Three Prospective Case Studies Examining Mifepristone's Efficacy in Patients with Treatment-Resistant PTSD.

Despite the availability of various treatment approaches for patients with posttraumatic stress disorder (PTSD), some patients do not respond to these therapies, and novel treatment approaches are needed. This study investigated the efficacy of mifepristone, a glucocorticoid receptor antagonist, in treatment-resistant PTSD patients. Three patients with PTSD who were resistant to standard psychological and pharmacological treatments were prescribed mifepristone (600-1,200 mg/day) for 1 week. A baseline-controlled single-case design was used, involving a 2-week baseline phase (no intervention), a 1-week intervention phase (mifepristone), and a 2-week postintervention phase. The primary outcome measure, self-reported PTSD symptom severity (PCL-5), was assessed daily, with participants providing their own control condition. Two of the three patients experienced a significant reduction in PTSD symptom severity after the intervention phase and no longer met the diagnostic criteria for PTSD. These positive results were maintained during long-term follow-up. These findings support the potential effectiveness of mifepristone in the treatment of patients with treatment-resistant PTSD. However, our findings must be interpreted with caution, and further studies with larger sample sizes and more rigorous designs are necessary to confirm the promising results.

Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression.

Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Embase, Medline Ovid, and Cochrane Controlled Trials Register databases for randomized controlled and crossover trials. Meta-analytic effects were calculated for each pharmaceutical agent and targeted neuromodulator system. Cognitive outcome measures were aggregated across cognitive domains. Of 8,216 articles, 41 studies (4,434 patients) were included. The noradrenergic agent methylphenidate showed a small, significant positive effect on cognitive functioning in patients with traumatic brain injury (TBI; k = 14, d = 0.34, 95% confidence interval: 0.12-0.56, P = 0.003). Specifically, methylphenidate was found to improve cognitive functions related to executive memory, baseline speed, inhibitory control, and variability in responding. The cholinergic drug donepezil demonstrated a large effect size, albeit based on a limited number of studies (k = 3, d = 1.68, P = 0.03). No significant effects were observed for other agents. Additionally, meta-regression analysis did not identify significant sources of heterogeneity in treatment response. Our meta-analysis supports the use of methylphenidate for enhancing cognitive functioning in patients with TBI. Although donepezil shows potential, it warrants further research. These results could guide clinical decision making, inform practice guidelines, and direct future pharmacotherapeutic research in ABI.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19.

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Rivastigmine for ECT-induced cognitive adverse effects in late life depression (RECALL study): A multicenter, randomized, double blind, placebo-controlled, cross-over trial in patients with depression aged 55 years or older: Rationale, objectives and methods.

Background: Cognitive side-effects are an important reason for the limited use of electroconvulsive therapy (ECT). Cognitive side-effects are heterogeneous and occur frequently in older persons. To date, insight into these side-effects is hampered due to inconsistencies in study designs and small sample sizes. Among all cognitive side-effects, confusion and delirious states are especially troublesome for patients, relatives and clinicians. In particular inter-ictal delirium-like states are worrisome, since they may lead to premature treatment discontinuation. Besides a need for further insight into determinants of cognitive side-effects of ECT, there is a great need for treatment options. Methods and design: The Rivastigmine for ECT-induced Cognitive Adverse effects in Late Life depression (RECALL) study combines a multicenter, prospective cohort study on older patients with depression, treated with ECT, with an embedded randomized, placebo-controlled cross-over trial to examine the effect of rivastigmine on inter-ictal delirium. Patients are recruited in four centers across the Netherlands and Belgium. We aim to include 150 patients into the cohort study, in order to be able to subsequently include 30 patients into the trial. Patients are included in the trial when inter-ictal delirium, assessed by the Confusion Assessment method (CAM), or a drop in Mini Mental State Examination (MMSE) score of ≥4 during ECT, develops. In the cohort study, comprehensive measurements of ECT-related cognitive side-effects-and their putative determinants-are done at baseline and during the ECT-course. The primary outcome of the clinical trial is the effectiveness of rivastigmine on inter-ictal delirium-severity, assessed with a change in the Delirium Rating Scale-Revised-98. Secondary outcomes of the clinical trial are several ECT-characteristics and side-effects of rivastigmine. Discussion: This study is the first clinical trial with a focus on ECT-induced, inter-ictal delirium. The cohort provides the basis for recruitment of patients for the cross-over trial and additionally provides an excellent opportunity to unravel cognitive side-effects of ECT and identify putative determinants. This paper describes the rationale and study protocol. Clinical trial registration: EudraCT 2014-003385-24.

Vitamin D supplementation in chronic obstructive pulmonary disease patients with low serum vitamin D: a randomized controlled trial.

BACKGROUND: Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients. OBJECTIVES: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD. METHODS: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life. RESULTS: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes. CONCLUSIONS: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627.

Implementation of a pharmacist-led transitional pharmaceutical care programme: Process evaluation of Medication Actions to Reduce hospital admissions through a collaboration between Community and Hospital pharmacists (MARCH).

WHAT IS KNOWN AND OBJECTIVE: The recently conducted Medication Actions to Reduce hospital admissions through a collaboration between Community and Hospital pharmacists (MARCH) transitional care programme, which aimed to test the effectiveness of a transitional care programme on the occurrence of ADEs post-discharge, did not show a significant effect. To clarify whether this non-significant effect was due to poor implementation or due to ineffectiveness of the intervention as such, a process evaluation was conducted. The aim of the study was to gain more insight into the implementation fidelity of MARCH. METHODS: A mixed methods design and the modified Conceptual Framework for Implementation Fidelity was used. For evaluation, the implementation fidelity and moderating factors of four key MARCH intervention components (teach-back, the pharmaceutical discharge letter, the post-discharge home-visit and the transitional medication review) were assessed. Quantitative data were collected during and after the intervention. Qualitative data were collected using semi-structured interviews with MARCH healthcare professionals (community pharmacists, clinical pharmacists, pharmacy assistants and pharmaceutical consultants) and analysed using thematic analysis. RESULTS AND DISCUSSION: Not all key intervention components were implemented as intended. Teach-back was not always performed. Moreover, 63% of the pharmaceutical discharge letters, 35% of the post-discharge home-visits and 44% of the transitional medication reviews were not conducted within their planned time frames. Training sessions, structured manuals and protocols with detailed descriptions facilitated implementation. Intervention complexity, time constraints and the multidisciplinary coordination were identified as barriers for the implementation. WHAT IS NEW AND CONCLUSION: Overall, the implementation fidelity was considered to be moderate. Not all key intervention components were carried out as planned. Therefore, the non-significant results of the MARCH programme on ADEs may at least partly be explained by poor implementation of the programme. To successfully implement transitional care programmes, healthcare professionals require full integration of these programmes in the standard work-flow including IT improvements as well as compensation for the time investment.

The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri®) in subjects with acute respiratory distress syndrome induced by COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact. METHODS: This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics. DISCUSSION: The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay. TRIAL STATUS: Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT04794088 . Registered on 11 March 2021.

Evaluation of marketing authorization and clinical implementation of ulipristal acetate for uterine fibroids.

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process.

The effect of a transitional pharmaceutical care program on the occurrence of ADEs after discharge from hospital in patients with polypharmacy.

INTRODUCTION: Transitional care programs (i.e. interventions delivered both in hospital and in primary care), could increase continuity and consequently quality of care. However, limited studies on the effect of these programs on Adverse Drug Events (ADEs) post-discharge are available. Therefore, the aim of this study was to investigate the effect of a transitional pharmaceutical care program on the occurrence of ADEs 4 weeks post-discharge. METHODS: A multicentre prospective before-after study was performed in a general teaching hospital, a university hospital and 49 community pharmacies. The transitional pharmaceutical care program consisted of: teach-back to the patient at discharge, a pharmaceutical discharge letter, a home visit by a community pharmacist and a clinical medication review by both the community and the clinical pharmacist, on top of usual care. Usual care consisted of medication reconciliation at admission and discharge by pharmacy teams. The primary outcome was the proportion of patients who reported at least 1 ADE 4 weeks post-discharge. Multivariable logistic regression was used to adjust for potential confounders. RESULTS: In total, 369 patients were included (control: n = 195, intervention: n = 174). The proportion of patients with at least 1 ADE did not statistically significant differ between the intervention and control group (general teaching hospital: 59% vs. 67%, ORadj 0.70 [95% CI 0.38-1.31], university hospital: 63% vs 50%, OR adj 1.76 [95% CI 0.75-4.13]). CONCLUSION: The transitional pharmaceutical care program did not decrease the proportion of patients with ADEs after discharge. ADEs after discharge were common and more than 50% of patients reported at least 1 ADE. A process evaluation is needed to gain insight into how a transitional pharmaceutical care program could diminish those ADEs.

Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Peripheral infiltration of remdesivir in 3 patients with COVID-19: Case series and discussion.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic resulted in accelerated market access to remdesivir worldwide. Therefore, data about complications experienced during use of the drug are limited. This is the first published case series (1 case report exists) to describe remdesivir infiltration in 3 patients with COVID-19. SUMMARY: In the first case, a 91-year-old woman experienced remdesivir infiltration resulting in edema, hematoma at the area of infiltration; on palpation, the affected area felt cooler than the surrounding areas. Swelling was still present after 6 weeks. In the second case, remdesivir infiltration occurred in a 72-year-old male, resulting in edema, hematoma, and pain at the area of infiltration. The hematoma lasted for 7 days. The third case concerned a 67-year-old woman, in whom remdesivir infiltration led to edema and a small hematoma. The hematoma regressed to a negligible size within 3 days. However, a week after infiltration, redness had reappeared. In 2 cases, the patient was immediately treated with hyaluronidase injections, but no specific treatments were provided in the other case. CONCLUSION: Based on the product information provided by remdesivir's manufacturer, we believe symptoms and signs observed in the 3 cases may have resulted from the low pH (~4) of the nonbuffered remdesivir solution, although the patients were not formally assessed for caustic injury. Previous experience with other noncytotoxic medications suggests that infusion-specific factors (eg, volume of leaked fluid) and patient-specific factors (eg, advanced age) may have a role in the outcome of remdesivir infiltration. The possibility of symptoms caused by cyclodextrins in the formulation or by intrinsic toxicity of remdesivir warrants exploration.

Therapeutic Drug Monitoring of Psychotropics as a Diagnostic Tool for CYP2D6 Poor Metabolizer Phenotype.

BACKGROUND: Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective. METHODS: In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated. RESULTS: Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%-99.6%), 93.0% (88.8%-97.2%), 97.8% (95.4%-100.0%), and 85.6% (78.0%-93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity. CONCLUSIONS: If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications.

Is Treatment in Patients With Suspected Nonradiographic Axial Spondyloarthritis Effective? Six-Month Results of a Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy of 16-week treatment with etanercept (ETN) in patients with suspected nonradiographic axial spondyloarthritis (SpA). METHODS: Tumor necrosis factor inhibitor-naive patients with inflammatory back pain with at least 2 SpA features and high disease activity (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), without the requirement of a positive finding on magnetic resonance imaging (MRI) of the sacroiliac (SI) joint and/or elevated C-reactive protein (CRP) level, were randomized (1:1) to receive ETN (n = 40) or placebo (n = 40) for 16 weeks and subsequently were followed up for a further 8 weeks (to 24 weeks from baseline) without study medication. The primary end point was the Assessment of SpondyloArthritis international Society 20 (ASAS20) response at 16 weeks. Secondary end points included the Ankylosing Spondylitis Disease Activity Score (ASDAS) and changes in disease parameters, including the Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP level, erythrocyte sedimentation rate (ESR), and Spondyloarthritis Research Consortium of Canada index scores (MRI of the SI joint), after 16 and 24 weeks. RESULTS: Patient characteristics at baseline were comparable between the ETN and placebo groups. At 16 weeks, there was no significant difference in the percentage of patients exhibiting ASAS20 response between the ETN group (6 patients [16.7%]) and the placebo group (4 patients [11.1%]) (relative risk 0.7 [95% confidence interval 0.2-2.2], P = 0.5). Only the ESR showed more improvement in the ETN group compared to the placebo group at 16 weeks (decreases of 2.2 mm/hour and 1.4 mm/hour, respectively), but the difference did not reach statistical significance. Between 16 and 24 weeks, without study medication, the BASMI, CRP level, and ESR had worsened to a greater extent in the ETN group compared to the placebo group, with the difference being significant for the CRP level. CONCLUSION: This study shows that in patients with suspected nonradiographic axial SpA with high disease activity but without the requirement of a positive finding on SI joint MRI and/or elevated CRP level, treatment with ETN is not effective.

Risk-efficacy balance of ulipristal acetate compared to surgical alternatives.

AIMS: Uterine fibroids are benign tumours that cause various complaints. These complaints may significantly compromise quality of life, necessitating a clinical intervention in 25-50% of the affected women. Hysterectomy, myomectomy or embolization may offer symptomatic relief, but are costly, include a recovery period, can cause serious side-effects, sometimes fail to treat symptoms completely and are not always desired by patients. Ulipristal is a conservative long-term treatment that has a fibroid-volume decreasing effect, acceptable side-effects while preserving fertility and may be an alternative to surgical alternatives. Currently, ulipristal is investigated by the European Medicine Agency and suspended from marketing authorization because it may cause drug-induced liver injury (DILI). However, many drugs can cause severe DILI and prospective studies estimate 14-19 DILI cases/100 000 people. METHODS: This overview will discuss the risk-benefit balance between ulipristal and DILI, describe the safety-efficacy balance of ulipristal and its alternative treatments and the arguments that led to the suspension of its marketing authorization. RESULTS: Ulipristal may be associated with DILI resulting in a risk of severe liver injury in 1.5:100 000 patients and fatal liver injury in 0.1:100 000 patients. This risk needs to be weighed against the higher mortality risk of >1:1000 and higher incidence of severe complications after surgery. CONCLUSION: The DILI risk of ulipristal is considerably lower than that of other medicines that are not suspended, nor need additional safety measures. When evaluating drugs and drug safety, risks that apply to the alternative nonpharmacological treatment options should be taken into consideration.

Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?

Investigator-initiated clinical trials are crucial for improving quality of care for children and pregnant women as they are often excluded from industry-initiated trials. However, trials have become increasingly time-consuming and costly since the EU Clinical Trial Directive entered into force in 2001. This directive made compliance with ICH-Good Clinical Practice Guidelines (ethical and quality standard for conducting human subject research) mandatory for all clinical trials, regardless of its risk-classification. By discussing two investigator-initiated, 'low-risk' drug trials, we aim to illustrate that compliance with all GCP requirements makes trials very laborious and expensive, while a clear rationale is missing. This discourages clinical researchers to start and carry out investigator-initiated research. However, the forthcoming EU Clinical Trial Regulation (No 536/2014) seems to provide a solution as it allows for less stringent rules for low-risk trials. We want to raise awareness for these developments in both the clinical research community and the European and national regulatory authorities. Implementation of this forthcoming Regulation regulatory policies should be done in such a way that investigator-initiated trials evaluating standard care interventions will become more feasible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research. What is Known • Investigator-initiated trials are indispensable for improving care for children and pregnant women as they are often excluded from industry-initiated trials • Trials have become increasingly time-consuming and costly because of mandatory compliance with ICH-GCP guidelines What is New • The forthcoming EU Clinical Trial Regulation allows less stringent rules for low-risk trials • The national legislator and regulatory authorities should recognize the importance of this opportunity and implement the Regulation in such a way that investigator-initiated trials will become more feasible.

Vitamin D supplementation for the prevention of depression and poor physical function in older persons: the D-Vitaal study, a randomized clinical trial.

BACKGROUND: Depressive symptoms and impaired physical functioning are prevalent among older adults. Supplementation with vitamin D might improve both conditions, particularly in persons with low vitamin D status. OBJECTIVE: The D-Vitaal study primarily aimed to investigate the effect of vitamin D supplementation on depressive symptoms, functional limitations, and physical performance in a high-risk older population with low vitamin D status. Secondary aims included examining the effect of vitamin D supplementation on anxiety symptoms, cognitive functioning, mobility, handgrip strength, and health-related quality of life. METHODS: This study was a randomized placebo-controlled trial with 155 participants aged 60-80 y who had clinically relevant depressive symptoms, ≥1 functional limitations, and serum 25-hydroxyvitamin D [25(OH)D] concentrations of 15-50/70 nmol/L (depending on season). Participants received 1200 IU/d vitamin D3 (n = 77) or placebo tablets (n = 78) for 12 mo. Serum 25(OH)D was measured at baseline and 6 mo; outcomes were assessed at baseline, 6 mo, and 12 mo. Linear mixed-models analyses were conducted to assess the effect of the intervention. RESULTS: The supplementation increased serum 25(OH)D concentrations in the intervention group to a mean ± SD of 85 ± 16 nmol/L compared with 43 ± 18 nmol/L in the placebo group after 6 mo (P < 0.001). No relevant differences between the treatment groups were observed regarding depressive symptoms, functional limitations, physical performance, or any of the secondary outcomes. CONCLUSIONS: Supplementation with 1200 IU/d vitamin D for 12 mo had no effect on depressive symptoms and physical functioning in older persons with relatively low vitamin D status, clinically relevant depressive symptoms, and poor physical functioning. This trial is registered with the Netherlands Trial Register (www.trialregister.nl) under NTR3845.