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- Benatar, Michael, et al.
(författare)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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- Dieval, Catherine, et al.
(författare)
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A case study of proton precipitation at Mars : Mars Express observations and hybrid simulations
- 2012
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117
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Tidskriftsartikel (refereegranskat)abstract
- Using the data from the Analyzer of Space Plasma and Energetic Atoms (ASPERA-3) experiment on board Mars Express and hybrid simulations, we have investigated the entry of protons into the Martian induced magnetosphere. We discuss one orbit on the dayside with observations of significant proton fluxes at altitudes down to 260 km on 27 February 2004. The protons observed below the induced magnetosphere boundary at an altitude of less than 700 km have energies of a few keV, travel downward, and precipitate onto the atmosphere. The measured energy flux and particle flux are 108–109 eV cm−2 s−1 and 105–106 H+ cm−2 s−1, respectively. The proton precipitation occurs because the Martian magnetosheath is small with respect to the heated proton gyroradius in the subsolar region. The data suggest that the precipitation is not permanent but may occur when there are transient increases in the magnetosheath proton temperature. The higher-energy protons penetrate deeper because of their larger gyroradii. The proton entry into the induced magnetosphere is simulated using a hybrid code. A simulation using a fast solar wind as input can reproduce the high energies of the observed precipitating protons. The model shows that the precipitating protons originate from both the solar wind and the planetary exosphere. The precipitation extends over a few thousand kilometers along the orbit of the spacecraft. The proton precipitation does not necessarily correlate with the crustal magnetic anomalies.
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- Edberg, Niklas J. T., et al.
(författare)
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Solar wind interaction with comet 67P : Impacts of corotating interaction regions
- 2016
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 121:2, s. 949-965
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Tidskriftsartikel (refereegranskat)abstract
- We present observations from the Rosetta Plasma Consortium of the effects of stormy solar wind on comet 67P/Churyumov-Gerasimenko. Four corotating interaction regions (CIRs), where the first event has possibly merged with a coronal mass ejection, are traced from Earth via Mars (using Mars Express and Mars Atmosphere and Volatile EvolutioN mission) to comet 67P from October to December 2014. When the comet is 3.1-2.7AU from the Sun and the neutral outgassing rate approximate to 10(25)-10(26)s(-1), the CIRs significantly influence the cometary plasma environment at altitudes down to 10-30km. The ionospheric low-energy (approximate to 5eV) plasma density increases significantly in all events, by a factor of >2 in events 1 and 2 but less in events 3 and 4. The spacecraft potential drops below -20V upon impact when the flux of electrons increases. The increased density is likely caused by compression of the plasma environment, increased particle impact ionization, and possibly charge exchange processes and acceleration of mass-loaded plasma back to the comet ionosphere. During all events, the fluxes of suprathermal (approximate to 10-100eV) electrons increase significantly, suggesting that the heating mechanism of these electrons is coupled to the solar wind energy input. At impact the magnetic field strength in the coma increases by a factor of 2-5 as more interplanetary magnetic field piles up around the comet. During two CIR impact events, we observe possible plasma boundaries forming, or moving past Rosetta, as the strong solar wind compresses the cometary plasma environment. We also discuss the possibility of seeing some signatures of the ionospheric response to tail disconnection events.
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- Gunell, H., et al.
(författare)
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Plasma penetration of the dayside magnetopause
- 2012
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Ingår i: Physics of Plasmas. - Melville, NY : AIP Publishing. - 1070-664X .- 1089-7674. ; 19:7, s. 072906-
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Tidskriftsartikel (refereegranskat)abstract
- Data from the Cluster spacecraft during their magnetopause crossing on 25 January 2002 are presented. The magnetopause was in a state of slow non-oscillatory motion during the observational period. Coherent structures of magnetosheath plasma, here typified as plasmoids, were seen on closed magnetic field lines on the inside of the magnetopause. Using simultaneous measurements on two spacecraft, the inward motion of the plasmoids is followed from one spacecraft to the next, and it is found to be in agreement with the measured ion velocity. The plasma characteristics and the direction of motion of the plasmoids show that they have penetrated the magnetopause, and the observations are consistent with the concept of impulsive penetration, as it is known from theory, simulations, and laboratory experiments. The mean flux across the magnetopause observed was 0.2%-0.5% of the solar wind flux at the time, and the peak values of the flux inside the plasmoids reached approximately 20% of the solar wind flux.
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