Reetta Kälviäinen

Background: Successful development of novel therapies requires that clinical trials are conducted in patient cohorts with the highest benefit-to-risk ratio. Population-based biobanks with comprehensive health and genetic data from large numbers of individuals hold promise to facilitate identification of trial participants, particularly when interventions need to start while symptoms are still mild, such as for Alzheimer’s disease (AD). However, few studies have yet tested whether recalling biobank participants into clinical follow-up studies is feasible. Objective: To establish a process for clinical recall studies from FinnGen and demonstrate the feasibility to systematically ascertain customized clinical data from FinnGen participants with ICD10 diagnosis of AD or mild cognitive disorder (MCD). Methods: Single-center cross-sectional study testing blood-based biomarkers and cognitive functioning in-person, computer-based and remote. Results: 19% (27/140) of a pre-specified FinnGen subcohort were successfully recalled and completed the study. Hospital records largely validated registry entries. For 8/12 MCD patients, other reasons than AD were identified as underlying diagnosis. Cognitive measures correlated across platforms, with highest consistencies for dementia screening (r=0.818) and semantic fluency (r=0.764), respectively, for in-person versus telephone-administered tests. GFAP (p<0.002) and pTau-181 (p<0.020) most reliably differentiated AD from MCD participants. Conclusions: Informative, customized clinical recall studies from FinnGen are feasible.

Background: A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology. Methods: The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice. Discussion: Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained. Core Outcome Set registration: COMET Initiative as study 118.

The outcome of status epilepticus (SE) can be improved by facilitating early recognition and treatment with antiepileptic drugs. The purpose of this study was to analyze the treatment delay of SE in a prospectively recruited patient cohort. Improvements to the treatment process are suggested. Consecutive adult patients with SE were recruited in the emergency department of Kuopio University Hospital (KUH) between March 23 and December 31, 2015. SE was defined as a prolonged (> 5 min) epileptic seizure or recurrent tonic-clonic seizures (≥ 3 seizures within any 24 h). Diagnostic and treatment delays and the features of SE were subject to statistical analysis. We recorded 151 cases of SE during the study period. First-line treatment was initiated outside of hospital in 79 cases (52.3%), with a significantly shorter median delay compared to intrahospital initiation (28 min vs. 2 h 5 min, p < 0.001). Forty-six episodes of SE (30.5%) were not recognized during the prehospital phase. The median delay in recognition of tonic-clonic SE (23 min) was significantly shorter than in focal aware (2 h 0 min, p = 0.045) or focal impaired awareness SE (2 h 25 min, p < 0.001). Second-line treatment was used in 91 cases (60.3%), with a median delay of 2 h 42 min. Anesthesia was used in seven cases (4.6%) with refractory SE, with a median delay of 6 h 40 min. SE is often not recognized during the prehospital phase of treatment, which delays the initiation of first-line treatment. Intrahospital delay could be reduced by streamlining patient transition between the three lines of treatment.

Clinical trials (CTs) are the “gold standard” to ensure the development of new effective treatments in medicine. A study was conducted to assess knowledge of, and attitudes toward, clinical trials among patients with Parkinson’s disease (PD), along with factors that motivate them to participate. A 50-item questionnaire on the views of patients with PD about CTs was developed. It included statements that the respondents assessed on a Likert scale from 1 (“strongly disagree”) to 5 (“strongly agree”). The questionnaire was mailed to a random sample (n = 2000) of members of the patient organization the Finnish Parkinson Association. In all, 708 response forms were returned, of which 681 were accepted after exclusion (a 34% response rate). In general, attitudes of patients with PD toward CTs were positive. Older subjects and patients with lower education levels had inadequate knowledge of general issues related to CTs. Older age, low level of education, and lower number of PD medications were significant predictors for failure to understand the nature and purpose of clinical research. Additionally, significant positive correlation was found between education level and willingness to participate in CTs. Patients with PD have important gaps in their knowledge of methodological issues associated with CTs. The oldest subjects and those with a low level of education have the greatest information needs. Investigators should pay more attention to ensuring the comprehensibility of the information provided to potential CT participants.

The aim was to determine predictors of hospital and 1-year mortality in patients with intensive care unit (ICU)-treated refractory status epilepticus (RSE) in a population-based study. This was a retrospective study of the Finnish Intensive Care Consortium (FICC) database of adult patients (16 years of age or older) with ICU-treated RSE in Finland during a 3-year period (2010–2012). The database consists of admissions to all 20 Finnish hospitals treating RSE in the ICU. All five university hospitals and 11 out of 15 central hospitals participated in the present study. The total adult referral population in the study hospitals was 3.92 million, representing 91% of the adult population of Finland. Patients whose condition had a post-anoxic aetiological basis were excluded. We identified 395 patients with ICU-treated RSE, corresponding to an annual incidence of 3.4/100,000 (95% confidence interval (CI) 3.04–3.71). Hospital mortality was 7.4% (95% CI 0–16.9%), and 1-year mortality was 25.4% (95% CI 21.2–29.8%). Mortality at hospital discharge was associated with severity of organ dysfunction. Mortality at 1 year was associated with older age (adjusted odds ratio (aOR) 1.033, 95% CI 1.104–1.051, p = 0.001), sequential organ failure assessment (SOFA) score (aOR 1.156, CI 1.051–1.271, p = 0.003), super-refractory status epilepticus (SRSE) (aOR 2.215, 95% CI 1.20–3.84, p = 0.010) and dependence in activities of daily living (ADL) (aOR 2.553, 95% CI 1.537–4.243, p < 0.0001). Despite low hospital mortality, 25% of ICU-treated RSE patients die within a year. Super-refractoriness, dependence in ADL functions, severity of organ dysfunction at ICU admission and older age predict long-term mortality. Retrospective registry study; no interventions on human participants.

Summary: Objective: To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht‐Lundborg disease (EPM1).Methods: Two prospective, multicenter, double‐blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, showing moderate–severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice‐daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2‐week up‐titration period, 12‐week stable‐dose maintenance period, and down‐titration or entry into long‐term follow‐up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale (UMRS). Primary efficacy end point was percent reduction from baseline in action myoclonus score (UMRS section 4) at last treatment visit. Safety assessments included treatment‐emergent adverse events (TEAEs).Results: N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min–max) percent reduction from baseline in action myoclonus score is the following—N01187: placebo 5.6 (−81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (−50.0 to 73.6), BRV 50 mg/day 26.3 (−35.8 to 69.2), BRV 150 mg/day 16.9 (−50.0 to 73.6); N01236: placebo 17.5 (−170 to 61.5), BRV 5 mg/day −4.6 (−430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (−58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAEs were reported by 72–75% placebo‐treated and 56–83% BRV‐treated patients.Significance: Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long‐term follow‐up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.