Sue Pavitt

Background: People with penicillin allergy labels receive more antibiotics, different antibiotics and have worse health outcomes when compared to people without a penicillin allergy label. Objective: To determine if a pre-emptive penicillin allergy assessment pathway can remove incorrect penicillin allergy labels, improve antibiotic prescribing and health outcomes, and is cost-effective. Design: A multi-work package programme to develop and evaluate a complex intervention (penicillin allergy assessment pathway), including rapid literature review (work package 1.1), behaviour change material development (work packages 1.2 and 1.3), medical record updating processes (work package 1.4), a pragmatic randomised controlled trial (work package 2.1) with nested pilot (work package 1.5), health economic evaluation (work package 2.2) and process evaluation (work package 2.3). Setting: English general practices and hospital sites in West Yorkshire, South Yorkshire and Cornwall. Participants: Trial participants were adult general practice patients with a record of penicillin allergy. Interview subjects were general practitioners and healthcare workers involved in penicillin allergy assessment, trial and non-trial participants with a penicillin allergy. Interventions: Complex intervention involving: identification of appropriate participants, risk stratifying and testing for penicillin allergy, promoting behaviour change and updating medical records. Main outcome measures: Penicillin prescribing, total antibiotic prescribing, treatment response failure, duration of symptoms, hospital admission/length of stay, mortality, meticillin-resistant Staphylococcus aureus status and Clostridioides difficile infection, penicillin allergy de-labelling’ rates. People’s views about penicillin allergy and testing. Results: Work package 1.1: Our review showed that patients had some worries about penicillin allergy testing but could see advantages. Clinicians were uncertain about referral criteria. Clinicians were wary about prescribing and patients were wary about consuming penicillins after a negative test. Fear of subsequent reactions were drivers. This informed WP1.3 development of resources to aid penicillin allergy assessment. Work package 1.2: Our qualitative research showed that patients were unaware of the benefits of penicillin allergy testing. Experience of negative effects of penicillin allergy labels motivated patients to be tested. Clinicians were reluctant to de-label patients using clinical judgement alone. Clinicians and patients were generally supportive of penicillin allergy testing. This informed work package 1.3. Work package 1.3: Materials were developed to increase knowledge of penicillin allergy testing, support beliefs about the importance of testing, and to increase confidence in performing the behaviours safely by providing a supportive environment. Materials comprised information booklets for general practitioners and participants, electronic health record (SystmOne) pop-ups, post testing result cards, trial work instructions/training material, participant and clinician letters. Work package 1.4: General practitioners were happy to update medical records after a negative test result. ‘Marking in error’ was used to update SystmOne if a participant had a negative penicillin allergy test, which removed allergy alerts but maintained an audit trail. General practitioner trial training/procedures informed general practitioners how to update records. SystmOne functions developed to facilitate de-labelling. Work package 1.5: Target recruitment for the pilot target was achieved. Identification of suitable patients from SystmOne was successful. Willingness of general practitioners to refer patients and participants to undergo testing was demonstrated. A data-secure ‘ALABAMA unit’ was set up within SystmOne. Processes for referring and following-up participants via the ALABAMA unit were established. Low symptom diary completion rate indicated case note data would also be needed. Work package 1.6: During the nested pilot trial, multiple measures were developed, approved and implemented to maximise recruitment for the main trial; including additional testing sites were recruited in South Yorkshire and Cornwall. Work package 2.1: The randomised controlled trial found there was a statistically significant increase in the number of patients de-labelled and penicillin prescribing was statistically significantly increased (adjusted relative risk 5.26) and median total defined daily dose of antibiotics was reduced by 25% in the intervention group. There were no significant differences in other secondary outcomes. Work package 2.2: Within-trial assessment indicated the assessment pathway was likely to be cost-effective. The cost-effectiveness modelling suggested the net benefit of testing was high but uncertainties were high. The value of information studies indicated another trial including health outcomes was worthwhile. Work package 2.3: General practitioners were motivated to join the trial because of perceived benefit to patients. General practitioners were positive about the trial design/delivery and support from the trial team. Many participants sought clarity about penicillin allergy status. Participants reported feeling safe and well looked after during testing. Most participants accepted test results and were relieved to receive a negative test that enabled them to take penicillin. The process evaluation provided important information on how to improve future National Health Service implementation. Specifically, the need for a safe, accessible and reliable service where general practitioners need to be provided with step-by-step guidance how to identify patients with different risk of true penicillin allergy to facilitate onward referral/assessment. The resources developed within the programme could be used as part of wider implementation to encourage and support patients and healthcare workers to engage with and deliver penicillin allergy assessment. Limitations: The coronavirus disease discovered in 2019 pandemic affected recruitment and reduced the sample size meaning the primary outcome had to be agreed and changed to an antibiotic prescribing outcome. The research was conducted using functionality developed in SystmOne; there needs to be consideration of how to maximise knowledge transfer this functionality to other electronic health record systems. Conclusion: The pre-emptive penicillin allergy assessment pathway was safe, increased penicillin prescribing reduced overall antibiotic prescribing, produced sustained de-labelling and was cost-effective. The assessment pathway was well received by participants and general practitioners. We conclude that patients who are recent users of antibiotics and are lower risk for true penicillin allergy would likely benefit from penicillin allergy assessment. Future work: A larger trial is needed to determine if penicillin allergy assessment can improve patient health outcomes. Implementation studies are needed to determine how best to safely embed penicillin allergy assessment into clinical practice and to widen access beyond the current referral guidelines. Trial registration: This clinical trial is registered as Current Controlled Trials ISRCTN20579216 and ClinicalTrials.gov NCT04108637. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-1214-20007) and is published in full in Programme Grants for Applied Research ; Vol. 14, No. 11. See the NIHR Funding and Awards website for further award information.

Introduction: Current treatments for multiple sclerosis (MS) do not address the pathological processes of neurodegeneration and chronic demyelination. This, coupled with the significant challenges of translating promising phase 2 results to phase 3 trial success, highlights the need for more efficient trial designs, such as platform multi-arm multi-stage (MAMS) trial approaches. MAMS trials have demonstrated success in areas such as oncology and infectious diseases. They are typified by a statistically robust core trial design that allows the addition of further treatment arms and utilisation of interim outcome analyses at pre-defined timepoints, to determine whether to terminate a treatment arm early or proceed to the final outcome analysis. To address the challenges in progressive multiple sclerosis (PMS) treatment discovery, the Optimal Clinical Trials Platform for PMS (OCTOPUS) trial was developed. It currently utilises MRI whole-brain atrophy as its interim outcome measure and the clinically relevant composite Expanded Disability Status Scale Plus (EDSS-Plus) as its final outcome measure. A rigorous and systematic drug selection process that assessed preclinical in vitro and animal model evidence, along with additional human data, led to the prioritisation of R/S-alpha lipoic acid (R/S-ALA) and metformin for testing against placebo, targeting pathobiological mechanisms relevant to PMS. All participants will be eligible to receive the current standard of care, including disease-modifying treatments (DMTs). Method and analysis: OCTOPUS will be a multi-centre, randomised, placebo-controlled, double-blind, phase 3, MAMS trial of participants aged 25 to 70 years (inclusive) with PMS and an EDSS score of 4.0 to 8.0 (inclusive). Steady progression must be the major cause of increasing disability rather than relapse in the preceding 2 years. In the trial’s first candidate drug cycle, participants will be allocated to R/S-ALA, metformin, or placebo in a 1:1:1 ratio. Cycle 1 active treatments will start as R/S-ALA 600 mg once daily, increased after 4 weeks to 600 mg twice daily, or metformin 1 g once daily, increased after 4 weeks to 1 g twice daily. The trial will be multinational, with participation from 28 hospitals across the UK and 10 hospitals in Australia. Clinician-reported measures will include: the EDSS-Plus and the individual components: EDSS, Timed 25 Foot Walk (T25FW); 9 Hole Peg Test (9HPT); Symbol Digit Modalities Test (SDMT); Sloan Low Contrast Visual Acuity (SLCVA); and Relapse assessment. Patient-reported outcomes include MS specific walking, fatigue, pain, and impact scales. We will include a health economic analysis. Analysis stage 1 will require randomisation of 125 participants per arm and utilise MRI percentage brain volume change (PBVC) with the Structural Image Evaluation using Normalisation of Atrophy (SIENA) technique from baseline to 78 weeks. A positive outcome in analysis stage 1 will detect a 0.15% per year whole brain atrophy difference with a one-sided alpha of 0.35 and power of 95%, ensuring a low probability of erroneously rejecting a treatment arm at this stage. Any arms that show a positive effect will proceed to final analysis stage 2. Analysis stage 2 will require 600 participants per arm. Participants included in stage 1 will also be included in the stage 2. Analysis stage 2 will evaluate time to 6-month confirmed disability progression in the EDSS-Plus, in order to detect a 25% hazard ratio reduction with 90% power and an alpha of 0.05. Assuming one treatment arm proceeds to analysis stage 2, the trial will recruit approximately 1,200 participants and last about 6 years. This is approximately two-thirds the size and half the duration of separately conducted two-arm phase 2 and 3 trials. Ethics and dissemination: The protocol was approved by the London Hampstead REC (22/LO/0622). This manuscript is based on protocol version 8.0 , 28 ^th August 2025. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations. There will be a close communication strategy developed with the UK MS Society (MSS) and full patient and public involvement and engagement (PPIE). Trial registration: ISRCTN: 14048364 EudraCT number: 2021-003034-37 CTA 20363/0445 IRAS number: 1003943 Secondary identifying numbers: ND001, CPMS 54274 Strengths and limitations: The OCTOPUS trial will be the first platform multi-arm multi-stage phase 3 trial in PMS, offering the potential to significantly expedite clinical trial processes with advantages in cost- and time-efficiency, focusing specifically on the poorly treated pathobiological processes of chronic neurodegeneration and demyelination It will begin by assessing two promising drug candidates, immediate-release metformin and R/S-ALA, and will expand over the duration of the trial to include more drug arms under the same trial master protocol The flexible and statistically robust trial design means that several components of the design (such as the early analysis stage 1 interim outcome) can be updated in line with evolving scientific knowledge It will ultimately be the largest ever investigator-initiated phase 3 trial in PMS It will include a range of national and international trial sites, including neuroscience centres and district general hospitals It will have a high inclusion limit for age (up to 70 years) and disability (up to EDSS 8.0) Several components (the telephone EDSS and virtual patient-reported outcome measures) will be amenable to remote collection increasing inclusivity and thus addressing public and participant suggestions, while minimising the risk of missing data The main challenges in this trial design are the statistical and methodological complexity involved in design and implementation, and interpretation of interim trial results. Conclusion: The trial launched cycle 1 in January 2023. Analysis stage 1 recruitment of 375 participants was achieved in November 2024, enabling planned interim analysis stage 1 to be conducted by late 2026 ( Figure 1 ). On the 1 ^st of June 2026, in the UK, 24 sites are active with a further 4 in set-up as part of stage 2, and in the Australian extension, Platform Adaptive Trial for Remyelination and Neuroprotection in Multiple Sclerosis (PLATYPUS), 1 site is active, with 9 additional sites in set-up.

Background: Tooth decay in secondary school children is one of the most prevalent non-communicable diseases in the UK and globally. Whilst almost entirely preventable, oral health inequalities remain a significant public health problem to reach and manage those most vulnerable. School-based prevention strategies targeted to localities with oral health inequality, and incorporating peer-to-peer interventions warrant further evaluation. These peer-to-peer interventions have a bidirectional benefit and are proposed to positively influence both the ‘peer leader’ and ‘peer recipient’; they rely on shared cultural backgrounds and relatability to reach students that may be missed by typical healthcare professional-led interventions. This protocol describes a feasibility trial which aims to establish RAISED in Yorkshire with its peer-to-peer delivery model within the secondary school setting supported by newly qualified dentists as an effective and sustainable approach to improve oral health awareness, skills (toothbrushing) and behaviours in adolescents from underserved at-risk communities. Methods: This is a UK school-based, assessor-blinded, parallel two-arm randomised controlled feasibility trial with a preliminary interim assessment in advance of progression to a larger scale trial in the future. The trial aims to recruit n = ~240 11–13-year-old participants and n = ~50 16–18-year-old peer leaders across five schools/colleges in West Yorkshire. The primary outcomes are related to feasibility in terms of recruitment and retention of participants, and the ability to deliver the intervention. The secondary outcomes include the oral health of participants (knowledge, attitudes and behaviour, plaque and gingival index) and process evaluation. Discussion: The findings of the feasibility trial will dictate whether the project is scalable and can be delivered to multiple schools regionally and nationally. The findings will also show whether it is an effective method to provide oral health education for 11–13-year-old adolescents when delivered collaboratively by trained 16–18-year-old peer leaders. Trial registration: ISRCTN registry, ISRCTN83511912. Registered on 8 August 2024, https://www.isrctn.com/ISRCTN83511912 .

Background: Penicillin allergy (PenA) prevalence is approximately 6%, but fewer than 10% of these people are expected to be truly allergic. Consequently, a significant proportion of the population are prescribed alternative antibiotics with potential increased risk of acquiring multi-drug resistant bacteria and worse health outcomes. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aimed to determine if a penicillin allergy assessment pathway (PAAP) initiated in primary care, is effective in de-labelling erroneous records, improving antibiotic prescribing and patient outcomes. Aim: To investigate healthcare professionals’ (HCPs’) experiences of the ALABAMA trial. Design & setting: Qualitative study using semi-structured interviews in general practice in England. Method: Semi-structured interviews were conducted with HCPs (including GPs, research nurses, pharmacists) who delivered the trial. Interviews explored their views about de-labelling incorrect PenA records, their role(s) in the trial, and, where relevant, their experience of prescribing following de-labelling. Results: HCPs ( n = 18) believed many patients were incorrectly labelled PenA, and were aware of the individual and public health risks this posed. However, GPs explained labels were rarely challenged in general practice because the perceived risks to patients and their professionalism were too great. The PAAP intervention, alongside the ‘protocolisation’ within the ALABAMA trial, was successful at mitigating these risks. Consequently, the trial was well-accepted and commended by HCPs. Conclusion: GPs welcomed and accepted the PAAP as a means of correcting erroneous PenA records. There is great potential for PAAP to be supported in primary care if testing becomes more accessible.

Objectives: Periodontitis is linked with many health conditions, but its genetic basis is not yet understood. This genome-wide association study (GWAS) aimed to investigate the genetic variants associated with periodontitis. Materials and methods: This study utilised UK Biobank participants of European descent. Individuals were categorised as “having periodontitis” if they self-reported having ‘painful gums’, ‘bleeding gums’ or ‘loose teeth’ (n = 68,482), or as “controls” for those without these symptoms (n = 307,342). We conducted GWAS of this binary periodontitis phenotype using logistic regression models with PLINK2.0 adjusting for age, sex and the first 15 principal components to account for population stratification. Results: There were 376,611 participants (mean baseline age = 57 ± 7.9 SD) included in the GWAS, and four significant loci were identified: rs775476621 on chromosome 11 (Odds Ratio, OR[T]: 3.08, p = 1.01 × 10^− 8), rs751014048 on chromosome 11 (OR[G]: 3.07, p = 1.04 × 10^− 8), rs149922301 on chromosome 4 near gene RP11-61G19.1 (OR[A]: 1.18, p = 2.71 × 10^− 8) and rs368467810 on chromosome 6 near gene HIST1H3L (OR[TTTA]: 0.96, p = 3.88 × 10^− 8). Conclusions: Within the current limitations, such as self-reported phenotype and older age of the study population, four loci were detected for periodontitis that have not previously been linked with this condition. Further exploration of the function of these loci may contribute to improved understanding of periodontitis aetiology and subsequent drug development. Clinical relevance: These findings offer new targets for future research to investigate the genetic impact on periodontitis and aid the future understanding of periodontitis pathology and the disease’s progression.

Objectives: The aim was to conduct a process evaluation of a multicomponent behaviour change intervention to reduce dental caries in secondary school children in the UK. The intervention was evaluated in the BRIGHT randomised controlled trial which investigated clinical and cost‐effectiveness. The trial involved 4680 participants from 42 schools with a follow‐up period of 2.5 years. Schools with an above‐average proportion of free school meal (FSM) eligibility, an indicator of low household income, were recruited. The intervention, an oral health classroom‐based session (CBS) delivered by school staff and twice‐daily text messages aimed to improve toothbrushing frequency with fluoride toothpaste.Methods: Key components of process evaluations were examined: Implementation (fidelity, dose delivered, adaptations and reach), mechanisms of impact (acceptability and dose received) and influential contextual factors. Data collection ran alongside that of the outcome evaluation. Mixed‐methods data collection comprised pupil self‐reported questionnaires, staff feedback questionnaires, CBS and text message delivery logs and semi‐structured interviews/focus groups with school staff and pupils. Quantitative data were summarised descriptively, while framework analysis was applied to the qualitative data.Results: The intervention was generally implemented as intended, albeit with some schools not confirming CBS delivery and a technical problem resulting in text messages being stopped prematurely. Some adaptations to the CBS were made by school staff. In terms of reach, 21.9% (n = 1025) of participants were FSM‐eligible. At baseline, 77.6% (n = 3631) of randomised participants reported brushing at least twice daily with no difference over time in the social cognitive determinants of toothbrushing behaviour. The intervention was generally found to be acceptable with varying levels of participant responsiveness reported. The actual dose received was unclear; some schools did not provide a CBS attendance register, and some participants reported blocking or muting the text messages.Conclusions: This evaluation raises the question of whether the intervention dose and quality of delivery were sufficient to support the required behaviour change mechanisms. Moreover, a high proportion of participants brushed twice daily at baseline; this also calls into question the intervention's ability to bring about significant change. The trial findings did not favour the implementation of the two‐component intervention (CBS and text messages) within a school setting. However, with oral health as part of the general health school curriculum, the BRIGHT CBS could be adopted within the UK curriculum as it was co‐developed with young people and was found acceptable to pupils and teachers.Trial Registration: ISRCTN number: 12139369

Introduction: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. Methods and analysis: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0–6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate. The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression. Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. Ethics and dissemination: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration numbers: NCT03387670 ; ISRCTN82598726 .

Background: The presence of dental caries impacts on children’s daily lives, particularly among those living in deprived areas. There are successful interventions across the United Kingdom for young children based on toothbrushing with fluoride toothpaste. However, evidence is lacking for oral health improvement programmes in secondary-school pupils to reduce dental caries and its sequelae. Objectives: To determine the clinical and cost effectiveness of a behaviour change intervention promoting toothbrushing for preventing dental caries in secondary-school pupils. Design: A multicentre, school-based, assessor-blinded, two-arm cluster randomised controlled trial with an internal pilot and embedded health economic and process evaluations. Setting: Secondary schools in Scotland, England and Wales with above-average proportion of pupils eligible for free school meals. Randomisation occurred within schools (year-group level), using block randomisation stratified by school. Participants: Pupils aged 11–13 years at recruitment, who have their own mobile telephone. Interventions: Two-component intervention based on behaviour change theory: (1) 50-minute lesson delivered by teachers, and (2) twice-daily text messages to pupils’ mobile phones about toothbrushing, compared with routine education. Main outcome measures: Primary outcome: presence of at least one treated or untreated carious lesion using D_ICDAS4–6MFT (Decayed, Missing and Filled Teeth) in any permanent tooth, measured at pupil level at 2.5 years. Secondary outcomes included: number of D_ICDAS4–6MFT; presence and number of D_ICDAS1–6MFT; plaque; bleeding; twice-daily toothbrushing; health-related quality of life (Child Health Utility 9D); and oral health-related quality of life (Caries Impacts and Experiences Questionnaire for Children). Results: Four thousand six hundred and eighty pupils (intervention, n = 2262; control, n = 2418) from 42 schools were randomised. The primary analysis on 2383 pupils (50.9%; intervention 1153, 51.0%; control 1230, 50.9%) with valid data at baseline and 2.5 years found 44.6% in the intervention group and 43.0% in control had obvious decay experience in at least one permanent tooth. There was no evidence of a difference (odds ratio 1.04, 95% confidence interval 0.85 to 1.26, p = 0.72) and no statistically significant differences in secondary outcomes except for twice-daily toothbrushing at 6 months (odds ratio 1.30, 95% confidence interval 1.03 to 1.63, p = 0.03) and gingival bleeding score (borderline) at 2.5 years (geometric mean difference 0.92, 95% confidence interval 0.85 to 1.00, p = 0.05). The intervention had higher incremental mean costs (£1.02, 95% confidence interval −1.29 to 3.23) and lower incremental mean quality-adjusted life-years (−0.003, 95% confidence interval −0.009 to 0.002). The probability of the intervention being cost-effective was 7% at 2.5 years. However, in two subgroups, pilot trial schools and schools with higher proportions of pupils eligible for free school meals, there was an 84% and 60% chance of cost effectiveness, respectively, although their incremental costs and quality-adjusted life-years remained small and not statistically significant. The process evaluation revealed that the intervention was generally acceptable, although the implementation of text messages proved challenging. The COVID-19 pandemic hampered data collection. High rates of missing economic data mean findings should be interpreted with caution. Conclusions: Engagement with the intervention and evidence of 6-month change in toothbrushing behaviour was positive but did not translate into a reduction of caries. Future work should include work with secondary-school pupils to develop an understanding of the determinants of oral health behaviours, including toothbrushing and sugar consumption, particularly according to free school meal eligibility. Trial registration: This trial is registered as ISRCTN12139369. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/166/08) and is published in full in Health Technology Assessment; Vol. 28, No. 52. See the NIHR Funding and Awards website for further award information.