Mesenchymal intravenous stromal cell infusions in children with recessive dystrophic epidermolysis bullosa: MissionEB protocol for a randomised, double-blinded, placebo-controlled, two-centre, crossover trial with an internal phase I dose de-escalation phase and open-label extension

Introduction Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic mucocutaneous fragility disorder characterised by chronic blistering, slow wound healing and increased risk of squamous cell carcinoma. Current management options are very limited. Methods This is a randomised (1:1), placebo-controlled, double-blinded crossover (A/B) trial with an internal phase I dose de-escalation (4+5 design) in the first 3 months and a 12-month continued treatment follow-on open-label study if 3-month outcome data from the crossover trial indicate safe and beneficial effects. RDEB is a rare condition, so we expect to recruit a maximum of 36 participants based on feasibility and not formal power considerations. Participants aged>6 months and <16 years will be recruited at Great Ormond Street Hospital and Birmingham Children’s Hospital. They will receive 2–3×106 cells/kg intravenous infusion of umbilical cord-derived mesenchymal stem cells or placebo at the start of each crossover period (day 0) and 14 days later. The dose will be de-escalated to 1–1.5×106 cells/kg depending on observed toxicity. For the main crossover trial, the primary outcome is the change in disease severity as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index at 3 months from day 0 infusion. Secondary outcomes measured at 3 and 6 months from day 0 infusion include changes in general clinical appearance of skin disease, pain and itch, and quality of life. Adverse events and serious adverse events will be monitored throughout the trial. Ethics and dissemination North East—York Research Ethics Committee approved the protocol (ref: 21/NE/0016) on 16 March 2021. Findings will be published in peer-reviewed scientific journals, presented at relevant national and international conferences, and an open-access final report submitted to the funder. Trial registration number ISRCTN14409785. Protocol V. 8.0, 14 November 2022

Mesenchymal stromal cell infusions of umbilical cord-derived mesenchymal stromal cells in children with recessive dystrophic epidermolysis bullosa (MissionEB): a randomised, double-blind, placebo controlled, crossover, phase 3 trial with an internal phase 1 dose de-escalation phase

Background Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder characterised by extensive mucocutaneous blistering. This study aimed to generate evidence to inform commissioning decisions on umbilical cord-derived mesenchymal stromal cells, UC-MSCs, (CORDStrom™) for RDEB. Methods In this double-blinded, randomised (1:1), placebo-controlled, two-period crossover phase 3 trial, children aged 6 months to 16 years of age with RDEB were enrolled at two UK specialist centres for epidermolysis bullosa (EB). Individuals were excluded if they had received oral or topical corticosteroids for more than 7 consecutive days within 30 days of enrolment into this study, excluding oral viscous budesonide and inhaled fluticasone used as prophylaxis to relieve oesophageal symptoms, an active infection that required treatment with oral or intravenous antibiotics within 7 days of screening, medical history or evidence of active malignancy, the presence of both positive collagen VII ELISA and a positive indirect immunofluorescence (IIF) with binding to the base of salt split skin, administration of MSCs from any source in the previous 9 months and participation in any other interventional trial within 3 months of enrolment into this study. This trial included an internal dose de-escalation (IDD) phase for safety gatekeeping. During IDD, 4 participants were randomised (3:1) to receive two infusions (2–3 × 106 cells/kg/infusion or placebo) on days 0 and 14 before the next participant begun treatment. The primary outcome was toxicity defined as a suspected unexpected serious adverse reaction (SUSAR) within 48 h of receiving an infusion. The DMEC reviewed the data and if one (or fewer) patients receiving the active treatment experienced a SUSAR, the dose would be reduced and toxicity evaluated in a further 5 patients randomised (3:2) to UC-MSCs or placebo. If there were no further toxicities, the trial progressed to the main two period crossover study. In the main crossover, patients were randomly assigned (1:1) using a web-based randomisation system SCRAM to receive two intravenous infusions (days 0 and 14), at a dose of 2–3x106 cells/kg UC-MSCs or placebo. There were 2 follow-up periods each of 6 months with a 3 month interval between periods, giving a 9 month duration between doses. Clinicians, caregivers, patients, and clinical trial personnel were fully blinded to treatment groups. Trial pharmacists and a team or independent research nurses who only performed administration of the infusion were unblinded to perform security checks of the product but were not involved in any assessments. The primary endpoint was change in disease severity as measured by Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) at three months post infusion assessed in the modified intention to treat (mITT) population (participants providing data at both period baselines and at least one 3-month follow-up). Prespecified subgroups included RDEB severity and age. Safety data were collected for all participants and safety assessment was based on all treatment emergent events in the safety population (those receiving at least one active or placebo infusion). This trial is registered with ISRCTN, ISRCTN14409785. Findings Between OCT 06, 2021, and JUL 15, 2024, 44 participants were screened; 37 were randomised (18 UC-MSCs/placebo; 19 Placebo/UC-MSCs), with 34 receiving at least one infusion and 30 in the mITT analysis (14 UC-MSCs/placebo; 16 placebo/UC-MSCs). No toxicities were seen in the IDD phase (primary outcome). At three months no changes in favour of UC-MSCs were seen in the primary outcome EBDASI. The between arm difference in EBDASI at 3 months showed a 3.75 point difference (effect size 0.06) in favour of placebo (95% CI of −1.46, 8.96, p = 0.15) with corresponding figures for UC-MSCs/Placebo and Placebo/UC-MSCs of 5.5 (95% CI of −2.53 to 13.53, p = 0.16) and 2 (95% CI of −5.33 to 9.33, p = 0.58). No serious adverse events were associated with UC-MSCs. Interpretation UC-MSCs infusions were safe and the primary outcome (EBDASI) did not show MSCs were beneficial. Further evaluation of the long-term efficacy of UC-MSCs is planned. The main strength is that Mission EB is the largest cell therapy study to date providing the most robust evidence on the safety and efficacy of UC-MSCs in children with RDEB. A limitation is that there are no robust validated outcome measures for RDEB. Funding National Research Collaboration Programme, an NHS England and NIHR partnership (NIHR 127963) and Cure EB

Assessment of disease progression in dysferlinopathy: A 1-year cohort study

ObjectiveTo assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.MethodsOne hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.ResultsThe functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.ConclusionCertain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.ClinicalTrials.gov identifier:NCT01676077

The MAGIC trial: a pragmatic, multicentre, parallel, noninferiority, randomised trial of melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia

\ua9 2023 The Author(s)Background: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results. Methods: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg−1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals. Results: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6–10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7–22.4) and 12.9 (3.1–22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm. Conclusion: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias. Clinical trial registration: ISRCTN registry: ISRCTN18296119

Assessment of disease progression in dysferlinopathy: A 1-year cohort study

ObjectiveTo assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.MethodsOne hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.ResultsThe functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.ConclusionCertain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.ClinicalTrials.gov identifier:NCT01676077

Melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia: the MAGIC non-inferiority RCT

Background Anxiety in children prior to general anaesthesia is common, with up to half displaying distress. Anxiety and distress may lead to unsuccessful anaesthesia, together with greater postoperative pain, agitation and behavioural changes after surgery including sleep disturbances. Midazolam is the current standard premedication; however, it has adverse effects such as the potential for respiratory suppression and unpredictable effects which may result in agitation rather than anxiolysis. Melatonin is an alternative preoperative anxiolytic; however, previous trials have delivered conflicting results. The aim of this non-inferiority trial was to evaluate the effectiveness of melatonin compared to midazolam in reducing anxiety in children undergoing general anaesthesia. Methods We undertook a randomised-controlled, parallel-group, double-blind, non-inferiority trial in 20 United Kingdom National Health Service trusts, with an embedded qualitative study and health economic evaluation. Anxious children having day case elective surgery under general anaesthesia were randomly assigned to either control (standard of care) group: midazolam; or intervention group: melatonin. The primary outcome was preoperative distress (non-inferiority hypothesis) as assessed by modified Yale Preoperative Anxiety Scale Short Form. Secondary outcomes included safety and efficacy objectives. Analyses were by intention to treat, with an additional per-protocol analysis. The sample size of the trial was 624 children. Results The trial was stopped early due to recruitment futility. Between 30 July 2019 and 9 November 2022, 110 children were recruited; 55 allocated to midazolam and 55 allocated to melatonin. Pre-planned analyses showed an adjusted mean difference of 13.1 (95% confidence interval 3.7 to 22.4) for the intention-to-treat population and 12.9 (95% confidence interval 3.1 to 22.6) for the per-protocol population, in favour of midazolam. In both analyses, the upper limit of the 95% confidence interval exceeds the predefined margin of 4.3; therefore, melatonin is not non-inferior to midazolam. The lower limit of the 95% confidence intervals excludes zero and thus melatonin is inferior to midazolam; the difference found is considered to be clinically meaningful. Adverse events in the midazolam arm (26%) were slightly higher than melatonin (18%); there were no serious adverse events in either arm. Challenges to recruitment included study-related factors (eligibility criteria and trial design), participant factors (caregiver stress on the day of treatment) and practitioner factors (valuing predictability). In terms of acceptability, preferences of the anaesthetist, patient and caregiver factors and medication side effects profile were influential and suggest the choice of preoperative anxiolytic is more complex than previously described. On average, costs over the 14 days post surgery were lower for those who received melatonin (−£46.20, 95% confidence interval −£166.14 to £66.74) with a mean incremental difference in procedure success of −0.02 (95% confidence interval −0.08 to 0.004), although there was uncertainty around the results. Conclusion In children with preoperative anxiety, midazolam is more effective than melatonin at reducing preoperative anxiety prior to general anaesthesia, although the early termination of the trial increases the likelihood of bias. Limitations The trial was prematurely terminated due to recruitment futility. Despite this, a clinically meaningful and statistically significant finding was observed about the primary outcome. Future work There remains a need to develop or repurpose another drug with a more favourable side effects profile to midazolam. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/80/08

The MAGIC trial: a pragmatic, multicentre, parallel, noninferiority, randomised trial of melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia

BACKGROUND: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results. METHODS: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg-1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals. RESULTS: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6-10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7-22.4) and 12.9 (3.1-22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm. CONCLUSION: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias. CLINICAL TRIAL REGISTRATION: ISRCTN registry: ISRCTN18296119

Parent, Child and Physiotherapist Perceptions of Effectiveness of Parent Performed Manually Assisted Cough on Children With Neuromuscular Disease

Published research exploring confidence and perceptions of effectiveness in performing a manually assisted cough on children with neuromuscular disease is not available. This descriptive study aimed to describe confidence and perceived effectiveness of parents, children, and therapists in parent performed manually assisted cough. A total of 28 children with neuromuscular disease, one of their parents, and physiotherapist participated. Overall, 40% of parents, 52% of children, and 46% of therapists were very confident in parents’ ability to perform effective manually assisted coughs. Parents, children, and therapists largely perceived the parental manually assisted coughs as somewhat effective (68%, 60%, and 57%, respectively). Approximately, half of parents (48%), children (52%), and therapists (50%) felt very confident in parents’ ability to retain the technique between clinic visits. Interestingly, percentage agreement statistics indicate that a reasonable proportion (30%) of pairs of respondents did not agree in their ratings. Overall, high percentages of favourable ratings were noted for all questions