Schlüßlberg, Austria

A Clinical Study on the Effect of Discontinuing Alendronate in Postmenopausal Women with Osteoporosis After a Treatment Period Without Fractures

FDG-PET/CT vs. CT for Monitoring Metastatic Breast Cancer

Background Breast cancer is the most commonly diagnosed cancer in Europe and worldwide. With a continuously increasing incidence, it is estimated that by 2040, the breast cancer burden will increase to more than three million new cases per year worldwide, with more than one million breast cancer-related deaths per year (50% increase). The prognosis of breast cancer is steadily improving due to the early detection of primary cancer through screening programs and revolutionising treatment development. Despite this, approximately one-third of patients diagnosed with primary breast cancer will develop metastatic disease. In the metastatic setting, therapy improvements have made breast cancer a chronic disease with declining mortality rates, and several effective treatment lines are available for metastatic breast cancer patients today and in the future. This favourable situation requires accurate methods to assess response to treatment to achieve the most effective treatment planning. FDG-PET/CT is increasingly used in cancer staging. Several studies have shown improved sensitivity of FDG-PET/CT compared with conventional imaging for diagnosing metastatic breast cancer in retrospective and smaller prospective studies. We expect FDG-PET/CT to detect disease progression earlier than CT in patients treated for metastatic breast cancer, enabling earlier start of second-line therapies. This has the potential to increase the beneficial effect of second-line therapies at the individual level and result in a delayed need for third-line therapies, prolonged overall survival, and improved quality of life compared with patients monitored with conventional CT. Currently, no specific recommendations are provided for a diagnostic modality to monitor treatment response in patients with metastatic breast cancer. European clinical practice guidelines (ESMO) state that there is no evidence of any staging or monitoring approach for metastatic breast cancer patients that provides overall survival benefit over another approach. ESMO suggests that FDG-PET/CT might provide earlier guidance in the monitoring of bone-only or bone-predominant metastasis, but it is emphasised that prospective trials are needed to study the impact of this on treatment decisions and overall survival. This is the evidence that MONITOR-RCT will deliver. Study objectives The primary objective of the MONITOR-RCT is to demonstrate that in patients with metastatic breast cancer, response monitoring based on FDG-PET/CT is superior to response monitoring based on CT with respect to overall survival. The objective will be based on applying standardized response evaluation criteria, using an appropriate adaptation of the PERCIST criteria for FDG-PET/CT and the RECIST1.1 criteria for CT. Secondary objectives of the MONITOR-RCT are to demonstrate superiority with respect to the quality of life and exposure to oncologic treatment and to investigate the cost-effectiveness. Consequently, the primary endpoint of the study is overall survival. Secondary endpoints are quality of life, exposure to oncologic treatment, and cost-effectiveness. Study design The MONITOR-RCT study will be an international multicenter study. The design will be a parallel group comparative randomized trial comparing an experimental monitoring strategy based on FDG-PET/CT with a standard monitoring strategy based on CT. Eight hospital sites in Denmark, two in Italy, and one in Germany will participate in patient recruitment and the conduction of the study. Inclusion criteria Criteria for inclusion will be: Women and men aged ≥18 years Diagnosis of distant relapsed metastatic breast cancer (biopsy-verified) or de novo breast cancer. In patients with distant relapsed metastatic breast cancer, biopsy verification from a distant metastasis is required. In patients with de novo metastatic breast cancer, biopsy verification of primary tumor and diagnostic imaging with distant metastasis with a typical pattern of metastatic breast cancer is required. Considered eligible for first-line systemic treatment Considered eligible for continuous treatment monitoring by scans. Signed informed consent Participants must have the ability to read and understand the following languages based on their country of participation: in Denmark, patients must be able to read and understand Danish; in Italy, they must be able to read and understand Italian or English; and in Germany, they must be able to read and understand German or English. Exclusion criteria Criteria for exclusion will be: Pregnant or lactating women Ongoing oncological treatment for another cancer Exclusively brain metastasis Allergy to FDG Target population Participating patients should have newly diagnosed metastatic breast cancer and be considered eligible for initiating first-line medicinal treatment and subsequent regular response monitoring. This is the patient population for whom a benefit from FDG-PET/CT-based response monitoring is expected. They are very similar to the criteria defining the populations investigated in Vogsen et al. (2023) and Naghavi-Behzad et al. (2022). Quality of life questionnaires Quality of life questionnaires will be completed at home every three months during the first year and every six months later. Two questionnaires will be used: EQ-5D-5L FACT-B In addition, patients can report complaints related to the conduct of scans in a final open question at the end of the questionnaires. Interventions The intervention of interest is the use of FDG-PET/CT for response monitoring compared with CT for response monitoring. The use of CT as a monitoring modality represents the usual care in patients with metastatic breast cancer. FDG-PET/CT scans will be evaluated using the standardized response evaluation criteria for patients with metastatic breast cancer (PREMIO criteria), whereas the CT scan will be evaluated using the RECIST 1.1 criteria. Both criteria aim at classifying the patient as having complete (metabolic) response (CR/CMR), partial (metabolic) response (PR/PMR), stable (metabolic) disease (SD/SMD), equivocal metabolic disease (EMD) or progressive (metabolic) disease (PD). The PREMIO set of response evaluation criteria is an adaptation of PERCIST (for monitoring patients with metastatic breast cancer. The PREMIO criteria are defined based on data from the MESTAR study, Vogsen et al. (2023), introducing the nadir scan for comparison in cases where the disease has regressed compared with the baseline scan. Clinical decision-making: For patients in the intervention group, clinical decision-making will be supported by FDG-PET/CT and PREMIO, while the conventional group will be supported by the CE-CT and RECIST 1.1. The decision-making will be in both groups following the current standard according to the local practice and following international guidelines. The decision-making may include a request for further imaging procedures. Parameters such as toxicity profile and the patient's general condition will also influence treatment decisions. Major components of patient management and the main reasons for treatment decisions will be registered throughout the study. Scan procedure and interpretation: All patients will have baseline scans performed before treatment and according to the randomization group. Treatment and follow-up scans will be approximated at regular intervals of 9-12 weeks or according to local guidelines. The choice of the diagnostic modality does not influence the monitoring intervals or time points. Contrast-enhanced CT of at least the thorax and abdomen will be performed using diagnostic scan quality. Pelvic CT may be added based on clinical need. The scan reports will be made by specialists in radiology with an assessment according to the RECIST 1.1 criteria. FDG-PET/CT will follow standard guidelines from the European Association of Nuclear Medicine. FDG-PET/CT scans will be conducted on EARL2 certified PET scanners, and the quantitative assessment, using the SULpeak value of the hottest metastatic lesion, will based on the EARL2 reconstruction. The CT performed along with the PET scan will be of diagnostic quality and will have contrast enhancement, if not contraindicated. The scans will be assessed by specialists in nuclear medicine according to the suggested PREMIO criteria. According to RECIST 1.1 and PREMIO, disease measurability will be evaluated at the baseline and during follow-up in each study group. In cases of no measurable disease according to the respective criteria applied, the patient's scans will be assessed qualitatively with a parallel response categorization. This categorization slightly differs from the one used in the case of measurable disease, but it still allows for the distinction of progressive disease from all other states. CT and FDG-PET/CT scans will be viewed based on the existing standard software. Viewing of FDG-PET/CT scans will be further supported by software developed as part of the establishment of the PREMIO criteria. Application of the criteria remains a task for radiologists or nuclear medicine specialists. Outcome variables The primary endpoint "Overall survival" will be addressed based on the primary outcome variable "Time from randomization until death". The secondary endpoint "Quality of life" will be addressed by two outcome variables. The first is the overall summary score of the FACT-B, the second the complaints related to the conduct of scans reported by the patients. The secondary endpoint "Exposure to oncologic treatment" will be addressed by the following outcome variables describing different aspects of oncological treatment: Experience of progression Start of a new treatment line because of progression Time to first progression Time from first to second progression Time from second to third progression Experiencing other diagnostic procedures Hospitalization The secondary endpoint "Cost-effectiveness" will be addressed based on relating the outcome variables "Overall survival" and "Quality of Life" to the outcome variable "Costs". These outcome variables correspond to the expected benefits described above. Sample size considerations Sample size considerations are based on using a direct comparison of the survival rates at 42 months. The statistical test finally used will be more powerful due to summarizing the information from all time points and adjustment for prognostic covariates. In the study of Naghavi-Behzad et al. (2022), the survival rate after 42 months was 34% in the CT group and 51% in the FDG-PET/CT group. Due to the introduction of new, more effective treatment lines in the last decade, we expect higher survival rates in this RCT. Sample size calculations are based on the assumption that true survival probabilities will be 39% and 56%, respectively. Under this assumption, we have to include overall 420 patients to reach a power of 87% (based on two-sided testing at the 5% level). According to the timeline of the study, the minimal (planned) follow-up time of the patients will be 36 months, and the maximal follow-up time will be 54 months. In the above calculations, a uniform distribution of the follow-up time was assumed. With respect to the primary outcome (survival), we do not expect drop outs, as we can rely also on national registries. Hence drop-outs are not accounted for in the sample size calculation. Significance level A significance level of 5% (two-sided) will be applied. Exposure to radiation The radiation dose is an issue of consideration. The average radiation dose per patient per scan procedure is estimated, in conventional diagnostic CT, to be 9 mSv and in conventional 18F-FDG-PET/CT to an additional 4 mSv, respectively.

Danish Prognostic Research on Embryonic Diagnostics Involving Chromosomal Testing.

Efficacy of Solifenacin, Mirabegron and Combination Therapy in Children with Daytime Urinary Incontinence (BeDry)

Background: According to International Children's Continence Society, first-line treatment of children with daytime urinary incontinence is standard urotherapy, eventually followed by pharmacotherapy of anticholinergics. The effect of medical treatment is sparsely investigated and primarily in non-randomized trials. Objectives: The primary objective is to evaluate if (1) combination therapy of solifenacin and mirabegron in low doses is superior to monotherapy of solifenacin in high dose and if (2) combination therapy of mirabegron and solifenacin in low doses is superior to monotherapy of mirabegron in high dose in treatment of daytime urinary incontinence among children aged 5 to 14 years who are none complete responders to respectively monotherapy of solifenacin in low dose or monotherapy of mirabegron in low dose. The secondary objective is to evaluate the treatment response of combination therapy of solifenacin and mirabegron in low doses, monotherapy in high dose and monotherapy in low doses as supplementary comparisons. Additionally, the secondary objective is to evaluate side effects, safety, and tolerability of the medical treatment as well as the effect of treatment on well-being and quality of life. Study design: The BeDry study is designed as a multicenter, randomized, single-blinded, controlled clinical trial. Included children will be randomized 1:1:1:1 to one of four treatment groups. Children aged 5-14 years diagnosed with daytime urinary incontinence refractory to standard urotherapy will be randomized. Initially two groups will receive solifenacin 5 mg and two groups will receive mirabegron 25 mg. After 6 weeks, non-complete respondsers will receive add-on treatment according to their primary randomization group; group 1A will reviece solifenacin 5 mg and add-on solifenacin 5 mg, group 1B will receive solifenacin 5 mg and add-on mirabegron 25 mg, group 2A will receive mirabegron 25 mg and add-on mirabegron 25 mg, group 2B will receive mirabegron 25 mg and add-on solifenacin 5 mg. Total treatment period will be 18 weeks. The primary endpoint measure is treatment response assessed by change from visit 2 to end of study, according to number of wet days pr. 7 days by DryPie. Perspectives: The trial has the potential to optimize medical treatment of children with daytime urinary incontinence, to shorten the treatment period, diminish side effects and minimized unnecessary medical expenses. Ethics: All pharmacological side effects will be handled in accordance with the Danish legislation. No risk or unknown side effects are expected to urotherapy, medical treatment or withdrawal. No risks are expected by the clinical examination and paraclinical measurements. The therapeutic potential for future patients justifies the project to be carried out. Participation in this study will not lead to any disadvantages for the patient in their treatment. The study will be conducted in accordance with the protocol, applicable regulatory requirements according to Good Clinical Practice and the ethical principles of the Declaration of Helsinki. The study is approved by the authorities. Significant additions or changes to the protocol may be conducted after the application for amendment is approved by the Regulatory Authority and the Ethics Committee. Information regarding the participants is protected according to the General Data Protection Regulation and the actual law. The study is registered at the research inventory of the Regions of Denmark (1-16-02-210-24) and at Aarhus University (ARG-2024-731-23829). The study is registered and authorized at CTIS (EU CT 2023-510187-13-00).

A Study of AZD0486 Monotherapy or in Combination With Other Anti-Cancer Agents for Mature B-Cell Malignancies

This is open-label, multi-center study to evaluate the safety and preliminary efficacy of AZD0486 administered as monotherapy and in combination with other anticancer agents in participants with mature B-cell hematologic malignancies. This master study currently includes 3 substudies and each substudy focusing on a defined population: Substudy 1: Relapsed/refractory (R/R) Chronic lymphocytic leukaemia (CLL)/ Small lymphocytic leukaemia (SLL) Substudy 2: R/R Mantle-cell lymphoma (MCL) Substudy 3: Large B-cell lymphoma (LBCL) or R/R B-cell non-Hodgkin lymphoma (B-NHL) (not applicable to US) The study will have the following sequential periods: 1. Screening period of 28 days 2. Treatment period 3. Follow-up period

Danish Evaluation of Early Catheter Ablation for Atrial Fibrillation in Patients With Heart Failure

Atrial fibrillation (AF) is the most common arrhythmia in patients with heart failure (HF), with rates ranging between 20-65%, depending on age, severity of HF, subtypes of HF and duration of HF. The two conditions have an intricate and often overlapping pathophysiology, with each condition leading to development of the other, as well as progression of disease. Studies have shown that the presence of AF in HF patients is associated with increased morbidity and mortality, deterioration in HF, exacerbated HF symptoms, and reduced quality of life. The optimal treatment of AF in the presence of HF remains unknown. Currently, there is a pull towards catheter ablation as first-line therapy for AF in HF patients. However, there is no solid scientific evidence to support this approach. Furthermore, it is unknown whether early rhythm control by catheter ablation in HF patients is beneficial. The investigators aim to conduct a pragmatic, randomized clinical trial designed to evaluate the efficacy and safety of early catheter ablation for AF in patients with HF compared with standard treatment. Eligible patients with HF and AF will be prospectively screened from all Danish hospitals and randomized 1:1 to early catheter ablation with pulmonary vein isolation (within 6 weeks) or standard guideline directed treatment for AF. Patients with reversible causes for AF, conditions that preclude the use of catheter ablation or previous catheter ablation for AF will be excluded from the study. Randomization and follow-up will be conducted at six specialized sites in Denmark. There will be one scheduled on-site 12-months follow-up visit after randomization. All clinical follow-up will be conducted at the patient's local hospital, according to standard practice and out of trial setting. Information regarding hospital visits/admissions, events, adverse events, changes in medication, cross-over, heart rhythm and rate, and results of relevant blood-work will be ascertained through systematic patient chart-review at pre-specified time-points. The results from this trial will mold future treatment of AF in HF patients. The investigators hypothesize that early catheter ablation reduces the risk of HF hospitalizations and mortality when compared with standard treatment, thereby significantly improving the clinical prognosis for patients with HF and AF.

AZD0486 as Monotherapy in Participants With Relapsed/Refractory (R/R) B-cell NHL

This is a modular, Phase II, multicenter, single-arm, open-label study to evaluate the efficacy and safety of AZD0486 monotherapy administered as an intravenous (IV) infusion in participants with relapsed or refractory B-NHL. The purpose of this study is to determine the efficacy and safety of AZD0486 administered at the RP2D in adults 18 to 80 years of age with relapsed or refractory B-NHL.

Intradialytic Kinetics of Cardiac Biomarkers During Hemodialysis and Hemodiafiltration

Patients treated with maintenance hemodialysis: Single-center, randomized, crossover study with 24 participants. The study will investigate the effect of high-flux HD (using the FX CorDiax 100 dialyzer) and post-dilution HDF (using the FX CorDiax 1000 dialyzer) on the intradialytic kinetics of selected cardiac biomarkers. The study will not be blinded, but the order of the interventions will be randomized. The two dialysis sessions will be conducted on the same weekday. Between the two interventions, the patient will have a wash-out period of 1-3 weeks with standard dialysis treatment. On both trial days, the following dialysis settings will be the same for each individual patient: - The dialysis sessions will last 4 hours. - The same dialysis machine will be used, either the Fresenius Medical Care 5008 or 6008 CAREsystem machine. - Same vascular access will be used. - The composition of electrolytes in the dialysate will be the same. - Blood flow rate will be >300 mL per minute and consistent. - Dialysate flow rate will be 500 mL per minute. - Ultrafiltration rate will be constant aiming at dry weight. - Routine anticoagulation protocol will be unchanged, but consistent on both trial days. - Routine dialysate temperature will be unchanged, but consistent on both trial days. On both trial days, different baseline characteristics will be gathered, including demographic data, clinical data, dialysis characteristics, and routine blood samples. Blood samples, for the analysis of the selected cardiac biomarkers, will be collected: - Before the dialysis session is started (baseline). - After 10, 30, 60, 120, 180, and 240 minutes of dialysis. All samples will be collected from the blood dialyzer inlet; however, halfway into the dialysis session (after 120 minutes), samples will also be collected from the blood dialyzer outlet and from the dialysate. - 30 minutes after dialysis cessation. However, if the patient will not stay 30 minutes, the post-dialysis sample will be gathered after 5 minutes. Sub-study of patients treated with peritoneal dialysis: In a sub-study, 24 patients treated with peritoneal dialysis, will be included for one or two venous blood samples (with a minimum of 1 week between) to determine the baseline concentration and week-to-week variation of the cardiac biomarkers of interest. On both trial days, different baseline characteristics will be gathered, including demographic data, clinical data, dialysis characteristics, and routine blood samples.

Effects of Tirzepatide on Alcohol Intake in Patients Diagnosed With Schizophrenia and Alcohol Use Disorder

The study is a randomised (1:1), double-blinded, placebo-controlled clinical trial including 26 weeks of treatment investigating whether tirzepatide vs placebo can reduce the number of heavy drinking days in patients with comorbid diagnoses of schizophrenia and AUD. The primary endpoint will be evaluated after 16 weeks of treatment. The study will conclude after a post-intervention follow-up 14 weeks after last treatment at week 40 of the study. 108 participants will be included. Alcohol consumption and secondary endpoints will be assessed at weeks 0, 4, 8, 12, 16, 20, 26, and 40, and all patients will be offered 6 sessions of supportive therapy, while participating in the study. The randomisation and administration of the weekly injections (tirzepatide/placebo) will be administered by an unblinded staff not involved in other trial activities. All patients will be blindfolded when receiving the injections. Eligible patients (n=50) will have an fMRI brain scan performed at baseline and in week 16. Blood tests for safety measures and secondary endpoint-measures will be performed at weeks 0, 16, 26, and 40.

A Phase III Renal Outcomes and Cardiovascular Mortality Study to Investigate the Efficacy and Safety of Baxdrostat in Combination With Dapagliflozin in Participants With Chronic Kidney Disease and High Blood Pressure

The purpose of this study is to investigate the efficacy, safety, and tolerability of baxdrostat in combination with dapagliflozin, compared with placebo and dapagliflozin, in reducing the risk of the composite of > 50% decline in eGFR, kidney failure, or CV death, in individuals with CKD and HTN. This study consists of a 4-week dapagliflozin Run-in Period for participants untreated with SGLT2i at screening, and a double-blinded period where participants will receive either baxdrostat/dapagliflozin or placebo/dapagliflozin. Site visits will take place at 2-, 4-, 8-, 16-, 34, and 52-weeks following randomisation. Thereafter visits will occur approximately every 4 months. The study closure procedures will be initiated when the predetermined number of primary endpoint events is predicted to have occurred ie, the PACD. All randomised participants including any participants who have prematurely discontinued study intervention will be scheduled for a SCV within a few weeks of the PACD. This period can be extended by the Sponsor. In case of premature discontinuation of blinded study intervention, participants will continue in the study and receive dapagliflozin 10 mg, unless the participant meets dapagliflozin specific discontinuation criteria. If study intervention is temporarily or permanently discontinued, the participant should remain in the study, and it is important that the scheduled study visits (including the PTDV for participants with permanent discontinuation of study intervention) and data collection continue according to the study protocol until the SCV.