Type-I-error rate inflation in mixed models for repeated measures caused by ambiguous or incomplete model specifications.

Pre-specification of the primary analysis model is a pre-requisite to control the family-wise type-I-error rate (T1E) at the intended level in confirmatory clinical trials. However, mixed models for repeated measures (MMRM) have been shown to be poorly specified in study protocols. The magnitude of a resulting T1E rate inflation is still unknown. This investigation aims to quantify the magnitude of the T1E rate inflation depending on the type and number of unspecified model items as well as different trial characteristics. We simulated a randomized, double-blind, parallel group, phase III clinical trial under the assumption that there is no treatment effect at any time point. The simulated data was analysed using different clusters, each including several MMRMs that are compatible with the imprecise pre-specification of the MMRM. T1E rates for each cluster were estimated. A significant T1E rate inflation could be shown for ambiguous model specifications with a maximum T1E rate of 7.6% [7.1%; 8.1%]. The results show that the magnitude of the T1E rate inflation depends on the type and number of unspecified model items as well as the sample size and allocation ratio. The imprecise specification of nuisance parameters may not lead to a significant T1E rate inflation. However, the results of this simulation study rather underestimate the true T1E rate inflation. In conclusion, imprecise MMRM specifications may lead to a substantial inflation of the T1E rate and can damage the ability to generate confirmatory evidence in pivotal clinical trials.

Impact of electrically assisted bicycles on physical activity and traffic accident risk: a prospective observational study.

Background: Electrically assisted bicycles (e-bikes) have become increasingly popular and may facilitate active commuting and recreational cycling. Objective: To evaluate the physical activity levels and usage characteristics of e-bikers and conventional cyclists under real-world conditions. Methods: We conducted a prospective observational study in Germany to examine the effects of e-biking compared with conventional cycling on reaching the World Health Organization (WHO) target for physical activity-at least 150 min of moderate-to-vigorous physical activity (MVPA) per week. Study participants (1250 e-bikers and 629 conventional bike users) were equipped with activity trackers to assess the time, distance and heart rate during cycling over four consecutive weeks. Questionnaires were used to assess any traffic accidents incurred over 12 months. Results: The proportion of participants reaching 150 min of MVPA per week was higher for conventional bike users than for e-bike users (35.0% vs 22.4%, p<0.001). In a multiple regression model, the odds of reaching the physical activity target were lower for e-biking than for conventional biking (OR=0.56; 95% CI 0.43 to 0.72) with age, sex, comorbidities and bike usage patterns as confounding factors. No significant differences were observed between bike groups for traffic accidents, yet when controlled for cycling time and frequency of cycling e-bikers had a higher risk of a traffic accident (OR=1.63; 95% CI 1.02 to 2.58). Conclusion: E-bikes are associated with a lower probability of reaching WHO targets for MVPA due to reduced duration and a reduced cardiovascular effort during riding. However, e-bikes might facilitate active transportation, particularly in older individuals or those with pre-existing conditions.

ONLINE-TICS: Internet-Delivered Behavioral Treatment for Patients with Chronic Tic Disorders.

Comprehensive Behavioral Intervention for Tics (CBIT) is considered a first-line therapy for tics. However, availability of CBIT is extremely limited due to a lack of qualified therapists. This study is a multicenter (n = 5), randomized, controlled, observer-blind trial including 161 adult patients with chronic tic disorders (CTD) to provide data on efficacy and safety of an internet-delivered, completely therapist-independent CBIT intervention (iCBIT Minddistrict®) in the treatment of tics compared to placebo and face-to-face (f2f) CBIT. Using a linear mixed model with the change to baseline of Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) as a dependent variable, we found a clear trend towards significance for superiority of iCBIT (n = 67) over placebo (n = 70) (-1.28 (-2.58; 0.01); p = 0.053). In addition, the difference in tic reduction between iCBIT and placebo increased, resulting in a significant difference 3 (-2.25 (-3.75; -0.75), p = 0.003) and 6 months (-2.71 (-4.27; -1.16), p < 0.001) after the end of treatment. Key secondary analysis indicated non-inferiority of iCBIT in comparison to f2f CBIT (n = 24). No safety signals were detected. Although the primary endpoint was narrowly missed, it is strongly suggested that iCBIT is superior compared to placebo. Remarkably, treatment effects of iCBIT even increased over time.

The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders.

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

The effect of adjuvant oral irrigation on self-administered oral care in the management of peri-implant mucositis: A randomized controlled clinical trial.

OBJECTIVES: This single-blinded randomized clinical trial evaluated the effect of adjuvant oral irrigation in addition to self-administered oral care on prevalence and severity of peri-implant mucositis. MATERIAL & METHODS: After randomization, patients suffering from peri-implant mucositis were assigned to the following: Group 1 (control) received oral hygiene instruction following a standardized protocol, including a sub- and supramucosal mechanical debridement. Group 2 and 3 additionally were instructed to use an oral irrigator with either water or 0.06% CHX solution. One implant per patient was considered for examination. Clinical examinations included Probing Depth, Bleeding on Probing (BOP-positive sites), and Modified Plaque and Gingival Index. A surrogate variable (mucositis severity score) was applied measuring severity of disease. Statistical analysis included linear regression models and sensitivity analysis. RESULTS: Sixty periodontally healthy patients were examined for presence and severity of peri-implant mucositis. 70% of all patients reached complete resolution of disease after 12 weeks. The prevalence of peri-implant mucositis after 12 weeks was 50% in group 1, 35% in group 2, and 5% in group 3. Average BOP-positive sites were reduced in all groups after 12 weeks (mean change from baseline: group 1: -1.5; group 2: -1.8; group 3: -2.3). CONCLUSION: Within the limits of the study, adjuvant use of an oral irrigator with 0.06% CHX in addition to mechanical biofilm removal and oral hygiene instruction can reduce the presence and severity of peri-implant mucositis after 12 weeks.

Maternal Vascular Health in Pregnancy and Postpartum After Assisted Reproduction.

Although most pregnancies after assisted reproduction are associated with a favorable outcome for the mother and infant, reports of abnormal vascular adaptation in early pregnancy and emerging maternal and perinatal pathology warrant further investigations. Herein we extended our previous work and further examined whether perturbations of blood pressure and endothelial function during the first trimester in conceptions with nonphysiological corpus luteum (CL) numbers would persist through the third trimester of pregnancy and into the postpartum period. We investigated both maternal and perinatal outcomes. Participants were grouped according to CL number and method of conception: 0 CL (programmed autologous frozen-thawed embryo transfer, N=10-18); 1 CL (spontaneous conception [N=16] and natural cycle frozen-thawed embryo transfer [N=12]); or >3 CL associated with autologous fresh embryo transfer [N=8-12]. Augmentation index was higher during the third trimester in the absence of a CL compared to 1 CL (P=0.03) and in frozen-thawed embryo transfer in a programmed compared to a natural cycle (P=0.02). Moreover, baseline pulse-wave amplitude was higher in >3 CL conceptions at all time points (all P<0.05). The incidence of preeclampsia and preeclampsia with severe features was significantly higher in the absence of a CL compared to the presence of one or >3 CL (P=0.045 and P=0.03). Infants from conceptions with >3 CL had lower birth weights (P=0.02) and a higher rate of low birth weight offspring (P=0.008). Deficient vascular adaptation during early gestation in conceptions with nonphysiological CL numbers might predispose women to adverse pregnancy outcomes, for example, preeclampsia.

Empirical evaluation of the implementation of the EMA guideline on missing data in confirmatory clinical trials: Specification of mixed models for longitudinal data in study protocols.

In confirmatory clinical trials, the prespecification of the primary analysis model is a universally accepted scientific principle to allow strict control of the type I error. Consequently, both the ICH E9 guideline and the European Medicines Agency (EMA) guideline on missing data in confirmatory clinical trials require that the primary analysis model is defined unambiguously. This requirement applies to mixed models for longitudinal data handling missing data implicitly. To evaluate the compliance with the EMA guideline, we evaluated the model specifications in those clinical study protocols from development phases II and III submitted between 2015 and 2018 to the Ethics Committee at Hannover Medical School under the German Medicinal Products Act, which planned to use a mixed model for longitudinal data in the confirmatory testing strategy. Overall, 39 trials from different types of sponsors and a wide range of therapeutic areas were evaluated. While nearly all protocols specify the fixed and random effects of the analysis model (95%), only 77% give the structure of the covariance matrix used for modeling the repeated measurements. Moreover, the testing method (36%), the estimation method (28%), the computation method (3%), and the fallback strategy (18%) are given by less than half the study protocols. Subgroup analyses indicate that these findings are universal and not specific to clinical trial phases or size of company. Altogether, our results show that guideline compliance is to various degrees poor and consequently, strict type I error rate control at the intended level is not guaranteed.

Acceptance and adverse events of the 2009 H1N1 vaccination in immunosuppressed pediatric liver transplant recipients.

A retrospective analysis of H1N1 vaccination in 127 children at ≥ 1 year after liver transplantation found only moderate acceptance (56%) of the vaccination. Physical adverse events were of moderate severity, but frequent (74%). Protection against infection was good, with infection rates of 4% in vaccinated children versus 25% in nonvaccinated children.