Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

B-cell-survival factors in multiple sclerosis and myasthenia gravis

Multiple sclerosis (MS) is a chronic, progressive neurological disease in which death of myelin-producing oligodendrocytes and axonal damage are prominent pathological features. The cause of MS is unknown but genetic and environmental factors have been proposed to be important. There is a paradigm shift in our understanding that demyelination may be the primary insult with secondary influx of inflammatory cells into the central nervous system (CNS) in MS. The function of B cells can be categorized into one of the four: antibody-production, antigen-presentation, cytokine production, and regulation of other immune cells. Except for antibody-production, none of the other functions are exclusive to B cells. Therefore, whether B cells are of any relevance in the pathogenesis of MS has been questioned. By contrast, the pathogenic potential of anti-acetylcholine receptors (AChR) antibodies is well understood in myasthenia gravis (MG). Binding of anti-AChR antibodies to AChR receptors present at the neuromuscular end-plate result in muscle weakness. The aim of this thesis was to understand whether B cells contribute to tissue healing or tissue injury, or do both in MS. Two molecules indispensable for B-cell survival - a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) - were studied. BAFF also rescues self-reactive B cells from apoptosis. APRIL and BAFF are secreted by monocytes and macrophages; they share two receptors, B-cell maturation antigen (BCMA) and transmembrane activator and calcium modulating and cyclophilin ligand interactor (TACI) whereas BAFF exclusively binds BAFF-receptor (BAFF-R). All three receptors are expressed by B cells. APRIL and BAFF mRNA were quantified in monocytes and T cells of MS patients and healthy controls (HC) using real-time PCR. BAFF-R, TACI, and BCMA mRNA in B cells were also quantified. The mRNA levels of all the molecules studied were increased in patients compared to levels in HC. In a second dataset of MS patients and age- and gender-matched headache controls (HEC), APRIL and BAFF protein, measured in plasma and cerebrospinal fluid (CSF) by ELISA, were comparable between patients and HEC. The surface expression of BAFF-R, TACI, and BCMA on B cells of HC, MS, and MG patients was studied using flow cytometry. The intensity of expression of these molecules was comparable between the three groups. Although mRNA levels of B-cellsurvival factors and the receptors that bind them are increased in patients than levels in controls, whether B cells do survive longer is unknown. Sensitization of AChR expressed by myoid cells in the thymus may underlie MG pathogenesis. The novel finding of APRIL and BAFF expression in the thymus - a T-cell organ - may explain that autoreactive B cells may use the thymus as a survival niche. Antibodies in the CSF can be used as a biomarker to predict disease outcome. Analysis of CSF and plasma of MS patients and controls revealed that lipid-reactive immunoglobulin (Ig) M in CSF was detectable in one-third of MS patients. Lipid-specific IgM predicted an adverse outcome, as defined by conversion to secondary progressive disease phase. B cells as agents of tissue injury or tissue healing is still not resolved. But antibodies are useful as biomarkers to predict disease outcome. In the course of this thesis work, it became evident that APRIL and BAFF are also expressed by astrocytes and is increased in MS plaques. The expression of B-cell-survival factors by CNS resident cells and their functional relevance in disease promises to be an exciting area of research

Duchenne_BMD_LVEF.xls

Data used for a retrospective cohort study of boys with Duchenne Muscular Dystrophy. Looked to see if low bone mineral density predicted the development of cardiovascular dysfunction as measured by LVEF. <br><br>The Relationship between Bone Mineral Density and Cardiovascular Function in Duchenne Muscular Dystrophy: A Retrospective Cohort Stud

Longitudinal Evaluation of Working Memory in Duchenne Muscular Dystrophy

Objective: The developmental maturation of forward and backward digit spans&mdash;indices of working memory&mdash;in boys with nonsense (nm) Duchenne muscular dystrophy (DMD) (nmDMD) was assessed using prospective, longitudinal data. Methods: Fifty-five boys of the 57 subjects with genetically confirmed nmDMD&mdash;who were from the placebo arm of a 48-week-long phase 2b clinical trial&mdash;were evaluated. Forward and backward digit spans were obtained every 12 weeks for a total of five assessments in all study subjects. Changes in forward and backward digit spans were evaluated based on age, corticosteroid treatment, and DMD mutation location. Results: Boys with nmDMD had lower mean scores on normalized forward digit span. Normalized forward digit spans were comparable between subjects stratified by age and between corticosteroid-na&iuml;ve and corticosteroid-treated subjects. When stratified by DMD mutation location, normalized forward digit spans were lower in nmDMD subjects with mutations downstream of DMD exon 30, exon 45, and exon 63, both at baseline evaluation and at follow-up evaluation at 48 weeks. On average, normalized backward digit span scores were stable over 48 weeks in these subjects. Developmental growth modeling showed that subjects with nmDMD mutations upstream of DMD exon 30, upstream of DMD exon 45, and upstream of DMD exon 63 appeared to make better gains in working memory than subjects with mutations downstream of DMD exon 30, downstream of DMD exon 45, and downstream of DMD exon 63. Conclusion: Performance in working memory shows deficits in nmDMD and differed based on nmDMD location. Maturation in cognition was seen over a 48-week period. The developmental trajectory of working memory in this cohort was influenced by DMD mutation location

A checklist for clinical trials in rare disease: Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate. © 2018 The Author(s)