Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy.

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.

Mental health and well-being trends among children and young people in the UK, 1995-2014: analysis of repeated cross-sectional national health surveys.

BACKGROUND: There is a growing concern about the mental health of children and young people (CYP) in the UK, with increasing demand for counselling services, admissions for self-harm and referrals to mental health services. We investigated whether there have been similar recent trends in selected mental health outcomes among CYP in national health surveys from England, Scotland and Wales. METHODS: Data were analysed from 140 830 participants (4-24 years, stratified into 4-12, 13-15, 16-24 years) in 36 national surveys in England, Scotland and Wales, 1995-2014. Regression models were used to examine time trends in seven parent/self-reported variables: general health, any long-standing health condition, long-standing mental health condition; Warwick-Edinburgh Mental Wellbeing Score (WEMWBS), above-threshold Strengths and Difficulties Questionnaire Total (SDQT) score, SDQ Emotion (SDQE) score, General Health Questionnaire (GHQ) score. RESULTS: Across all participants aged 4-24, long-standing mental health conditions increased in England (0.8-4.8% over 19 years), Scotland (2.3-6.0%, 11 years) and Wales (2.6-4.1%, 7 years) (all p < 0.001). Among young children (4-12 years), the proportion reporting high SDQT and SDQE scores decreased significantly among both boys and girls in England [SDQE: odds ratio (OR) 0.97 (0.96-0.98), p < 0.001] and girls in Scotland [SDQE: OR 0.96 (0.93-0.99), p = 0.005]. The proportion with high SDQE scores (13-15 years) decreased in England [OR 0.98 (0.96-0.99), p = 0.006] but increased in Wales [OR 1.07 (1.03-1.10), p < 0.001]. The proportion with high GHQ scores decreased among English women (16-24 years) [OR 0.98 (0.98-0.99), p = 0.002]. CONCLUSIONS: Despite a striking increase in the reported prevalence of long-standing mental health conditions among UK CYP, there was relatively little change in questionnaire scores reflecting psychological distress and emotional well-being.

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.

Children and young people's versus parents' responses in an English national inpatient survey.

OBJECTIVE: Despite growing interest in children and young people's (CYP) perspectives on healthcare, they continue to be excluded from many patient experience surveys. This study investigated the feasibility of, and additional information gained by, measuring CYP experiences of a recent hospital admission. DESIGN: Cross-sectional analysis of national survey data. SETTING: Inpatients aged 8-15 years in eligible National Health Service hospitals, July-September 2014. PARTICIPANTS: 6204 parents/carers completed the parent section of the survey. The CYP section of the survey was completed by CYP themselves (n=3592), parents (n=849) or jointly (n=1763). MAIN OUTCOME MEASURES: Pain relief, involvement, quality of staff communication, perceived safety, ward environment, overall experience. ANALYSES: Single-measures intraclass correlations (ICCs) were used to assess the concordance between CYP and parent responses about the same inpatient episode. Multilevel logistic regression models, adjusted for individual characteristics, were used to compare the odds of positive responses when the CYP section of the survey was completed by parents, by CYP themselves or jointly. RESULTS: The CYP section of the survey was completed independently by 57.8% of CYP. Agreement between CYP and parent responses was reasonably good for pain relief (ICC=0.61 (95% CI 0.58 to 0.63)) and overall experience (ICC=0.70 (95% CI 0.68 to 0.72)), but much lower for questions comparing professionals' communication with CYP and with their parents (ICC range=0.28 (95% CI 0.24 to 0.32) to 0.51 (95% CI 0.47 to 0.54)). In the regression models, CYP were significantly less likely than parents to report feeling safe (adjusted OR (AOR)=0.54 (95% CI 0.38 to 0.76)), involvement in decisions (AOR=0.66 (95% CI 0.46 to 0.94)) or adequate privacy (AOR=0.68 (95% CI 0.52 to 0.89)). CONCLUSIONS: Including CYP (8-15 years) in patient experience surveys is feasible and enhances what is known from parents' responses.

Improving the use of phlebotomy services in a paediatric inpatient setting.

The aim of this project was to improve the use of the current Paediatric Phlebotomy service. The main problem identified was the lack of a system to notify medical teams of unsuccessful blood requests. A phlebotomy process map was constructed to help analyse reasons why failure to notify occurred. Pre and post intervention audits were conducted using the number of unsuccessful blood requests notified as a baseline measurement. The initial intervention was modified based on feedback during the process. A 44% improvement in the number of unsuccessful blood requests notified and a potential cost savings of £6240 was demonstrated in the post-intervention audit. Further work is required as to whether these improvements can be increased, sustained and be cost effective.