Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

BACKGROUND: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington\u27s disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. METHODS: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington\u27s disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington\u27s Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). FINDINGS: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. INTERPRETATION: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. FUNDING: Teva Pharmaceutical Industries

Combined Digital Economic-Epidemic Model for the Evaluation of Economic Results of Several Scenarios of Quarantine Measures

Purpose: Substantiation of the selection of the potential option of the implementation of quarantine measures and of the obtaining of evaluations of its potential economic consequences for Moscow on the basis of the use of instruments of the combined digital economic-epidemic model, developed by authors. Methods: In order to carry out the research the modified SIR-model was used as the basic epidemic one. As the economic growth model was used the model of probability of mixed economic systems, developed by authors. The consolidation of such models to its lowest terms allowed to form the combined digital economic-epidemic model. As basic ones were considered three potentially possible options for the implementation of quarantine measures. On the basis of the model, developed by authors, were developed feasibility studies for each of three options of quarantine measures. While carrying out calculations as initial terms was adopted the dynamics of the daily accrual of people, infected withCOVID-19 for the week between 01.04 and 08.04.2020. Result: On the basis of the combined digital economic-epidemic model were determined possible economic consequences at the implementation of basic options of quarantine measures, feasibility studies were provided, its scientific analysis has been performed with the substantiation of the development of one of considered options. As most optimal option of the implementation of quarantine measures B option was selected. Conclusion: The offered model and settlements, performed on its basis, can be applied in all regions of Russia in order to select the potential option of the implementation of quarantine measures and of the evaluation of possible economic consequences for each region. This is a universal model. With it can be studied events of all epidemiologic periods and world regions. © 2021, Springer Nature Switzerland AG

Combined Digital Economic-Epidemic Model for the Evaluation of Economic Results of Several Scenarios of Quarantine Measures

Purpose: Substantiation of the selection of the potential option of the implementation of quarantine measures and of the obtaining of evaluations of its potential economic consequences for Moscow on the basis of the use of instruments of the combined digital economic-epidemic model, developed by authors. Methods: In order to carry out the research the modified SIR-model was used as the basic epidemic one. As the economic growth model was used the model of probability of mixed economic systems, developed by authors. The consolidation of such models to its lowest terms allowed to form the combined digital economic-epidemic model. As basic ones were considered three potentially possible options for the implementation of quarantine measures. On the basis of the model, developed by authors, were developed feasibility studies for each of three options of quarantine measures. While carrying out calculations as initial terms was adopted the dynamics of the daily accrual of people, infected withCOVID-19 for the week between 01.04 and 08.04.2020. Result: On the basis of the combined digital economic-epidemic model were determined possible economic consequences at the implementation of basic options of quarantine measures, feasibility studies were provided, its scientific analysis has been performed with the substantiation of the development of one of considered options. As most optimal option of the implementation of quarantine measures B option was selected. Conclusion: The offered model and settlements, performed on its basis, can be applied in all regions of Russia in order to select the potential option of the implementation of quarantine measures and of the evaluation of possible economic consequences for each region. This is a universal model. With it can be studied events of all epidemiologic periods and world regions

Implementation of market methods of price forming in the field of power industry with the application of the consolidated balance-market model of economic systems

Object. The power industry of Russia is being developing with the use of its natural resources, advanced ideas, implementation of existing opportunities. So, the key task of the energy strategy of Russia till 2035 is the transfer from the commodity-heavy to the resource-innovative development of both the power industry and the economics of the country. All conditions have been created for its solution as of now - the power industry is expected to increase by 20-25% if demand for the hydrocarbon raw materials falls on the immediate horizon. In this juncture such branch as the power industry seems to be a crutial and sophisticated object of the research on the dynamics of economic systems infrastructural transformations. Anyway, its implementation in the field of the power industry involved quasi-market mechanisms of the preservation of existing ones and the building of new non-competitive powers with the use of such mechanisms as "adhesion contract"and "marginal price forming". The work shows the inhibiting impact of these mechanisms on the economic system. The offer for its replacement to increase the pace of the power industry development and of the Russian economics substantiates. The research purpose is to substantiate the application of the consolidated balance-market model of economic systems for the analysis of the dynamics of the development of the technologically heterogenic branch, interacting with the other economic system, provided Leontief correlations. The power industry was selected as the studied one. Peculiarities of the reforming of power price rates, combining both market and regulating (quasi-market) mechanisms, were considered. Methods. The random balance-market model became the methodologic basis for mixed economic systems in the option of the self-consistent field of Leontief matrices. It make it possible to solve practical issues of the development of most important multi-agent branches in its interaction with the other economic system. In the work this model is applied in the quasitensor form for the evaluation of mixed mechanisms of the regulation of price rates in the power industry. Results. It was revealed that the common use of such mechanisms as "marginal price forming"and "adhesion contracts"fully suppresses the economic growth in all branches of economics. In order to find the way out was offered the consolidated random model of mixed economic systems in the quasitensor form. Its application will make it possible to obtain the new distribution of the capital by goods and agents with the better use of its technical advantages with such level of power rates. Conclusions. The possibility of the subtle analysis of the dynamics of the specialization and localization of agents was shown for the following development of distributed centralized energoinformational systems in the Russian Federation. It is expedient to use offered approach and developed algorithms of modeling for the evaluation of the accelerated economic growth of other key branches of the Russian economics. © Published under licence by IOP Publishing Ltd

Safety analysis of 10 clinical trials and for 13 years after first approval of ioflupane 123I injection (DaTscan)

Ioflupane is an analog of cocaine that binds reversibly with high affinity to the dopamine transporter (DaT) protein, a marker for presynaptic terminals in dopaminergic nigrostriatal neurons. Ioflupane 123I Injection is also known as DaTscan or DaTSCAN (123I-ioflupane is also called 123I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane or 123I-FP-CIT). The diagnostic efficacy of DaTscan has been described elsewhere. Here, we present a comprehensive analysis of the safety of DaTscan starting from initiation of clinical development through 13 y after the date of first market approval. Safety data in the sponsor’s clinical development safety database from 10 completed DaTscan clinical trials were pooled, and postapproval experience was summarized from standardized aggregate safety reports submitted to regulatory agencies. A total of 1,180 clinical trial subjects (92% of 1,284 subjects planned to receive DaTscan in the clinical trials) received DaTscan. Percentages of subjects with adverse events by category were as follows: all (22%), considered at least possibly related to DaTscan by the investigator (4%), any severe (3%), headache (4%), nausea (2%), dizziness (2%), nasopharyngitis (1%), and injection site hematoma (1%). Four percent of subjects had at least 1 serious adverse event; 5 subjects (<1%) had serious adverse events that led to death. All serious adverse events, including those that led to death, were deemed by an expert clinician to be unrelated to DaTscan. An estimated half a million market doses of DaTscan (for single use) were administered from July 2000 through the July 2013 reporting period. In postapproval safety assessment, 1 death was reported 20 d after (and unrelated to) DaTscan administration. Two spontaneously reported serious adverse drug reactions (ADRs) and 32 spontaneously reported nonserious ADRs were submitted, approximately half of which are identified in labeling. Headache (in clinical trials) and injection site pain (postapproval) were the most commonly reported events or reactions. Although adverse events were reported for 1 in 5 clinical trial subjects, most were mild and considered unrelated to DaTscan administration. Severe events were uncommon, and no serious adverse event occurring in more than 1 subject was deemed related to DaTscan administration. In postapproval experience, the frequency of ADRs spontaneously reported was less than 1 per 10,000 doses administered. Comprehensive safety data show that DaTscan was well tolerated