example, separately analysing the pre-COVID-19 data. A second blind review of trial data in December 2022 revealed that the required number of 367 primary endpoint events for the pre-planned interim analysis had not been achieved. Because the probability for early trial termination due to overwhelming efficacy was very low, the initially planned interim analysis was not performed. Consequently, the full alpha of 0.05 can be used for the final analysis and 716 primary endpoint events need to be observed to demonstrate the expected hazard ratio of 0.811 with a power of 80%. The most recent protocol amendment (Version 8.0, date 20 July 2023, in online supplementary material) re-defined the key secondary endpoints of all-cause death, HFH and (recurrent) HFH. Analysis of time to first HFH alone is not of high clinical relevance as it ignores the fatal worsening event death, which constitutes about 30% of the primary endpoint events in the current trial (based on a blind review). Furthermore, censoring patients who had not experienced HFH before death is statistically inappropriate, as this leads to informative censoring. Therefore, including death as a fatal worsening event is more meaningful from both clinical and statistical aspects. As this coincides with the primary endpoint, time to first HFH was removed from the list of key secondary endpoints. The absolute and relative frequency of the first HFH as a component of the primary endpoint will be presented. Analysis of recurrent HFH would have similar problems if death is ignored. Furthermore, including death as an additional event may better prevent a potential type I error inflation associated with the analysis of recurrent HFH alone.5 Therefore, the composite of recurrent HFH and all-cause death instead of recurrent HFH was defined as a new key secondary endpoint. To control the overall type I error, a hierarchical testing procedure for the primary and key secondary endpoints was pre-specified with the following testing order: (1) superiority of digitoxin versus placebo in the primary endpoint, (2) non-inferiority of digitoxin versus placebo regarding time to all-cause death, (3) superiority of digitoxin versus placebo regarding the composite of recurrent HFH and all-cause death. The testing order reflects the relative clinical relevance/importance of the endpoints and implies the clinical decision-making process. For example, all-cause mortality is the first key secondary endpoint after the primary endpoint, since the most important component of the composite endpoint should not be negatively impacted by the experimental treatment. Composite recurrent HFH endpoint is the second key secondary endpoint after all-cause mortality. As indicated in the European Medicines Agency chronic HF guideline,6 the main challenge in the analysis and interpretation of recurrent event endpoints is the presence of terminal events (e.g. death), which limit the number of events per subject. In consequence, a lower number of events in one as compared to the other treatment group may simply be the result of an increased mortality in the former treatment group. Thus, excluding a detrimental effect on all-cause mortality in the first step is a pre-requisite for concluding a positive effect on the composite recurrent HFH endpoint. If all confirmatory null hypotheses of the main study can successfully be rejected, substudies will be assessed confirmatory in the pre-defined order. Otherwise, substudies will be evaluated descriptively with a two-sided alpha of 5%. The primary analysis will be conducted on the intention-to-treat (ITT) population including all randomized patients who took at least one dose of the study drug. Patients will be analysed as randomized regardless of their actual treatment (digitoxin or placebo). Initially, the per-protocol population was specified to all patients who achieved the target serum concentration of digitoxin (preferably 8–18 ng/ml [10.5–23.6 nmol/L]), complied with the study protocol until the end of the observational period, and remained in the treatment arm to which they were allocated by randomization. This was further refined to all patients of the ITT population that had attended visit 3 (12 months ± 7 days), achieved digitoxin serum concentrations of <2.5 nmol/L (if randomized to placebo) or had a digitoxin serum concentration of 5–30 nmol/L (if randomized to digitoxin), and experienced no active decision against the randomized therapy. As various win ratio analyses have been performed in recent HF trials, we further pre-specified secondary analyses of (1) hierarchical composite of all-cause death, number of HFH, and time to first HFH, and (2) hierarchical composite of all-cause death, number of HFH, time to first HFH, change from baseline in New York Heart Association class and change from baseline in quality of life, both assessed using a win ratio method, to provide additional insights into the understanding of the treatment effect (statistical analysis plan, sections S2.4 and S10 in online supplementary material). During the recruitment phase of DIGIT-HF, recommendations of the European Society of Cardiology for pharmacological treatment of HFrEF were extended to also include angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors.7, 8 Because the aim of the trial was to investigate a potential benefit of digitoxin in HFrEF patients on top of standard of care based on guideline recommendations, standard of care for study participants in the trial protocol was extended by these substance classes. The principal findings of the DIGIT-HF trial are anticipated to be made available in 2025, potentially offering important new insights into the efficacy and safety of cardiac glycosides, specifically digitoxin, in the treatment of advanced HFrEF. Open Access funding enabled and organized by Projekt DEAL. The DIGIT-HF study is funded by the Federal Ministry of Education and Research, Germany (BMBF: 01KG1303 and 01KG1907) the Braukmann-Wittenberg-Herzstiftung, and the German Heart Foundation. Conflict of interest: U.B. and J.B. represent the study heads of the DIGIT-HF-study and applied for funding of DIGIT-HF described above. U.B., J.B., A.K., H.v.d.L., C.V., S.S., and M.B. are members of the DIGIT-HF trial steering committee. U.B. received travel support and honoraria for lectures/consulting from Alnylam Pharmaceutical, Amgen, AstraZeneca, Bayer Vital, Novartis, and Pfizer and institutional research support from Alnylam Pharmaceuticals, all not related to the current manuscript. D.B. was competitively selected for 'CORE100Pilot', which is an advanced clinician-scientist programme co-funded by the Else Kröner Fresenius Foundation and the Ministry for Science and Culture of the State of Lower Saxony. D.B. received honoraria for lectures/consulting from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Pfizer, all not related to the current manuscript. P.M.B reports personal fees from AstraZeneca, Ingelheim Boehringer and the German Research Foundation, all not related to the current manuscript. C.V. reports honorary for lectures or consulting from Abbott, Medtronic, BMS and Zoll. M.B. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Edwards, Medtronic, Novartis, ReCor, Servier and Vifor during the conduct of the study. J.B. received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards, Roche not related to this article; and research support for the department from Zoll, CVRx, Abiomed, Norgine, Roche, all not related to the current manuscript. All other authors have nothing to disclose. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

AIMS:This report presents the baseline characteristics of patients enrolled in the DIGIT-HF trial and compares them with participants from recent trials with improved outcomes in patients with heart failure (HF) and a reduced ejection fraction (HFrEF). METHODS AND RESULTS:DIGIT-HF, a randomized, double-blind, placebo-controlled, multicentre trial enrolling patients with symptomatic HFrEF (New York Heart Association [NYHA] functional class II and left ventricular ejection fraction [LVEF] ≤30%, or NYHA class III-IV and LVEF ≤40%), compares the efficacy and safety of digitoxin versus placebo in addition to standard treatment. Most baseline characteristics of the intention-to-treat population (1212 patients, mean age 66 ± 11 years, 20% women, mean LVEF 29 ± 7%) were similar to those in recent HFrEF trials. The distribution of NYHA class II, III, and IV was 30%, 66% and 4%, respectively, and indicates that the patients were sicker than in comparator HFrEF trials. Less patients had atrial fibrillation (27%) than those in recent HFrEF trials, but prescription rates of background therapy with beta-blockers (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (95%), mineralocorticoid receptor antagonists (76%), and diuretics (87%) were high and similar. Overall, 40% of patients were on angiotensin receptor-neprilysin inhibitors, 19% on sodium-glucose cotransporter 2 inhibitors, and 9% on ivabradine. Rates of implantable cardioverter-defibrillator (ICD, 64%) and cardiac resynchronization therapy (CRT, 25%) devices were much higher than in recent HFrEF trials. CONCLUSIONS:Patients included in DIGIT-HF display a more severe HF symptom burden and higher rates of ICD/CRT implants compared to participants in recent HFrEF trials, while pharmacotherapy was largely similar. CLINICAL TRIAL REGISTRATION:EudraCT (2013-005326-38).

Conducting randomized clinical trials (RCTs) is challenging. For this reason, in earlier phases of drug development and rare diseases with limited sample sizes, there is a tendency to omit control groups and to replace them with historical information for perceived feasibility arguments. This has significant implications for interpretation of trial results. We present headline results from a trial in stem cell transplantation, where fludarabine and clofarabine were investigated for induction chemotherapy in high-risk acute myeloid leukaemia or advanced myelodysplastic syndrome. The trial was initially designed as single-arm trial (SAT) and is discussed here from the planning and assessment perspective. Changes in the treatment setting or patient selection may lead to 'promising results' in SATs, which are difficult to identify and may raise unwarranted hopes which cannot be confirmed in a subsequent randomized trial. RCTs should be used to achieve a straightforward interpretation of the results, even if the sample size is small. Interpreting SATs is only straightforward in very rare instances where the underlying treatment effect is large and the outcome in each individual patient surpasses all previous clinical experience.

BACKGROUND:The therapeutic efficacy of the cardiac glycoside digitoxin in patients with heart failure and reduced ejection fraction is not established. METHODS:In this international, double-blind, placebo-controlled trial, we randomly assigned patients with chronic heart failure who had a left ventricular ejection fraction of 40% or less and a New York Heart Association (NYHA) functional class of III or IV or a left ventricular ejection fraction of 30% or less and an NYHA functional class of II in a 1:1 ratio to receive digitoxin (at a starting dose of 0.07 mg once daily) or matching placebo in addition to guideline-directed medical therapy. The primary outcome was a composite of death from any cause or hospital admission for worsening heart failure, whichever occurred first. RESULTS:Among 1240 patients who underwent randomization, 1212 fulfilled the criteria for inclusion in the modified intention-to-treat population: 613 patients in the digitoxin group and 599 in the placebo group. Over a median follow-up of 36 months, a primary-outcome event occurred in 242 patients (39.5%) in the digitoxin group and 264 (44.1%) in the placebo group (hazard ratio for death or first hospital admission for worsening heart failure, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03). Death from any cause occurred in 167 patients (27.2%) in the digitoxin group and 177 (29.5%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.69 to 1.07). A first hospital admission for worsening heart failure occurred in 172 patients (28.1%) in the digitoxin group and 182 (30.4%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.69 to 1.05). At least one serious adverse event occurred in 29 patients (4.7%) in the digitoxin group and 17 (2.8%) in the placebo group. CONCLUSIONS:Treatment with digitoxin led to a lower combined risk of death from any cause or hospital admission for worsening heart failure than placebo among patients with heart failure and reduced ejection fraction who received guideline-directed medical therapy. (Funded by the German Federal Ministry of Research, Technology, and Space and others; DIGIT-HF EudraCT number, 2013-005326-38.).

In clinical trials for chronic heart failure (CHF), time to a composite of first hospitalization for worsening heart failure or death is a widely accepted primary efficacy measure. Motivated by lower event rates in recent CHF trials, there are proposals to use endpoints accounting for recurrent heart failure hospitalization (HFH) events (e.g., recurrent HFH events plus death as an additional event) as the primary endpoint to better quantify disease burden and to improve trial efficiency. However, analysis and interpretation of recurrent event endpoints may be complicated by the terminal event death. In a previous simulation study it was shown that the Type I error rate was well-controlled for the analysis of the composite recurrent event endpoint using the negative binomial (NB) model and the Lin-Wei-Yang-Ying (LWYY) model. As these results were based on limited scenarios, we extended the previous simulation study and identified situations where the Type I error rate is no longer controlled for the analysis of the composite recurrent event endpoint using the LWYY model, despite a neutral effect on HFH and a detrimental effect on death of the experimental treatment. Therefore, depending on clinical settings, the LWYY model should be applied and interpreted with more caution.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that causes the formation of cysts primarily in the kidneys. The continuous growth of multiple cysts leads to the destruction of functional parenchyma, which may progress to end-stage kidney disease. Tolvaptan is the only drug specifically approved for slowing down the progression of ADPKD. Sodium-glucose transporter 2 inhibitors might provide additional benefits but there is currently no information on safety and outcome effects of SGLT2i in patients with ADPKD, as these patients were excluded in SGLT2i trials. In particular, there has been speculation that SGLT2i might increase cyst growth and accelerate the loss of kidney function in ADPKD. The EMPA-PKD trial is assessing the safety of empagliflozin in patients with rapid progressive ADPKD with and without concomitant tolvaptan use by monitoring the total kidney volume and the loss of kidney function.Methods and analysis This is an investigator-initiated, double-blind, single-centre, placebo-controlled, randomised clinical trial including patients with rapidly progressive ADPKD (n=44). Participants will be randomly allocated (1:1) to receive a daily dose of either empagliflozin (10 mg/day) or placebo for 18 months. Patients will be stratified according to concomitant tolvaptan use. The primary endpoint is the progression of cystic kidney growth by monitoring MRI-based changes in total kidney volume and the secondary endpoint is the change in glomerular filtration rate. Additional endpoints include changes in copeptin levels, albuminuria and blood pressure.Ethics and dissemination The protocol has been approved by the German Federal Institute for Drugs and Medical Devices (BfArM) after review by the independent ethics committee Landesarztekammer Rheinland-Pfalz. Participation in this study will be voluntary and informed consent will be obtained. Regardless of the outcome, the results will be disseminated through a peer-reviewed international medical journal.Trial registration numbers EU-CT number 2023-505890-34-00, NCT06391450.

The European Medicines Agency adopted their Geriatric Medicines Strategy more than a decade ago. The strategy aims at elucidating the evidence basis for marketing authorization of new medicines which will be used in the older population, and at ensuring the appropriate communication of findings to the patient and healthcare provider. During the past decade new tools and data sources have emerged to support the strategy goals, and their use should be considered. Possible concrete actions are presented to improve the design of clinical trials, the data collection both pre- and post-approval, the assessment of the findings, and the communication to assist informed prescription and safe medicine taking. Implementation and prioritization of these actions should be done from the perspective of addressing the needs of patients while maximizing efficient use of resources, with the aim of integrating geriatric aspects into routine medicines development and assessment.

Importance Progressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment. Objective To determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus-specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent. Design, Setting, and Participants A retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab. Exposure Fresh DIAVIS T cells were administered with a maximum dose of 2 x 10(4) CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later. Main Outcomes and Measures Primary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition. Results The study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%). Conclusion and Relevance This case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

The COVID-19 pandemic triggered an unprecedented research effort to develop vaccines and therapeutics. Urgency dictated that development and regulatory assessment were accelerated, while maintaining all standards for quality, safety and efficacy. To speed up evaluation the European Medicines Agency (EMA) implemented "rolling reviews" allowing developers to submit data for assessment as they became available. We discuss the clinical trial designs and the applied statistical approaches in vaccine efficacy trials, focusing on aspects such as multiple testing, interim and updated analyses, and reporting of results for the first four vaccines recommended for approval by the EMA. The fast accrual of COVID-19 cases in the clinical vaccine efficacy trials led to multiple data updates within a short time frame, which had consequences for the evaluation and interpretation of results. Key trial results are discussed in the light of these aspects. Notably, the aspects discussed did not affect the benefit/risk relationship in a meaningful way, which was clearly positive for all four vaccines. Assessment of the development and evaluation of the four vaccine trials during the pandemic has led to a proposal for standardized terminology for trials with multiple analyses and a recommendation to appropriately preplan the timing of primary and updated analyses. For the reporting of updated estimates of vaccine efficacy, we discuss how to best describe the uncertainty around estimates of vaccine efficacy (e.g., via confidence intervals). Finally, we briefly highlight the benefit of a comprehensive discussion on estimands for vaccine efficacy trials. for this article are available online.

Introduction/Background Radical hysterectomy with pelvic lymphadenectomy represents the standard treatment for early-stage cervical cancer (<4 cm tumour size; ESCC). Results from a randomized trial ('LACC') demonstrated that minimally invasive surgery (MIS) is inferior to laparotomy with regards to disease-free and overall survival. Retrospective studies suggest that tumour spillage might be the cause for poorer outcomes after MIS. Another randomized phase III trial ('SHAPE') comparing radical versus simple hysterectomy (SH) in low-risk ESCC showed non-inferiority of SH with better quality of life and sexual health measures. However, the question whether MIS is comparable to laparotomy regarding survival was not addressed. This highlights the need to evaluate preventive surgical methods in the MIS radical hysterectomy arm to assure tumour hygiene and to address MIS vs laparotomy for simple hysterectomy in low-risk ESCC. Methodology Patients will be randomized to either undergo conventional standard radical hysterectomy including lymphadenectomy by laparotomy or MI radical hysterectomy (either by conventional laparoscopy or robotic-assisted) using preventive surgical methods in form of either performing a LEEP/cone prior to surgery or closure of the vagina before colpotomy and avoiding intrauterine manipulators. According to the SHAPE trial, a simple hysterectomy can be considered in patients with low-risk ESCC (tumour-size < 2cm and < 10 mm depth of stromal invasion after LEEP/cone). Results The primary endpoint is disease-free survival (DFS). Non-inferiority of MIS compared to laparotomy will be declared if the upper boundary of the two-sided 95% confidence interval (CI) for the hazard ratio (MIS/laparotomy) is below the predefined non-inferiority margin of 2.3. Secondary endpoints include overall survival, disease recurrence, quality of life, complications and treatment-associated morbidity, treatment costs and cost effectiveness. Conclusion This RCT aims to answer the question whether MIS is oncologically safe in ESCC with the advantage of fewer peri-operative complications and superior patient-reported outcomes. Disclosures DD reports the receipt of honoraria/consultation fees from: AstraZeneca, Eisai, GSK, Intuitive, KLS Martin, MSD, PharmaMar, Seagen. The remaining authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this abstract.

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. 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

Background: Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS) and other chronic tic disorders (CTD) resulting in a reduction of tics and an improvement of psychiatric comorbidities and quality of life. This study aimed to examine efficacy and safety of the cannabis extract nabiximols in patients with TS/CTD.Methods: In this randomized, multicenter, placebo-controlled, phase IIIb study, adult patients with TS/CTD were randomized with a 2:1 ratio to nabiximols or placebo. The primary efficacy endpoint was defined as a tic reduction of > 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Secondary outcomes included assessments of tics, comorbidities, and quality of life. The primary analysis was performed using a Mantel-Haenszel estimate.Findings: A total of 97 patients (75·3% males, mean age=36·6 years) were treated. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated (risk difference for placebo – nabiximols: -0·13 [95%: -0·28 to 0·01, p = 0·07])). In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder (ADHD). There were no relevant safety issues.Interpretation: Although superiority of nabiximols could formally not be demonstrated, we found clear trends for an improvement of tics, depression, and quality of life after treatment with nabiximols. Our results suggest that males, patients with more severe tics and those with comorbid ADHD may benefit better from treatment with cannabis-based medication.Funding Information: This study was funded by the DFG (MU 1527/2-1).Declaration of Interests: KMV has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7- PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner Fresenius-Stiftung, and GW, Abide Therapeutics, Lundbeck, Syneos Health, Therapix Biosciences Ltd, Almirall Hermal GmbH, GW pharmaceuticals. She has received consultant’s honoraria from Abide Therapeutics, Tilray, Resalo Vertrieb GmbH, Columbia Care, Bionorica Ethics GmbH, Lundbeck and Eurox Deutschland GmbH. She is a consultant or advisory board member for Abide Therapeutics, Alirio, The Academy of Medical Cannabis Limited, CannaMedical Pharma GmbH, CannaXan GmbH, Columbia Care, Canopy Growth, Leafly Deutschland GmbH, Lundbeck, Nomovo Pharm, Nuvelution TS Pharma Inc., Resalo Vertrieb GmbH, Sanity Group, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, Wayland Group, Zynerba Pharmaceuticals, and CTC Communications Corporation. She has received speaker’s fees from Tilray, Wayland Group, Emalex, Eurox group, PR Berater, Aphria, Ever pharma GmbH, and Cogitando GmbH. She has received royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer. She holds shares of Nomovo Pharm. She served as a Guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” is Associate editor for “Cannabis and Cannabinoid Research” and Editorial Board Member for “Medical Cannabis and Cannabinoids.” The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AM received commercial research support from Pharm Allergan, Ipsen, Merz Pharmaceuticals, Actelion, honoraria for lectures from GlaxoSmithKline, Desitin, Teva, Takeda and consultancies from Desitin, Merz Pharmaceuticals, Admedicum, PTC Therapeutics, Novartis, Barmer. He was supported by the Possehl-Stiftung (Lübeck, Germany), the Margot und Jürgen Wessel Stiftung (Lübeck, Germany), the Tourette Syndrome Association (Germany), the Interessenverband Tourette Syndrom (Germany), CHDI, and the Damp-Stiftung (Kiel, Germany). He received academic research support by the Deutsche Forschungsgemeinschaft (DFG): projects 1692/3-1, 4-1, SFB 936, and FOR 2698 (project numbers 396914663, 396577296, 396474989), by the European Reference Network – Rare Neurological Diseases (ERN – RND; Project ID No 739510). He receives royalties for the book Neurogenetics (Oxford University Press). AM is member of the advisory boards of the German Tourette syndrome Association and the alliance of patients with chronic rare diseases. RM has received financial research support from the EU (H2020 No. 754740), the Tourette Gesellschaft Deutschland e.V., Abide Therapeutics, Böhringer-Ingelheim, Emalex, Lundbeck, Nuvelution TS Pharma Inc., Otsuka Pharmaceuticals, Therapix Biosciences. He has received speakers’ honoraria from Otsuka Pharmaceuticals and Lundbeck. RM is member of the advisory board of the Tourette Gesellschaft Deutschland e.V. NS has received financial or material research support by Polish Ministry of Health, Polish Neurological Society, Foundation for Polish Science, American Academy of Neurology, Tourette Association of America, American Brain Foundation and European Stroke Organisation. She received speakers’ honoraria from Biogen and 90 Consulting and was supported to attend meetings by Biogen. She is the Secretary of the European Society for the Study of Tourette Syndrome. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Ethics Approval Statement: Patients were randomized between 4/2018 and 11/2020 at 6 study centers across Germany (Hannover, Lübeck, Aachen, München, Köln, Freiburg). The study protocol, patient consent form, and all amendments were approved by local ethics committees of the participating centers.Trial Registration: NCT03087201