Miyoshi, Japan

FeAsiBility of a Treatment Free Interval in Newly Diagnosed MM Patients Treated With Daratumumab-lenalidomide-dexamethasone (HOVON174MM)

Study to Evaluate the Effect of Balcinrenone/Dapagliflozin in Patients With Heart Failure and Impaired Kidney Function

The purpose of this study is to investigate the effect of balcinrenone/dapagliflozin compared with dapagliflozin, on the risk of CV death, HF event with and without hospitalisation, in patients with chronic HF, impaired kidney function, and who have had a recent HF event. Eligible patients will randomly be assigned with a 1:1:1 ratio to receive once daily administration of one capsule and one tablet of one of the following treatments: 1. Balcinrenone/dapagliflozin 15 mg/10 mg capsule and matching placebo for dapagliflozin 10 mg tablet 2. Balcinrenone/dapagliflozin 40 mg/10 mg capsule and matching placebo for dapagliflozin 10 mg tablet 3. Dapagliflozin 10 mg tablet and matching placebo for balcinrenone/dapagliflozin capsule The study is event driven, and the average study duration for a participant is estimated to be 22 months including screening period, 20 months blinded treatment period and a one-month follow-up period on open-label dapagliflozin. The study will be conducted at approximately 700 sites in approximately 40 countries globally.

A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) - ACCLAIM-Lp(a)

DOSAGE Study: Upfront Dose-Reduced Chemotherapy in Older Patients with Metastatic Colorectal Cancer

Treating older adults with chemotherapy remains a challenge, as they are strongly underrepresented in clinical trials and no robust guidelines for treating older patients exist. Moreover, older adults are at increased risk of chemotherapy-related toxicity, resulting in decreased quality of life (QoL), increased hospital admissions and high health care costs. Therefore, the aim of the DOSAGE study is to demonstrate that upfront dose-reduced chemotherapy in patients with metastasized colorectal cancer is non-inferior to full-dose treatment with regard to progression-free survival (PFS). Treatment plans (monotherapy or doublet chemotherapy) will be based on expected risk of treatment toxicity for the individual patient (according to the Geriatric 8 (G8) questionnaire). The investigators expect that this treatment strategy will lead to less grade ≥3 toxicity, less early treatment continuation and hospitalizations and a better QoL and physical functioning. The DOSAGE study is a phase III, open-label, non-inferiority, randomized controlled clinical trial in patients aged ≥70 years with metastasized colorectal cancer eligible for palliative chemotherapy. All participating patients will undergo geriatric screening by the G8 questionnaire and will be classified as "low risk of toxicity" (G8-score of 15 or higher) or "high risk of toxicity" (G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist). Patients classified as low risk will be randomized between a fluoropyrimidine and oxaliplatin in either full-dose, or with an upfront dose-reduction of 25%. Patients classified as high risk will be randomized between fluoropyrimidine monotherapy in either full-dose or upfront dose-reduction. Addition of targeted treatment (bevacizumab or epidermal growth factor receptor (EGFR) inhibition) is allowed. Patients with a moderate renal impairment (GFR 30- 50 mL/min) will be treated with 25% reduced starting dose of capecitabine when randomized for full dose treatment and treated with 40% reduced starting dose when randomized for upfront dose reduction. Primary outcome is PFS. Secondary endpoints include grade ≥3 toxicity, QoL, physical functioning, overall survival, number of treatment cycles, dose reductions, hospital admissions, cumulative received dosage and cost-effectiveness. Given a non-inferiority margin of 8 weeks, 587 patients will be included (293/292 patients per arm).

High-Risk prostatE Cancer radiatiOn Versus surgERy

Detailed description: Robot assisted radical prostatectomy (RARP) and external beam radiotherapy (EBRT) combined with Androgen Deprivation Therapy (ADT) are widely used treatment modalities for high-risk non-metastatic prostate cancer (HR-PCa). Both treatments are associated with adverse effects and can have a great impact on health-related quality of life (HRQoL). To date there is no consensus on which of both is the optimal treatment for men with HR-PCa, as it is unclear which treatment is superior in terms of HRQoL, cost-effectiveness, progression-free survival (PFS) and distant metastases-free survival (DMFS). This is reflected in substantial variation between individual hospitals in the utilization of both treatment options that is not explained by patient- and tumor characteristics or patient preferences. In the RECOVER study we aim to address this knowledge gap. The insights gained can be used to tailor recommendations in (national) guidelines and in shared decision-making tools. This allows healthcare professionals to better inform their patients and allows patients to make well-informed choices.

LT4/LT3 Combination Therapy Versus LT4 Monotherapy in Patients with Autoimmune Hypothyroidism.

After obtaining informed consent we will enroll patients with autoimmune hypothyroidism and persistent tiredness despite normalized TSH levels on LT4 monotherapy. A general physical examination will be performed, and in- and exclusion criteria will be checked. This also includes an ECG to prevent including patients with a functional or structural abnormal heart. The study will start with a run-in period, during which all patients switch to blinded generic LT4, which is produced and distributed by the trial pharmacy. This is because there are seven LT4 preparations available in the Netherlands with different pharmacokinetic properties, which would otherwise introduce substantial bias. Previous research has shown that 36% of patients need dose adjustments when switching to other LT4 preparations. Therefore, serum TSH levels are measured every 8 weeks, and medication dosages adjusted if needed, in order to obtain normal serum TSH levels, defined as TSH levels within the assay-specific reference range. For trial feasibility, patients will be excluded from this study and referred back to their referring physician when a normal TSH cannot be reached with a maximum of two dose adjustments. Once a normal TSH has been measured, the final run-in TSH measurement will be performed 8 weeks later. This is because we want to ensure that we only enroll patients with a stable (i.e. normal) TSH on a stable dose of generic LT4, as recent dose adjustments could otherwise impact the tiredness questionnaire scores at the start of the RCT. This TSH measurement will be combined with a repeat ECG and the patient will be asked whether tiredness with a large negative impact on daily life is still present. Patients will enter Stage 2 (RCT) when they have a normal TSH, no ECG abnormalities, and indicate they have persistent tiredness. Patients not fulfilling these criteria will be excluded from this study and referred back to their referring physician. The expected duration of the run-in period will be 4-8 months, depending on the number of dose adjustments. Stage 2 includes a 1-year double-blind randomized placebo-controlled trial comparing LT4/LT3 with LT4/placebo treatment. At baseline, patients are randomized to either LT4/LT3 or LT4/placebo treatment. Serum TSH levels are measured at every visit, and medication dosages adjusted if needed, with the goal to normalize serum TSH levels, defined as TSH levels within the assay-specific reference range. Patients are excluded and referred back to their referring physician in case a normal TSH cannot be reached with the available study medication dosages (62,5 - 237,5 µg LT4 monotherapy dose). Visits will take place at baseline, and weeks 8, 16, 26, 39 and 52. The density of visits is higher at the beginning as this is the period when dose adjustments are particularly expected. At every visit, patients are asked to complete questionnaires on thyroid related complaints and quality of life (ThyPRO), general quality of life (EuroQoL-5D-5L and EuroQoL-5D-VAS), medical consumption (iMCQ) and productivity losses (iPCQ). At baseline and 52 weeks, additional blood will also be drawn to determine genetic variants, (thyroid hormone) metabolites and collect material for biobanking, as these data will be key to identify subgroups who are likely to respond to LT4/LT3 combination therapy. Although we do not expect any detrimental effects of these low physiological LT3 dosages, and previous studies neither reported any detrimental effects, we will explore the effects of LT4/LT3 combination therapy on the most important thyroid hormone target organs (bone, cardiovascular, metabolic and brain). This will improve communication between medical professionals and patients, providing them with comprehensive information on the balance between the potential benefits and harms of combination therapy vs monotherapy and will enable shared-decision making that better addresses individual needs of patients. For bone, serum bone markers will be determined at baseline and 52 weeks, and DXA scans will be performed at baseline and 52 weeks in a subgroup of 200 individuals. For cardiovascular and metabolic endpoints, blood pressure, pulse rate, weight, and waist circumference are measured at every visit. Fat percentages will be assessed on the beforementioned DXA scans. A repeat ECG will be performed at 52 weeks. To objectively explore effects on neurocognitive function, next to the subjective ThyPRO questionnaire scores, neurocognitive tests will be performed in a subgroup of 200 patients at baseline and 52 weeks.

Gut Microbiome Dynamics in Metastasized or Irresectable Colorectal Cancer

Although systemic treatment for metastasized or irresectable colorectal cancer (CRC) is becoming increasingly effective, overall survival is still poor and side effects of current treatment modalities are substantial. There is an urgent need for novel therapies, and in addition, better predictive tools are needed to select the right drug to the right patient. New data suggest that modulation of the microbiome of the gut might provide opportunities to increase anti-tumor efficacy of immunotherapy. Whereas the relation between the gut microbiome and immunotherapy is intensively studied, the relation between the gut microbiome and efficacy of conventional chemotherapy is unknown. A better understanding of the composition, function and dynamics of the gut microbiome before and during chemotherapy might help to identify factors that can be influenced during the treatment of patients with metastasized or irresectable CRC. Therefore, in this study the characteristics and alterations of the gut microbiome during chemotherapy for metastasized or irresectable CRC are studied, as well as the relation between the gut microbiome and the effects of chemotherapy.

Minimal Invasive Axillary Staging and Treatment After Neoadjuvant Systemic Therapy in Node Positive Breast Cancer

The MINIMAX is a multicenter registry study that includes node positive breast cancer patients, who are treated with NST (chemotherapy and ± immunotherapy), in order to gain insight in the oncologic safety and impact on QoL of less and more invasive axillary staging and treatment strategies. Patients who are included in this study will complete Patient Reported Outcome Measures (PROMs) at baseline (time of diagnosis), and 1 and 5 years after diagnosis to assess impact on QoL. A database will be built by the Netherlands Cancer Registry. Data on patient-, tumor-, pre-NST staging-, post-NST staging- and treatment-characteristics will be retrieved from patients' records by trained data registrars of the Netherlands Comprehensive Cancer Organisation (IKNL) using electronic case report forms (eCRFs). Five-year survival and recurrence will be evaluated to determine oncologic safety. The results will be incorporated in the national guidelines. In case of an equilibrium between less and more invasive strategies, the data of this study will at least be extremely suitable to be used in the shared decision making process.

Prospective Data Collection Initiative on Colorectal Cancer

Objectives - To start a prospective observational cohort study of CRC, small bowel and anal cancer patients from their primary diagnosis until death. - After obtaining Informed Consent, to prospectively collect data on medical history, comorbidities, baseline clinical parameters, imaging results, pathology results, tumor characteristics, treatment, treatment outcomes, hospital stays, interventions and (S)AEs. - After obtaining separate Informed Consent for collecting data on health related quality of life and work ability, to collect data on patient reported outcome measures. - After obtaining separate Informed Consent, to collect blood, (tumor) tissue or other body material, obtained during routine practice, for observational studies or storage in the biobank. - The cohort will serve as an infrastructure geared towards efficient, safe and comprehensive clinical evaluation of new interventions for patients with CRC according to the Trials within Cohorts (TwiCs) design. Expected outcome - More accurate data on the treatment and clinical and patient reported outcomes of CRC, small bowel and anal cancer in daily practice. - A continuous infrastructure for a large variety of research purposes including: A. Prognostic and predictive research. B. Molecular research and (epi)genetic research. C. Comparison of new interventions for patients with CRC, small bowel and anal cancer according to the Trials within Cohorts (TwiCs) design. D. Health care policies and cost-effectiveness studies.

Management of Low-risk (Grade I and II) DCIS

Background of the study: The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists. We hypothesize that asymptomatic, low-risk DCIS (grade I and II DCIS) can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be lowgrade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. It also may save many low-risk DCIS patients from intensive treatment. Objective of the study: The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years. Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate and patient reported outcomes. To determine whether low- risk DCIS can safely (measured by ipsilateral invasive breast cancer rate at 10 years) be managed by an active surveillance strategy or if the conventional treatment, being either wide local excision (WLE) only, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy, will remain the standard of care. Study design: Phase III, open-label, non-inferiority, multi-center, non-randomized clinical trial. By patient's preference, women will be included into one of the following arms: active surveillance or standard treatment according to local policy, being either WLE alone, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of five years and an additional two mammograms at year seven and ten.