Can children swallow tablets? Outcome data from a feasibility study to assess the acceptability of different-sized placebo tablets in children (creating acceptable tablets (CAT)).

OBJECTIVE: Feasibility study to investigate the acceptability of different-sized placebo tablets in children aged 4-12 years. DESIGN AND SETTING: Clinical Research Facilities, inpatient wards and outpatient clinics within a Regional Paediatric Hospital and/or District General Hospital. Healthy children and National Health Service (NHS) patients were asked to swallow three placebo tablets: 6 mm, 8 mm and 10 mm, smallest to largest. The researcher observed children's facial expressions and behaviours on swallowing and measured the volume of water consumed. Participants completed a questionnaire about the overall acceptability; including swallowability, taste and volume of water consumed. For analysis, participants were stratified by age: 4-8 years and 9-12 years. RESULTS: The feasibility study led to an estimated recruitment rate of 0.8% for NHS inpatients and 211 healthy children over a 1-year period. In total, 55 participants were recruited, 30 to the younger group, of which 77% had never taken a tablet before. 84% of the 25 older children had previously taken a tablet. All participants attempted to swallow the smallest sized tablet. The children aged 4-8 years found the larger tablets easier to swallow, however the older children found little difference between the tablet sizes. The younger children required more water to swallow each tablet size compared with the older children where an increasing volume of water was consumed as tablet size increased. Taste was rated highly for both age groups. The 8 mm tablets were deemed the most acceptable tablet size by all participants. CONCLUSION: Tablets are potentially an acceptable formulation for children aged 4-12 years. Most children aged 4-8 years who attempted to swallow tablets successfully did so. Recruitment of NHS inpatients to medicine acceptability studies is challenging, however, recruitment of children of staff proved an effective strategy. Valuable lessons have been learnt from this feasibility study which will inform the design of a larger definitive trial.

Evaluation of patient-reported outcome measurements as a reliable tool to measure acceptability of the taste of paediatric medicines in an inpatient paediatric population.

OBJECTIVE: To evaluate the age appropriateness and suitability of patient-reported outcome measures to assess the acceptability of the taste of oral liquid medicines in children. DESIGN AND SETTING: An observational mixed-methods study involving children aged 2-16 years taking oral liquid medicine in paediatric inpatient wards across the West Midlands (UK). Assessment tools included patient-reported scores on the taste of medicines via a five-point Facial Hedonic Scale; a Visual Analogue Scale (VAS); a question, 'Did you think the medicine tasted OK?' and researcher observations of facial expressions and behaviours immediately before, during and after administration. RESULTS: 611 children participated. The percent unable to complete the scales was 7% (n=46) for the VAS; 2% (n=15) for the hedonic scale and 1% (n=7) for the question about taste. Significant correlations (Spearman's r) were observed between the patient-reported outcome measures: 0.80 and 0.78 for the taste question and hedonic and VAS, respectively, and 0.84 for the hedonic and VAS. Researcher observations demonstrated the ability of the patient to take the medicine as intended but did not provide sensitive measures of taste. 5% of administrations were not taken as intended by the children. Medicines known to have poor taste (clarithromycin and prednisolone) showed mean hedonic and VAS scores of ≥3.5 and >65 mm, respectively. CONCLUSIONS: Patient-reported outcome measures correlate with each other and are a useful means to assess the taste (and acceptability) of medicines. Hedonic scales are better understood by children and should be the first choice tool in the assessment of medicines taste.

Acceptability of placebo multiparticulate formulations in children and adults.

Patient acceptability is an important consideration in the design of medicines for children. The aim of this study was to investigate acceptability of multiparticulates in healthy children and adults. A randomised, single-blind acceptability testing was performed involving 71 children (4-12 years) and 61 adults (18-37 years). Each participant received three 500 mg samples of microcrystalline cellulose pellets administered on a medicine spoon with water at 5-10 minutes intervals. Acceptability was measured based on voluntary intake of the samples, facial expressions, ratings on hedonic scales and reported willingness to take multiparticulates everyday as a medicine. Multiparticulates were voluntarily swallowed by 92% of children and 100% of adults. However, palatability issues were identified, with emphasis on textural aspects. Grittiness perception received negative ratings on hedonic scales by 60% of children and 51% of adults. Researcher observations revealed that 72% of children and 42% of adults displayed negative facial expressions towards the samples. Children reported their willingness to take multiparticulates as a medicine in 30% of the cases, compared to 74% in adults. This study demonstrates that multiparticulates may be a suitable formulation platform for children and adults, although palatability concerns have been highlighted. Additional work is required to define acceptability criteria and to standardise methodologies.

Methodology Used to Assess Acceptability of Oral Pediatric Medicines: A Systematic Literature Search and Narrative Review.

BACKGROUND: Regulatory guidelines require that any new medicine designed for a pediatric population must be demonstrated as being acceptable to that population. There is currently no guidance on how to conduct or report on acceptability testing. AIM: Our objective was to undertake a review of the methods used to assess the acceptability of medicines within a pediatric population and use this review to propose the most appropriate methodology. METHODS: We used a defined search strategy to identify literature reports of acceptability assessments of medicines conducted within pediatric populations and extracted information about the tools used in these studies for comparison across studies. RESULTS: In total, 61 articles were included in the analysis. Palatability was the most common (54/61) attribute measured when evaluating acceptability. Simple scale methods were most commonly used, with visual analog scales (VAS) and hedonic scales used both separately and in combination in 34 of the 61 studies. Hedonic scales alone were used in 14 studies and VAS alone in just five studies. Other tools included Likert scales; forced choice or preference; surveys or questionnaires; observations of facial expressions during administration, ease of swallowing, or ability to swallow the dosage; prevalence of complaints or refusal to take the medicine; and time taken for a nurse to administer the medicine. CONCLUSIONS: The best scale in terms of validity, reliability, feasibility, and preference to use when assessing acceptability remains unclear. Further work is required to select the most appropriate method to justify whether a medicine is acceptable to a pediatric population.

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

BACKGROUND: The palatability of flucloxacillin oral liquid is poor. Parents/carers use strategies to aid the administration of poorly palatable medicines. AIM: To assess views on the palatability of flucloxacillin oral liquid and identify factors associated with successful administration. METHODS: A 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. RESULTS: A 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%). CONCLUSION: The 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.

Evidence of acceptability of oral paediatric medicines: a review.

OBJECTIVES: The aim of this review was to map the currently available evidence on acceptability of oral paediatric medicines to aid in the selection of suitable platform formulations for the development of new acceptable paediatric products. METHODS: This process used a defined search strategy of indexed publications and included methods to assess the quality of the evidence retrieved. KEY FINDINGS: Taste/palatability was the most extensively studied area of paediatric medicine acceptability yet standard methods or criteria that define what is classed as acceptable to children is still to be defined. There have been many reports on the acceptability of medicines to paediatric populations yet major gaps in the acceptability knowledge base exist including the shape and dimensions of tablets, minitablets and capsules swallowed whole in infants and children; size and overall volume of multiparticulates; volume of liquids completely swallowed in infants and children; duration of retention within the oral cavity, size and taste of orodispersible tablets, lozenges and chewable tablets and the number of solid units dosed at each time point. CONCLUSIONS: The review highlights where further information is required to support knowledge around acceptability of age-appropriate medicines. An algorithm to aid in selection of a formulation that is likely to be acceptable based on the age range to be treated by the medicine is presented as a result of this review.

Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency.

Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRß sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21(lo) B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class-switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease.

Urinary biomarkers of acute kidney injury in deceased organ donors--kidney injury molecule-1 as an adjunct to predicting outcome.

BACKGROUND: Deceased kidney donors are increasingly "marginal," and many have risk factors for acute kidney injury (AKI) that may impact on subsequent renal transplant outcome. Despite this, determining the presence of AKI at the time of deceased organ donation remains difficult. METHODS: Urine samples from 182 brainstem dead multi-organ donors (all of whom donated hearts that were transplanted) were analyzed for a Luminex(™) panel of biomarkers linked with AKI. This included KIM-1, NGAL, IFN-γ, TNF-α, cystatin C, Fractalkine and vascular endothelial growth factor. Levels were correlated to early renal transplant outcomes, most specifically delayed graft function. RESULTS: Donor urinary KIM-1 levels were significantly higher in donors whose kidneys displayed aberrant early function (p = 0.011). Fractalkine levels showed a trend toward elevation in such donors but uncorrected this did not attain significance. No correlation occurred with the remaining biomarkers. CONCLUSIONS: KIM-1 appears to show promise as a marker for AKI in deceased cardiac organ donors. The availability of a lateral flow device (Renastick(™) ) for KIM-1 that also demonstrates higher urinary KIM-1 levels in donors whose kidneys show aberrant initial function (p = 0.03), makes KIM-1 a potential indicator of AKI that may merit further evaluation for its application at the donor bedside.