Potential impact of COVID-19 on ongoing clinical trials: a simulation study with the neurological Yale Global Tic Severity Scale based on the CANNA-TICS study.

The COVID-19 pandemic has manifold impacts on clinical trials. In response, drug regulatory agencies and public health bodies have issued guidance on how to assess potential impacts on ongoing clinical trials and stress the importance of a risk-assessment as a pre-requisite for modifications to the clinical trial conduct. This article presents a simulation study to assess the impact on the power of an ongoing clinical trial without the need to unblind trial data and compromise trial integrity. In the context of the CANNA-TICS trial, investigating the effect of nabiximols on reducing the total tic score of the Yale Global Tic Severity Scale (YGTSS-TTS) in patients with chronic tic disorders and Tourette syndrome, the impact of the two COVID-19 related intercurrent events handled by a treatment policy strategy is investigated using a multiplicative and additive data generating model. The empirical power is examined for the analysis of the YGTSS-TTS as a continuous and dichotomized endpoint using analysis techniques adjusted and unadjusted for the occurrence of the intercurrent event. In the investigated scenarios, the simulation studies showed that substantial power losses are possible, potentially making sample size increases necessary to retain sufficient power. However, we were also able to identify scenarios with only limited loss of power. By adjusting for the occurrence of the intercurrent event, the power loss could be diminished to different degrees in most scenarios. In summary, the presented risk assessment approach may support decisions on trial modifications like sample size increases, while maintaining trial integrity.

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).

Predictions for the COVID-19 pandemic in Germany using the modified Bateman SIZ model.

AIMS OF THE STUDY: To obtain predictions for the course of the COVID-19 pandemic in Germany using the modified Bateman SIZ model and input variables based on the status quo in July 2020. To predict the effect of a change in tα on the course of the pandemic. To evaluate the robustness and sensitivity of the model in response to a change in the input parameters. MATERIALS AND METHODS: Start parameters for the modified Bateman SIZ model were obtained from observational data published by the Robert-Koch-Institute in Berlin for the period June 1 to July 13, 2020. The robustness and sensitivity of the model were determined by changing the input parameter for the doubling-time (tα) by ± 5% and ± 10%. RESULTS: The predictions show that small changes, ± 5%, in the doubling-time, tα for the rate of increase in the number of new infections, can have a major effect, both positive and negative, on the course of the pandemic. The model predicted that the number of persons infected with the virus would reach 1 million within 8 years. A 5% longer tα would reduce the number of infected persons by ~ 75%. In contrast, a 5% shorter doubling-time would increase the number of infections over 8 years to ~ 9 million when the number of infectious persons would exceed 100,000 at the end of 2022. The pandemic is predicted to have disappeared by the end of 2024. DISCUSSION: Predictions for the course of the COVID-19 pandemic in Germany based on the status quo up to July 13, 2020 have been obtained using the modified Bateman SIZ model. There are several important assumptions necessary to apply the model and thus the results must be interpreted with caution. The model, previously used to predict the course of the COVID-19 pandemic in the city of Heidelberg (pop. 166,000) gives comparable predictive data for the whole of Germany (pop. 83 million) and thus appears to be both sensitive and robust. CONCLUSION: Since a shorter doubling-time for the number of infectious persons by only 5% would result in a major clinical emergency, interventional measures such as vaccination are urgently needed. Taking into consideration that a SARS-CoV-2 vaccine is not yet available and the efficacy of the Corona-Warn-App has yet to be shown, a relaxation in the lockdown conditions in Germany in 2020 appears premature.

Diagnostic evaluation of the hospital depression scale (HADS) and the Beck depression inventory II (BDI-II) in adults with congenital heart disease using a structured clinical interview: Impact of depression severity.

OBJECTIVE: The purpose of this study was the diagnostic evaluation of the hospital anxiety and depression scale total score, its depression subscale and the Beck depression inventory II in adults with congenital heart disease. METHODS: This cross-sectional study evaluated 206 patients with congenital heart disease (mean age 35.3 ± 11.7 years; 58.3% men). Major depressive disorder was diagnosed by a structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders IV and disease severity with the Montgomery-Åsberg depression rating scale. Receiver operating characteristics provided assessment of diagnostic accuracy. Youden's J statistic identified optimal cut-off points. RESULTS: Fifty-three participants (25.7%) presented with major depressive disorder. Of these, 28 (52.8%) had mild and 25 (47.2%) had moderate to severe symptoms. In the total cohort, the optimal cut-off of values was >11 in the Beck depression inventory II, >11 in the hospital anxiety and depression scale and >5 in the depression subscale. Optimal cut-off points for moderate to severe major depressive disorder were similar. The cut-offs for mild major depressive disorder were lower (Beck depression inventory II >4; hospital anxiety and depression scale >8; >2 in its depression subscale). In the total cohort the calculated area under the curve varied between 0.906 (hospital anxiety and depression scale) and 0.93 (Beck depression inventory II). Detection of moderate to severe major depressive disorder (area under the curve 0.965-0.98) was excellent; detection of mild major depressive disorder (area under the curve 0.851-0.885) was limited. Patients with major depressive disorder had a significantly lower quality of life, even when they had mild symptoms. CONCLUSION: All scales were excellent for detecting moderate to severe major depressive disorder. Classification of mild major depressive disorder, representing 50% of cases, was limited. Therapy necessitating loss of quality of life is already present in major depressive disorder with mild symptoms. Established cut-off points may still be too high to identify patients with major depressive disorder requiring therapy. External validation is needed to confirm our data.

Digoxin-mortality: randomized vs. observational comparison in the DIG trial.

AIMS: The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations. Recent observational studies reported increased mortality with digoxin treatment. We present further analyses of the DIG trial displaying the inability to control bias in observational treatment comparisons despite extensive statistical adjustments. METHODS AND RESULTS: Forty-four percent of the 6800 patients in the DIG trial had been treated with digoxin before randomization, and half of them were randomly withdrawn from digoxin treatment. We contrast the main randomization-based result of the DIG trial with the observational non-randomized comparison of patients pre-treated or not pre-treated with digoxin. Mortality [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.12-1.34; P < 0.001] and heart failure hospitalizations (HR 1.47, 95% CI 1.33-1.61; P < 0.001) were significantly higher in patients pre-treated with digoxin even after adjustment for baseline population differences. The higher risks for both outcomes in those who had previously received digoxin persisted even if they received placebo during the trial (HR 1.24, 95% CI 1.10-1.40; P < 0.001). This sharply contradicts the neutral effect on mortality and the significant reduction in heart failure hospitalizations observed in the randomized comparison. CONCLUSION: Prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments in the DIG trial where patients were well-characterized. It is unlikely that weaker research approaches (observational studies of administrative data or registries) can provide more reliable estimates of the effects of cardiac glycosides.

Patients with primary sclerosing cholangitis require more sedation during endoscopic retrograde cholangiography.

Background and study aims Patients with primary sclerosing cholangitis (PSC) require repeated endoscopic retrograde cholangiography (ERC). Our aim was to evaluate whether patients with PSC require higher doses of sedation during ERC. Patients and methods We retrospectively analyzed all patients undergoing ERC from 2006 to 2013 who received conscious sedation with propofol and midazolam. The duration of the intervention and a potential progression of propofol consumption or intervention time by visit number were analyzed. Univariable and multivariable analyses were performed to identify independent factors which influence propofol consumption. Results A total of 2962 ERC procedures were performed in 1211 patients. Patients with PSC (n = 157) underwent 461 ERC procedures whereas patients without PSC (n = 1054) had 2501 ERC examinations. The total median propofol dose was 450 mg (290 - 630 mg) for patients with PSC and 300 mg (200 - 450 mg) for the non-PSC group (P < 0.05). The propofol consumption in patients with PSC was increased by a factor of 1.24 (P = 0.0071) independent of intervention time. Younger age (< 60.8 years) and duration of the intervention were associated with a higher need for sedation by factors of 1.21 and 1.71, respectively (P < 0.0001). The robustness of the results was tested in a sensitivity analysis which confirmed the results (P < 0.0001). Conclusions Patients with PSC may require higher doses of sedation for ERC compared to other patient groups independent of age and duration of ERC. The higher dosage of sedation has to be taken into account when using ERC to treat a patient with PSC.

Evaluation of 68Ga-Glutamate Carboxypeptidase II Ligand Positron Emission Tomography for Clinical Molecular Imaging of Atherosclerotic Plaque Neovascularization.

OBJECTIVE: Intraplaque neovascularization contributes to the progression and rupture of atherosclerotic lesions. Glutamate carboxypeptidase II (GCPII) is strongly expressed by endothelial cells of tumor neovasculature and plays a major role in hypoxia-induced neovascularization in rodent models of benign diseases. We hypothesized that GCPII expression may play a role in intraplaque neovascularization and may represent a target for imaging of atherosclerotic lesions. The aim of this study was to determine frequency, pattern, and clinical correlates of vessel wall uptake of a 68Ga-GCPII ligand for positron emission tomographic imaging. APPROACH AND RESULTS: Data from 150 patients undergoing 68Ga-GCPII ligand positron emission tomography were evaluated. Tracer uptake in various arterial segments was analyzed and was compared with calcified plaque burden, cardiovascular risk factors, and immunohistochemistry of carotid specimens. Focal arterial uptake of 68Ga-GCPII ligand was identified at 5776 sites in 99.3% of patients. The prevalence of uptake sites was highest in the thoracic aorta; 18.4% of lesions with tracer uptake were colocalized with calcified plaque. High injected dose (P=0.0005) and obesity (P=0.007) were significantly associated with 68Ga-GCPII ligand accumulation, but other cardiovascular risk factors showed no association. The number of 68Ga-GCPII ligand uptake sites was significantly associated with overweight condition (P=0.0154). Immunohistochemistry did not show GCPII expression. Autoradiographic blocking studies indicated nonspecific tracer binding. CONCLUSIONS: 68Ga-GCPII ligand positron emission tomography does not identify vascular lesions associated with atherosclerotic risk. Foci of tracer accumulation are likely caused by nonspecific tracer binding and are in part noise-related. Taken together, GCPII may not be a priority target for imaging of atherosclerotic lesions.