Manchester, Lancashire, Midlands, Wales, Scotland, United Kingdom

DAHANCA 35: Proton Versus Photon Therapy for Head-neck Cancer

DAHANCA 35 is two parallel conducted, but separate randomized studies, within the same trial (DAHANCA 35D and DAHANCA 35X) by the Danish Head-Neck Cancer Study Group (DAHANCA). In patients with squamous cell carcinoma of the pharynx or larynx planned for primary radiotherapy a proton and a photon doseplan is prepared. If proton radiotherapy reduces the anticipated absolute risk of dysphagia >= grade 2 (DAHANCA scale, DAHANCA 35D) or severe xerostomia >= grade 4 (EORTC Head-Neck 35, DAHANCA 35X) more than 5%, the patient is randomised to either proton therapy or photon therapy, 2:1. The anticipated risk of xerostomia and dysphagia is estimated using Normal-Tissue Complication Models (NTCP). Patient are analysed according to the primary endpoint (dysphagia and/or xerostomia) after which they were enrolled. DAHANCA 35D is expected to enroll 360 patients and DAHANCA 35X 240 patients (in total 600 patients).

Senicapoc in COVID-19 Patients With Severe Respiratory Insufficiency

The investigators discovered that in an animal model with a knockout of a potassium channel with intermediate conductance (KCa3.1), the knockout protected against lung damage and accumulation of liquid in the lung. In subsequent studies, the investigators have developed a mouse model showing that genetic deletion of the KCa3.1 channels and senicapoc, a blocker of KCa3.1 channels, protects against the accumulation of liquid in the lung. Moreover, senicapoc treatment possesses anti-inflammatory effects illustrated as lower leukocyte accumulation inside the lungs after injury. Importantly, it also increases the FiO2/PaO2 ratio (ratio of inhaled to blood oxygen), hence preserving lung function in mice with an ARDS-like disease. In addition, there is evidence that senicapoc has antiviral properties. Aarhus University has patented senicapoc for use in the treatment of acute respiratory disease. In this case, respiratory disease is caused by an infection with a coronavirus. Senicapoc has been developed for the treatment of sickle cell disease and has been administered to 500 patients without observation of major treatment-related adverse effects.

Weight-Adjusted Dosing of 3-OHB in Patients With Chronic Heart Failure

Blood Pressure Reduction in Patients With Asymptomatic Aortic VALVE Stenosis

When to INDuce for OverWeight? (WINDOW)

Background The World Health Organization (WHO) defines overweight as a body mass index (BMI) of ≥25 kg/m2 and obesity as a BMI of ≥30 kg/m2. Overweight and obesity are rising dramatically worldwide. In fertile women, the prevalence of obesity is one third in the United States, 20% in the United Kingdom, and 12-13% in Denmark. The association between obesity in pregnancy and the risk of gestational complications increases with increasing BMI. Among other complications, obesity in pregnancy is associated with increased risk of caesarean delivery. Delivery by caesarean section further adds significant risks of wound infection or other infectious morbidity in obese women as compared to normal weight women. The longer the woman is pregnant, the longer the risk of pregnancy complications remains. In an otherwise low-risk pregnant woman at term, it is an on-going clinical dilemma, whether the benefits of elective induction of labor (eIOL) and termination of the pregnancy will outweigh the potential harms from the concomitant induction and delivery process. Regarding delivery complications, based on data from historical cohorts, eIOL has traditionally been associated with an increased risk of caesarean section and instrumental delivery. Therefore, expectant management has been the preferred clinical option. This interpretation has now been challenged by a randomized trial (ARRIVE) with >6000 low-risk pregnant women where eIOL at 39 weeks of gestation was associated with lower caesarean delivery rates. There are no randomized studies in obese women, but two larger observational studies did find lower odds of caesarean delivery in obese women with eIOL as compared to awaiting labor onset. Hence, a randomized trial that would compare caesarean delivery among obese women whose labor is induced with those expectantly managed is warranted. The proposed study will provide new and important knowledge into the area of induction of labor among overweight and obese women with potential great international impact for the future raising number of pregnant women in this subgroup. With this trial, the investigators aim to compare the risk of caesarean section in obese (BMI ≥ 30 kg/m2), but otherwise low-risk women with eIOL as compared to expectant management. Materials and methods The study is a multicenter randomized controlled trial with an allocation ratio of 1:1 in the two following arms: - Intervention arm/elective induction of labor in pregnancy at 39 gestational week and 0 to 3 days: Induction is performed according to local policy for induction of labor. - Comparison arm/expectant management: Waiting for spontaneous onset of labor unless a situation develops necessitating either induction of labor or caesarean section. 1900 low-risk pregnant women with a pre- or early pregnancy BMI ≥ 30 carrying a singleton pregnancy will be recruited from the Danish delivery wards. In each trial site, a physician investigator will be responsible for the enrolment, the electronically randomization, and data collection. The primary endpoint is the caesarean section rate. Among others there will be secondary endpoints on instrumental delivery, onset of labor, methods of induction, perinatal and postpartum complications both maternal and neonatal along with data on women's experience on birth measured by a questionnaire survey four to six weeks post-partum. Ethics The study will be conducted in accordance with the ethical principles outlined in the latest version of the 'Declaration of Helsinki' and the 'Guideline for Good Clinical Practice' related to experiments on humans. The Central Denmark Region Committee on Biomedical Research Ethics, and The Danish Health Authorities have approved the study. Perspectives In perspective, more than 39% of the world's population is overweight and 13% are obese by the WHO classification. Pregnant overweight women are at increased risk of pregnancy and delivery complications, and there is a need to improve maternity care for this subgroup of women. The results of this trial have the potential to generate important knowledge for the improvement of delivery in obese women and they will add key information to an on-going discussion of the effects of labor induction before term. Any possible harm or disadvantage to the individual study participant is outweighed by the possible benefit to the increasing number of obese women who will be pregnant in the future.

The MASTER Study (MAmmary Cancer STatin ER Positive Study)

Cholesterol-lowering drugs such as statins are currently used to lower cholesterol levels and prevent cardiovascular events. Statins have, however, received substantial scientific attention as cancer-inhibiting drugs. Previous findings were recently supported in a large-scaled study again demonstrating the beneficial effects of statins on breast cancer outcome this time nested within a large, international, randomized clinical trial of modern adjuvant cancer therapy. Given the compelling evidence supporting a protective effect of statins on breast cancer recurrence, calls for prospective clinical trials have been expressed. In this trial - the MASTER trial - we hypothesize that the addition of statin treatment to the current breast cancer treatment will improve the prognosis of women with early breast cancer. Thus, the primary objective of the MASTER trial is to determine the clinical efficacy of the statin - atorvastatin - as measured by invasive disease-free survival among patients with primary breast cancer. The trial is nationwide throughout Denmark and a total of 3,360 women are to be included in the trial. Women eligible for the trial have been diagnosed with an estrogen receptor positive breast cancer and are candidates for systemic cancer therapy, either prior to or following breast surgery. Upon eligibility and signed informed consent, trial participants will be randomized in a 1:1 manner to either standard treatment and atorvastatin 80 mg/day or standard treatment and placebo. The randomization is blinded. The treatment with atorvastatin or placebo will continue for two years unless side effects are experienced and further treatment with atorvastatin or the placebo is deemed inadequate. The standard treatment will of course continue as planned. The trial participants will follow the standard clinical routines in terms of follow-up and in addition they are asked to fill in questionnaires, i.e. regarding potential side effects or new events or diagnoses, up to ten years following inclusion. Potential breast cancer recurrences are hereby identified and a follow-up of at least 61/2 years will be required for the trial the demonstrate the estimated clinical difference between the randomized groups of patients.

A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment

This is a multicenter study with 2 arms, and will include 3 phases: a) screening phase of up to 28 days before randomization during which participants will complete a 14-day washout period from all prior therapies including JAK-inhibitor treatment, and the participant's eligibility will be reviewed; b) treatment phase, from randomization until study treatment (imetelstat or BAT) discontinuation; and c) post treatment follow-up phase, that begins when the participant discontinues treatment, and will continue until death, lost to follow-up, withdrawal of consent, or study end, whichever occurs first. Participants will be randomized (2:1) into 2 Arms (Arm A will receive imetelstat and Arm B will receive BAT). Participants who meet progressive disease criteria and discontinue BAT, may crossover to receive imetelstat treatment after sponsor's approval.

A Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Treatment With AP1189 in Patients With iMN and Severe Proteinuria

This study is an exploratory, randomized, double-blind, multicenter, placebo-controlled study with repeated doses of AP1189. The study population will consist of patients with idiopathic membranous nephropathy (iMN) and severe proteinuria who are on ACE inhibitor or angiotensin II receptor blocker treatment. Following a successful screening, subjects who fulfill the enrollment criteria will be randomized in a 2:1 ratio in group A and B: - Group A (12 subjects): AP1189 dose 100 mg, once daily for 12 weeks (28 days) as an add-on to any ongoing treatment, including ACE inhibitors/ angiotensin II receptor blocker - Group B (6 subjects): placebo for 12 weeks (28 days) as an add-on to any ongoing treatment including ACE inhibitors/ angiotensin II receptor blocker.

Eosinophil-guided Reduction of Inhaled Corticosteroids

Inhaled corticosteroid (ICS) treatment is recommended by Global Initiative for Obstructive Lung Disease (GOLD) for patients with frequent and/or servere exacerbations and blood eosinophils > 0.3 x 10^9 cells/L and in those with ≥ 0,1 x 109 cells blood-eosinophils and recurrent exacerbations while on bronchodilators. ICS treatment, however, is associated with side effects such as diabetes, osteoporosis and pneumonia which is costly for both patients and society. By studying the effects of a personalized, eoseosinophil-guided approach to direct ICS in COPD patients with frequent AECOPDs through a randomized clinical trial this study will examine the possibilities of reducing ICS overtreatment and thus ICS-related adverse events. Long term ICS treatment is known for affecting the bacterial load in stable COPD patients. Azithromycin exerts multiple effects on the structure and composition of the lower airway microbiota and has anti-inflammatory effects. This study will, moreover, investigate whether an oral low-dose prophylactic treatment with Azithromycin 250 mg three times weekly can reduce the number of moderate-severe AECOPD and improves time alive and out of hospital. This study is a randomized, double-blinded, multicentre, four-arm intervention clinical trial and is conducted based on the principles of good clinical practise (GCP).

Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Acute Heart Failure