Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials.

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1-18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively.

Effects of weight loss through dietary intervention on pain characteristics, functional mobility, and inflammation in adults with elevated adiposity.

Background: The relationship between adiposity and pain is complex. Excess weight increases the risk for chronic musculoskeletal pain (CMP), driven by increased biomechanical load and low-grade systemic inflammation. Pain limits physical function, impacting energy balance contributing to weight gain. The primary aims of this study were to profile pain characteristics in participants with overweight or obesity and determine if weight loss through dietary-induced energy restriction, and presence of CMP, or magnitude of weight loss, was associated with changes in adiposity, pain, functional mobility, and inflammation. Methods: This was a secondary analysis of data from adults (25-65 years) with overweight or obesity (BMI 27.5-34.9 kg/m2) enrolled in a 3-month, 30% energy-restricted dietary intervention to induce weight loss (January 2019-March 2021). Anthropometric measures (weight, waist circumference and fat mass), pain prevalence, pain severity (McGill Pain Questionnaire, MPQ), pain intensity (Visual Analog Scale, VAS), functional mobility (timed up and go, TUG) and inflammation (high sensitivity C-Reactive Protein, hsCRP) were assessed at baseline and 3-months. Results: One hundred and ten participants completed the intervention and had weight and pain assessed at both baseline and 3-months. Participants lost 7.0 ± 0.3 kg, representing 7.9% ± 3.7% of body mass. At 3-months, functional mobility improved (TUG -0.2 ± 0.1 s, 95% CI -0.3, -0.1), but there was no change in hsCRP. Compared to baseline, fewer participants reported CMP at 3-months (n = 56, 51% to n = 27, 25%, p < 0.001) and presence of multisite pain decreased from 22.7% to 10.9% (p < 0.001). Improvements in anthropometric measures and functional mobility did not differ between those presenting with or without CMP at baseline. Improvements in pain were not related to the magnitude of weight loss. Conclusion: Weight loss was effective in reducing pain prevalence and improving functional mobility, emphasizing the importance of considering weight-loss as a key component of pain management. Clinical trial registration: identifier, ACTRN12618001861246.

Characterising concurrent pain experience and dietary patterns in people with chronic musculoskeletal pain: a feasibility study protocol.

INTRODUCTION: Nutrition-related factors linked to pain chronicity and disability include weight status and dietary behaviours. Dietary patterns associated with concurrent pain episodes, however, remain poorly characterised. This paper outlines the protocol for a feasibility study that aims to characterise pain-related dietary and lifestyle behaviours in people experiencing chronic musculoskeletal pain. METHODS: The study will recruit participants who experience musculoskeletal pain on 5 or more days of the week for at least 3 months. Participants will attend two in-person clinic visits where physical measurements and a series of pain and lifestyle questionnaires will be completed. Visits will be conducted pre and post a 2-week self-monitoring period where participants will self-report concurrent diet, sleep, mood, and pain on four days and will wear a wrist-worn activity monitor (GENEActiv). Key feasibility metrics will evaluate participant recruitment, enrolment and retention rates, and compliance with the study data collection protocol. DISCUSSION: There remains a lack of evidence behind dietary advice as an adjunct pain management tool. Upon completion of the protocol, feasibility outcomes will identify challenges to guide the design and delivery of a dietary intervention for chronic musculoskeletal pain.

269th ENMC international workshop: 10 years of clinical trials in Duchenne muscular dystrophy - What have we learned? 9-11 December 2022, Hoofddorp, The Netherlands.

There are multiple avenues for therapeutic development in Duchenne muscular dystrophy (DMD), which are highlighted in the first section of this report for the "10 years of Clinical trials in DMD - What have we learned?" workshop. This report then provides an overview of the presentations made at the workshop grouped into the following core themes: trial outcomes, disease heterogeneity, meaningfulness of outcomes and the utility of real-world data in trials. Finally, we present the consensus that was achieved at the workshop on the learning points from 10 years of clinical trials in DMD, and possible action points from these. This includes further work in expanding the scope and range of trial outcomes and assessing the efficacy of new trial structures for DMD. We also highlight several points which should be addressed during future interactions with regulators, such as clinical meaningfulness and the use of real-world data.

Fertilization using manure minimizes the trade-offs between biodiversity and forage production in agri-environment scheme grasslands.

A common practice used to restore and maintain biodiversity in grasslands is to stop or decrease the use of fertilizers as they are a major cause of biodiversity loss. This practice is problematic for farmers who need fertilizers to increase forage and meet the nutritional needs of livestock. Evidence is needed that helps identify optimal fertilizer regimes that could benefit biodiversity and livestock production simultaneously over the long-term. Here, we evaluated the impact of different fertilizer regimes on indicators related to both biodiversity (plant, pollinator, leaf miners and parasitoid Shannon-Weiner diversity, bumblebee abundance, nectar productivity and forb species richness), and forage production (ash, crude protein, ruminant metabolizable energy and dry matter). To this end, we used data from a grassland restoration experiment managed under four nutrient inputs schemes for 27 years: farmyard manure (FYM; 72 kg N ha-1 yr-1), artificial nitrogen-phosphorus and potassium (NPK; 25 kg N ha-1 yr-1), FYM + NPK (97 kg N ha-1 yr-1) and no-fertilizer. Results showed strong trade-offs between biodiversity and forage production under all treatments even in applications lower than the critical load in the EU. Overall, farmyard manure was the fertilizer that optimized production and biodiversity while 97 kg N ha-1 yr-1 of fertilizer addition (FYM+NPK) had the most negative impact on biodiversity. Finally, forage from places where no fertilizer has been added for 27 years did not meet the nutritional requirements of cattle, but it did for sheep. Rethinking typical approaches of nutrient addition could lead to land management solutions suitable for biological conservation and agriculture.

Extraction-Free Detection of SARS-CoV-2 Viral RNA Using LumiraDx's RNA Star Complete Assay from Clinical Nasal Swabs Stored in a Novel Collection and Transport Medium.

Background: The rapid detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is vital for patient care. The LumiraDx™ SARS-CoV-2 RNA Star Complete (RSC) is an Emergency Use Authorization-recognized molecular test using nasal/nasopharyngeal swabs immersed in a viral/universal transport medium (VTM/UTM). However, there is a critical need for an alternative medium for point-of-care testing (POCT). This study aimed to investigate Xtract-Free (XF), a novel collection medium for transport and direct (extraction-free) use with nucleic acid tests. Methods: Using serially diluted SARS-CoV-2 viral RNA (vRNA) in a routine UTM and XF, a limit of detection (LOD) was established via an RSC test and a quantitative reverse transcription PCR (RT-qPCR). Additionally, the results obtained from a panel of 108 clinical "car-side" nasal swabs collected in XF during the coronavirus pandemic and assessed using the "gold-standard" RT-qPCR assay were compared to Lumira's RSC assay. Results: The average replicate RT-qPCR cycle threshold (CT) values for vRNA in XF and UTM were observed to be equivalent. An LOD for which five out of five replicates were detected using XF or VTM was approximately 2000 copies/mL. The nasal swabs collected in XF exhibited 93.9% positive percent agreement (sensitivity) and 100% negative percent agreement (specificity) compared to the RT-qPCR. Three specimens tested positive via an RT-qPCR were negative when tested via RSC; however, all three samples had CT values ≥ 36.4. Conclusions: XF is equivalent to VTM/UTM and is compatible for use with the RSC test. Furthermore, XF can be used directly with RT-qPCRs and rapid antigen testing without the requirement for separate nucleic acid extraction (an extraction-free process), making it ideal for cost-effective high-throughput and decentralized respiratory testing. Impact Statement: This study is the first to evaluate LumiraDx's SARS-CoV-2 RNA Star Complete assay in concert with Xtract-Free (XF), a novel collection medium containing a proprietary RNase-inactivating technology for the rapid, "extraction-free" detection of SARS-CoV-2 RNA from clinical nasal swabs. Specimens collected in XF combined with rapid LumiraDx detection provide a safe and sensitive alternative to VTM/UTM, and Molecular Transport medium (MTM) for high throughput, "extraction-free" molecular detection.

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials.

BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally 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 eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: More 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 in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. DISCUSSION: These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study.

A formal evaluation of The Ottawa Hospital Pain Clinic orientation session: A quality improvement project.

Background: Chronic pain affects approximately one in every five Canadians and has a substantial impact on psychological well-being, relationships, ability to attend work or school, and overall functioning.The Ottawa Hospital Pain Clinic introduced orientation sessions, with the aim of providing new patients with pain education to help prepare patients for engagement with multimodal pain management strategies. This report summarizes the results of a formative evaluation of the orientation session at The Ottawa Hospital Pain Clinic to determine whether patients perceived the orientation session as beneficial. Methods: Interviews were conducted, transcribed, and then thematically analyzed to understand patients' perspectives on the orientation session. Coding was done by two team members using the constant comparison analyses method with key ideas, concepts, and patterns identified and compared to identify similarities. Results: Between September 6 and October 18, 2019, 18 patients attended an orientation session and 12 consented to participation and completed telephone interviews. The six themes identified included (1) feeling of community, (2) participants feeling heard by providers, (3) appreciation of the holistic approach, (4) availability of community resources, (5) barriers to access, and (6) discordant feelings of preparedness for the physician appointment. Conclusion: Results from this evaluation indicate that the orientation session offered at The Ottawa Hospital Pain Clinic improves chronic pain literacy, reduces feeling of isolation, and instills hope. As such, it appears to be a valuable component of pain clinic programs.

Contexte: La douleur chronique touche environ un Canadien sur cinq et a des répercussions sur le bien-être psychologique, les relations, la capacité à aller au travail ou à l'école, et l'ensemble du fonctionnement. La Clinique de la douleur de l'Hôpital d'Ottawa a lancé des séances d'orientation, dans le but de fournir aux nouveaux patients une formation sur la douleur pour les aider à se préparer à adopter des stratégies multimodales de prise en charge de la douleur. Ce rapport résume les résultats d'une évaluation formative de la séance d'orientation à la Clinique de la douleur de l'Hôpital d'Ottawa visant à déterminer si les patients perçoivent la session d'orientation comme bénéfique.Méthodes: Les entrevues ont été menées, transcrites, puis analysées de maniére thématique pour comprendre les points de vue des patients sur la séance d'orientation. Le codage a été effectué par deux membres de l'équipe à l'aide d'une méthode d'analyse par comparaison constante avec des idées, des concepts et des modéles clés répertoriés et par rapport à l'identification de similitudes.Résultats: Entre le 6 septembre et le 18 octobre 2019, 18 patients ont assisté à une séance d'orientation. Parmi ceux-ci, 12 ont accepté de participer et ont complété des entrevues téléphoniques. Les six thémes répertoriés comprenaient (1) le sentiment de communauté, (2) le sentiment des participants d'étre entendus des prestataires, (3) l'appréciation de l'approche holistique, (4) la disponibilité des ressources communautaires, (5) les obstacles à l'accés, et (6) des sentiments discordants de préparation pour le rendez-vous chez le médecin.Conclusion: Les résultats de cette évaluation indiquent que la séance d'orientation offerte à la Clinique de la douleur de l'Hôpital d'Ottawa améliore la littératie en matiére de douleur chronique, réduit le sentiment d'isolement et suscite l'espoir. Ainsi, elle semble étre un élément précieux des programmes de la Clinique de la douleur.

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls.

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.

Differences in treatment and survival of older patients with operable breast cancer between the United Kingdom and the Netherlands - A comparison of two national prospective longitudinal multi-centre cohort studies.

BACKGROUND: Previous studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has been hypothesised that these differences in survival outcomes could be related to treatment variation. OBJECTIVES: We aimed to compare patient and tumour characteristics, treatment selection and survival outcomes between two large prospective cohorts of older patients with operable breast cancer from the United Kingdom (UK) and The Netherlands. METHODS: Women diagnosed with operable breast cancer aged ≥70 years were included. A baseline comprehensive geriatric assessment was performed in both cohorts, with data collected on age, comorbidities, cognition, nutritional and functional status. Baseline tumour characteristics and treatment type were collected. Univariable and multivariable Cox regression models were used to compare overall survival between the cohorts. RESULTS: 3262 patients from the UK Age Gap cohort and 618 patients from the Dutch Climb cohort were included, with median ages of 77.0 (IQR: 72.0-81.0) and 75.0 (IQR: 72.0-81.0) years, respectively. The cohorts were generally comparable, with slight differences in rates of comorbidity and frailty. Median follow-up for overall survival was 4.1 years (IQR 2.9-5.4) in Age Gap and 4.3 years (IQR 2.9-5.5) in Climb. In Age Gap, both the rates of primary endocrine therapy and adjuvant hormonal therapy after surgery were approximately twice those in Climb (16.6% versus 7.3%, p < 0.001 for primary endocrine therapy, and 62.2% versus 38.8%, p < 0.001 for adjuvant hormonal therapy). There was no evidence of a difference in overall survival between the cohorts (adjusted HR 0.94, 95% CI 0.74-1.17, p = 0.568). CONCLUSIONS: In contrast to previous studies, this comparison of two large national prospective longitudinal multi-centre cohort studies demonstrated comparable survival outcomes between older patients with breast cancer treated in the UK and The Netherlands, despite differences in treatment allocation.

Minimal changes in telomere length after a 12-week dietary intervention with almonds in mid-age to older, overweight and obese Australians: results of a randomised clinical trial.

Diet is a modifiable risk factor for chronic disease and a potential modulator of telomere length (TL). The study aim was to investigate associations between diet quality and TL in Australian adults after a 12-week dietary intervention with an almond-enriched diet (AED). Participants (overweight/obese, 50-80 years) were randomised to an AED (n 62) or isoenergetic nut-free diet (NFD, n 62) for 12 weeks. Diet quality was assessed using a Dietary Guideline Index (DGI), applied to weighed food records, that consists of ten components reflecting adequacy, variety and quality of core food components and discretionary choices within the diet. TL was measured by quantitative PCR in samples of lymphocytes, neutrophils, and whole blood. There were no significant associations between DGI scores and TL at baseline. Diet quality improved with AED and decreased with NFD after 12 weeks (change from baseline AED + 9·8 %, NFD - 14·3 %; P < 0·001). TL increased in neutrophils (+9·6 bp, P = 0·009) and decreased in whole blood, to a trivial extent (-12·1 bp, P = 0·001), and was unchanged in lymphocytes. Changes did not differ between intervention groups. There were no significant relationships between changes in diet quality scores and changes in lymphocyte, neutrophil or whole blood TL. The inclusion of almonds in the diet improved diet quality scores but had no impact on TL mid-age to older Australian adults. Future studies should investigate the impact of more substantial dietary changes over longer periods of time.

Ventilation/carbon dioxide output relationships during exercise in health.

"Ventilatory efficiency" is widely used in cardiopulmonary exercise testing to make inferences regarding the normality (or otherwise) of the arterial CO2 tension (P aCO2 ) and physiological dead-space fraction of the breath (V D/V T) responses to rapid-incremental (or ramp) exercise. It is quantified as: 1) the slope of the linear region of the relationship between ventilation (V'E) and pulmonary CO2 output (V'CO2 ); and/or 2) the ventilatory equivalent for CO2 at the lactate threshold (V'E/V'CO2 [Formula: see text]) or its minimum value (V'E/V'CO2 min), which occurs soon after [Formula: see text] but before respiratory compensation. Although these indices are normally numerically similar, they are not equally robust. That is, high values for V'E/V'CO2 [Formula: see text] and V'E/V'CO2 min provide a rigorous index of an elevated V D/V T when P aCO2 is known (or can be assumed) to be regulated. In contrast, a high V'E-V'CO2 slope on its own does not, as account has also to be taken of the associated normally positive and small V'E intercept. Interpretation is complicated by factors such as: the extent to which P aCO2 is actually regulated during rapid-incremental exercise (as is the case for steady-state moderate exercise); and whether V'E/V'CO2 [Formula: see text] or V'E/V'CO2 min provide accurate reflections of the true asymptotic value of V'E/V'CO2 , to which the V'E-V'CO2 slope approximates at very high work rates.

Differential effects of fertilisers on pollination and parasitoid interaction networks.

Grassland fertilisation drives non-random plant loss resulting in areas dominated by perennial grass species. How these changes cascade through linked trophic levels, however, is not well understood. We studied how grassland fertilisation propagates change through the plant assemblage into the plant-flower-visitor, plant-leaf miner and leaf miner-parasitoid networks using a year's data collection from a long-term grassland fertiliser application experiment. Our experiment had three fertiliser treatments each applied to replicate plots 15 m2 in size: mineral fertiliser, farmyard manure, and mineral fertiliser and farmyard manure combined, along with a control of no fertiliser. The combined treatment had the most significant impact, and both plant species richness and floral abundance decreased with the addition of fertiliser. While insect species richness was unaffected by fertiliser treatment, fertilised plots had a significantly higher abundance of leaf miners and parasitoids and a significantly lower abundance of bumblebees. The plant-flower-visitor and plant-herbivore networks showed higher values of vulnerability and lower modularity with fertiliser addition, while leaf miner-parasitoid networks showed a rise in generality. The different groups of insects were impacted by fertilisers to varying degrees: while the effect on abundance was the highest for leaf miners, the vulnerability and modularity of flower-visitor networks was the most affected. The impact on the abundance of leaf miners was positive and three times higher than the impact on parasitoids, and the impact on bumblebee abundance was negative and double the magnitude of impact on flower abundance. Overall, our results show that while insect species richness was unaffected by fertilisers, network structure changed significantly as the replacement of forbs by grasses resulted in changes in relative abundance across trophic levels, with the direction of change depending on the type of network. Synthesis. By studying multiple networks simultaneously, we were able to rank the relative impact of habitat change on the different groups of species within the community. This provided a more holistic picture of the impact of agricultural intensification and provides useful information when deciding on priorities for mitigation.

Study protocol for a 9-month randomised controlled trial assessing the effects of almonds versus carbohydrate-rich snack foods on weight loss and weight maintenance.

INTRODUCTION: Epidemiological studies indicate an inverse association between nut consumption and body mass index (BMI). However, clinical trials evaluating the effects of nut consumption compared with a nut-free diet on adiposity have reported mixed findings with some studies reporting greater weight loss and others reporting no weight change. This paper describes the rationale and detailed protocol for a randomised controlled trial assessing whether the inclusion of almonds or carbohydrate-rich snacks in an otherwise nut-free energy-restricted diet will promote weight loss during 3 months of energy restriction and limit weight regain during 6 months of weight maintenance. METHODS AND ANALYSIS: One hundred and thirty-four adults aged 25-65 years with a BMI of 27.5-34.9 kg/m2 will be recruited and randomly allocated to either the almond-enriched diet (AED) (15% energy from almonds) or a nut-free control diet (NFD) (15% energy from carbohydrate-rich snack foods). Study snack foods will be provided. Weight loss will be achieved through a 30% energy restriction over 3 months, and weight maintenance will be encouraged for 6 months by increasing overall energy intake by ~120-180 kcal/day (~500-750kJ/day) as required. Food will be self-selected, based on recommendations from the study dietitian. Body composition, resting energy expenditure, total daily energy expenditure (via doubly labelled water), physical activity, appetite regulation, cardiometabolic health, gut microbiome, liver health, inflammatory factors, eating behaviours, mood and personality, functional mobility and pain, quality of life and sleep patterns will be measured throughout the 9-month trial. The effects of intervention on the outcome measures over time will be analysed using random effects mixed models, with treatment (AED or NFD) and time (baseline, 3 months and 9 months) being the between and within factors, respectively in the analysis. ETHICS AND DISSEMINATION: Ethics approval was obtained from the University of South Australia Human Research Ethics Committee (201436). Results from this trial will be disseminated through publication in peer-reviewed journals, national and international presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618001861246).

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.

Prognostic factors for changes in the timed 4-stair climb in patients with Duchenne muscular dystrophy, and implications for measuring drug efficacy: A multi-institutional collaboration.

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.

Implementation of the Ottawa Hospital Pain Clinic stepped care program: A preliminary report.

BACKGROUND: Access to multidisciplinary pain management treatment in Canada is limited, with wait times up to 4 years. Stepped care approaches to mental health treatment have led to substantial reduction and elimination of wait times and may be applicable to chronic pain settings. There is no unifying framework for stepped care chronic pain programs. A systematic review of the efficacy of stepped care in chronic pain management conducted by the Canadian Agency for Drugs and Technologies reported varied results that may be due to heterogeneous stepped care models across facilities. AIM: We propose a unifying framework for multidisciplinary stepped care chronic pain programs and present its application at The Ottawa Hospital Pain Clinic. The Ottawa Hospital stepped care framework is an eight-tiered approach that allows patients the opportunity to decide collaboratively with a health care professional which treatment program will best suit their needs for the management of chronic pain. As levels of stepped care increase, the time and resource commitment to each step will also increase. Treatment is stepped up or down, depending on patient needs. METHOD: This is a descriptive case study. RESULTS: Implementing the interprofessional model of care with the stepped care program has eliminated wait times for access to The Ottawa Hospital Pain Clinic Interprofessional Chronic Pain Management Program and has improved communication between professions of the interprofessional team, resulting in better care for patients. CONCLUSION: More research is needed to further develop and evaluate the clinical efficacy of stepped care to manage chronic pain.

Contexte: L'accès à la prise en charge multidisciplinaire de la douleur au Canada est limité, avec des délais d'attente pouvant aller jusqu'à quatre ans. Les approches de soins de santé mentale par paliers ont donné lieu à une réduction et une élimination des temps d'attente et peut être applicable aux contextes de soins pour la douleur chronique. Il n'existe pas de cadre unificateur pour les programmes de soins par paliers pour la douleur chronique. Un examen systématique de l'efficacit' des soins par paliers dans la prise en charge de la douleur chronique menée par l'Agence canadienne des médicaments et des technologies de la santé a fait état de résultats variés qui peuvent être attribuables à l'hétérogénéité des modèles de soins par paliers dans les vtablissements.Objectifs: Nous proposons un cadre unificateur pour les programmes de soins multidisciplinaires par paliers pour la douleur chronique et présentons son application à la Clinique de la douleur de l'Hôpital d'Ottawa. Le cadre de soins par paliers de l'Hôpital d'Ottawa est une approche à huit niveaux qui donne aux patients la possibilité de décider, en collaboration avec un professionnel de la santé, du programme de traitement qui répondra le mieux à leurs besoins pour la prise en charge de leur douleur chronique. À mesure que les niveaux de soins par paliers augmentent, le temps et les ressources nécessaires à chaque palier augmentent également. Le traitement est intensifié ou réduit, en fonction des besoins du patient.Méthodes: Il s'agit d'une étude de cas descriptive.Résultats: La mise en œuvre du modèle interprofessionnel de soins avec le programme de soins par paliers a éliminé les délais d'attente pour l'accès au programme de prise en charge interprofessionnelle de la douleur chronique de la clinique de la douleur de l'Hôpital d'Ottawa et a amélioré la communication entre les professions de l'équipe interprofessionnelle, ce qui a donné lieu à une meilleure prise en charge des patients.Conclusions: Des recherches supplémentaires sont nécessaires pour développer et évaluer davantage l'efficacité clinique des soins par paliers pour la prise en charge de la douleur chronique.

Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy.

Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement-or static behavior-by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.

Application of an Australian Dietary Guideline Index to Weighed Food Records.

The Dietary Guideline Index (DGI) is a validated diet quality index that reflects adherence to the Australian Dietary Guidelines. The aim of the current study was to establish a novel methodology that applied the DGI to dietary data collected via gold standard, weighed food records (WFR). Consisting of 10 components with a maximal score of 120, the DGI reflected the food-based recommendations of the current Australian Dietary Guidelines and included indicators to score adequacy and quality of core food components and discretionary choices within the diet. The DGI was applied to WFR collected from a sample of 141 adults (84 women, 57 men). Differences between gender for each indicator, as well as subscores for core and noncore components of the DGI were examined. Construct validity was assessed by evaluating the relationship between total DGI score and intake of key nutrients of interest. Overall, the median DGI score was low, 50.87 (range 20.6-104.1). Higher DGI scores were associated with lower intakes of saturated fat, added sugars and sodium (P < 0.05). This methodological approach of applying the DGI to WFR may improve our ability to quantify diet quality, thereby providing a tool to assess changes in dietary intake over time and allow the quantification of diet quality as a variable in relation to health outcomes.