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Background Displaced ankle fractures classified as Weber types B and C are common across all age groups. The standard treatment involves open reduction and internal fixation, followed by a rehabilitation program that includes 6 weeks of partial weightbearing. During this period, both passive and active range-of-motion exercises are performed under the supervision of a physiotherapist. Recently, a new device has become available, allowing active controlled motion of the ankle joint at home on top of the normal rehabilitation protocol. The purpose of this controlled randomized trial was to evaluate the superiority of this device as a supplement in standard rehabilitation protocols after distal fibular fractures. Methods This prospective controlled multicenter trial will include a minimum of 58 patients who have undergone surgical treatment for isolated distal fibular fractures of Weber types B and C. These patients will be randomized into 2 groups: Group 1 will undergo a standardized rehabilitation protocol with active and passive physiotherapy under partial weightbearing for 6 weeks with the active controlled motion device at home on top. Group 2 will receive the same rehabilitation without the device. Three German hospitals with different levels of care and 6 rehabilitation centers are involved in this study. The estimated study duration of 12 months started in October 2024. The follow-up will last 6 months after the recruitment of the last patient. The following assessments are performed: baseline after surgery; after 6 weeks; at 3 and 6 months; and with check-in calls after 2 and 4 weeks. The evaluation of effectiveness is based on FAOS, NRS, and SF-36 scores; changes in employment during the study; return-to-work; return-to-sports; and time-to-unrestricted weightbearing. Discussion This trial aims to collect valid data to determine whether the use of an active controlled motion device as a supplement to a standardized physiotherapy protocol after surgical treatment of ankle fractures leads to significantly improved outcomes. After evaluation of the results by the German Joint Federal Committee, a final assessment is made to make this device part of a future treatment protocol in the aftercare of surgically treated distal fibular fractures of Weber types B and C. Trial registration The trial is registered in the International Clinical Trials Registry Platform of the World Health Organization with the Main-ID DRKS00034202 on July 22nd, 2024 ( https://trialsearch.who.int/Trial2.aspx ?TrialID=DRKS00034202).

Only 2–5% of patients who have a stroke receive thrombolytic treatment, mainly because of delay in reaching the hospital. We aimed to assess the efficacy of a new approach of diagnosis and treatment starting at the emergency site, rather than after hospital arrival, in reducing delay in stroke therapy. We did a randomised single-centre controlled trial to compare the time from alarm (emergency call) to therapy decision between mobile stroke unit (MSU) and hospital intervention. For inclusion in our study patients needed to be aged 18–80 years and have one or more stroke symptoms that started within the previous 2·5 h. In accordance with our week-wise randomisation plan, patients received either prehospital stroke treatment in a specialised ambulance (equipped with a CT scanner, point-of-care laboratory, and telemedicine connection) or optimised conventional hospital-based stroke treatment (control group) with a 7 day follow-up. Allocation was not masked from patients and investigators. Our primary endpoint was time from alarm to therapy decision, which was analysed with the Mann-Whitney U test. Our secondary endpoints included times from alarm to end of CT and to end of laboratory analysis, number of patients receiving intravenous thrombolysis, time from alarm to intravenous thrombolysis, and neurological outcome. We also assessed safety endpoints. This study is registered with ClinicalTrials.gov, number NCT00153036. We stopped the trial after our planned interim analysis at 100 of 200 planned patients (53 in the prehospital stroke treatment group, 47 in the control group), because we had met our prespecified criteria for study termination. Prehospital stroke treatment reduced the median time from alarm to therapy decision substantially: 35 min (IQR 31–39) versus 76 min (63–94), p<0·0001; median difference 41 min (95% CI 36–48 min). We also detected similar gains regarding times from alarm to end of CT, and alarm to end of laboratory analysis, and to intravenous thrombolysis for eligible ischaemic stroke patients, although there was no substantial difference in number of patients who received intravenous thrombolysis or in neurological outcome. Safety endpoints seemed similar across the groups. For patients with suspected stroke, treatment by the MSU substantially reduced median time from alarm to therapy decision. The MSU strategy offers a potential solution to the medical problem of the arrival of most stroke patients at the hospital too late for treatment. Ministry of Health of the Saarland, Germany, the Werner-Jackstädt Foundation, the Else-Kröner-Fresenius Foundation, and the Rettungsstiftung Saar.

Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O 2 -saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O 2 -saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).

Background Interstitial lung diseases in children (chILD) are rare and consist of many different entities that affect the parenchyma of the lungs, leading to a chronic lung disease. The natural course of many of these diseases is connected with a high morbidity and significant mortality. Symptomatic treatment consists of oxygen supplementation, adequate nutrition adapted to the high energy demand generated by the disease due to the increased breathing effort required, as well as immunization against respiratory pathogens to prevent exacerbations through respiratory infections. No proven pharmacological treatments are available to date. This placebo-controlled study aims to evaluate the efficacy and safety of the mid-term use of hydroxychloroquine in chILD. Methods and design The study is an explorative, prospective, randomized, double-blind, placebo-controlled investigation of hydroxychloroquine (HCQ) in chILD. Patients can be included into the trial when diagnosed with a chronic (≥ 3 weeks’ duration) diffuse parenchymal lung disease (chILD) (1) genetically defined, (2) histologically defined or (3) diagnosed with idiopathic pulmonary hemorrhage (hemosiderosis). The study contains of two different study blocks, a START and a STOP block, which can be initiated in any sequence. Each patient can participate in each block only once. In the START block subjects are randomized to parallel groups for 4 weeks treatment, then the placebo group is switched to the active drug. In the STOP block, subjects taking HCQ are randomized into parallel groups treated with placebo or HCQ. Discussion This study is the first international, investigator-initiated, prospective and controlled investigation of a pharmacological treatment in chILD. The block design was selected as it has the advantage of accommodating patients who are initiating or withdrawing from HCQ therapy, thus allowing the participation of those who were previously started on off-label HCQ. The cross-over design and selected outcome parameters enables us to include appropriate numbers of patients of all age groups from neonates to adults suffering from these rare diseases. Trial registration This is an exploratory, Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD. Study title: Hydroxychloroquine in pediatric ILD: START randomized controlled in parallel groups, then switch placebo to the active drug, and STOP randomized controlled in parallel groups to evaluate the efficacy and safety of hydroxychloroquine (HCQ). Short title: HCQ in pediatric ILD, particularly 4surfdefect. EudraCT, ID: 2013–003714-40. Registered on 2 July 2013. ClinicalTrials.gov, ID: NCT02615938 . Registered on 8 November 2015. IZKS trial code: 2013–006; Sponsor: University Hospital, Ludwig-Maximilians University of Munich. Responsible Party: Prof. Dr. med. Matthias Griese, University Hospital, Ludwig-Maximilians University of Munich, Germany.

Background In Major Depressive Disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease ≥20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome. Methods/Design The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17 ≤7) on treatment day 56 compared to patients treated according to current guideline recommendation (treatment as usual; TAU). In level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to an EMC strategy or TAU. The EMC strategy for this study schedules a first medication change on day 15; in case of non-improvement between days 15-28, a second medication change will be performed. TAU schedules the first medication change after 28 days in case of non-response (HAMD-17 decrease <50%). Both interventions will last 42 days. In levels 2 and 3, EMC strategies will be compared with TAU strategies in improvers on day 14, who experience a stagnation of improvement during the course of treatment. The trial is supported by the German Federal Ministry of Education and Research (BMBF) and will be conducted in cooperation with the BMBF funded Interdisciplinary Centre Clinical Trials (IZKS) at the University Medical Centre Mainz and at six clinical trial sites in Germany. Discussion If the EMC strategies lead to significantly more remitters, changes of clinical practice, guidelines for the treatment of MDD as well as research settings can be expected. Trial Registration Clincaltrials.gov Identifier : NCT00974155; EudraCT : 2008-008280-96.

Background The global prevalence of diabetes among adults will be 6.4% in 2010 and will increase to 7.7% by 2030. Diabetes doubles the odds of depression, and 9% of patients with diabetes are affected by depressive disorders. When subclinical depression is included, the proportion of patients who have clinically relevant depressive symptoms increases to 26%. In patients aged over 65 years, the interaction of diabetes and depression has predicted increased mortality, complications, disability, and earlier occurrence of all of these adverse outcomes. These deleterious effects were observed even in minor depression, where the risk of mortality within 7 years was 4.9 times higher compared with diabetes patients who did not have depressive symptoms. In this paper we describe the design and methods of the Minor Depression and Diabetes trial, a clinical trial within the 'Competence Network for Diabetes mellitus', which is funded by the German Federal Ministry of Education and Research. Methods/Design Patients' inclusion criteria are: Type 2 diabetes mellitus, 65 to 85 years of age, 3 to 6 depressive symptoms (minor depression or mild major depression). Our aim is to compare the efficacy of diabetes-specific cognitive behavioural therapy adapted for the elderly vs. intensified treatment as usual vs. a guided self-help intervention regarding improvement of health related quality of life as the primary outcome. The trial will be conducted as a multicentre, open, observer-blinded, parallel group (3 groups) randomized controlled trial. Patients will be randomized to one of the three treatment conditions. After 12 weeks of open-label therapy in all treatment conditions, both group interventions will be reduced to one session per month during the one-year long-term phase of the trial. At the one-year follow-up, all groups will be re-examined regarding the primary and secondary parameters, for example reduction of depressive symptoms, prevention of moderate/severe major depression, improvement of glycaemic control, mortality, and cost effectiveness. Depending on additional funding, the sample will be continuously observed as a prospective cohort; the primary outcome will be changed to mortality for all subsequent follow-up measurements. Trial registration Current Controlled Trials Register (ISRCTN58007098).

Our aim was to assess the efficacy of a part-standardised verum acupuncture procedure, in accordance with the rules of traditional Chinese medicine, compared with that of part-standardised sham acupuncture and standard migraine prophylaxis with beta blockers, calcium-channel blockers, or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment. This study was a prospective, randomised, multicentre, double-blind, parallel-group, controlled, clinical trial, undertaken between April 2002 and July 2005. Patients who had two to six migraine attacks per month were randomly assigned verum acupuncture (n=313), sham acupuncture (n=339), or standard therapy (n=308). Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs. Primary outcome was the difference in migraine days between 4 weeks before randomisation and weeks 23–26 after randomisation. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN52683557. Of 1295 patients screened, 960 were randomly assigned to a treatment group. Immediately after randomisation, 125 patients (106 from the standard group) withdrew their consent to study participation. 794 patients were analysed in the intention-to-treat popoulation and 443 in the per-protocol population. The primary outcome showed a mean reduction of 2 ·3 days (95% CI 1·9–2·7) in the verum acupuncture group, 1·5 days (1·1–2·0) in the sham acupuncture group, and 2·1 days (1·5–2·7) in the standard therapy group. These differences were statistically significant compared with baseline (p<0·0001), but not across the treatment groups (p=0·09). The proportion of responders, defined as patients with a reduction of migraine days by at least 50%, 26 weeks after randomisation, was 47% in the verum group, 39% in the sham acupuncture group, and 40% in the standard group (p=0·133). Treatment outcomes for migraine do not differ between patients treated with sham acupuncture, verum acupuncture, or standard therapy.

BackgroundRight ventricular (RV) function plays a critical role in the pathophysiology and acute prognosis of pulmonary embolism (PE). We analyzed the temporal changes of RV function in the cohort of a prospective multicentre study investigating if an early switch to oral anticoagulation in patients with intermediate-risk PE is effective and safe.MethodsEchocardiographic and laboratory examinations were performed at baseline (PE diagnosis), 6 days and 6 months. Echocardiographic parameters were classified into categories representing RV size, RV free wall/tricuspid annulus motion, RV pressure overload and right atrial (RA)/central venous pressure.ResultsRV dysfunction based on any abnormal echocardiographic parameter was present in 84% of patients at baseline. RV dilatation was the most frequently abnormal finding (40.6%), followed by increased RA/central venous pressure (34.6%), RV pressure overload (32.1%), and reduced RV free wall/tricuspid annulus motion (20.9%). As early as day 6, RV size remained normal or improved in 260 patients (64.7%), RV free wall/tricuspid annulus motion in 301 (74.9%), RV pressure overload in 297 (73.9%), and RA/central venous pressure in 254 (63.2%). At day 180, the frequencies slightly increased. The median NT-proBNP level decreased from 1448 pg/ml at baseline to 256.5 on day 6 and 127 on day 180.ConclusionIn the majority of patients with acute intermediate-risk PE switched early to a direct oral anticoagulant, echocardiographic parameters of RV function normalised within 6 days and remained normal throughout the first 6 months. Almost one in four patients, however, continued to have evidence of RV dysfunction over the long term.

We performed a prospective, observational, cohort study of children newly diagnosed with children’s interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3–7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88–96). Death (n=20, 16%) was the most common in those <6 months of age with SpO2<94% and developmental/surfactant disorders. We report for the first time that ChILD survivors improved multiple clinical parameters within 8–12 weeks of diagnosis. These data can inform family discussions and support clinical trial measurements.

Background Angulated fractures of the distal forearm are very frequent lesions in childhood. Currently, there are no standard guidelines on whether these children should be treated conservatively with a cast; with reduction and a cast; or with reduction, pinning and a cast under anesthesia. Minor prospective and retrospective studies have shown that the distal physis of the forearm possesses high remodeling capacity leading to reliable correction of malalignment. The aim of this trial is to answer the question about whether operative and conservative treatment show equivocal results. Methods/Design This is a prospective, multinational, multicenter, randomized, observer-blinded, actively controlled, parallel group trial, with 24 months of observation. The primary objective of this trial is to assess whether or not the long-term functional outcome in remodeling patients is inferior to patients receiving closed reduction and K-wire pinning. The trial should include 742 patients with acute fracture. The patients will be included in 30 medical centers in Germany, Switzerland and Austria. All patients 5 to 11 years of age presenting at the emergency department with an angulated distal fracture of the forearm will be randomized online after informed consent. The primary endpoint is the Cooney Score after 24 months. The secondary endpoint is the grade of radiological displacement at 12/24 months. Discussion Therapy of angulated fractures is a matter of intensive debate. Primary manipulation and pinning under general anesthesia is recommended in order to avoid malalignment. No major study has proven the advantage of manipulation and pinning over immobilization alone. Should remodeling appear to be a safe alternative, manipulation under general anesthesia, K-wire pinning and removal of pins could be avoided, thus sparing significant costs. Trial registration DRKS00004874 , 30 October 2013.