Pharmacy and formulation support for paediatric clinical trials in England

Availability and sourcing of investigational drugs for paediatric clinical trials is known to be a challenge for investigator-led clinical trials. The National Institute of Health Research Clinical Research Network: Children (CRN: Children) provides support for formulations and pharmacy related issues to researchers planning and setting up paediatric clinical trials within England. This paper reviews pharmacy and formulation support provided to a consecutive series of investigator-led clinical studies supported by CRN:Children. Case studies are included to describe some of the unique pharmaceutical challenges encountered. 44 trials were reviewed and a total of 103 products were required to support these clinical trials. UK authorised products were suitable for use for 62 of these 103 products. In the remaining 41 cases, 4 could be sourced as an authorised product within the European Union and the remaining 37 required bespoke manufacture. Bespoke manufacture of an investigational drug or placebo is costly. Typical costs for the initial development and testing of a bespoke investigational drug or placebo were in the range of £30,000–100,000 per product. The estimated cost for 19 out of 45 trials was available; in summary, the costs on a per patient per day of therapy basis ranged from under £1 to almost £600; short studies involving multiple agents are obviously the most expensive. This range is dependent upon the need for bespoke manufacture and also the number of participants within the trial. The arrangements for investigational drug supply can greatly affect the study design, regulatory requirements, trial logistics, as well as the total cost of research. As investigational product related activities are often costly, necessitating months of advance planning, it is imperative that specialist inputs are sought from the very start of the study design and planning process

Vitamin D prescribing in children in UK primary care practices:a population-based cohort study

OBJECTIVE: To examine temporal changes in the incidence and patterns of vitamin D supplementation prescribing by general practitioners (GPs) between 2008 and 2016. DESIGN: Population-based cohort study. SETTING: UK general practice health records from The Health Improvement Network. PARTICIPANTS: Children aged 0 to 17 years who were registered with their general practices for at least 3 months. OUTCOME MEASURES: Annual incidence rates of vitamin D prescriptions were calculated, and rate ratios were estimated using multivariable Poisson regression to explore differences by sociodemographic factors. Data on the type of supplementation, dose, dosing schedule, linked 25-hydroxyvitamin D (25(OH)D) laboratory test results and clinical symptoms suggestive of vitamin D deficiency were analysed. RESULTS: Among 2 million children, the crude annual incidence of vitamin D prescribing increased by 26-fold between 2008 and 2016 rising from 10.8 (95% CI: 8.9 to 13.1) to 276.8 (95% CI: 264.3 to 289.9) per 100 000 person-years. Older children, non-white ethnicity and general practices in England (compared with Wales/Scotland/Northern Ireland) were independently associated with higher rates of prescribing. Analyses of incident prescriptions showed inconsistent supplementation regimens with an absence of pre-supplementation 25(OH)D concentrations in 28.7% to 56.4% of prescriptions annually. There was an increasing trend in prescribing at pharmacological doses irrespective of 25(OH)D concentrations, deviating in part from UK recommendations. Prescribing at pharmacological doses for children with deficient status increased from 3.8% to 79.4%, but the rise was also observed in children for whom guidelines recommended prevention doses (0% to 53%). Vitamin D supplementation at pharmacological doses was also prescribed in at least 40% of children with no pre-supplementation 25(OH)D concentrations annually. CONCLUSIONS: There has been a marked and sustained increase in vitamin D supplementation prescribing in children in UK primary care. Our data suggests that national guidelines on vitamin D supplementation for children are not consistently followed by GPs

A mixed methods study of the administration of flucloxacillin oral liquid; identifying strategies to overcome administration issues of medicines with poor palatability.

BackgroundThe palatability of flucloxacillin oral liquid is poor. Parents/carers use strategies to aid the administration of poorly palatable medicines.AimTo assess views on the palatability of flucloxacillin oral liquid and identify factors associated with successful administration.MethodsA mixed methods study which included a structured review of online forums and a survey of parent/carers of children with cystic fibrosis (CF) to obtain parent/carer views on the administration of flucloxacillin oral liquid.ResultsA total of 18 strategies to aid the administration of flucloxacillin suspension to children were identified on 10 different public online forums. A total of 255 responses to the open online survey were received with 47% of respondents reporting that administration of flucloxacillin was more problematic compared to other medicines and 38% reporting the need to improve the palatability. The brand of flucloxacillin oral liquid significantly influenced the degree of difficulty associated with administration to children. A significant relationship was found between the concentration of flucloxacillin and the reported number of doses successfully administered. The use of food and drink to aid administration was more commonly stated in online forums (44%) compared to the survey data of parents/carers of children with CF (15.9%).ConclusionThe administration of flucloxacillin oral liquid is perceived as a challenge by parent/carers because of palatability. For chronic use, a more concentrated oral liquid and certain brands are likely to improve acceptability

Bioelectrical impedance analysis to estimate body composition, and change in adiposity, in overweight and obese adolescents: Comparison with dual-energy x-ray absorptiometry

© 2014 Wan et al.; licensee BioMed Central Ltd.Background: There is a need for a practical, inexpensive method to assess body composition in obese adolescents. This study aimed to 1) compare body composition parameters estimated by a stand-on, multi-frequency bioelectrical impendence (BIA) device, using a) the manufacturers' equations, and b) published and derived equations with body composition measured by dual-energy x-ray absorptiometry (DXA) and 2) assess percentage body fat (%BF) change after a weight loss intervention.Methods: Participants were 66 obese adolescents, mean age (SD) 12.9 (2.0) years. Body composition was measured by Tanita BIA MC-180MA (Tanita BIA8) and DXA (GE-Lunar Prodigy). BIA resistance and reactance data at frequencies of 5, 50, 250 and 500 kHz, were used in published equations, and to generate a new prediction equation for fat-free mass (FFM) using a split-sample method. Approximately half (n = 34) of the adolescents had their body composition measured by DXA and BIA on two occasions, three to nine months apart.Results: The correlations between FFM (kg), fat mass (kg) and %BF measured by BIA and DXA were 0.92, 0.93 and 0.78, respectively. The Tanita BIA8 manufacturers equations significantly (P < 0.001) overestimated FFM (4.3 kg [-5.3 to 13.9]) and underestimated %BF (-5.0% [-15 to 5.0]) compared to DXA. The mean differences between BIA derived equations and DXA measured body composition parameters were small (0.4 to 2.1%), not significant, but had large limits of agreements (~ ±15% for FFM). After the intervention mean %BF loss was similar by both methods (~1.5%), but with wide limits of agreement.Conclusion: The Tanita BIA8 could be a valuable clinical tool to measure body composition at the group level, but is inaccurate for the individual obese adolescent.Link_to_subscribed_fulltex

Comparison of real-world treatment outcomes of systemic immunomodulating therapy in atopic dermatitis patients with dark and light skin types

Background Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types. Objective To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type. Methods In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated. Results A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P .05). Limitations Unblinded, non-randomized. Conclusion Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab

eHealth literacy was associated with anxiety and depression during the COVID-19 pandemic in Nigeria: a cross-sectional study

BackgroundElectronic health (eHealth) literacy may play an important role in individuals’ engagement with online mental health-related information.AimTo examine associations between eHealth literacy and psychological outcomes among Nigerians during the Coronavirus disease-2019 (COVID-19) pandemic.MethodsThis was a cross-sectional study among Nigerians conducted using the ‘COVID-19’s impAct on feaR and hEalth (CARE) questionnaire. The exposure: eHealth literacy, was assessed using the eHealth literacy scale, and psychological outcomes were assessed using the PHQ-4 scale, which measured anxiety and depression; and the fear scale to measure fear of COVID-19. We fitted logistic regression models to assess the association of eHealth literacy with anxiety, depression, and fear, adjusting for covariates. We included interaction terms to assess for age, gender, and regional differences. We also assessed participants’ endorsement of strategies for future pandemic preparedness.ResultsThis study involved 590 participants, of which 56% were female, and 38% were 30 years or older. About 83% reported high eHealth literacy, and 55% reported anxiety or depression. High eHealth literacy was associated with a 66% lower likelihood of anxiety (adjusted odds ratio aOR, 0·34; 95% confidence interval, 0·20–0·54) and depression (aOR: 0·34; 95% CI, 0·21–0·56). There were age, gender, and regional differences in the associations between eHealth literacy and psychological outcomes. eHealth-related strategies such as medicine delivery, receiving health information through text messaging, and online courses were highlighted as important for future pandemic preparedness.ConclusionConsidering that mental health and psychological care services are severely lacking in Nigeria, digital health information sources present an opportunity to improve access and delivery of mental health services. The different associations of e-health literacy with psychological well-being between age, gender, and geographic region highlight the urgent need for targeted interventions for vulnerable populations. Policymakers must prioritize digitally backed interventions, such as medicine delivery and health information dissemination through text messaging, to address these disparities and promote equitable mental well-being

International survey for assessing COVID-19’s impact on fear and health: study protocol

Introduction COVID-19, caused by the SARS-CoV-2, has been one of the most highly contagious and rapidly spreading virus outbreak. The pandemic not only has catastrophic impacts on physical health and economy around the world, but also the psychological well-being of individuals, communities and society. The psychological and social impacts of the COVID-19 pandemic internationally have not been well described. There is a lack of international study assessing health-related impacts of the COVID-19 pandemic, especially on the degree to which individuals are fearful of the pandemic. Therefore, this study aims to (1) assess the health-related impact of the COVID-19 pandemic in community-dwelling individuals around the world; (2) determine the extent various communities are fearful of COVID-19 and (3) identify perceived needs of the population to prepare for potential future pandemics. Methods and analysis This global study involves 30 countries. For each country, we target at least 500 subjects aged 18 years or above. The questionnaires will be available online and in local languages. The questionnaires include assessment of the health impacts of COVID-19, perceived importance of future preparation for the pandemic, fear, lifestyles, sociodemographics, COVID-19-related knowledge, e-health literacy, out-of-control scale and the Patient Health Questionnaire-4. Descriptive statistics will be used to describe participants’ characteristics, perceptions on the health-related impacts of COVID-19, fear, anxiety and depression, lifestyles, COVID-19 knowledge, e-health literacy and other measures. Univariable and multivariable regression models will be used to assess the associations of covariates on the outcomes. Ethics and dissemination The study has been reviewed and approved by the local ethics committees in participating countries, where local ethics approval is needed. The results will be actively disseminated. This study aims to map an international perspective and comparison for future preparation in a pandemic

Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial

Background: Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment. Methods: We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients 99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care –1·4 days, 95% CrI –4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment. Interpretation: Moderate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care

Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol

Background: Kawasaki disease (KD) is an acute self-limiting inflammatory vasculitis affecting predominantly medium-sized arteries, particularly the coronary arteries. A number of recent studies conducted in different European countries have demonstrated alarmingly high coronary complications despite treatment with intravenous immunoglobulin (IVIG). These high complication rates now emphasize the need for an urgent reappraisal of IVIG as the sole primary therapeutic agent for KD. The Kawasaki disease CAA prevention (KD-CAAP) trial will test the hypothesis that immediate adjunctive corticosteroid treatment to standard of care IVIG and aspirin will reduce coronary artery aneurysm (CAA) rates in unselected KD patients across Europe. Methods: KD-CAAP is a multicentre, randomised, controlled, open-label, blinded endpoint assessed trial that will be conducted across Europe supported by the conect4children pan-European clinical trials network. Patients with KD who satisfy the eligibility criteria will be randomised (1:1) to receive either oral prednisolone 2 mg/kg/day plus standard of care therapy IVIG (2 g/kg) and aspirin (40 mg/kg/day); or IVIG and aspirin alone. Further management is dictated by temperature and C-reactive protein (CRP) responses. Co-primary outcomes are as follows: (i) any CAA within the 3 months of trial follow-up; (ii) average estimate of maximum coronary Z-score at weeks 1, 2 and 6 adjusting for rescue treatment. Additional outcomes will be assessed including cost effectiveness, quality of life, corticosteroid toxicity and other safety outcomes. Discussion: Several recent studies have indicated that coronary complications associated with KD across Europe are much higher than early trials of IVIG had initially suggested. KD-CAAP directly addresses this issue by exploring the therapeutic benefit of adjunctive corticosteroids in unselected KD cases. If we find that corticosteroids prevent CAA and are safe, this is a cheap and widely available intervention that could be implemented immediately for the benefit of children. Trial registration: ISRCTN71987471- March 31, 2020; Eudract 2019–004433-17