This thesis contributes to the evidence-base of the influence of patient factors, surgical approach and implant design on outcomes after total hip replacement (THA).A systematic review (SR) shows... Show moreThis thesis contributes to the evidence-base of the influence of patient factors, surgical approach and implant design on outcomes after total hip replacement (THA).A systematic review (SR) shows that there is strong evidence for BMI, age, comorbidity, preoperative functioning and mental health as predictors of physical functioning. A predictive model based on data from this thesis emphasizes preoperative functioning, mental health and pain as predictors.To treat hip fractures, the posterolateral (PLA) and direct lateral surgical approach (DLA) are the most commonly used. The PLA may cause more dislocations, but seems to result in less walking problems and abductor insufficiency than the DLA. All investigated surgical approaches for primary THA resulted in a significant improvement in patient reported outcome measures (PROMs). The anterior and posterolateral approaches provided greater improvement in physical function and pain, but clinical differences were small.A multicenter randomized trial comparing two hip stems is described. No significant difference has been demonstrated between the Collum Femoris Preserving (CFP) and Zweymüller stem in physical function at 5 years or implant survival at 12 years, although CFP may be inferior in cup revisions. A SR suggests lower dislocation rates and revisions for dual mobility cups in THA, but high quality evidence is lacking. Therefore, we designed an RCT comparing dual mobility cups with unipolar cups in older patients.In addition to providing insights into the influence of patient, surgical and implant characteristics on outcome after (total) hip arthroplasty, this thesis provides suggestions for the design of future clinical trials. Show less
BackgroundAlthough reduced work ability is a substantial problem among people with inflammatory arthritis (IA), work ability is an underexposed area in clinical practice. Evidence on vocational... Show moreBackgroundAlthough reduced work ability is a substantial problem among people with inflammatory arthritis (IA), work ability is an underexposed area in clinical practice. Evidence on vocational interventions in IA is limited, but favourable results of delivery by a physiotherapist (PT) warrant the need for further research. Therefore, we aim to evaluate the (cost-)effectiveness of a multimodal, PT-led, vocational intervention in (self-)employed people with IA compared to usual care.MethodsThis randomized controlled trial will include 140 people with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) who are (self-)employed and have reduced work ability (Work Ability Index – Single Item Scale (WAS) ≤ 7/10) and/or RA/axSpA related sick leave (≤ 6 months). Participants will be randomized 1:1 to the intervention or control condition (usual care). The intervention, delivered by primary care PTs, will be personalized to each patient, consisting of 10 to 21 sessions over 12 months. The intervention will be multimodal, comprising of 1) exercise therapy and a physical activity plan, 2) education/self-management support, 3) work-roadmap to guide participants in finding relevant other care, with optionally 4) online self-management course and 5) workplace examination. Assessments will be performed at baseline and after 3, 6, and 12 months. The primary outcome measure of effectiveness is work ability, as measured with the WAS at 12 months. For the cost-effectiveness analysis, the EuroQol (EQ-5D-5L), self-reported healthcare use, sick leave and productivity while at work will be used to estimate the trial based cost-utility from a societal perspective. A process evaluation, including assessments of adherence and treatment fidelity, will be undertaken using the registrations of the PTs and semi-structured interviews at 12 months follow-up in a random sample of the intervention group.DiscussionThe results of this study will provide insights in the (cost-)effectiveness of a multimodal, PT-led, vocational intervention in people with IA and a reduced work ability. Show less
BackgroundCerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the... Show moreBackgroundCerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients.MethodsThe BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics.DiscussionThe results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. Show less
Koekenbier, E.L.; Fohse, K.; Maat, J.S. van de; Oosterheert, J.J.; Nieuwkoop, C. van; Hoogerwerf, J.J.; ... ; BCG-PRIME Study Grp 2023
ObjectivesTo test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more... Show moreObjectivesTo test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities.MethodsCommunity-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events.ResultsA total of 6112 participants with a median age of 69 years (interquartile range, 65–74) and median of 2 (interquartile range, 1–3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87–1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46–1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35–1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group.Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66–1.28).DiscussionBCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs. Show less
BackgroundMajor depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and... Show moreBackgroundMajor depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone.MethodsThe RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology—Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained.DiscussionThe RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. Show less
Dam, C.J. van; Velzen, M. van; Kramers, C.; Schellekens, A.; Olofsen, E.; Niesters, M.; Dahan, A. 2023
Background Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous... Show moreBackground Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain.Methods Trial design: a single-center, randomized, three-arm, open-label, exploratory trial.Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists.Intervention: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol (R), containing 6.3% delta(9)-tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period.Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia.Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations.Discussion The trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia. Show less
In the current dissertation the effectiveness and cost-effectiveness of Featback, an internet-based self-help intervention for eating disorders, and online support by individuals with a lived... Show moreIn the current dissertation the effectiveness and cost-effectiveness of Featback, an internet-based self-help intervention for eating disorders, and online support by individuals with a lived experience of an eating disorder were investigated. The findings suggest that low-threshold internet-based interventions for eating disorders, such as Featback, can complement existing treatment options in three ways. First, they have been repeatedly found to be effective in reducing eating disorder symptomatology. Second, such interventions can reach individuals that are currently not reached by other forms of treatment and stimulate them to get professional help. Finally, internet-based interventions are likely to be cost-effective compared to care as usual. Concordantly, implementing highly scalable and easily accessible interventions like Featback likely helps to reduce both the individual and societal burden of eating disorders. Show less
Ritchlin, C.T.; Coates, L.C.; Mease, P.J.; Heijde, D. van der; Song, J.; Jiang, Y.S.; ... ; Rahman, P. 2023
Background: Guselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2... Show moreBackground: Guselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naive patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were-0.66 for guselkumab Q4W (p=0.011) and-0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression. Methods: Patients are eligible for APEX if they have had PsA for >= 6 months and active disease (> 3 swollen and >= 3 tender joints, CRP > 0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheu-matic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with >= 2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving >= 20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/ guselkumab Q4W/placebo are expected to provide > 99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as >= 90% (Q4W vs placebo) and >= 80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haen-szel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively. Discussion: DISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression. Show less
Ritchlin, C.T.; Coates, L.C.; Mease, P.J.; Heijde, D. van der; Song, J.; Jiang, Y.S.; ... ; Rahman, P. 2023
BackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2... Show moreBackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression.MethodsPatients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively.DiscussionDISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression. Show less
Background: Chronic pancreatitis (CP) is an inflammatory disease that may be complicated by abdominal pain, pancreatic dysfunction, nutritional deficiencies, and diminished bone density.... Show moreBackground: Chronic pancreatitis (CP) is an inflammatory disease that may be complicated by abdominal pain, pancreatic dysfunction, nutritional deficiencies, and diminished bone density. Importantly, it is also associated with a substantially impaired quality of life and reduced life expectancy. This may partly be explained by suboptimal treatment, in particular the long-term management of this chronic condition, despite several national and international guidelines. Standardization of care through a structured implementation of guideline recommendations may improve the level of care and lower the complication rate of these patients. Therefore, the aim of the present study is to evaluate to what extent patient education and standardization of care, through the implementation of an evidence-based integrated management algorithm, improve quality of life and reduce pain severity in patients with CP. Methods: The COMBO trial is a nationwide stepped-wedge cluster-randomized controlled trial. In a stepwise manner, 26 centers, clustered in 6 health regions, cross-over from current practice to care according to an evidence-based integrated management algorithm. During the current practice phase, study participants are recruited and followed longitudinally through questionnaires. Individual patients contribute data to both study periods. Co-primary study endpoints consist of quality of life (assessed by the PANQOLI score) and level of pain (assessed by the Izbicki questionnaire). Secondary outcomes include process measure outcomes, clinical outcomes (e.g., pancreatic function, nutritional status, bone health, interventions, medication use), utilization of healthcare resources, (in) direct costs, and the level of social participation. Standard follow-up is 35 months from the start of the trial. Discussion: This is the first stepped-wedge cluster-randomized controlled trial to investigate whether an evidence-based integrated therapeutic approach improves quality of life and pain severity in patients with CP as compared with current practice. Show less
Snijders, R.J.A.L.M.; Stoelinga, A.E.C.; Gevers, T.J.G.; Pape, S.; Biewenga, M.; Verdonk, R.C.; ... ; Dutch Autoimmune Hepatitis Working 2022
Background: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which... Show moreBackground: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Method:s: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Show less
Het doel van de dissertatie van David Gast is: het onderzoeken in hoeverre voedingssupplementen (vitaminen, mineralen en omega-3 vetzuren) in de praktijk gebruikt kunnen worden als interventie voor... Show moreHet doel van de dissertatie van David Gast is: het onderzoeken in hoeverre voedingssupplementen (vitaminen, mineralen en omega-3 vetzuren) in de praktijk gebruikt kunnen worden als interventie voor het verminderen van agressief gedrag bij mensen met een verstandelijke beperking (Chapter 1). Daartoe zijn verschillende studies verricht, te beginnen met een onderzoek naar de kwaliteit van voedingspatroon(Chapter 2). De tweede studie is een focusgroep onderzoek, waarin wordt onderzocht in hoeverre professionals en cliënten in de gehandicaptenzorg een interventie met voedingssupplementen accepteren als interventie voor moeilijk verstaanbaar gedrag (Chapter 3). De derde en vierde studies zijn RCT’s waarin het effect van voedingssupplementen wordt onderzocht op agressief gedrag bij respectievelijk gedetineerden (Chapter 4), en mensen met een verstandelijke beperking (Chapter 5). Het laatste onderzoek (Chapter 6) is een meta-analyse van de door ons gevonden studies naar het effect van een interventie met multivitaminen- mineralen op agressief gedrag. Om toekomstig onderzoek met voedingssupplementen in een kwetsbare populatie te faciliteren hebben we de door ons geleerde lessen geordend en van kanttekeningen voorzien (Chapter 7). Tot slot volgt een samenvatting en algemene discussie over de inhoud van de dissertatie (Chapter 8). Show less
Doesschate, T. ten; Vaart, T.W. van der; Debisarun, P.A.; Taks, E.; Moorlag, S.J.C.F.M.; Paternotte, N.; ... ; Werkhoven, C.H. van 2022
Objectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Gue?rin (BCG) vaccine may provide non-specific protection against respiratory infections... Show moreObjectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Gue?rin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. Methods: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). Results: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication.Conclusions: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. Show less
Background The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not... Show moreBackground The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. Methods DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. Discussion When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. Show less
Rohrbach, P.J.; Dingemans, A. E.; Spinhoven, P.; Ginkel, J.R. van; Fokkema, M.; Wildermans, T.F.; ... ; Furth, E.F. van 2022
Objective: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the... Show moreObjective: Many individuals with an eating disorder do not receive appropriate care. Low-threshold interventions could help bridge this treatment gap. The study aim was to evaluate the effectiveness of Featback, a fully automated online self-help intervention, online expert-patient support and their combination.Method: A randomized controlled trial with a 12-month follow-up period was conducted. Participants aged 16 or older with at least mild eating disorder symptoms were randomized to four conditions: (1) Featback, a fully automated online selfhelp intervention, (2) chat or email support from a recovered expert patient, (3) Featback with expert-patient support and (4) a waiting list control condition. The intervention period was 8 weeks and there was a total of six online assessments. The main outcome constituted reduction of eating disorder symptoms over time. Results: Three hundred fifty five participants, of whom 43% had never received eating disorder treatment, were randomized. The three active interventions were superior to a waitlist in reducing eating disorder symptoms (d = -0.38), with no significant difference in effectiveness between the three interventions. Participants in conditions with expert-patient support were more satisfied with the intervention. Discussion: Internet-based self-help, expert-patient support and their combination were effective in reducing eating disorder symptoms compared to a waiting list control condition. Guidance improved satisfaction with the internet intervention but not its effectiveness. Low-threshold interventions such as Featback and expert-patient support can reduce eating disorder symptoms and reach the large group of underserved individuals, complementing existing forms of eating disorder treatment. Public significance statement: Individuals with eating-related problems who received (1) a fully automated internet-based intervention, (2) chat and e-mail support by a recovered individual or (3) their combination, experienced stronger reductions in eating disorder symptoms than those who received (4) usual care. Such brief and easyaccess interventions play an important role in reaching individuals who are currently not reached by other forms of treatment. Show less
Purpose: Scalp cooling can prevent chemotherapy-induced alopecia (CIA). Previously, the post-infusion cooling time (PICT) could be successfully reduced in docetaxel-treated patients from 90 to 45... Show morePurpose: Scalp cooling can prevent chemotherapy-induced alopecia (CIA). Previously, the post-infusion cooling time (PICT) could be successfully reduced in docetaxel-treated patients from 90 to 45 and 20 min. Therefore, it seems plausible that the PICT can be shortened for paclitaxel-treated patients as well. Methods: Patients treated with weekly paclitaxel were included in this multi-centre trial and randomly assigned to a PICT of 45 or 20 min. The results were compared to a standard PICT of 90 min, derived from prospective collected data from the Dutch Scalp Cooling Registry. The primary endpoint was the percentage of patients who decide to not wear a wig or head covering. Secondary endpoints were the degree of CIA assessed with the Dean scale for assessment of hair loss; alopecia graded according to NCI CTC toxicity version 4.03 (CTCAE4.03); tolerance of scalp cooling and perceived distress of CIA. Results: Ninety-one patients were enrolled in this study; 74 patients were evaluable for hair loss. Hair preservation was successful in 27 patients (75%) with a PICT of 45 min and in 31 patients (82%) with a PICT of 20 min. There was no difference in success rate with the standard PICT of 90 min (85%, p = 0.29). Similar success rates were seen when using the Dean scale and CTCAE assessment, with no differences between groups (p = 0.12 and p = 0.38). Conclusions: A 20 min PICT is as effective as 45 and 90 min to prevent weekly paclitaxel-induced alopecia and should be the new standard of care. Show less
Background: The rapidly increasing number of elderly (>= 65 years old) with TBI is accompanied by substantial medical and economic consequences. An ASDH is the most common injury in elderly with... Show moreBackground: The rapidly increasing number of elderly (>= 65 years old) with TBI is accompanied by substantial medical and economic consequences. An ASDH is the most common injury in elderly with TBI and the surgical versus conservative treatment of this patient group remains an important clinical dilemma. Current BTF guidelines are not based on high-quality evidence and compliance is low, allowing for large international treatment variation. The RESET-ASDH trial is an international multicenter RCT on the (cost-)effectiveness of early neurosurgical hematoma evacuation versus initial conservative treatment in elderly with a t-ASDHMethods: In total, 300 patients will be recruited from 17 Belgian and Dutch trauma centers. Patients >= 65 years with at first presentation a GCS >= 9 and a t-ASDH > 10 mm or a t-ASDH < 10 mm and a midline shift > 5 mm, or a GCS < 9 with a traumatic ASDH < 10 mm and a midline shift < 5 mm without extracranial explanation for the comatose state, for whom clinical equipoise exists will be randomized to early surgical hematoma evacuation or initial conservative management with the possibility of delayed secondary surgery. When possible, patients or their legal representatives will be asked for consent before inclusion. When obtaining patient or proxy consent is impossible within the therapeutic time window, patients are enrolled using the deferred consent procedure. Medical-ethical approval was obtained in the Netherlands and Belgium. The choice of neurosurgical techniques will be left to the discretion of the neurosurgeon. Patients will be analyzed according to an intention-to-treat design. The primary endpoint will be functional outcome on the GOS-E after 1 year. Patient recruitment starts in 2022 with the exact timing depending on the current COVID-19 crisis and is expected to end in 2024.Discussion: The study results will be implemented after publication and presented on international conferences. Depending on the trial results, the current Brain Trauma Foundation guidelines will either be substantiated by high-quality evidence or will have to be altered. Show less
Linden, S.D. van der; Rutten, G.J.M.; Dirven, L.; Taphoorn, M.J.B.; Satoer, D.D.; Dirven, C.M.F.; ... ; Gehring, K. 2021
Background Evidence-based cognitive rehabilitation programs for brain tumor patients are not widely available, despite the high need. We aimed to evaluate the effects of a tablet-based cognitive... Show moreBackground Evidence-based cognitive rehabilitation programs for brain tumor patients are not widely available, despite the high need. We aimed to evaluate the effects of a tablet-based cognitive rehabilitation program on cognitive performance, cognitive complaints, fatigue, and psychological distress in primary brain tumor patients following neurosurgery. Also, attrition, adherence and patient satisfaction with the program were evaluated. Methods Adults with presumed low-grade glioma and meningioma were recruited before surgery. Three months thereafter, participants were allocated to the intervention group or waiting-list control group using minimization. The 10-week eHealth app ReMind, based on the effective face-to-face intervention, consisted of psychoeducation, strategy-training and attention retraining. Performance-based cognitive outcomes and patient-reported outcomes were assessed before surgery and 3, 6 and 12 months thereafter. Mean scores, percentages of cognitively impaired individuals and reliable change indices (RCIs) were compared between groups. Results Sixty-two out of 183 eligible patients were randomized. Of the people who declined, 56% reported that participation would to be too burdensome. All participants found a tablet-app suitable for delivery of cognitive rehabilitation and 90% rated the program as "good" or "excellent". Performance-based cognitive outcomes and patient-reported outcomes did not significantly differ in group means over time nor RCIs between the intervention (final n = 20) and control group (final n = 25). Conclusions Recruitment at this early stage was difficult, resulting in limited statistical power. No significant effects were demonstrated, while adherence and satisfaction with the eHealth program were good. In clinical practice, ReMind may be helpful, if timing would be adapted to patients' needs. Show less
Aims The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment... Show moreAims The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment.Methods and results Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm.Conclusions For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.[GRAPHICS]. Show less
Background Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo... Show moreBackground Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.MethodsThis nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and <= 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as <= 90 degrees arterial and <= 270 degrees venous involvement without occlusion. Patients receive 8cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36Gy in 15 fractions) during the second cycle, followed by surgery and 4cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3years and 1.5years follow-up.DiscussionThe PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.Trial registrationPrimary registry and trial identifying number: EudraCT: 2017-002036-17.Date of registration: March 6, 2018.Secondary identifying numbers: The Netherlands National Trial Register - NL7094, NL61961.078.17, MEC-2018-004. Show less
