Magnetic Resonance Imaging Endpoints Research Articles

From strength to precision: A systematic review exploring the clinical utility of 7-Tesla magnetic resonance imaging in abdominal imaging.

After approval for clinical use in 2017 early investigations of ultra-high-field abdominal magnetic resonance imaging (MRI) have demonstrated the feasibility as well as diagnostic capabilities of liver, kidney, and prostate MRI at 7-Tesla. However, the elevation of the field strength to 7-Tesla not only brought advantages to abdominal MRI but also presented considerable challenges and drawbacks, primarily stemming from heightened artifacts and limitations in Specific Absorption Rate, etc. Furthermore, evidence in the literature is relatively scarce concerning human studies in comparison to phantom/animal studies which necessitates an investigation into the evidence so far in humans and summarizing all relevant evidence. To offer a comprehensive overview of current literature on clinical abdominal 7T MRI that emphasizes current trends, details relevant challenges, and provides a concise set of potential solutions. This systematic review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A PubMed search, utilizing Medical Subject Headings terms such as "7-Tesla" and organ-specific terms, was conducted for articles published between January 1, 1985, and July 25, 2023. Eligibility criteria included studies exploring 7T MRI for imaging human abdominal organs, encompassing various study types (in-vivo/ex-vivo, method development, reviews/meta-analyses). Exclusion criteria involved animal studies and those lacking extractable data. Study selection involved initial identification via title/abstract, followed by a full-text review by two researchers, with discrepancies resolved through discussion. Data extraction covered publication details, study design, population, sample size, 7T MRI protocol, image characteristics, endpoints, and conclusions. The systematic review included a total of 21 studies. The distribution of clinical 7T abdominal imaging studies revealed a predominant focus on the prostate (n = 8), followed by the kidney (n = 6) and the hepatobiliary system (n = 5). Studies on these organs, and in the pancreas, demonstrated clear advantages at 7T. However, small bowel studies showed no significant improvements compared to traditional MRI at 1.5T. The majority of studies evaluated originated from Germany (n = 10), followed by the Netherlands (n = 5), the United States (n = 5), Austria (n = 2), the United Kingdom (n = 1), and Italy (n = 1). Further increase of abdominal clinical MRI field strength to 7T demonstrated high imaging potential, yet also limitations mainly due to the inhomogeneous radiofrequency (RF) excitation field relative to lower field strengths. Hence, further optimization of dedicated RF coil elements and pulse sequences are expected to better optimize clinical imaging at high magnetic field strength.

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

BackgroundIn the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE).ObjectiveTo determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI).MethodsThis post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter.ResultsCompared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96 weeks. Similar results were observed with the 5.25 mg/kg dosage.ConclusionIn participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation).

A Phase I Study of Allogeneic Mesenchymal Stem Cell Therapy in Patients with Heart Failure Secondary to Anthracycline-induced Cardiomyopathy: The Cctrn Stem Cell Injection in Cancer Survivors (Seneca) Trial

Background Anthracycline-induced cardiomyopathy (AIC) can be irreversible with a poor prognosis, and disproportionately affects women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure treatment. Allo-MSCs are known to favorably affect fibrosis, apoptosis, and inflammation, which are key features of AIC. Methods This phase I study evaluated 37 adult cancer survivors (68% female) with left ventricular dysfunction secondary to chronic AIC. The study included a six-subject open-label, lead-in phase followed by 31 subjects randomized 1:1 to receive 1 × 108 allo-MSCs or vehicle via 20 transendocardial injections. Subjects were followed for 1 year to assess safety and feasibility (Fisher's test). Secondary efficacy measures included cardiac function/structure measured by magnetic resonance imaging (MRI), functional capacity, quality of life (MLHFQ), and biomarkers. These were assessed by ANCOVA adjusting for baseline values. Results Ninety-seven percent of subjects underwent successful study product injections, all allo-MSC-assigned subjects received the target dose. Follow-up visits were well attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-MRI compatible devices, MRI endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes including major adverse cardiac events, other significant adverse events, and days alive and out of the hospital. Ten of the 13 efficacy measures numerically favored the allo-MSC group including a lower MLHFQ score (p = .048). Conclusion In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible and MRI was successfully performed in the majority of patients with devices. This study provides crucial information for designing Phase II trials aimed at assessing efficacy of cell therapy in patients with AIC.

Gray Matter Nucleus Hyperintensity After Monthly Triple-Dose Gadopentetate Dimeglumine With Long-term Magnetic Resonance Imaging.

Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial. Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed with t test. During monthly scanning, all gray matter structures demonstrated a significant (P < 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout). Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.

Bovine Milk Oligosaccharides with Sialyllactose Improves Cognition in Preterm Pigs.

Optimal nutrition is important after preterm birth to facilitate normal brain development. Human milk is rich in sialic acid and preterm infants may benefit from supplementing formula with sialyllactose to support neurodevelopment. Using pigs as models, we hypothesized that sialyllactose supplementation improves brain development after preterm birth. Pigs (of either sex) were delivered by cesarean section at 90% gestation and fed a milk diet supplemented with either an oligosaccharide-enriched whey with sialyllactose (n = 20) or lactose (n = 20) for 19 days. Cognitive performance was tested in a spatial T-maze. Brains were collected for ex vivo magnetic resonance imaging (MRI), gene expression, and sialic acid measurements. For reference, term piglets (n = 14) were artificially reared under identical conditions and compared with vaginally born piglets naturally reared by the sow (n = 12). A higher proportion of sialyllactose supplemented preterm pigs reached the T-maze learning criteria relative to control preterm pigs (p < 0.05), and approximated the cognition level of term reference pigs (p < 0.01). Furthermore, supplemented pigs had upregulated genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in hippocampus. Sialyllactose supplementation did not lead to higher levels of sialic acid in the hippocampus or change MRI endpoints. Contrary, these parameters were strongly influenced by postconceptional age and postnatal rearing conditions. In conclusion, oligosaccharide-enriched whey with sialyllactose improved spatial cognition, with effects on hippocampal genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in preterm pigs. Dietary sialic acid enrichment may improve brain development in infants.

Bowel wall healing assessed using magnetic resonance imaging predicts sustained clinical remission and decreased risk of surgery in Crohn's disease.

Endoscopic mucosal healing is considered as the best therapeutic target in Crohn's disease (CD) as it is associated with better long-term outcomes. We investigated whether bowel wall healing (BWH) assessed using magnetic resonance imaging (MRI) could predict favorable outcomes and could be a potential therapeutic target. We performed a post hoc analysis from two prospective studies (n = 174 patients). All the patients with previous objective signs of bowel inflammation and assessed by MRI for therapeutic efficacy had a standardized and blinded evaluation, and underwent MRI. Complete BWH was defined as no segmental MaRIA > 7 or no segmental Clermont score > 8.4 and BWH as no segmental MaRIA > 11 or no segmental Clermont score > 12.5. Clinical corticosteroid-free remission (CFREM) was defined as no reappearance or worsening of clinical manifestation leading to therapeutic modification, hospitalization or CD-related surgery. Multivariate analyses were performed including all the relevant parameters. Overall, 63 patients with CD were included (mean follow-up = 4.8 ± 3.1 semesters). In multivariate analysis (n = 303 semesters), complete BWH or BWH was associated with sustained CFREM according to MaRIA [OR = 4.42 (2.29-26.54); p = 0.042 and OR = 3.43 (1.02-27.02); p = 0.047, respectively] or Clermont score [OR = 3.09 (1.01-12.91); p = 0.049 and OR = 3.88 (1.40-13.80); p = 0.036, respectively]. In multivariate analysis (n = 63 patients), complete BWH or BWH was associated with decreased risk of surgery using MaRIA [HR = 0.16 (0.043-0.63); p = 0.008 and HR = 0.24 (0.07-0.77); p = 0.017, respectively] or Clermont score [HR = 0.24 (0.07-0.78); p = 0.016 and HR = 0.23 (0.07-0.76); p = 0.016, respectively]. MRI endpoints are predictive of favorable outcomes after medical therapy and could be used as therapeutic target in daily practice and clinical trials.

Whole-body Magnetic Resonance Imaging in Axial Spondyloarthritis: Reduction of Sacroiliac, Spinal, and Entheseal Inflammation in a Placebo-controlled Trial of Adalimumab.

To investigate whether adalimumab (ADA) reduces whole-body (WB-) magnetic resonance imaging (MRI) indices for inflammation in the entheses, peripheral joints, sacroiliac joints, spine, and the entire body in patients with axial spondyloarthritis (axSpA). An investigator-initiated, randomized, placebo-controlled, double-blinded 48-week followup trial included 49 patients with axSpA, who had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4.0 despite treatment with nonsteroidal antiinflammatory drugs and a clinical indication for tumor necrosis factor inhibitor treatment. Patients were randomized to subcutaneous ADA 40 mg or placebo every other week for 6 weeks; thereafter, all patients received ADA. Conventional MRI and WBMRI were performed at weeks 0, 6, 24, and 48. The primary WBMRI endpoint was the proportion of patients with an improvement in WBMRI total inflammation index above the smallest detectable change (SDC) at Week 6. The primary WBMRI endpoint (improvement of SDC > 2.3) was met in 11 (44%) patients in the ADA group and 3 (13%) patients in the placebo group (p = 0.025, Fisher's exact test). The primary conventional MRI endpoint, the minimally important change in Spondyloarthritis Research Consortium of Canada Spine MRI Inflammation Index at Week 6, was achieved by 9 (36%) patients in the ADA group and 4 (17%) patients in the placebo group (p = 0.20). The primary clinical endpoint, BASDAI reduction > 50% or 2.0 at Week 24, was attained by 32 (65%) patients. ADA provided significant reductions in WBMRI indices of peripheral, axial, and whole-body inflammation in patients with axSpA. WBMRI is promising for objective assessment and monitoring of peripheral and axial disease activity in future clinical trials.

Towards a dendritic cell-based vaccine for the treatment of multiple sclerosis (MS): interim safety data of the first dose cohort of the MS-tolDC phase I clinical trial

Towards a dendritic cell-based vaccine for the treatment of multiple sclerosis (MS): interim safety data of the first dose cohort of the MS-tolDC phase I clinical trial

P 1 Effect of ocrelizumab on magnetic resonance imaging markers of neurodegeneration in patients with relapsing multiple sclerosis – analysis of the phase III, double-blind, double-dummy, interferon beta-1a- controlled OPERA I and OPERA II studies

Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs interferon beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44 μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p = 0.0001), and from Week 24 to Week 96 by 22.8% ( p = 0.0042) and 14.9% ( p = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p = 0.0024); in OPERA II, there was no difference ( p = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network “Patients with Intermittent Claudication Injected with ALDH Bright Cells” (CCTRN PACE) study

Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies. The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDHbr stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI). The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization. Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.

MRI of the left atrium at 3T: evaluation of measurement reproducibility in healthy volunteers and patients with cardiovascular disease.

Background Left ventricular (LV) function has traditionally been the focus for cardiac magnetic resonance imaging (MRI) investigations, but similar methods can also be applied to the left atrium (LA). Previous studies elsewhere have almost entirely involved the use of 1.5T systems, but 3T MRI can provide faster data acquisition with thinner image slices, and may be more suitable for quantifying the structure and function of the LA. Purpose To evaluate 3T-MRI for LA volume assessments in: (i) healthy volunteers (HV); (ii) patients with LV-hypertrophy and ischemia (LVHI); and (iii) patients with LV-hypertrophy and diabetes (LVHD). Material and Methods Participants were imaged using a balanced steady-state free precession sequence. Healthy volunteers were scanned twice and patients were scanned on one occasion. Volumes were segmented by two observers, and coefficients of repeatability (CoR) were derived. Results For LA volumes (indexed to body surface area), CoRs were in the range of 1.3-4.6 mL/m2. The LVHI patients had enlarged LA volumes (diastolic, 46.4 mL/m2; systolic, 25.9 mL/m2) and reduced ejection fraction (EF) (44.9%) relative to the HV (diastolic, 39.0 mL/m2; systolic, 17.8 mL/m2; EF, 54.5%) and LVHD groups (diastolic, 41.4 mL/m2; systolic, 20.2 mL/m2; EF, 50.7%). LA volumes were moderately correlated with LV mass in the HV group (R2 = 0.59 for LA end-systolic volume), but became weaker (R2 ≤ 0.17) for patient groups. Conclusion 3T-MRI derived LA volume measurements are simple and repeatable, and can elicit clear differences between LVHI patients and HVs. These MRI endpoints provide scope for improved radiological interpretation of LA structure and function, and the high degree of repeatability validates their use for longitudinal investigations where precision work is essential.

A placebo randomized controlled study to test the efficacy and safety of GNbAC1, a monoclonal antibody for the treatment of multiple sclerosis – Rationale and design

BackgroundGNbAC1, a humanized monoclonal antibody, is an innovative treatment currently in development for multiple sclerosis (MS) which, contrary to the immunomodulation/immunosuppressive mechanism of action of most of the MS drugs, targets specifically a protein of endogenous retroviral origin supposed to be critical in MS pathogenesis. MethodsThis trial is a randomized placebo controlled 4-arm study with the objective of demonstrating the efficacy of repeated doses of GNbAC1 on the cumulative number of T1 Gd-enhancing lesions measured from Week 12 to 24 in patients with relapsing remitting MS (RRMS). Two hundred sixty patients with RRMS are planned to be included. Three doses of GNbAC1 will be tested versus placebo: 6mg/kg, 12mg/kg and 18mg/kg, administered intravenously, with 4-week administration intervals. The design is based on the classic 24-week placebo-controlled repeated brain MRI trial design (Period 1), with an extension of 24 weeks during which placebo patients will be re-randomized to one of the three doses of GNbAC1 to assess efficacy and safety of prolonged treatment of GNbAC1 (Period 2). The primary endpoint is the cumulative number of new Gadolinium enhanced T1 lesions measured using repeated brain magnetic resonance imaging (MRI) scans from Week 12 to 24; secondary endpoints, including additional MRI and clinical endpoints, will be assessed at the end of both Periods 1 and 2. Pharmacokinetics and biomarkers will be assessed in serum in all patients at several time points and also in cerebrospinal fluid in a subgroup of patients. To alleviate potential ethical concerns regarding placebo administration in MS, an early escape from trial will be implemented for patients with a worsening clinical condition during trial. ConclusionThis dose-finding study should provide the first proof-of-concept of an innovative therapeutic approach for MS. The constraints of using a placebo group in RRMS patients while optimizing the trial power to evidence a new mechanism of action is discussed.

Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial.

Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity. The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.

Using magnetic resonance imaging to quantify the inflammatory response following allergen challenge in allergic rhinitis.

Current rhinometric and flow assessments measure nasal patency and are often poorly correlated with rhinitis symptoms. To evaluate magnetic resonance imaging (MRI) as a new method to measure inflammatory changes in nasal and sinus mucosa following nasal allergen challenge. A pilot study (n = 6) determined the optimal technical settings for MRI to measure inflammatory change which were then adopted for the main study. This study was a single blind, placebo-controlled, three-way crossover trial in 14 subjects with seasonal allergic rhinitis. Effects of cetirizine, cetirizine and pseudoephedrine (Cet+PE), or placebo on total nasal symptom scores (TNSS), peak nasal inspiratory flow (PNIF), nasal nitric oxide (nNO), acoustic rhinometry, and MRI end points following nasal intranasal allergen challenge were measured. There were significant changes in all parameters after allergen challenge (P < 0.01), except for nNO. MRI end points were less variable and more consistent than PNIF and acoustic rhinometry in detecting changes after allergen challenge. Total nasal airspace volume was the most sensitive and reproducible MRI measurement, with a mean reduction from -5.37 cm(3) (95%CI -7.35, -3.38; P < 0.001), which was maximal 60 min after allergen challenge. A change of one in TNSS corresponded to a change in MRI volume of -0.57 cm(3). There was an improvement in all parameters (except nNO) in subjects taking Cet+PE compared with placebo, however this did not achieve significance probably because of the small study size (overall analysis P > 0.07; comparison of active versus placebo P > 0.09). MRI provides novel insights into the anatomical inflammatory changes post allergen challenge and provides a new method for assessment of nasal patency and objective measurement of inflammatory responses.

Peginterferon beta-1a: a review of its use in patients with relapsing-remitting multiple sclerosis.

Peginterferon beta-1a (Plegridy™), an interferon beta-1a conjugated to a methoxy polyethylene glycol (PEG) molecule, is available in the EU and the USA for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS). In a 96-week multinational, phase III study in this patient population (ADVANCE), subcutaneous peginterferon beta-1a 125 µg every 2 weeks significantly reduced the adjusted annualized relapse rate over 48 weeks, compared with placebo, corresponding to 36% fewer relapses per patient-year. Significant reductions versus placebo were also observed in the risk of relapse and disability progression, the number of new or newly enlarging T2-weighted hyperintense lesions, and various other magnetic resonance imaging endpoints. The efficacy of peginterferon beta-1a was sustained over 96 weeks, with preliminary data from the first year of an ongoing 2-year extension of ADVANCE indicating continued benefit longer-term. In ADVANCE, peginterferon beta-1a had an acceptable tolerability profile that was consistent with that of established interferon beta treatments. Adverse events were generally mild or moderate in severity, with injection-site erythema and influenza-like illness reported most commonly. Amongst other adverse events of special interest, peginterferon beta-1a was not associated with an increased risk of autoimmune disorders, depression/suicidal ideation, infections or seizures. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of peginterferon beta-1a versus existing therapies are not yet possible. Although final data from the extension of ADVANCE are awaited, current evidence suggests subcutaneous peginterferon beta-1a every 2 weeks extends the treatment options currently available for adults with RRMS, with the dosing regimen imparting potential compliance advantages over non-PEGylated interferon beta formulations that require more frequent administration.

Effects of Delayed-Release Dimethyl Fumarate (DMF) on Health-Related Quality of Life in Patients With Relapsing-Remitting Multiple Sclerosis: An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies

PurposeDelayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years. MethodsPatients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL. FindingsThe integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were ≥5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of ≥2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a ≥5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age ≤40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores. ImplicationsThese HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT00420212; NCT00451451.

Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow-derived ALDH(br) cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH(br) cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points.

Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis

To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS). We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2) = 0.48, p = 0.001) and on active MRI lesions (R(2) = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2) = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression. In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.

In Vitro and In Vivo Models of Cerebral Ischemia Show Discrepancy in Therapeutic Effects of M2 Macrophages

The inflammatory response following ischemic stroke is dominated by innate immune cells: resident microglia and blood-derived macrophages. The ambivalent role of these cells in stroke outcome might be explained in part by the acquisition of distinct functional phenotypes: classically (M1) and alternatively activated (M2) macrophages. To shed light on the crosstalk between hypoxic neurons and macrophages, an in vitro model was set up in which bone marrow-derived macrophages were co-cultured with hippocampal slices subjected to oxygen and glucose deprivation. The results showed that macrophages provided potent protection against neuron cell loss through a paracrine mechanism, and that they expressed M2-type alternative polarization. These findings raised the possibility of using bone marrow-derived M2 macrophages in cellular therapy for stroke. Therefore, 2 million M2 macrophages (or vehicle) were intravenously administered during the subacute stage of ischemia (D4) in a model of transient middle cerebral artery occlusion. Functional neuroscores and magnetic resonance imaging endpoints (infarct volumes, blood-brain barrier integrity, phagocytic activity assessed by iron oxide uptake) were longitudinally monitored for 2 weeks. This cell-based treatment did not significantly improve any outcome measure compared with vehicle, suggesting that this strategy is not relevant to stroke therapy.

MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study

We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (p < 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (p < 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (p < 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (p < 0.001 for all analyses of patients with ≤1 or 2 relapses; p ≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS.