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Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted.
Background: Selective outcome reporting in clinical trials introduces bias in the body of evidence distorting clinical decision making. Trial registration aims to prevent this bias and is suggested by the International Committee of Medical Journal Editors (ICMJE) since 2004.
Methods: The 585 randomized controlled trials (RCTs) published between 1965 and 2017 that were included in a recently published Cochrane review on antiemetic drugs for prevention of postoperative nausea and vomiting were selected. In a retrospective study, we assessed trial registration and selective outcome reporting by comparing study publications with their registered protocols according to the ‘Cochrane Risk of bias’ assessment tool 1.0.
Results: In the Cochrane review, the first study which referred to a registered trial protocol was published in 2004. Of all 585 trials included in the Cochrane review, 334 RCTs were published in 2004 or later, of which only 22% (75/334) were registered. Among the registered trials, 36% (27/75) were pro- and 64% (48/75) were retrospectively registered. 41% (11/27) of the prospectively registered trials were free of selective outcome reporting bias, 22% (6/27) were incompletely registered and assessed as unclear risk, and 37% (10/27) were assessed as high risk. Major outcome discrepancies between registered and published high risk trials were a change from the registered primary to a published secondary outcome (32%), a new primary outcome (26%), and different outcome assessment times (26%). Among trials with high risk of selective outcome reporting 80% favoured at least one statistically significant result. Registered trials were assessed more often as ‘overall low risk of bias’ compared to non-registered trials (64% vs 28%).
Conclusions: In 2017, 13 years after the ICMJE declared prospective protocol registration a necessity for reliable clinical studies, the frequency and quality of trial registration in the field of PONV is very poor. Selective outcome reporting reduces trustworthiness in findings of clinical trials. Investigators and clinicians should be aware that only following a properly registered protocol and transparently reporting of predefined outcomes, regardless of the direction and significance of the result, will ultimately strengthen the body of evidence in the field of PONV research in the future.
Anxiolytic drugs often have sedative effects that impair the ability to drive. Our double-blind, randomized crossover trial investigated the effect of Silexan, a non-sedating, anxiolytic herbal medicinal product, on driving performance in healthy volunteers. Part 1 aimed at demonstrating equivalence between 80 mg/d Silexan and placebo. Part 2 was performed to demonstrate superiority of 160 and 320 mg Silexan over 1 mg lorazepam and included a placebo arm for assay sensitivity. Driving performance was assessed in a validated, alcohol-calibrated simulator test. The primary outcome was the standard deviation of the lane position (SDLP). Secondary outcomes included driving errors and sleepiness. Fifty and 25 subjects were randomized in Parts 1 and 2, respectively. In Part 1, Silexan 80 mg was confirmed to be equivalent to placebo after single administration (equivalence range: δ = ±2 cm). The 95% confidence interval (CI) for the SDLP marginal mean value difference Silexan–placebo for single administration was −1.43; +1.38 and thus similar to the 95% CI of −1.45; +0.79 cm for 7 days’ multiple dosing. In Part 2, 95% CIs for SDLP marginal mean value differences to lorazepam were −8.58; −5.42 cm for Silexan 160 mg and −8.65; −5.45 cm for 320 mg (p < 0.001). Confirmatory results were supported by secondary outcomes, where results for Silexan were comparable to placebo and more favorable than for lorazepam. The study demonstrates that single doses of up to 320 mg Silexan and multiple doses of 80 mg/d have no adverse effect on driving performance.
In the last few years, monoclonal antibodies (mAbs) such as elotuzumab and daratutumab have brought the treatment of multiple myeloma (MM) into the new era of immunotherapy. More recently, chimeric antigen receptor (CAR) modified T cell, a novel cellular immunotherapy, has been developed for treatment of relapsed/refractory (RR) MM, and early phase clinical trials have shown promising efficacy of CAR T cell therapy. Many patients with end stage RRMM regard CAR T cell therapy as their “last chance” and a “hope of cure”. However, severe adverse events (AEs) and even toxic death related to CAR T cell therapy have been observed. The management of AEs related to CAR T cell therapy represents a new challenge, as the pathophysiology is not fully understood and there is still no well-established standard of management. With regard to CAR T cell associated toxicities in MM, in this review, we will provide an overview of experience from clinical trials, pathophysiology, and management strategies.
Background
ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML).
Methods
Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 106 plaque-forming units (PFU) to 1.8 × 107 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment.
Results
No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients’ blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition.
Conclusions
Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility.
Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018.
Aims
Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF).
Methods
Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF.
Conclusion
The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.
Background:
Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap.
Methods:
Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients.
Results:
There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients.
Conclusions:
Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.
Background
Improvement of the long-term effectiveness of multidisciplinary ortho-paedic rehabilitation (MOR) in the management of chronic non-specific low back pain (CLBP) remains a central issue for health care in Germany. We developed an interprofessional and interdisciplinary, biopsychosocial rehabilitation concept named "PASTOR" to promote self-management in adults with CLBP and compared its effectiveness with the current model of MOR.
Methods
A multicentre quasi-experimental study with three measurement time points was implemented. 680 adults aged 18 to 65 with CLBP were assed for eligibil-ity in three inpatient rehabilitation centres in Germany. At first the effects of the MOR, with a total extent of 48 hours (control group), were assessed. Thereafter, PASTOR was implemented and evaluated in the same centres (intervention group). It consisted of six interprofessional modules, which were provided on 12 days in fixed groups, with a total extent of 48 hours. Participants were assessed with self-report measures at baseline, discharge, and 12 months for functional ability (primary outcome) using the Hannover Functional Ability Questionnaire (FFbH-R) and vari-ous secondary outcomes (e.g. pain, health status, physical activity, pain coping, pain-related cognitions).
Results
In total 536 participants were consecutively assigned to PASTOR (n=266) or MOR (n=270). At 12 months, complete data of 368 participants was available. The adjusted between-roup difference in the FFbH-R at 12 months was 6.58 (95% CI 3.38 to 9.78) using complete data and 3.56 (95% CI 0.45 to 6.67) using available da-ta, corresponding to significant small-to-medium effect sizes of d=0.42 (p<0.001) and d=0.10 (p=0.025) in favour of PASTOR. Further improvements in secondary out-comes were also observed in favour of PASTOR.
Conclusion
The interprofessional and interdisciplinary, biopsychosocial rehabilita-tion program PASTOR shows some improvements of the long-term effectiveness of inpatient rehabilitation in the management of adults with CLBP. Further insights into mechanisms of action of complex intervention programs are required.
Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.
Immunotherapy of malignant gliomas with autologous dendritic cells (DCs) in addition to surgery and radiochemotherapy has been a focus of intense research during the past decade. Since both children and adults are affected by this highly aggressive brain tumor, 10–15% of the several hundred vaccinated patients represent children, making pediatric glioma patients the largest uniform pediatric vaccination cohort so far. In general, DC vaccination in malignant gliomas has been shown to be safe and several studies with a non-vaccinated control group could clearly demonstrate a survival benefit for the vaccinated patients. Interestingly, children and adolescents below 21 years of age seem to benefit even more than adult patients. This review summarizes the findings of the 25 clinical trials published so far and gives a perspective how DC vaccination could be implemented as part of multimodal therapeutic strategies in the near future.