Suggestions for improving the design of clinical trials in multiple sclerosis - results of a systematic analysis of completed phase III trials

This manuscript reviews the primary and secondary endpoints of pivotal phase III trials with immunomodulatory drugs in multiple sclerosis (MS). Considering the limitations of previous trial designs, we propose new standards for the planning of clinical trials, taking into account latest insights into MS pathophysiology and patient-relevant aspects. Using a systematic overview of published phase III (pivotal) trials performed as part of application for drug market approval, we evaluate the following characteristics: trial duration, number of trial participants, comparators, and endpoints (primary, secondary, magnetic resonance imaging outcome, and patient-reported outcomes). From a patient perspective, the primary and secondary endpoints of clinical trials are only partially relevant. High-quality trial data pertaining to efficacy and safety that stretch beyond the time frame of pivotal trials are almost non-existent. Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking. Concrete proposals for the trial designs of relapsing (remitting) multiple sclerosis/clinically isolated syndrome, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (e.g., study duration, mechanism of action, and choice of endpoints) are presented based on the results of the systematic overview. Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere "relapse-prevention" approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease. This personalized provision takes patient preferences as well as disease-related factors into consideration such as objective clinical and radiographic findings but also very burdensome symptoms such as fatigue, depression, and cognitive impairment. Future trial designs in MS will have to assign higher relevance to these patient-reported outcomes and will also have to implement surrogate measures that can serve as predictive markers for individual treatment response to new and investigational immunotherapies. This is an indispensable prerequisite to maximize the benefit of individual patients when participating in clinical trials. Moreover, such appropriate trial designs and suitable enrolment criteria that correspond to the mode of action of the study drug will facilitate targeted prevention of adverse events, thus mitigating risks for individual study participants

Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes

Site-specific deletions in the tal-1 gene are reported to occur in 12-26% of T cell acute lymphoblastic leukemias (T-ALL). So far two main types of tal-1 deletions have been described. Upon analysis of 134 T-ALL we have found two new types of tal-1 deletions. These four types of deletions juxtapose the 5' part of the tal-1 gene to the sil gene promoter, thereby deleting all coding sil exons but leaving the coding tal-1 exons undamaged. The recombination signal sequences (RSS) and fusion regions of the tal-1 deletion breakpoints strongly resemble the RSS and junctional regions of immunoglobulin/T cell receptor (TCR) gene rearrangements, which implies that they are probably caused by the same V(D)J recombinase complex. Analysis of the 134 T-ALL suggested that the occurrence of tal-1 deletions is associated with the CD3 phenotype, because no tal-1 deletions were found in 25 TCR-gamma/delta + T-ALL, whereas 8 of the 69 CD3- T-ALL and 11 of the 40 TCR-alpha/beta + T-ALL contained such a deletion. Careful examination of all TCR genes revealed that tal-1 deletions exclusively occurred in CD3- or CD3+ T-ALL of the alpha/beta lineage with a frequency of 18% in T-ALL with one deleted TCR-delta allele, and a frequency of 34% in T-ALL with TCR-delta gene deletions on both alleles. Therefore, we conclude that alpha/beta lineage commitment of the T-ALL and especially the extent of TCR-delta gene deletions determines the chance of a tal-1 deletion. This suggests that tal-1 deletions are mediated via the same deletion mechanism as TCR-delta gene deletions

On noise treatment in radio measurements of cosmic ray air showers

Precise measurements of the radio emission by cosmic ray air showers require an adequate treatment of noise. Unlike to usual experiments in particle physics, where noise always adds to the signal, radio noise can in principle decrease or increase the signal if it interferes by chance destructively or constructively. Consequently, noise cannot simply be subtracted from the signal, and its influence on amplitude and time measurement of radio pulses must be studied with care. First, noise has to be determined consistently with the definition of the radio signal which typically is the maximum field strength of the radio pulse. Second, the average impact of noise on radio pulse measurements at individual antennas is studied for LOPES. It is shown that a correct treatment of noise is especially important at low signal-to-noise ratios: noise can be the dominant source of uncertainty for pulse height and time measurements, and it can systematically flatten the slope of lateral distributions. The presented method can also be transfered to other experiments in radio and acoustic detection of cosmic rays and neutrinos.Comment: 4 pages, 6 figures, submitted to NIM A, Proceedings of ARENA 2010, Nantes, Franc

The LOPES experiment - recent results, status and perspectives

The LOPES experiment at the Karlsruhe Institute of Technology has been taking radio data in the frequency range from 40 to 80 MHz in coincidence with the KASCADE-Grande air shower detector since 2003. Various experimental configurations have been employed to study aspects such as the energy scaling, geomagnetic dependence, lateral distribution, and polarization of the radio emission from cosmic rays. The high quality per-event air shower information provided by KASCADE-Grande has been the key to many of these studies and has even allowed us to perform detailed per-event comparisons with simulations of the radio emission. In this article, we give an overview of results obtained by LOPES, and present the status and perspectives of the ever-evolving experiment.Comment: Proceedings of the ARENA2010 conference, Nantes, Franc

The spectrum of high-energy cosmic rays measured with KASCADE-Grande

The energy spectrum of cosmic rays between 10**16 eV and 10**18 eV, derived from measurements of the shower size (total number of charged particles) and the total muon number of extensive air showers by the KASCADE-Grande experiment, is described. The resulting all-particle energy spectrum exhibits strong hints for a hardening of the spectrum at approximately 2x10**16 eV and a significant steepening at c. 8x10**16 eV. These observations challenge the view that the spectrum is a single power law between knee and ankle. Possible scenarios generating such features are discussed in terms of astrophysical processes that may explain the transition region from galactic to extragalactic origin of cosmic rays.Comment: accepted by Astroparticle Physics June 201

Nuclear Level Density and the Determination of Thermonuclear Rates for Astrophysics

The prediction of cross sections for nuclei far off stability is crucial in the field of nuclear astrophysics. We discuss the model mostly employed for such calculations: the statistical model (Hauser-Feshbach). Special emphasis is put on the uncertainties arising from nuclear level density descriptions and an improved global description is presented. Furthermore, criteria for the applicability of the statistical model are investigated and a "map" for the applicability of the model to reactions of stable and unstable nuclei with neutral and charged particles is given.Comment: REVTeX paper + 7 B/W figures + 2 color figures; PRC, in press. Also available at http://quasar.physik.unibas.ch/preps.htm

Studies of the cosmic ray spectrum and large scale anisotropies with the KASCADE-Grande experiment

KASCADE-Grande is an air shower observatory devoted to the detection of cosmic rays in the 10$^{16}$ − 10$^{18}$eV energy range. For each event the arrival direction, the total number of charged particles (Nch) and the total number of muons (Nμ), at detection level (i.e. 110 m a.s.l.), are measured. The detection of these observarbles, with high accuracy, allows the study of the primary spectrum, chemical composition and large scale anisotropies, that are the relevant informations to investigate the astrophysics of cosmic rays in this energy range. These studies are of main importance to deeply investigate the change of slope of the primary spectrum detected at ∼ 4×10$^{15}$eV , also known as the knee, and to search for the transition from galactic to extra-galactic cosmic rays. The two-dimensional (Nch vs Nμ) spectrum is the basis for the cosmic-ray chemical composition studies. EAS and detection fluctuations prevent the measurement of the primary mass on an event by event basis, nevertheless the precision obtained by the KASCADE-Grande experiment allows to separate events into mass groups. A search for anisotropies in the arrival directions of primary cosmic rays has been performed using the East-West analysis technique with the events detected by the Grande array. First harmonic modulation has been derived from the distributions (in sidereal, solar and anti-sidereal times) of the counts difference from the East and West sectors. In this contribution we present and discuss the latest experimental results