Can acupuncture increase microcirculation in peripheral artery disease and diabetic foot syndrome? - a pilot study.

Background: Globally, 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 methods: In 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. Results: After 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. Discussion: These 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.

Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive post-remission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia.

Not available.

Estimation of treatment effects in early-phase randomized clinical trials involving external control data.

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.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD.

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/m2 bidaily day one to day three, mitoxantrone 10mg/m2 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.

HELP - Heidelberg decision aid for lung cancer patients: a randomized controlled clinical trial.

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.

Treatment Tolerability and Toxicity of Postoperative Proton Beam Therapy for Gynecologic Malignancies: Results of the Prospective Phase 2 APROVE Trial.

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 × 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 α = 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.

Health-related quality of life and patient-reported symptoms after postoperative proton beam radiotherapy of cervical and endometrial cancer: 2-year results of the prospective phase II APROVE-trial.

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).

Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial.

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.

GPs´ Personal Spirituality, Their Attitude and Spiritual Competence: A Cross-Sectional Study in German General Practices.

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.

Translation and psychometric properties of the German version of the "Interprofessional Socialization and Valuing Scale" (ISVS-21-D).

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.

Communication with patients with limited prognosis-an integrative mixed-methods evaluation study.

PURPOSE: Oncological societies advocate the continuity of care, specialized communication, and early integration of palliative care. To comply with these recommendations, an interprofessional, longitudinally-structured communication concept, the Milestone Communication Approach (MCA), was previously developed, implemented, and evaluated. Our research question is: what are possible explanations from the patient perspective for prognosis and advance care planning being rarely a topic and for finding no differences between MCA and control groups concerning distress, quality of life, and mood? METHODS: A pragmatic epistemological stance guided the study. A mixed-methods design was chosen including a pragmatic randomized trial (n = 171), qualitative interviews with patients (n = 13) and caregivers (n = 12), and a content analysis (133 milestone conversations, 54 follow-up calls). Data analysis involved the pillar integration process. RESULTS: Two pillar themes emerged: 1 "approaching prognosis and advance care planning"; 2 "living with a life-threatening illness". Information on prognosis seemed to be offered, but patients' reactions were diverse. Some patients have to deal with having advanced lung cancer while nonetheless feeling healthy and seem not to be ready for prognostic information. All patients seemed to struggle to preserve their quality of life and keep distress under control. CONCLUSION: Attending to patients' questions, worries and needs early in a disease trajectory seems key to helping patients adjust to living with lung cancer. If necessary clinicians should name their predicament: having to inform about prognosis versus respecting the patients wish to avoid it. Research should support better understanding of patients not wishing for prognostic information to successfully improve communication strategies. TRIAL REGISTRATION: Registration: German Clinical Trial Register No. DRKS00013649, registration date 12/22/2017, ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013649 ) and No. DRKS00013469, registration date 12/22/2017, ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013469 ).

"University students' economic situation during the COVID-19 pandemic: A cross-sectional study in Germany".

The COVID-19 pandemic caused a major economic downturn that disproportionally affected university students. This empirical research investigated effects and risk factors of the pandemic on students' economic situation with focus on financial distress and financial limitations. Data was collected using an online survey in May and June 2020 from students (n = 917) enrolled at universities in Germany. 80.6% were enrolled in bachelor programs (n = 738), the mean semester was 3.8 (standard deviation (SD = 2.0) and students' mean age was 23.1 years (SD = 4.1). 51.8% (n = 472) were female and 47.4% (n = 432) male. 56.7% (n = 506) of students worked before the pandemic. More than one third reported a decrease in income (36.5%; n = 334) and an increase in financial constraints (38.7%; n = 354). A multivariate logistic regression analysis showed that students with regular income were less likely to experience financial distress compared to those without (odds ratio (OR) = 0.456; p = 0.014). Furthermore, working part-time as associated with a higher financial distress compared to those without part-time employment (OR = 1.811; p = 0.003). Students who worked part-time before the pandemic also had a higher probability of increased financial restriction (or constraint) compared to those who did not work part-time (OR = 2.094; p < 0.001). University students were disproportionally affected by the economic consequences of the COVID-19 pandemic, which increased students' economic uncertainty. To offset such problems, financial aid schemes for students need to be made available to alleviate distress and to allow students to focus on their studies but should not compound problems by leading to financial hardship at a later point in time.

Protocol of the TREASURE study: Thoracic RadiothErapy with Atezolizumab in Small cell lUng canceR Extensive disease - a randomized, open-label, multicenter phase II trial.

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.

A Comprehensive Comparison of Additional Benefit Assessment Methods Applied by Institute for Quality and Efficiency in Health Care and European Society for Medical Oncology for Time-to-Event Endpoints After Significant Phase III Trials-A Simulation Study.

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.

Monotonicity conditions for avoiding counterintuitive decisions in basket trials.

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.

Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy.

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0-5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was >1.5-fold upregulated in 40% (95% CI 23.9-57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.

ON-ICE trial: Investigation of the combined effects of oxytocin and naltrexone on stress-induced and alcohol cue-induced craving in alcohol use disorder-Study protocol of a phase II randomised double-blind placebo-controlled parallel-group trial.

INTRODUCTION: Although alcohol dependence (AD) is highly prevalent, only few medications are approved for its treatment. While currently approved medications, such as naltrexone (NTX), reduce craving and relapse risk to a certain extent, new approaches are needed to complement these pharmaca. One potential compound is oxytocin (OXY), which proved beneficial effects on alcohol craving and stress reactivity in preliminary clinical studies and synergism with NTX effects. METHODS AND ANALYSIS: This clinical phase II trial is a monocentre two-armed, placebo (PLC)-controlled, 1:1 randomised, double-blind, parallel-group study. 62 participants with AD will be randomised to receive either intranasal OXY spray (24 IU) or PLC spray plus oral NTX (50 mg) for 2 days, and alcohol craving will be assessed using a validated combined stress-exposure and cue-exposure experiments and MRI. The primary outcome will be the intensity of alcohol craving, assessed using the Alcohol Urge Questionnaire (AUQ), 60 min after OXY/PLC application, directly after the stress and cue exposures. Secondary outcomes include subjective stress, negative affect, cortisol and OXY plasma levels, and neural response to alcohol and emotional cues and natural rewards. Follow-up drinking data were collected over 90 days. The primary efficacy analysis will test the difference between the verum and the PLC group in the distribution of AUQ craving scores. Appropriate statistical analysis will be used for the evaluation of the secondary outcomes. ETHICS AND DISSEMINATION: This trial has been approved by the ethics committee of Heidelberg University and competent authority. All participants in the trial will provide written informed consent. The study will be conducted according to the principles of the Declaration of Helsinki and in accordance to the German Medicinal Products act. Results of this study will be disseminated in peer-reviewed scientific journals and deidentified data, and the statistical analysis plan will be made available via open-access online repositories. TRIAL REGISTRATION NUMBERS: EudraCT 2021-003610-40 and NCT05093296.

An adaptive design for early clinical development including interim decision for single-arm trial with external controls or randomized trial.

In early clinical development, randomized controlled trials (RCT) or single-arm trials with external controls (SATwEC) are design options, which allow adjustment for confounding: RCT via design, SATwEC via analysis using propensity score methods. SATwEC requires less investment than RCT. However, if the confounder space substantially differs between the experimental and external control group, the SATwEC might lead to inappropriate decisions for further development. We develop an adaptive two-stage design (ATD) for early clinical development that reduces the risk of unreliable decision-making at the end of a SATwEC. In Stage I, subjects are solely assigned to the experimental group. If at the interim the propensity score distributions of internal and external data are comparable based on the preference score, the subjects in stage II will again be solely assigned to the experimental arm; if not, a randomized stage II will be conducted. In a simulation study guided by a motivating example, data is generated using a time-to-event model with observable and unobservable confounders. The confounder space is varied to investigate the impact on false go/stop probabilities as well as a loss function, which reflects the quality of treatment effect estimates and decision-making. The proposed ATD provides a compromise between optimizing quality (as expressed by false go/stop probabilities and the loss function) and investment (defined by sample size and trial duration).