To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS).
This multicenter, randomized, double-blind, placebo-controlled, ...parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk.
Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose.
This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.
Summary Background Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, ...sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. Methods We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov , number NCT00127530. Findings The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0·0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25·2% (95% CI 21·5% to 28·8%) and 4·7% (1·0% to 8·4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (−6·84, 95% CI −9·65 to −4·02) than timed walk non-responders (0·05, −1·48 to 1·57; p=0·0002). Safety data were consistent with previous studies. Interpretation Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit. Funding Acorda Therapeutics Inc.
To report low-income homebound older adults' experience of telehealth problem-solving therapy (tele-PST) and aging-service case managers' (CMs') experience/perception of client-level personal ...barriers to accessing psychotherapy in general and PST specifically.
The study sample consisted of 42 homebound older adults who participated in the feasibility and efficacy trial of tele-PST and completed 36-week follow-up assessments and 12 CMs of a large home-delivered meals program who referred their clients to the tele-PST trial. In-depth interviews with the older adults and written feedback and focus group discussions with the CMs provided the data.
Older adults reported a high rate of approval of PST procedures and acknowledged its positive treatment effect. Tele-PST participants were satisfied with videoconferenced sessions because they were convenient and allowed them to see their therapist. However, CMs reported that only about 10%-20% of potentially eligible older adults gave oral consent for PST. Significant treatment engagement barriers were the older adults' lack of motivation, denial of depression, perceived stigma, and other personal attitudinal factors.
The real-world implementation of tele-PST or other psychotherapies needs to include educating and motivating depressed homebound elders to recognize their depression and accept treatment.
We present a broadband (~0.3−70 keV) spectral and temporal analysis of NuSTAR observations of the luminous infrared galaxy NGC 6240 combined with archival Chandra, XMM-Newton, and BeppoSAX data. NGC ...6240 is a galaxy in a relatively early merger state with two distinct nuclei separated by ~1.̋5. Previous Chandra observations resolved the two nuclei and showed that they are both active and obscured by Compton-thick material. Although they cannot be resolved by NuSTAR, we were able to clearly detect, for the first time, both the primary and the reflection continuum components thanks to the unprecedented quality of the NuSTAR data at energies >10 keV. The NuSTAR hard X-ray spectrum is dominated by the primary continuum piercing through an absorbing column density which is mildly optically thick to Compton scattering (τ ≃ 1.2, NH ~ 1.5 × 1024 cm-2). We detect moderately hard X-ray (>10 keV) flux variability up to 20% on short (15−20 ks) timescales. The amplitude of the variability is largest at ~30 keV and is likely to originate from the primary continuum of the southern nucleus. Nevertheless, the mean hard X-ray flux on longer timescales (years) is relatively constant. Moreover, the two nuclei remain Compton-thick, although we find evidence of variability in the material along the line of sight with column densities NH ≤ 2 × 1023 cm-2 over long (~3−15 yr) timescales. The observed X-ray emission in the NuSTAR energy range is fully consistent with the sum of the best-fit models of the spatially resolved Chandra spectra of the two nuclei.
Euclid preparation Aghanim, N.; Bermejo-Climent, J. R.; Paoletti, D. ...
Astronomy and astrophysics (Berlin),
01/2022, Letnik:
657
Journal Article
Recenzirano
Odprti dostop
The combination and cross-correlation of the upcoming
Euclid
data with cosmic microwave background (CMB) measurements is a source of great expectation since it will provide the largest lever arm of ...epochs, ranging from recombination to structure formation across the entire past light cone. In this work, we present forecasts for the joint analysis of
Euclid
and CMB data on the cosmological parameters of the standard cosmological model and some of its extensions. This work expands and complements the recently published forecasts based on
Euclid
-specific probes, namely galaxy clustering, weak lensing, and their cross-correlation. With some assumptions on the specifications of current and future CMB experiments, the predicted constraints are obtained from both a standard Fisher formalism and a posterior-fitting approach based on actual CMB data. Compared to a
Euclid
-only analysis, the addition of CMB data leads to a substantial impact on constraints for all cosmological parameters of the standard Λ-cold-dark-matter model, with improvements reaching up to a factor of ten. For the parameters of extended models, which include a redshift-dependent dark energy equation of state, non-zero curvature, and a phenomenological modification of gravity, improvements can be of the order of two to three, reaching higher than ten in some cases. The results highlight the crucial importance for cosmological constraints of the combination and cross-correlation of
Euclid
probes with CMB data.
The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with ...treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies. Each substudy was a phase 2 trial of a therapy matched to a genomic alteration, with a primary endpoint of objective tumor response by RECIST criteria. In this Perspective, we summarize the outcomes of the initial 27 substudies in NCI-MATCH, which met its signal-seeking objective with 7/27 positive substudies (25.9%). We discuss key aspects of the design and operational conduct of the trial, highlighting important lessons for future precision medicine studies.
Context. Recent NuSTAR observations revealed a somewhat unexpected increase in the X-ray flux of the nucleus of NGC 1068. We expect the infrared emission of the dusty torus to react on the intrinsic ...changes of the accretion disk. Aims. We aim to investigate the origin of the X-ray variation by investigating the response of the mid-infrared environment. Methods. We obtained single-aperture and interferometric mid-infrared measurements and directly compared the measurements observed before and immediately after the X-ray variations. The average correlated and single-aperture fluxes as well as the differential phases were directly compared to detect a possible change in the structure of the nuclear emission on scales of ~2 pc. Results. The flux densities and differential phases of the observations before and during the X-ray variation show no significant change over a period of ten years. Possible minor variations in the infrared emission are ≲6%. Conclusions. Our results suggest that the mid-infrared environment of NGC 1068 has remained unchanged for a decade. The recent transient change in the X-rays did not cause a significant variation in the infrared emission. This independent study supports previous conclusions that stated that the X-ray variation detected by NuSTAR observations is due to X-ray emission piercing through a patchy section of the dusty region.
Background: A prior Phase 3 study of sustained-release fampridine (4-aminopyridine) in MS showed beneficial effects on ambulation and leg strength. Objective: To confirm the efficacy and safety of ...fampridine (Fampridine-SR) in an independent study of patients with ambulatory deficits due to multiple sclerosis (MS). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study comparing 10 mg sustained-release fampridine bid and placebo. A 2-week placebo run-in was followed by 9 week treatment and 2 week follow-up periods. Eligibility criteria included: definite MS of any subtype; age 18-70; completion of the Timed 25-Foot Walk (T25FW) within 8-45 seconds at screening; stable concomitant medications. The pre-specified primary outcome was the proportion of patients with consistent improvement in walking speed on the T25FW during the treatment period (Timed Walk Responders). The clinical validity of the response criterion was previously established by correlation with the 12-Item MS Walking Scale, subject and clinician global impression scales. The secondary outcome was manually assessed leg strength, comparing Timed Walk Responders and Non-Responders with placebo-treated patients. Results: A total of 239 patients were randomized; 120 received fampridine and 119 placebo. 227 patients completed the trial (n = 113, 114). The fampridine-treated group had a higher proportion of Timed Walk Responders, compared to the placebo group (42.9 % v. 9.3 %; p<0.001) across all MS subtypes. Walking speed in Timed Walk Responders improved by approximately 25% from baseline, throughout the treatment period. Leg strength was significantly improved in Timed Walk Responders versus placebo-treated patients (p = 0.028). Adverse events were similar to those observed in previous studies of fampridine in MS. Three serious adverse events led to discontinuation, only one of which (patellar fracture) was in the fampridine group. Conclusions: Fampridine consistently improved walking speed and leg strength in a significant proportion of MS patients during 9 weeks of treatment.
Background:
In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine ...modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS).
Objectives:
Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT).
Methods:
Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW.
Results:
We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders.
Conclusions:
The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.
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