Lessons Learned From Translational Research in Neuromuscular Diseases: Impact on Study Design, Outcome Measures and Managing Expectation

Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), two of the most common, child onset, rare neuromuscular disorders, present a case study for the translation of preclinical research into clinical work. Over the past decade, well-designed clinical trials and innovative methods have led to the approval of several novel therapies for SMA and DMD, with many more in the pipeline. This review discusses several features that must be considered during trial design for neuromuscular diseases, as well as other rare diseases, to maximise the possibility of trial success using historic examples. These features include well-defined inclusion criteria, matching criteria, alternatives to placebo-controlled trials and the selection of trial endpoints. These features will be particularly important in the coming years as the investigation into innovative therapy approaches for neuromuscular diseases continues

Dystrophin isoform deficiency and upper-limb and respiratory function in Duchenne muscular dystrophy

\ua9 2025 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press. Aim: To investigate the associations between mutations expected to differentially affect Dp140 expression and long-term trajectories of respiratory and upper-limb motor outcomes in Duchenne muscular dystrophy (DMD). Method: In a retrospective analysis of population-based longitudinal data from three real-world and natural history data sources, individuals with DMD aged 5 years to 18 years were subdivided according to the predicted effects of the participants\u27 DMD mutation on dystrophin isoform expression (group 1, Dp427 absent, Dp140/Dp71 present; group 2, Dp427/Dp140 absent, Dp71 present). Results: A total of 459 participants were studied, with upper-limb outcomes assessed in 71 (27 in group 1 and 44 in group 2) and forced vital capacity percentage predicted (%pred) assessed in 434 (224 in group 1 and 210 in group 2). Mean grip strength %pred was on average 7.1 percentage points lower in group 2 than in group 1 (p = 0.03). Mean pinch strength %pred was on average 9.2 percentage points lower in group 2 than in group 1 (p = 0.04). Mean forced vital capacity %pred was on average 4.3 percentage points lower in group 2 than in group 1 (p = 0.01). Interpretation: In individuals with DMD, DMD mutations predicted to affect Dp140 expression were associated with more severe trajectories of respiratory and upper-limb motor outcomes

Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy

The North Star ambulatory assessment (NSAA) is a functional motor outcome measure in Duchenne muscular dystrophy (DMD), widely used in clinical trials and natural history studies, as well as in clinical practice. However, little has been reported on the minimal clinically important difference (MCID) of the NSAA. The lack of established MCID estimates for NSAA presents challenges in interpreting the significance of the results of this outcome measure in clinical trials, natural history studies and clinical practice. Combining statistical approaches and patient perspectives, this study estimated MCID for NSAA using distribution-based estimates of 1/3 standard deviation (SD) and standard error of measurement (SEM), an anchor-based approach, with six-minute walk distance (6MWD) as the anchor, and evaluation of patient and parent perception using participant-tailored questionnaires. The MCID for NSAA in boys with DMD aged 7 to 10 years based on 1/3 SD ranged from 2.3-2.9 points, and that on SEM ranged from 2.9-3.5 points. Anchored on the 6MWD, the MCID for NSAA was estimated as 3.5 points. When the impact on functional abilities was considered using participant response questionnaires, patients and parent perceived a complete loss of function in a single item or deterioration of function in one to two items of the assessment as an important change. Our study examines MCID estimates for total NSAA scores using multiple approaches, including the impact of patient and parent perspective on within scale changes in items based on complete loss of function and deterioration of function, and provides new insight on evaluation of differences in these widely used outcome measure in DMD

North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up

Introduction The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. Materials and methods We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. Results The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). Discussion Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. Conclusion Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations

DMD genotypes and motor function in Duchenne muscular dystrophy

Background and ObjectivesClinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-ditionally compare treated patients with untreated patients with the same DMD genotype class.This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligiblecontrols, increasing challenges for trial enrollment in this already rare disease. To evaluate thesuitability of genotypically unmatched controls in DMD, we quantified effects of genotype classon 1-year changes in motor function endpoints used in clinical trials.MethodsMore than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX,North Star UK, Cincinnati Children’s Hospital Medical Center, and the DMD Italian Group),with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable,nonsense, and other mutations. Associations between genotype class and 1-year changes inNorth Star Ambulatory Assessment total score (DNSAA) and in 10-m walk/run velocity(D10MWR) were studied in each data source with and without adjustment for baselineprognostic factors.ResultsThe studied genotype classes accounted for approximately 2% of variation in DNSAA outcomesafter 12 months, whereas other prognostic factors explained >30% of variation in large datasources. Based on a meta-analysis across all data sources, pooled effect estimates for the studiedskip-amenable mutation classes were all small in magnitude (1-year follow up), smaller than clinically important differences in NSAA, and were preciselyestimated with standard errors Functional Genomics of Muscle, Nerve and Brain Disorder

Sustainability of an HIV PEP Program for Sexual Assault Survivors: “Lessons Learned” from Health Care Providers

This study explored challenges to continuing an HIV post-exposure prophylaxis (PEP) program of care provided to sexual assault survivors in the province of Ontario, Canada. Data were collected as part of an implementation and evaluation of a universal offering of HIV PEP (known as the HIV PEP Program) at 24 of 34 provincial hospital-based sexual assault treatment centres. Experienced health care providers were surveyed (n = 132) and interviewed in four focus groups (n = 26) about their perceptions of what, if any, factors threatened their ability to maintain the HIV PEP Program. All focus groups were audio-recorded and the recordings transcribed. The transcriptions and open-ended survey responses were analyzed using content analysis. Administrator, nurse, physician, social worker, and pharmacist respondents perceived important barriers to sustainability of the HIV PEP Program. Eight constructs were identified within four broad themes: resources (inadequate funds, overworked and unacknowledged staff), expertise (insufficient external supports, insufficiently trained and knowledgeable staff), commitment (lack of institutional support, physician resistance to offering HIV PEP), and accommodation (lack of flexibility in addressing specific client and community needs, inaccessibility and lack of clarity of tools). We discuss the implications of these findings and the actions that were taken to address the challenges

Presentation of child sexual abuse cases to Queen Elizabeth Central Hospital following the establishment of an HIV post-exposure prophylaxis programme

Aim To review the presentation and management of child sexual abuse cases presenting to Queen Elizabeth Central Hospital(QECH), Blantyre, since the introduction of an HIV postexposure prophylaxis programme. Methods Demographic and medical data was collected from all children presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi between January 2005 and February 2007 with alleged child sexual abuse (CSA). Results Between January 2005 and February 2007, 217 children presented with alleged CSA. This an average of 3 more per month since the previous year, a 57 percent increase. Physical examination showed signs of trauma 60% (130/217) of cases. 63% (137/217) of the cases presented within 72 hours of defilement. Overall in 42% (92/217) of children a one month course of HIV PEP was indicated and given. In 58% (125/217) HIV PEP was not indicated in view of normal examination, presentation too late (>72 hrs after abuse), multiple abuse episodes in the last 6 months, HIV test positive or HIV test refused. In 66% (144/217) of assessed children antibiotic treatment was given for the prevention and/ or treatment of sexually transmitted infections (STIs). Conclusions The introduction of an HIV PEP programme for victims of CSA has lead to increased numbers presenting and being treated. In conclusion it is likely that a significant number of children have been prevented from acquiring HIV and other STIs following CSA. The key area where our service needs to be improved is in establishing documented follow up of all cases to monitor medication compliance, side effects and rates of HIV seroconversion following CSA

Presentation of child sexual abuse cases to Queen Elizabeth Central Hospital following the establishment of an HIV post-exposure prophylaxis programme

Aim To review the presentation and management of child sexual abuse cases presenting to Queen Elizabeth Central Hospital(QECH), Blantyre, since the introduction of an HIV postexposure prophylaxis programme. Methods Demographic and medical data was collected from all children presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi between January 2005 and February 2007 with alleged child sexual abuse (CSA). Results Between January 2005 and February 2007, 217 children presented with alleged CSA. This an average of 3 more per month since the previous year, a 57 percent increase. Physical examination showed signs of trauma 60% (130/217) of cases. 63% (137/217) of the cases presented within 72 hours of defilement. Overall in 42% (92/217) of children a one month course of HIV PEP was indicated and given. In 58% (125/217) HIV PEP was not indicated in view of normal examination, presentation too late (>72 hrs after abuse), multiple abuse episodes in the last 6 months, HIV test positive or HIV test refused. In 66% (144/217) of assessed children antibiotic treatment was given for the prevention and/ or treatment of sexually transmitted infections (STIs). Conclusions The introduction of an HIV PEP programme for victims of CSA has lead to increased numbers presenting and being treated. In conclusion it is likely that a significant number of children have been prevented from acquiring HIV and other STIs following CSA. The key area where our service needs to be improved is in establishing documented follow up of all cases to monitor medication compliance, side effects and rates of HIV seroconversion following CSA