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Sample size calculation | G* Power was used to conduct an a-priori sample size calculation. Based on previous research [ | PMC10508026 | ||
Results | Due to participant drop-out and failed attention checks, N = 1126 participants (94% of intended sample) were included in the final sample for analyses. See Fig.
Participant characteristics overall, and across the four conditionsCategorical variables are represented by counts/percentages, and continuous variables by means/standard deviations. | PMC10508026 | ||
Primary analyses | PMC10508026 | |||
Food orders | Mean orders for the four conditions are presented fully in Supplementary material VIII. Data of size choice are visually represented in Fig.
The proportion of participants opting for a larger size option for all three outlets across the four conditions | PMC10508026 | ||
Exploratory analyses | Exploratory analyses were conducted to investigate the source of the unexpected increased kcals ordered from the fast food outlet in proportional pricing conditions (Supplementary material XI). There was no main effect of pricing condition on kcals ordered from meals ordered, but there was for kcals from additional optional side dish orders; being in the proportional pricing condition was associated with increased kcals ordered from additional sides (54.44kcals, 95% CI 37.94 to 70.93). | PMC10508026 | ||
Questionnaire responses | The majority (> 75%) of participants agreed that the virtual delivery app was representative of existing food delivery apps, and reported their orders where typical of what they would normally order. 20% of participants agreed that the food choices they made were influenced by how many calories they thought were in the food options and 33% agreed they were influenced by price. Over 60% of participants agreed with the use of calorie labelling and proportional pricing policies in the out of home food sector and tended to believe these policies would help people to make healthier choices (See online supplementary Material IV), | PMC10508026 | ||
Discussion | SAID, SHOP | This study examined the impact of calorie labelling and proportional pricing in a virtual online food delivery platform on portion size choice, kcals ordered and hypothetical spend from beverage, sandwich and fast food outlets. Compared to non-labelling conditions, calorie labelling had no significant impact on portion size selection of food or beverages from the coffee shop, sandwich shop, fast food outlet or when data were combined across all three outlet types. Calorie labelling did however significantly reduce total energy ordered in the coffee shop (-18.95kcals) and fast food outlet (-54.19kcals), but not significantly from the sandwich outlet (-0.43kcals). When data across outlets were combined, there was a small overall main effect of calorie labelling on energy ordered. For the fast food outlet only, calorie labelling was associated with a reduced total spend and in pooled analyses across the three outlets there was no difference in total spend based on calorie labelling condition. Presenting food and beverage items with proportional pricing (as opposed to standard value pricing) was associated with a decreased likelihood of choosing a larger beverage size from the coffee shop outlet by 42%. This statistically significant decrease was not found for the sandwich shop (21% reduction) or fast food outlet (7% reduction). However, when data were combined across outlets, there was an overall effect of proportional pricing, whereby presence of proportional pricing was associated with the participant selecting the larger portion size 0.2 times less (out of a possible 0–3 times) on average across the three outlets (a 7% reduction in number of times large portion size was chosen). Unexpectedly participants in the proportional pricing condition had a significantly higher total energy content of orders for the fast food outlet, as opposed to small non-significant decreases in the other two outlets. In all three outlets, proportional pricing was associated with increased hypothetical spend, and likewise a main effect of pricing condition was observed for combined outlets. No consistent interactions between a range of participant characteristics and interventions were identified across the different outlet types. Nor did we find any evidence that the effect of calorie labelling differed as a function of pricing condition for any of the outcomes.There was no evidence that calorie labelling had an effect on portion size selection of food or beverages across any outlet, but consistent with some research examining hypothetical food choice, labelling was associated with reductions in energy ordered [The majority of participants were supportive of calorie label interventions in the out-of-home food sector, which is consistent with findings from others studies [In proportional pricing conditions vs. standard value pricing, when data across outlets were combined, participants overall selected a larger portion size less frequently. For the separate outlets, this relationship was only significant for beverage purchases from the coffee shop. The same trends were observed for the sandwich shop (-21%) and fast food outlet (-7%) although differences were not statistically significant. It may be that a larger impact would be observed if a smaller size was offered for a proportionately lower price. In this study, participants were only able to choose between medium and large portion sizes. Previous research has found that increasing the number of options at the larger end of the scale (i.e., adding an extra-large option to small, medium, large) increased the number of people opting for the large size [Proportional pricing was associated with small non-significant decreases in total energy ordered in the coffee shop and sandwich outlets, but an unexpected increase in the fast food outlet. Exploratory analyses revealed that proportional pricing was associated with increased ordering of optional additional side dishes. In the study, proportional pricing was not presented for all side dishes (due to there being only one size) and many of the additional sides were low in price. Therefore, the effect of proportional pricing on total energy ordered may reflect lower priced items being perceived as better value for money when relative prices of larger meals increased (due to proportional pricing). Previous research has shown that many people rate the financial value of food products over factors such as nutritional content [In all three food outlets, proportional pricing was significantly associated with increased spend, showing that larger options are still attractive to many consumers even when more expensive. Although participants were broadly in support of proportional pricing (> 60%), across all three outlets, 90% of participants said that orders were typical for them (in terms of content and size). The lack of consistent effects of proportional pricing in the present study indicate that other complementary approaches, such as reformulation of existing food products, will be valuable in the out of home food sector [In the present study, we found a small increased spend in individuals with a greater BMI in proportional pricing conditions (relative to value pricing) for two of the three outlets, but no interactions with kcals ordered. There was also a small amount of inconsistent evidence that calorie labelling may exert a slightly stronger effect on kcals ordered among participants higher in weight control motives. Given the overall lack of convincing evidence across outcomes for moderation of calorie labelling or proportional pricing on outcomes by a range of participant level characteristics (including indicators of SEP) effects of these interventions may be largely similar across different sociodemographic groups. It is important to consider the role of habitual behaviour and preference in food purchasing. Specifically, it would be interesting to examine whether interventions such as those tested in the present study can override habitual behaviour and existing preferences, or whether intervention effects are limited to non-habitual choice and purchasing behaviours. Research suggests that when a behaviour is habitual, little information is required to make decisions, and individuals pay little attention to alternatives [ | PMC10508026 | |
Strengths and limitations | eating disorders | SHOP | This study was pre-registered and was stratified to represent the UK population in terms of gender and education. While virtual methodologies for food ordering are widely used [As is standard practice in eating behaviour research, individuals who were currently dieting, fasting, or had a history of eating disorders we ineligible to take part in this study, and so our findings are not generalisable to these groups. Some previous research has found interactions of calorie labelling with ethnicity [For two of the three outlets, participants had the option to order additional sides, but for the third outlet (a coffee shop) participants were instructed to only order a drink to ensure participant’s focus was on beverage choice per se, rather than considering the beverage as a side option to a food purchase. As we found some evidence in one of the outlets that proportional pricing was associated with increased purchase of side dishes, it is unclear if the same pattern of results would have been observed in the coffee shop outlet. It may be beneficial for future research to consistently include the option of additional sides to be better placed to examine intervention effects on overall diet. Due to the design of the delivery app, participants were required to complete the study on a computer or laptop, but food delivery orders are often made through mobile phones applications. This is shown by the large number of mobile downloads of such apps, for example the UberEats app was downloaded by 3.5 million people in the UK in 2022 alone [Only three outlet types were examined, all of which were large chains. A wider range of food and beverage outlets are available on food delivery apps. It would be particularly beneficial to know whether orders from smaller non-chain businesses (currently exempt from calorie labelling laws in the US and UK [ | PMC10508026 |
Conclusions | Calorie labelling on food delivery platforms may effectively reduce calories ordered. Proportional pricing may prompt consumers to select smaller portion sizes, although further research in real-world settings will now be valuable. | PMC10508026 | ||
Authors’ contributions | AF conceptualised the study, developed methodology, collected the data, validated the data, analysed the data, wrote the initial draft and had responsibility for the final manuscript. ER conceptualised the study, developed the methodology, and critically reviewed and revised the manuscript. AJ advised and helped to develop the methodology, and critically reviewed the manuscript. RW assisted with analysing the data and critically reviewed the manuscript. EB critically reviewed the manuscript.Acknowledgements. | PMC10508026 | ||
Funding | Obesity | OBESITY | The first author (AF) is funded by an ESRC case studentship, grant no: ES/P000665/1, with a contribution from the Obesity Health Alliance. ER is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant reference: PIDS, 803194) and the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The research is also supported by ESRC grant ES/W007932/1. | PMC10508026 |
Data Availability | The data that supports these findings will be available from the Open Science Framework repository upon publication (osf.io/kaju5 [ | PMC10508026 | ||
Declarations | PMC10508026 | |||
Ethics approval and consent to participate | Ethical approval was obtained from the University of Liverpool ethics committee (approval code: 4612), and informed consent was obtained from all participants before they took part in the study. | PMC10508026 | ||
Consent for publication | Consent for publication has been obtained. | PMC10508026 | ||
Competing interests | ER has previously received research funding from Unilever and the American Beverage Association for unrelated research projects. Other authors have no competing interests. | PMC10508026 | ||
Abbreviations | KilocaloriesSocioeconomic positionBody Mass IndexSubjective Social Status | PMC10508026 | ||
References | PMC10508026 | |||
Background | Lateral Elbow Tendinopathy | The OPTimisE intervention was developed to address uncertainty regarding the most effective physiotherapy treatment strategy for people with Lateral Elbow Tendinopathy (LET). | PMC10843168 | |
Objectives | To assess the feasibility of conducting a fully-powered randomised controlled trial (RCT) evaluating whether the OPTimisE intervention is superior to usual physiotherapy treatment for adults with LET. | PMC10843168 | ||
Design | A mixed-methods multi-centred, parallel pilot and feasibility RCT, conducted in three outpatient physiotherapy departments in the UK. | PMC10843168 | ||
Method | Patients were independently randomised 1:1 in mixed blocks, stratified by site, to the OPTimisE intervention or usual care. Outcomes were assessed using pre-defined feasibility progression criteria. | PMC10843168 | ||
Results | ADVERSE EVENTS | 50 patients were randomised (22 Female, 28 Male), mean age 48 years (range 27–75). Consent rate was 71% (50/70), fidelity to intervention 89% (16/18), attendance rate in the OPTimisE group 82% (55/67) vs 85% (56/66) in usual care, outcome measure completion 81% (39/48) at six-month follow-up. There were no related adverse events. Patients and physiotherapists reported that the OPTimisE intervention was acceptable but suggested improvements to the trial design. 49 patients were recruited from physiotherapy referrals vs one from primary care records. Outcome measure return rates were higher when completed online (74%) compared to postal questionnaire (50%). Exploratory analysis showed improvements in both groups over time. | PMC10843168 | |
Conclusions | It is methodologically feasible to conduct a fully powered RCT comparing the clinical and cost-effectiveness of the OPTimisE intervention versus usual physiotherapy treatment. Considering the similar improvements observed in both groups, careful consideration is needed regarding the priority research question to be addressed in future research. | PMC10843168 | ||
Introduction | elbow pain, Lateral elbow tendinopathy | TENNIS ELBOW | Lateral elbow tendinopathy (LET), also known as Tennis Elbow, is a common cause of elbow pain affecting sleep and basic daily activities, as well as sports, work and hobbies (The OPTimisE intervention was designed in consultation with patients and clinicians to reflect the current evidence base in a way that could be implemented into real-world clinical practice. We combined research evidence with the opinions of patients, physiotherapists with a special interest in LET and physiotherapy service managers, to form a consensus on what the intervention should comprise ( | PMC10843168 |
Method | PMC10843168 | |||
Trial design | We conducted a parallel two-arm, multi-centre pilot and feasibility randomised controlled trial across three sites. The detailed protocol has previously been published ( | PMC10843168 | ||
Feasibility outcomes | RECRUITMENT, SECONDARY | Our primary aim was to determine feasibility (criteria shown in Consent rate (number consented from those eligible after screening for inclusion/exclusion criteria)Intervention fidelity in the intervention group (measured as a binary outcome if participants were given the orthosis, taught the progressive exercise regimen and received advice/education on a minimum of 6 of the 12 specified topics)Attendance rate in the intervention group (number of physiotherapy appointments attended from the total appointments booked)Outcome measure completion rate at six months post-randomisationFeasibility criteria for a future main trial.Recruitment feasibility of 25% was selected based upon 50 patients being recruited from 200 patients referred per year – data that the three sites had provided from historic referral patterns. The fidelity criterion was determined by the research team as no precedent has been set. Attendance rate of 70% was set based upon previously published data for physiotherapy outpatient attendance (The secondary aims were to assess:Outcome measure completion rate at 6 weeks and 12 weeks post-randomisationCompletion of a grip-strength physical measure at two time points using the Squegg devicePatient-reported outcome measures (PROMs) at baseline, 6 weeks, 12 weeks and 6 months post-randomisation (analysed descriptively)Responsiveness to change analysis of individual PROMs questionnaires compared with patient perceived overall treatment effect, to determine the most appropriate PROMs for a future trialAdherence to exercise therapy treatment (measured using a self-reported exercise diary and Exercise Adherence Rating Scale (EARS))(Acceptability of the optimised physiotherapy treatment package and trial processes, investigated through the nested qualitative study | PMC10843168 | |
Participants | elbow pain, Maudsley, pain, PIS | TENNIS ELBOW | We piloted two methods of participant identification: screening of General Practice (GP) computer records and screening of referrals at physiotherapy sites. Those patients identified from GP records were sent a self-screening checklist and invitation letter to contact the trial team if they wished to be considered. Their GP was then asked to refer them to their local physiotherapy site. All physiotherapy referrals for elbow pain were screened at one of three National Health Service (NHS) physiotherapy sites, in either Birmingham, Derby or Sheffield. Patients deemed potentially eligible were sent a patient information sheet (PIS) then telephoned by the site principal investigator (PI) to check eligibility and invite for clinical assessment screening. Inclusion criteria: adults aged 18 or over; physiotherapist-diagnosed tennis elbow which included pain on palpation of the common extensor origin and on gripping; either a positive Cozen's, Mills', or Maudsley's test ( | PMC10843168 |
Randomisation | Following assessment, we invited eligible patients to provide informed consent, complete baseline questionnaires and they were then randomised via an online service (Sealed Envelope™) using 1:1 allocation in mixed blocks or 2 and 4, stratified by treatment site. We also asked if they consented to be contacted about participation in the qualitative study nested within the trial, following their course of treatment. | PMC10843168 | ||
Interventions | orthosis, Epi-Hit®, pain | We allocated participants to receive either the OPTimisE intervention or usual physiotherapy care. We did not standardise usual care in this pragmatic trial but we recorded treatments received by participants, to allow comparison with the OPTimisE intervention. Physiotherapists providing usual care treatment had no restrictions on the treatments they could offer. Physiotherapists provided treatments for one intervention arm only, to minimise contamination. Those providing usual care did not receive training in the OPTimisE intervention.The OPTimisE intervention consisted of three elements: condition-specific and general health advice, supported by printed and online resources; a progressive exercise regime working within limits of pain deemed acceptable by individual patients; and the provision of a counter-force orthosis. Exercises were progressed when the existing exercise was no longer painful, or regressed if the exercise provoked unacceptable levels of pain. The OPTimisE Intervention Handbook is supplied as a supplementary file, providing full details of the intervention.At the first appointment, those in the OPTimisE arm were provided with a Patient Manual containing advice/education material, exercise instructions and a password to access online resources. Advice and education topics were then discussed with the physiotherapist. Participants were supplied with an orthosis (Epi-Hit® Classic), as a means of providing short-term symptomatic relief, and instructed how to fit it correctly, then taught an exercise regimen that they could progress or regress based upon their symptom response. Follow-up appointments, to review progress, discuss advice/education topics further and review/adjust exercises, were arranged at the discretion of the physiotherapist but guidance was that appointments should be spaced at least four weeks apart, as recommended by patients during the intervention design. Appointments could be face-to-face, online or by telephone. | PMC10843168 | |
Blinding | Due to the nature of the interventions, neither participants nor physiotherapists could be blinded. Data analysis was not masked to allocation. | PMC10843168 | ||
Data collection | TENNIS ELBOW | We gathered patient-reported data using a questionnaire containing the recommended Core Outcome Set for LET (Patient-Rated Tennis Elbow Evaluation (PRTEE),Participants were given the choice of receiving questionnaires by post or online, using the Amplitude Pro-One™ system ( | PMC10843168 | |
Analytical methods | PMC10843168 | |||
Quantitative data analysis | Descriptive statistics were used to summarise the distribution of baseline variables across each of the randomisation groups. The continuous baseline variables (e.g. age) were reported with means and 95% confidence intervals (95% CI), if shown to be normally distributed, otherwise were reported with medians and Interquartile Ranges (IQR). The categorical variables (e.g. sex) were reported with frequencies & percentages. Similarly, we analysed data descriptively to explore the outcome measure scores in the intervention and control groups at baseline and follow-up, to explore changes in LET health status over time. The study was not powered for analysis of results between groups. We also assessed external responsiveness to change of PROMs using Spearman's rank correlation, with GPE-11 scores as the anchor. SPSS Statistics software (version 27) was used for the analysis. | PMC10843168 | ||
Qualitative interviews | PIS | RECRUITMENT | At least three months after randomisation, we sent a purposive sample of patients a PIS and invitation letter to take part in a qualitative interview. We followed this up by telephone or email to gain provisional consent and organise a mutually convenient time. Similarly, physiotherapists involved in the trial were approached at the end of recruitment. Interviews were conducted face-to-face, by telephone or video-conference via Microsoft Teams, at the participant's preference. We audio-recorded all interviews and asked participants to formally consent verbally after reading a consent form. Interview recordings were transcribed verbatim using an online service ( | PMC10843168 |
Data management | Data were collected using a mix of paper and electronic methods. Where possible a patient ID number was used rather than identifiable information. Data from paper forms were transcribed into an electronic database in Microsoft Excel stored on secure NHS servers. Paper hard copies were stored at Derby CTSU and in the relevant Investigator Site Files (ISF). Study documentation was stored securely to maintain participant confidentiality and study data integrity.Electronic data captured at trial sites was uploaded to a secure electronic ISF on Microsoft Sharepoint. Online outcome data collection was managed by Amplitude Clinical in ISO27001 Tier 3+ data centres approved for use by the NHS. | PMC10843168 | ||
Results | We recruited the target of 50 patients (stipulated by the funder) within the allocated 12-month time-period. Baseline data are displayed in Summary of baseline data.The CONSORT diagram is shown in CONSORT diagram. | PMC10843168 | ||
Feasibility outcomes | RECRUITMENT | We enrolled the target of 50 participants six weeks ahead of schedule (as shown in Recruitment graph. | PMC10843168 | |
Secondary outcomes | orthosis, injuries | ADVERSE EVENTS, RECRUITMENT | Of the two patient recruitment methods, physiotherapy referral screening provided 49 participants, whereas only 1 participant was recruited from GP record screening (having identified 15 potentially eligible people).The outcome measure return rate at six weeks was 59% (66% online vs 36% paper); at 12 weeks was 65% (68% online vs 55% paper); at six months was 81% (28/38 online versus 5/10 paper, plus four minimum data telephone collections and two paper returns after requests from participants who had originally opted for online). 27/39 (69%) of 6-month data returns included grip-strength measurements using the Squegg device.The descriptive analysis of the patient-reported outcome measures is presented in Descriptive analysis of patient-reported outcome measures.The external responsiveness of individual outcome measures, correlated against the GPE-11 anchor, is displayed in External responsiveness of outcome measures to GPE-11 anchor.Exercise adherence score (median (IQR values)), measured using the EARS questionnaire, at 12 weeks was 15.5 (9.5–21.5) in the OPTimisE group compared to 16 (12–20.75) in the usual care group; at six months 13 (8-21) and 16 (12-23) respectively. Only 6/18 (33%) participants who received the OPTimisE intervention returned their exercise diaries, reporting median adherence of 81% (IQR 74-93).The review of clinical report forms from the usual care group showed that all patients received basic advice about LET and were taught exercises. Few were provided with advice related to lifestyle factors or modifiable risk factors. Exercises often lacked a clear dosing strategy or progression. Three patients received manual therapy treatment from the physiotherapist and one was taught to perform self-administered manual therapy. No patients were provided with an orthosis, although two patients requested advice on how to fit orthoses that they had previously purchased themselves.No related adverse events were reported. One participant was involved in a road traffic collision during their period of treatment. They did not sustain serious injuries and were able to continue their trial participation.From the qualitative interviews, patient and physiotherapist participants both found the OPTimisE intervention to be acceptable and physiotherapists perceived key differences to usual care, related to exercise selection, dose, educational content and provision of the orthosis. The slowing of recruitment after month seven was perceived to be due to a change in referral patterns, with more patients with LET managed by First Contact Practitioners (FCPs)[ | PMC10843168 |
Discussion | disability, NRS, pain | Our results suggest that it is feasible to conduct a full-scale trial to compare the clinical and cost-effectiveness of the OPTimisE intervention compared with usual NHS physiotherapy care. We successfully recruited to target ahead of schedule, but the number of eligible patients identified was lower than predicted based upon site referral data at the planning stage of the project. This was offset by consent rates being far greater (71%) than the conservative feasibility target (25%) set In terms of fidelity, the OPTimisE intervention was delivered as intended to the majority of patients (89%). The pre-defined quantitative criteria for fidelity were binary (i.e. fidelity was achieved or not) but in two cases, fidelity was not achieved because physiotherapists only delivered five of the twelve advice/education topics instead of the six required to satisfy the fidelity criteria. The other remaining criteria, related to exercise prescription and provision of the counterforce brace, were all satisfied.Of the two patient identification methods, the screening of referrals at physiotherapy clinics was most successful, accounting for 49/50 patients recruited. The database screening at GP practices only generated three expressions of interest, with two of those already identified from referral screening, so this method is unlikely to be worthwhile within a future main trial.We found that questionnaire returns were low at six-week follow-up (59%). The follow-up questionnaires were sent at time points determined from the date of randomisation. Some patient participants told us in the interviews that they had not returned the questionnaire due to the fact that they had not yet started treatment or only recently started treatment at the time the questionnaire was sent, due to waiting times for initial physiotherapy appointments. Returns increased by 12-week follow-up to 65% but did not meet the feasibility threshold. We introduced a protocol amendment to allow telephone reminders and minimum data collection at this stage which, coupled with the pre-agreed £20 voucher incentive for six-month data return, resulted in an 81% response, surpassing the feasibility threshold.When we examined the responsiveness of the different PROMs included, the PRTEE measure of function and NRS for pain on gripping showed the highest correlation with patient perceived overall treatment effect. The PRTEE is the recommended primary outcome measure in the core outcome set for LET and the NRS for pain on gripping is recommended for interim use, pending psychometric evaluation (We piloted a method of grip-strength self-measurement using the Squegg device. Grip-strength data were provided in 77% of questionnaire returns, suggesting not all participants could/would use the device. Qualitative data suggested that some participants relied upon the assistance of family to use the device and one person was unable to connect it to their smartphone (Adherence to exercise remains a challenge in physiotherapy trials and is difficult to measure (Although the focus of this pilot and feasibility trial was not on between-group differences (and we did not conduct statistical tests to compare outcomes), the descriptive analysis of the data showed improvements in both groups in health outcomes over 6 months. In some outcomes, the trend was towards greater improvement in the usual care group than the intervention group for disability and perceived overall treatment effect, which was not expected. This may be explained by the usual care provided by the research-active sites involved in the trial being of higher quality than that provided by non-research-active centres more generally. Whilst a fully-powered future RCT would help ascertain whether the intervention is more clinically- or cost-effective than usual care, a future trial using the same intervention approach is unlikely to be desirable given the results of this pilot. A recent systematic review and meta-analysis of LET trials including placebo or wait-and-see controls suggested that following enrolment in a clinical trial, patients experience improvements over time without any active treatment, regardless of symptom duration prior to enrolment (The strengths of this study are that we were able to pilot different methods of participant identification, data collection and outcomes questionnaires, with clear quantitative and qualitative findings that allow us to refine the method of a future main trial. We included patient and public experience in our intervention and trial design. The design was limited by the lack of translation services, potentially resulting in fewer underserved communities being represented, but this could be addressed in the main trial design. | PMC10843168 | |
Conclusion | It is methodologically feasible to conduct a fully powered RCT to compare the clinical and cost-effectiveness of the OPTimisE treatment protocol against usual physiotherapy treatment. However, both intervention and usual care groups showed similar improvements over time, questioning the importance of a future comparative main trial. Future research might now consider comparing whether diagnosis, reassurance and comprehensive self-help advice is non-inferior to usual physiotherapy care in terms of cost-effectiveness. Any future trial would need to be adapted to simplify patient identification, shorten outcome questionnaires and include incentivisation, use online data collection by default, add monthly SMS text message outcomes, include minimum data collection by telephone, and incorporate language translation. | PMC10843168 | ||
Ethics approval and consent to participate | Approvals were received from the Yorkshire & The Humber - Sheffield Research Ethics Committee (reference 21-YH-0121) and the UK Health Research Authority (reference 297637) on June 22nd | PMC10843168 | ||
Trial registration | Registered with the ISRCTN database 19/7/2021. | PMC10843168 | ||
Funding | BATEMAN | Marcus Bateman is funded by a | PMC10843168 | |
Patient and public involvement | orthosis | Patient volunteers were involved with the design of the OPTimisE intervention, selection of orthosis from a range of available products, generation of trial website frequently asked questions and review of trial resources. KC is a member of both the OPTimisE Patient and Public Involvement Group and Trial Management Group, contributing to the trial design, trial website, trial management, interpretation of the data and writing of this report. | PMC10843168 | |
Authors’ contributions | MB, CL, NF, BS, BV and DD were involved in the preliminary design and funding application. MB, CL, NF, BS, JCH, BV, JB, KC, AS and DD designed the trial protocol. All authors contributed to the conduct and management of the trial. MB, BS, CL, KC and JCH conducted the qualitative data analysis. MB and JB conducted the quantitative analysis. All authors contributed to this manuscript. | PMC10843168 | ||
Declaration of competing interest | The authors have no conflicts of interest to declare.This paper presents independent research funded by the | PMC10843168 | ||
References | PMC10843168 | |||
Supplementary data | The following are the Supplementary data to this article. | PMC10843168 | ||
Multimedia component 1 | PMC10843168 | |||
1. Introduction | scaly, injury or cutaneous inflammation, SD | PATHOPHYSIOLOGY, INFLAMMATORY SKIN DISEASE, FACIAL SEBORRHEIC DERMATITIS, SEBORRHEIC DERMATITIS | Facial seborrheic dermatitis (SD) is an inflammatory skin disease characterized by erythematous and scaly lesions on the skin with high sebaceous gland activity. The yeast Seborrheic dermatitis (SD) is a chronic inflammatory skin disease characterized by erythematous, scaling, and indurated papules and plaques on the face, scalp, and upper chest that affects up to 3% of the general population. While aberrant immunological responses are integral to its pathophysiology, these appear to be induced or exacerbated by multiple co-factors, such as an impaired barrier function, environmental factors, and microbial disturbances [Microbial involvement is characterized by the commensal yeast While it is hypothesized that the presence of Based on the high degree of microbial involvement, targeting both the fungal and bacterial microbiome through antimicrobial peptides (AMPs) is hypothesized to be a promising therapeutic option. AMPs are part of the skin’s innate immune response and are upregulated upon injury or cutaneous inflammation, providing an immediate host response against pathogens on the skin [Omiganan is an AMP that is analogous to indolicidin, a bovine member of the cathelicidin family. Its naturally occurring human counterpart LL-37 and derivatives have shown to be effective against selected Ultimately, the broader spectrum activity of AMPs such as omiganan could make these compounds a valuable therapeutic option for patients with SD that might render combination with corticosteroids unnecessary. In this study, we investigated the clinical efficacy, safety, tolerability, microbiological, and pharmacodynamic effects of omiganan 1.75% versus ketoconazole and a placebo in patients with mild-to-moderate facial SD. | PMC10531869 |
2. Results | A total of 115 patients were screened, of which 37 were enrolled into the study and 36 successfully completed the study ( | PMC10531869 | ||
2.1. Omiganan Does Not Show Clinical Improvement Compared to Placebo | DISEASE | Disease severity did not significantly decrease in the omiganan group compared to the placebo, as scored by SDASI (−1.5, CI −3.6 to 0.5, | PMC10531869 | |
2.2. Neither Omiganan Nor Ketoconazole Show Effects on Clinical Imaging Compared to Placebo | Erythema | ERYTHEMA | Erythema was comparable to the placebo in the omiganan group (−0.1682, 95% CI −2.9839 to 2.6475, | PMC10531869 |
2.3. Skin Barrier Function Improves upon Treatment with Ketoconazole | TEWL was not significantly reduced compared to the placebo at EOT for omiganan (−5.935, 95% CI −12.265 to 0.395, | PMC10531869 | ||
2.4. Ketoconazole but Not Omiganan Reduces Malassezia Abundances | Treatment with omiganan did not result in significant mycobial changes, with a −3.662% decrease in | PMC10531869 | ||
3. Discussion | SD, reduction of cutaneous inflammation | DISEASE, ATOPIC DERMATITIS, PATHOPHYSIOLOGY | The use of topical AMPs holds promise for the treatment of SD since both antifungal and antibacterial involvement has been previously established in this disease. In this randomized, comparator- and placebo-controlled clinical trial, the efficacy of 1.75% omiganan gel was compared to its vehicle and standard-of-care 2% ketoconazole cream in a cohort of 36 patients with facial SD. Twice daily administration of omiganan did not result in significantly decreased clinical scores compared to the placebo. In contrast, a significant decrease in disease activity compared to the placebo was observed in the ketoconazole-treated group, which was paralleled by an improved barrier function and a reduced abundance of Multiple physician-reported scores were used to establish a treatment effect that yielded conclusive evidence of disease improvement in the ketoconazole-treated group versus the placebo. Clinical photography and OCT were performed to objectively reinforce these outcomes, but no differences were observed, even though these methods could detect a reduction of cutaneous inflammation over time in previous studies [The absence of significant clinical effects in the omiganan-treated group was unexpected considering the clear microbiome-modulating effects found in vitro and in vivo [While bacterial involvement might not be integral to SD pathophysiology, the involvement of In contrast to omiganan, ketoconazole demonstrated potent fungicidal effects. It remains debated whether ketoconazole’s therapeutic effect can be contributed solely to its ability to impair mycobial cell wall synthesis [Interestingly, the analysis of skin permeability and underlying molecular ceramide markers of barrier integrity yielded significant differences for ketoconazole compared to the placebo. Barrier impairment is a hallmark of atopic dermatitis, and barrier recovery is associated with clinical improvement [In conclusion, this randomized controlled study showed that topical administration of the AMP omiganan was safe and well tolerated but did not lead to clinical improvement in patients with facial SD. Microbial abundances and skin barrier parameters were not significantly altered compared to the placebo, either. In contrast, clinical scores significantly decreased in the ketoconazole group along with a potent fungicidal effect and an improved skin barrier function. This study underlines the efficacy of ketoconazole for the treatment of SD. Additionally, our comprehensive overview of the treatment response of ketoconazole as a comparative treatment supports the idea that | PMC10531869 |
4. Materials and Methods | PMC10531869 | |||
4.1. Materials | ALDRICH | Chloroform (Honeywell, Charlotte, NC, USA), methanol (Biosolve, Valkenswaard, The Netherlands), heptane (LiChorSolv, Merck, Darmstadt, Germany), UPLC-grade isopropyl alcohol (Biosolve, Valkenswaard, The Netherlands), and ethanol (Biosolve, Valkenswaard, The Netherlands) were of HPLC grade or higher. Reagent-grade potassium chloride (Sigma Aldrich, St. Louis, MO, USA) and ultrapure water from a Milli-Q Advantage A10 system (Merck, Darmstadt, Germany) were used. Synthetic ceramides and deuterated standards were purchased from Avanti Polar Lipids (Alabaster, AL, USA) or provided by Evonik (Essen, Germany). | PMC10531869 | |
4.2. Study Design, Randomization, and Treatments | The trial was registered under ClinicalTrials.gov Identifier NCT03688971 and EudraCT number 2017-003106-41. The study was performed from November 2019 to January 2022 at the Centre for Human Drug Research (Leiden, The Netherlands) following the Declaration of Helsinki principles and after obtaining ethical approval from the Stichting Beoordeling Ethiek Biomedisch Onderzoek (Assen, The Netherlands). Patients provided written informed consent prior to participation in the study. This was an evaluator- and subject-blinded parallel design evaluating the synthetic indolicidin analog, omiganan pentahydrochloride, a 12-amino-acid cationic peptide of H-Ile-Leu-Arg-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-Lys-NH | PMC10531869 | ||
4.3. Patients | IGA, SD | Included patients exhibited mild-to-moderate facial SD, as defined by an Investigator’s Global Assessment (IGA) score of ≤2 at screening, without any other clinically significant conditions, recent tanning, or recent exposure to other SD treatments. Recent exposure was defined as two weeks for topical treatments and anti-dandruff shampoo, three weeks for phototherapy, and four weeks for systemic treatment. Diagnosis of SD was confirmed by a dermatologist. | PMC10531869 | |
4.4. Physician- and Patient-Reported Scoring | SEBORRHEIC DERMATITIS | SD severity was scored by the Seborrheic Dermatitis and Severity Index (SDASI) [ | PMC10531869 | |
4.5. Cutaneous Imaging | erythema | ERYTHEMA | Cross-polarized facial photography was performed using a VISIA-CR (Canfield Scientific, Parsippany-Troy Hills, NJ, USA). The erythema index was determined through ImageJ (version 1.51 h CITE) based on Yamamoto et al. [ | PMC10531869 |
4.6. Trans-Epidermal Water Loss Measurements | Trans-epidermal water loss (TEWL) was determined using an AquaFlux AF200 (Biox Systems Ltd., London, UK) after the subjects acclimatized to the controlled environmental conditions (humidity < 60%, temperature 22 ± 2 °C) for at least 15 min. TEWL was normalized with an additional measurement of non-lesion skin elsewhere on the face to account for between-day variation, as described before [ | PMC10531869 | ||
4.7. Lipidomics Analysis Using Sebum Measurements and Liquid Chromatography-Mass Spectrometry after Tape-Stripping | Sebum levels were measured in triplicate on adjacent skin using a Sebumeter SM815 (Courage and Khazaka, Cologne, Germany). The average of three measurements was calculated. For lipidomics, the stratum corneum was sampled with 5 subsequent polyphenylene sulfide tape strips (Nichiban, Tokyo, Japan), of which the first one was discarded. Pressure was applied to each tape with a D500 D-squame Pressure Instrument (CuDerm Corporation, Dallas, TX, USA). A 16 mm-diameter hole was punched out from the section that was pressed onto the skin, and the tape was stored in chloroform:methanol (2:1). For extraction, tapes were shaken at 40 °C for one hour each in chloroform:methanol (2:1), chloroform:methanol:water (1:2:0.5), chloroform:methanol (1:1), and heptane:isopropylalcohol (1:1). The solvent was collected, and a liquid–liquid extraction was performed with the addition of 0.25 M potassium chloride. The organic layer was washed with chloroform, filtered with 0.45 µm PVDF syringe filters (Grace, Deerfield, IL, USA), and concentrated. Analysis was performed as described by Boiten et al. [ | PMC10531869 | ||
4.8. Microbial Profiling | SKIN, STERILE, LYSIS | Skin was swabbed for 10 s while constantly rotating using a sterile polyester-tipped applicator (Puritan, Guilford, ME, USA) soaked in 0.9% NaCl. Swabs were stored in DNA/RNA shield lysis buffer and beat beads (Zymo Research, Irvine, CA, USA) at −80 °C until analysis. Extraction, sequencing, and data generation were performed at Baseclear B.V. (Leiden, The Netherlands). Extraction was performed using a ZymoBIOMICS DNA Miniprep Kit (Zymo Research) according to the manufacturer’s instructions. The sample was split, and 16s RNA region v3–v4 or internal transcribed spacer region 2 (ITS2) sequencing was performed on a NovaSeq 6000 or MiSeq (Illumina, San Diego, CA, USA) after the appropriate sample quality control, for bacterial and fungal profiling, respectively. The reads were classified using the RDP database for bacterial [ | PMC10531869 | |
4.9. Malassezia Species Identification by Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry | Agar plates of 5.5 cm in diameter with modified Dixon agar medium (Tritium Microbiology B.V., Eindhoven, The Netherlands) were pressed against the skin for 20 min. Plates were transferred to the Alrijne Hospital (Leiden, The Netherlands) and cultured for up to 21 days at 33 °C. If mycological growth was observed, an isolate was taken and frozen in microbank 2D tubes (pro-lab diagnostics, Richmond Hill, ON, Canada). Isolates were transported to the Westerdijk Fungal Biodiversity Institute (Utrecht, The Netherlands), defrosted, and further cultured on modified Leeming and Notman medium before analysis using matrix-assisted laser desorption ionization–time of flight mass spectrometry, as described by Kolecka et al. [ | PMC10531869 | ||
4.10. Statistical Analysis | Calculations were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Group size was based on a previous trial with omiganan with significant clinical effects rather than a formal power calculation [ | PMC10531869 | ||
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10531869 | ||
Author Contributions | Conceptualization, M.B.A.v.D., R.R., J.B., T.N.-v.d.K., G.L.F., M.S. and J.R.; methodology, M.B.A.v.D., R.R., T.N.-v.d.K., G.L.F., M.L.d.K. and J.R.; software, H.E.C.v.d.W.; formal analysis, M.L.d.K., H.E.C.v.d.W. and J.R.; investigation, M.B.A.v.D., T.N.-v.d.K., J.H., B.T., T.G., L.P., A.N., M.S. and J.R.; data curation, T.N.-v.d.K., J.H., H.E.C.v.d.W., B.T., T.G., L.P., A.N., M.S. and J.R.; writing—original draft preparation, J.R.; writing—review and editing, M.B.A.v.D., R.R., J.A.B., T.N.-v.d.K., G.L.F., B.T., A.N., L.P., M.S. and J.R.; visualization, M.L.d.K. and J.R.; supervision, M.B.A.v.D., R.R. and J.A.B.; funding acquisition, R.R., M.B.A.v.D. and G.L.F. All authors have read and agreed to the published version of the manuscript. | PMC10531869 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and reviewed and approved by the Stichting Beoordeling Ethiek Biomedisch Onderzoek (IRB approval number: CHDR1733, NL62759.056.18, approved on 5 September 2018). | PMC10531869 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10531869 | ||
Data Availability Statement | The data that support the findings of this study are available from the corresponding author and/or trial sponsor upon reasonable request. | PMC10531869 | ||
Conflicts of Interest | Cutanea | MINOR | G.L.F. was an employee of Cutanea Life Sciences and involved in the design of the study and review and approval of the final manuscript. Comments made by G.L.F. were minor and did not change the message of the manuscript. The other authors have no conflict of interest to declare. | PMC10531869 |
References | ADVERSE EVENTS | (((The change in relative abundance of (Demographics of the study population and adverse events. | PMC10531869 | |
Background | Blinding drugs through simulation techniques is an important means to control the subjective bias of investigators and subjects. However, clinical trials face significant challenges in the placebo production of drugs, and many trials cannot be double-blinded. | PMC10636892 | ||
Objective | BLIND | This study was conducted to ascertain the consistency between non-blind and blind evaluation results in clinical trials and to pioneer strategies to control information bias, particularly in trials where double-blinding is not feasible. | PMC10636892 | |
Methods | Diabetic Foot (IWGDF), was used as the primary, DFIs | DIABETIC FOOT INFECTIONS, INFECTIOUS DISEASE | In this investigation, a randomized controlled trial (RCT) studying diabetic foot infections (DFIs) was utilized as a representative case. In this trial, the grading of DFIs, as per guidelines by the Infectious Disease Society of America (IDSA) and International Working Group on Diabetic Foot (IWGDF), was used as the primary efficacy indicator. A sample of sixteen patients was randomly chosen from the RCT, and DFI grading was assessed jointly by both non-blinded investigators and blinded center-reading investigators. A consistency test was then deployed to compare the evaluation results, forming the basis for our proposed strategies for effective blinded evaluation. In addition, other perspectives were collected at the end of this study, including with those involved in designing and conducting the recent blinded evaluation trial. | PMC10636892 |
Results | Five subjects were excluded due to the quality of photos or the lack of post-treatment visits. The post-treatment IDSA/IWGDF grading results were compared in 11 subjects (experimental group=6, control group=5), and the consistency test showed inconsistent results between the non-blinded and center reading blinded evaluations (Kappa=0.248, | PMC10636892 | ||
Conclusions | The study highlighted that evaluations from non-blinded site investigators may potentially exaggerate the efficacy of the experimental group and that deep wounds can present challenges for observation via center-reading photos. These findings underline the vital necessity for objective assessment in open clinical trials, especially those where wound observation serves as the primary efficacy indicator. The study suggests the adoption of independent blinded investigators at each site, complemented by a comprehensive set of standard operating procedures for blinding evaluation. These measures could serve as an effective counterbalance to subjective bias, thereby augmenting the credibility and consistency of results in open clinical trials. The implications of these findings and recommendations could be of great significance for the design and execution of future open clinical trials, potentially bolstering the quality of clinical research in this area. | PMC10636892 | ||
Trial registration | ChiCTR2000041443. Registered on December 2020 | PMC10636892 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07652-y. | PMC10636892 | ||
Keywords | PMC10636892 | |||
Introduction | EVENT, BLIND | The application of the most reliable evidence to address individual clinical issues underpins the core principle of evidence-based medicine [However, due to the particularity of certain interventions, it becomes challenging to blind participants and investigators in some clinical trials. Recent investigations have highlighted that traditional Chinese medicine (TCM) clinical trials encounter significant obstacles in placebo production, rendering some medications unsuitable for double-blind controlled trials [In this study, we use an open randomized controlled trial of TCM as an example to compare the outcomes of unblinded and blinded evaluations. Furthermore, we propose several strategies for implementing blinded evaluations in clinical trials, which encompass aspects such as staff allocation, training, participant management, trial drug administration, efficacy indicator collection, and safety event management. | PMC10636892 | |
Methods | PMC10636892 | |||
Designs | trauma, DFIs | DIABETIC FOOT INFECTIONS | A multicenter RCT on diabetic foot infections (DFIs) was taken as an example. This trial evaluated the efficacy and safety of a Chinese patent medicine. Patients with DFI, aged between 18 and 75 years, and IDSA/IWGDF grade 2 were included [There is a greater risk of using a placebo control for patients in this trial. Furthermore, placebos are challenging to match the investigational drug in terms of color, texture, and odor [To ensure the objectivity and consistency of the test results, using objective evaluation methods to evaluate the efficacy indicators is necessary. We envisioned a blinded evaluation of efficacy indicators using a center-reading blinded method. The center-reading blinded method refers to using a digital camera to take pictures of the condition of the subject’s foot and using the image analysis software ImageJ to analyze the trauma area. We compared the differences between unblinded and center-reading blinded evaluations to investigate whether this method better reflects an accurate picture of efficacy. In addition, other perspectives were collected at the end of this study, including with those involved in designing and conducting the recent blinded evaluation trial. | PMC10636892 |
Setting | This was an exploratory study, and we randomly selected only about 10% of the completed clinical trial subjects for blinded and unblinded evaluations ( | PMC10636892 | ||
Non-blinded investigators | infection, fever, pain | INFECTION, APPENDIX | The IDSA/IWGDF grading of DFI was determined and recorded by a non-blinded investigator at the study center for post-treatment patients. A note was made as to whether the subject had local pressure or pain, local fever, systemic symptoms, or symptoms of infection at the time of photography. For the randomly selected subjects, the results of IDSA/IWGDF grading and notes will be filled in the “Study Center Grading Results Evaluation Form” (Appendix | PMC10636892 |
Blinded investigators | center-reading | BLIND | Based on the “Study Center Grading Results Evaluation Form,” the center-reading investigators made independent determinations back-to-back in a blind state. A third center-reading investigator made a second determination if two center-reading investigators made inconsistent determinations. | PMC10636892 |
Evaluation | IDSA/IWGDF grading: Assessing the IDSA/IWGDF grading of non-blinded and blinded investigators. | PMC10636892 | ||
Quality control and assurance | Previously, we provided better training to the investigators involved in this study’s blinded and unblinded clinical assessment. We believe that the main source of the difference between blinded and unblinded researchers’ evaluation of post-treatment outcomes is evaluation bias, which is the effect of unblinded personnel’s knowledge of the grouping on the evaluation results. For quality improvement methods, data analysis, and reporting, Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) were referenced [ | PMC10636892 | ||
Statistical analysis | An independent statistician will carry out statistical analysis using the SPSS 25 software. All statistical tests will be two-sided, | PMC10636892 | ||
Results | PMC10636892 | |||
Results for blinded evaluation | Among the 16 randomly enrolled patients, one was excluded due to a lack of post-treatment follow-ups, and 4 were unable to be analyzed as the central reader could not discern the deeper parts of the wounds from the photographs. The randomization and follow-up process for patients is illustrated in Fig. Flow chart for subjectThe post-treatment IDSA/IWGDF gradings were compared across 11 subjects, revealing inconsistencies between non-blinded and center-reading blinded evaluations according to the consistency test (Kappa=0.248, Within the experimental group, three cases were deemed grade 1 by the non-blinded evaluation and were rated grade 2 by the center-reading blinded evaluation. Inconsistencies were also observed within this group between non-blinded and blinded evaluations (Kappa=0.273, In the control group, three cases considered grade 2 in the non-blinded evaluation were rated as grade 1 in the center-reading blinded evaluation. Here too, inconsistencies between non-blinded and blinded evaluations were detected (Kappa=0.273, Comparison of IDSA/IWGDF grading results after treatmentComparison of IDSA/IWGDF assessment results after treatment in the trial groupComparison of IDSA/IWGDF assessment results after treatment in the control group | PMC10636892 | ||
Considerations for blinded evaluation | In open clinical trials where wound observation serves as the primary efficacy measure, we recommend the appointment of an independent blinded investigator at each trial site, accompanied by the implementation of a series of standard operating procedures (SOPs) for blinded evaluation. The ensuing considerations for blinded evaluation are explored from three perspectives: safeguarding participants' rights, minimizing bias, and optimizing clinical operability. | PMC10636892 | ||
Personnel roles and training | BLIND | We advise establishing clearly delineated roles among the research team, which may include treatment investigators, blinded evaluation investigators, research nurses, quality control officers, medication administrators, and documentation managers.The investigator responsible for efficacy evaluation remains blinded throughout the study, while all other personnel are unblinded. Staff roles should be defined and authorized prior to the trial (refer to Table List of responsibilities of principal investigators1. Receipt of medication into storage and maintenance;2. Distribution and recovery of drugs, medication compliance records.1. Requesting randomization and medication numbers for patients on the central randomization system;2. Prescribing.3. Wound clearing and dressing changes were performed on the subjects1. Pick-up medication;2. Assisting the treatment investigator with wound cleaning and medication change operations.1. Screening of subjects;2. Observation and evaluation of the efficacy index and safety index.1. Develop a quality control plan;2. Audit to maintain a blind state of operating procedures;3. Implement quality control according to the quality control plan.1. Preparation, organization, and filing of all documents;2. Manage and save files separately by blind and non-blind types. | PMC10636892 | |
Management of participants | Given the external nature of the treatment employed in this study, achieving absolute blinding of participants was challenging. First, both treatment investigators and research nurses should be strictly instructed not to reveal specific treatment protocol details to patients. Secondly, to minimize the potential for inter-patient communication, it is advisable to avoid accommodating patients from different treatment groups in the same room. Lastly, patients must receive thorough education and it must be emphasized that they should not share their treatment information with anyone except their treating physician and research nurse. The participants’ understanding of these crucial blinding maintenance requirements will be assessed during the participant screening process. Any participant unable to comprehend these requirements will not be included in the study. | PMC10636892 | ||
Management of experimental medications | EVENT | It is recommended that a medication manager be appointed within the study team, responsible for the receipt, storage, maintenance, distribution, and retrieval of medications. The medications should be stored in opaque medicine cabinets. Prior to prescribing, the treatment investigator must obtain a randomization number and drug number from the central randomization system, following which the study nurse is instructed to retrieve the medication from the medication manager. During this process, the medication manager should ensure neither the blinded study personnel nor patients are present. The study nurse collects the medication and directly transfers it to the treatment investigator, taking care to avoid the presence of blinded center-reading investigators. If for any reason the medication cannot be immediately utilized following collection, it should be temporarily stored in areas inaccessible to blinded personnel. In the event a participant withdraws from the trial, the study nurse should promptly return the unused medication to the medication manager. | PMC10636892 | |
Collection of efficacy indicators | infection, purulent | INFECTION, EPITHELIALIZATION | Though the wounds in this study were documented using digital photography and analyzed with image analysis software, factors such as environment, operational procedure, and patient positioning may influence the quality of the images. As such, a blinded assessment investigator should be assigned to document wound healing rates. Additionally, within this study, blinded investigators at the research center should determine the infection control rate, the score for quantitative TCM evidence, and the degree of epithelialization in wound healing. Prior to collecting these indicators, it is recommended that the following process and division of labor be adhered to (i) the treatment investigator and study nurse should remove all dressings, document any purulent discharge from the wound, and perform routine disinfection and cleaning of the wound; (ii) the study nurse should then notify the blinded evaluation investigator; and (iii) the blinded evaluator should proceed with the efficacy evaluation and capture the necessary photographs. | PMC10636892 |
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