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Anthropometric and Body Composition Data | Participants who were unable to come to the study site were asked to provide a self-reported weight. These weights were not included in the final analyses, but the number of participants self-reporting weights are included in the CONSORT diagram to indicate continued engagement with the study ( | PMC9857469 | ||
Dietary and Questionnaire Data | Participants completed three 24-hour dietary recalls, which were averaged to create a mean energy intake at each time point (baseline and 3, 6, 12, and 24 months). Participants were also asked what medications they were currently taking. Dietary adherence was assessed by examining recommended animal product intake for 5 food groups via the averaged dietary recalls at each assessment time point. Participants received 1 point for each food group (omni: eggs, ≤0.3 servings per day; seafood, ≥0.3 servings per day; poultry, ≤1 serving [3 oz; 84 g] per day; red meat, ≤0.67 serving [2 oz; 56 g] per day; and dairy, ≥2 servings per day; vegan: received 1 point for 0 servings per day within each food group). Adherence scores were dichotomized such that scores of 2.5 or higher were considered mostly adherent. | PMC9857469 | ||
CVD Risk Factors | CVD, blood pressure | To assess changes in risk factors for CVD, blood pressure was taken along with a fasting lipid panel (total, LDL, and high-density lipoprotein cholesterol, and triglycerides), glucose, and insulin. Details on these procedures have been provided elsewhere. | PMC9857469 | |
Dietary and Behavioral Interventions | Apart from the diet prescribed, participants received similar behavioral interventions. Participants attended weekly group-based classes for 6 months, biweekly for 6 months, and monthly for 12 months. Participants were provided with additional electronic content: a website to access study materials and recordings of class sections, which they could view to make up a missed class; a private Facebook group starting at 6 months; and biweekly podcasts and newsletters starting at 12 months. Behavioral strategies for the classes were informed by Social Cognitive TheoryThe diets used in NEW Soul are described elsewhere, | PMC9857469 | ||
CONSERVE (CONSORT and SPIRIT Extension for Randomized Clinical Trials Revised in Extenuating Circumstances) Detailing the Alterations Made to Intervention and Assessments Based on COVID-19 | Questionnaires were all conducted online. In-person weight and laboratory assessments were delayed until June 2020 when approval from the university was granted. The following adjustments were made to laboratory procedures to ensure social distancing and safety of participants:Appointment times were lengthened to avoid overlap between participants.For cohort 1, 24-mo weight, blood pressure, and blood samples were collected.No dual-energy x-ray absorptiometry scans or body circumference measures were taken to reduce appointment time and close contact.For cohort 2, 12-mo weight, blood pressure, blood samples, and dual-energy x-ray absorptiometry were collected.For participants who did not want to return to in-person assessments, staff provided an option for participants to have their weight assessed outside or to provide a self-reported weight.We continued the nutrition intervention components until assessments could be completed. | PMC9857469 | ||
Statistical Analysis | weight loss | Data analysis was performed from March to June 2022. The study statisticians (E.A.F. and B.H.) were blinded to group assignment when completing all analyses. Descriptive statistics were used to present baseline characteristics, and independent Subanalyses were also conducted to examine 12-month weight loss in cohort 1 (before COVID-19) and cohort 2 (after COVID-19 onset). The model used to compare weight change between treatment conditions was modified to examine differences in weight change between cohorts. Rather than group, time, and group-by-time interaction effects, this model contained cohort, time, and group-by-cohort effects for both treatment groups combined. Covariates were the same as in the primary weight loss model. All analyses were conducted as planned in our original analysis plan, except for the analysis by cohort, which was conducted before unblinding of the data and after analysis of the initial results to compare weight loss among participants in the study before and during the COVID-19 pandemic.Sample size calculations have been described elsewhere. | PMC9857469 | |
Results | The CONSORT diagram for the study is shown in | PMC9857469 | ||
Main Outcomes of Weight Loss and Changes in Lipids, by Group | high-density lipoprotein | Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.SI conversion factors: To convert HDL cholesterol to millimoles per liter, multiply by 0.0259; LDL cholesterol to millimoles per liter, multiply by 0.0259; total cholesterol to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0259.All models were adjusted for baseline socioeconomic status (education and employment), food security status, sex, age, and use of medications that may impact the examined outcome. For lipid outcomes, use of lipid-lowering medications at the examined time point were included in the model.Primary outcomes occurred at the 12-month assessment measure. | PMC9857469 | |
Changes in Secondary Outcomes of Energy Intake, Body Composition, and Glucose, Insulin, and Blood Pressure, by Group | pandemic).Weight loss, Weight loss, weight loss, hypertensive | SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; high-density lipoprotein cholesterol to millimoles per liter, multiply by 0.0259; insulin to picomoles per liter, multiply by 6.945.All models were adjusted for baseline socioeconomic status (education and employment), food security status, sex, age, and use of medications that may impact the examined outcome. For glucose and insulin outcomes, use of diabetes-related medications at the examined time point were included in the model. For blood pressure, use of hypertensive medications at the examined time point were included in the model.Primary outcomes occurred at the 12-month assessment measure.Because of the COVID-19 pandemic, body circumference measures were not taken after the 6-month assessments (which were all conducted prior to the pandemic).Weight loss that occurred in cohort 1 (67 participants) was compared with weight loss that occurred in cohort 2 (92 participants). Weight loss did not differ at 3 months (mean, cohort 1 vs cohort 2, –1.65 kg [95% CI, –2.76 to –0.53 kg] vs –1.56 kg [95% CI, –2.50 to –0.62 kg]; | PMC9857469 | |
Discussion | Weight loss, weight loss | CVD, HEART | NEW Soul is one of the first long-term, randomized clinical trials comparing the effects of 2 different healthy soul food diets on changes in body weight and CVD risk factors among African American individuals. Although most outcomes were in the hypothesized direction, there were no differences between the groups, and the magnitude of changes overall was small. It is possible that the COVID-19 pandemic impacted the results. Weight loss was greatest at 6 months, which is similar to other weight loss interventions among adults withIt is also possible that the diets selected were too similar to produce significant differences. Both diets were based on the Oldways African Heritage Diet, which is heavily focused on PBDs. The 6 lessons in the A Taste of African Heritage program all centered around plants (herbs and spices, greens, whole grains, beans and rice, tubers and stews, and fruits and vegetables).In addition, the COVID-19 pandemic had significant impacts on diet and physical activity interventions,Few weight-loss and CVD risk factor reduction randomized clinical trials have been conducted solely among African American individuals. Many previous weight loss interventions have included both African American and White adults, included mostly women,There have also been limited studies conducted with African American individuals that examine the adoption of different dietary patterns. As part of the Heart Healthy Lenoir Project, African American individuals who enrolled in a 6-month Mediterranean diet intervention to reduce CVD risk factors had improvements in dietary intake, physical activity, and blood pressure, but saw modest weight loss. | PMC9857469 |
Limitations | CVD | The results of this study should be considered within the context of its limitations. The study population was highly educated, mostly women, and living in the South and, therefore, may not be generalizable to other populations. Although objective measures were used for weight, body composition, and CVD risk factors, dietary intake and food security status were self-reported. High-density lipoprotein cholesterol levels can differ by sex, | PMC9857469 | |
Conclusions | weight loss | CVD | In this randomized clinical trial examining weight loss and CVD risk factor reduction among African American individuals, there were no significant differences in weight loss and changes in lipids and blood pressure among African American individuals randomized to either healthy soul food vegan or omnivorous diets. The changes in intervention delivery that necessitated a switch to online classes most likely reduced the impact of the study, lessening the differences between the groups. Future research should examine additional strategies to enhance adherence to PBDs, such as testing the intervention in a nonuniversity, community-based setting or providing ready-to-eat meals. | PMC9857469 |
References |
Trial Protocol and Statistical Analysis Plan
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Data Sharing Statement
Click here for additional data file. | PMC9857469 | ||
Background: | fatigue, anxiety, cancer, depression, Cancer | CANCER, CANCER | Cancer patients often suffer from psychological symptoms and need psychological support. Especially during the COVID-19 pandemic, eHealth interventions might be helpful to overcome the obstacles of the pandemic. This study evaluates the effectiveness of a video sequence-based eHealth intervention on anxiety, fatigue, and depression in cancer patients. | PMC9940180 |
Methods: | tumor, anxiety | TUMOR, SECONDARY | Patients (N = 157) with different tumor entities were randomly assigned to the video intervention group (IG) and the waiting control group (CG). Patients in the IG received a video intervention comprising 8 video sequences over 4 weeks. The videos included psychoeducation on distress and psychological symptoms, Acceptance and Commitment Therapy elements, and Yoga and Qigong exercises. Patients’ anxiety and fear of progression (primary outcomes) and secondary outcomes were assessed before randomization (T1) and after the end of the intervention for IG or the waiting period for CG (T2) using self-reported questionnaires (GAD-7, PA-F-KF, EORTC QLQ-FA12, PHQ-8). | PMC9940180 |
Results: | anxiety | Patients of the IG showed no significant improvement in anxiety (GAD-7; | PMC9940180 | |
Conclusions: | The video intervention was ineffective in reducing the psychological burden compared to a waiting CG. The findings support prior observations of the value of therapeutic guidance and promoting self-management for improving patients’ psychological burdens. Further studies are required to evaluate the effectiveness of psycho-oncological eHealth delivered through video sequences. | PMC9940180 | ||
Introduction | tumor, fatigue, anxiety, cancer, depression | CANCER, TUMOR | Every year about 500.000 people in Germany develop cancer.The COVID-19 pandemic could have worsened these problems,We hypothesized:(1) The participants in the video sequence-based IG will have significantly more improved anxiety levels and fear of progression than the participants in the waiting CG after the end of therapy (primary outcome).(2a) The participants in the video sequence-based IG will have significantly more improved values for fatigue after the end of therapy than the participants in the waiting CG.(2b) The participants in the video sequence-based IG will have significantly more improved values for depression after the end of therapy than the participants in the waiting CG.Moreover, we investigated the following exploratory questions regarding the further implementation of digital psycho-oncological offers for cancer patients within the acute care setting.Are there certain patient groups who benefit more from the intervention than others, regarding sex, therapy status, therapy goal and tumor entity?Does therapy adherence have an effect on the outcomes within the IG? | PMC9940180 |
Methods | PMC9940180 | |||
Trial Design | tumor, Cancer | TUMOR, CANCER | The study was a single-center, prospective, randomized, controlled intervention study with a waiting CG performed at the University Hospital of Wuerzburg, Comprehensive Cancer Center Mainfranken (CCCMF). The Ethics Committee of the University of Würzburg approved the study on 23.04.2021 (Nr. 123/20-me).Cancer patients with diverse tumor entities and acute appointments in institutions of the CCCMF (interdisciplinary oncological therapy outpatient clinic (IOT), various oncological stations of the University Hospital Wuerzburg, and ambulatory psycho-oncology patients) were evaluated by medical records. Eligible patients were contacted on site or by telephone and asked to participate in the study. Afterward, we sent a written patient information sheet and consent form to interested patients contacted by telephone. After signing the consent form and completing the first questionnaire to collect the baseline values (T1), participants were randomly assigned to the IG or CG using a computer-generated list of random numbers. We used a randomization procedure with an allocation ratio of 1:1. A list of participants’ anonymous study numbers was used for external randomization. A scientific member of the Institute of Clinical Epidemiology, University of Wuerzburg, performed randomization (central randomization per envelope), guaranteeing allocation concealment.Then the participants of the IG received the video intervention for 4 weeks, while the participants of the CG had a 4-week waiting period and did not receive any comparable therapy. Both groups completed another questionnaire at the end of this period (T2). After the post-intervention survey, the CG also received a 4-week intervention.Sample size was powered to detect a medium-sized between-group effect ( | PMC9940180 |
Participants | malignant tumor disease | The inclusion criteria were a malignant tumor disease in the history of the patient, a minimum age of 18 years, and informed consent to participate in the study. There was no preselection regarding the current stress level. Exclusion criteria were insufficient German language ability and severe physical or mental impairments. The patients were recruited from June to September 2020 within the CCCMF facilities. Patient flow | PMC9940180 | |
Intervention | Overall, the intervention comprised 8 videos, each about 10 to a maximum of 30 minutes in length. The structure of all units was similar. Each sequence started with imparting knowledge on the respective topic. There was both an explanation of the backgrounds and meanings of the respective symptoms and assistance using elements of different psycho-oncological tools in order to be able to manage symptoms. The psychoeducation was supported in each case by text slides and illustrations. Yoga, relaxation, or Qigong exercises were implemented at the end of each video. Two ACT core processes (ie, contact with the present moment and defusion) are addressed through parts of the education and exercises in specific video sequences. An experienced psycho-oncologists/psychotherapist who is also a certified yoga teacher performed the video intervention (7 out of 8 sequences). The Qigong sequence was administered by an experienced psycho-oncologist/psychotherapist who is also a qualified Qigong instructor. The yoga exercises were already evaluated in previous trials.Video Sequences.The participants were given access to a website, on which 2 video sequences were provided weekly for 4 weeks. The patients could watch them via desktop/laptop or tablet as often as they wanted and save the videos and a summary of the exercises. Participants were notified by email each time new videos were available. Technical problems could be announced to an assistant, but problems were rare. | PMC9940180 | ||
Measures | PMC9940180 | |||
Statistical Analysis | breast cancer, tumor, hem, hemato-oncological malignancies | BREAST CANCER, TUMOR, DELETION | For the analysis, the differences in the outcomes of T1 and T2 were calculated to retain the target variable change. These changes were compared between IG and CG. Questionnaires with missing values were removed from the evaluation. Thus, outcomes were analyzed by pair-wise deletion. Shapiro-Wilk and Levene tests were used to test for normality and homogeneity. Wilcoxon Rank Sum Tests for independent samples were used where the assumptions were not met. Furthermore, we explored intervention effects within specific subgroups, that is, gender (female, male), therapy status (currently in therapy, currently not in therapy), therapy goal (curative, palliative), and the 2 most common tumor entities (hemato-oncological malignancies (hem), breast cancer (bc)). Additionally, the influence of therapy adherence on the outcome was explored within the IG with unpaired 2-sample Wilcoxon Rank Sum Tests comparing the outcomes of participants who watched all the video sequences and participants who watched only part of the videos. All statistical analysis was performed using IBM SPSS Statistics (International Business Machines Corporation Statistical Package for Social Sciences), Version 26, R (Software Version 4.1.1), and RStudio (Version 1.4.1717). | PMC9940180 |
Results | PMC9940180 | |||
Intervention Adherence and Evaluation | The intervention had a high level of acceptance as 93.9% stated that their initial expectations regarding the intervention were at least more likely to be fulfilled and 88.2% stated they would be at least likely to participate in such an intervention again, and 98.5% would recommend it to other patients. Mean ratings of content, selection of exercises, and the usefulness of the sequences were good (Evaluation and Use of the Video Sequences.Abbreviations: n, number of patients; SD, standard deviation. | PMC9940180 | ||
Discussion | tumor, fatigue, anxiety, cancer, depression | CANCER, TUMOR, BLIND | This study showed no improvement in anxiety, fatigue, and depression after a 4-week eHealth intervention in video sequences compared to a waiting CG. A follow-up study 3 months after the end of the intervention will examine the possible long-term changes. Though the results of IG and CG did not significantly differ, there was a high recommendation rate of the intervention among the participants of the IG. Unlike most other studies in this field, this study included a very heterogeneous population, which corresponds to the need for studies on a broader range of cancer patients.The study has several limitations that need to be considered. First, the trial had a waiting-only CG that received no treatment. Participants were not blind to the allocated intervention. Second, there was no possibility of controlling intervention adherence as the participants watched the videos at home. Third, the results of this trial are not generalizable to all tumor entities. However, we included patients with subjective needs for psycho-oncological support. Fourth, we conducted no screening concerning psychological burden. More significant changes might have been achieved in cancer patients with higher symptom severity. Finally, we used different therapeutic tools to create the intervention. Therefore, it is impossible to determine which of the methods used have the highest potential to reduce the symptom burden for each objective in each patient. | PMC9940180 |
Conclusions | fatigue, depression, anxiety | The intervention could not improve the anxiety, fear of progression, fatigue, or depression compared to the waiting CG. However, both groups showed decreased symptoms during the intervention period. In addition, there was high satisfaction and adherence with the intervention among the participants of the IG. Hence, our findings support the observation that more interactive therapeutic guidance and self-management tools might be necessary to improve the impact on patients’ mental health. Thus, further studies are required to evaluate the effectiveness of eHealth delivered through video sequences. Those studies might focus on only 1 or 2 of the therapeutic elements used in this trial to increase the results’ generalizability and informative value. This trial can serve as a further step toward the development of a digital model for the delivery of psycho-oncologic content that is highly scalable, widely disseminable at low cost, and works regardless of the pandemic situation while giving a direction for future targeted eHealth interventions for the management of the examined target variables. | PMC9940180 | |
Supplemental Material | PMC9940180 | |||
References | PMC9940180 | |||
Background | Overconsumption is one of the most serious public health challenges in the UK and has been linked to increased consumption of food ordered through delivery platforms. This study tested whether repositioning foods and/or restaurant options in a simulated food delivery platform could help to reduce the energy content of users’ shopping basket. | PMC10197857 | ||
Methods | REGRESSIONS | UK adult food delivery platform users (N = 9,003) selected a meal in a simulated platform. Participants were randomly allocated to a control condition (choices listed randomly) or to one of four intervention groups, (1) food options listed in ascending order of energy content, (2) restaurant options listed in ascending order of average energy content per main meal, (3) interventions 1 and 2 combined (4) interventions 1 and 2 combined, but food and restaurant options repositioned based on a kcal/price index to display options lower in energy but higher in price at the top. Gamma regressions assessed the impact of interventions on total energy content of baskets at checkout. | PMC10197857 | |
Results | The energy content of participants’ baskets in the control condition was 1382 kcals. All interventions significantly reduced energy content of baskets: Compared to control, repositioning both foods and restaurants purely based on energy content of options resulted in the greatest effect (-209kcal; 95%CIs: -248,-168), followed by repositioning restaurants (-161kcal; 95%CIs: -201,-121), repositioning restaurants and foods based on a kcal/price index (-117kcals; 95%CI: -158,-74) and repositioning foods based on energy content (-88kcals; 95%CI: -130,-45). All interventions reduced the basket price compared to the control, except for the intervention repositioning restaurants and foods based on a kcal/price index, which increased the basket price. | PMC10197857 | ||
Conclusions | This proof-of-concept study suggests repositioning lower-energy options more prominently may encourage lower energy food choices in online delivery platforms and can be implemented in a sustainable business model. | PMC10197857 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12966-023-01456-8. | PMC10197857 | ||
Keywords | PMC10197857 | |||
Background | OVERWEIGHT AND OBESITY | Overweight and obesity contribute to poor health globally [Analyses of major UK restaurant chains showed that only 9% of dishes had an energy content of less than 600 kcals a meal, and 47% of dishes were at least 1000 kcals or more, which equates to half of the daily-recommended energy intake for a woman [The environments in which food is purchased influence our behaviours. Automatic reactions to how options are presented to us in our environment, sometimes lead to choices and behaviours that may detrimentally affect our health [Studies looking at the impact of such choice architecture interventions in restaurant-type settings have found that increasing availability of healthy foods, promotion and pricing changes were all effective in changing purchasing decisions [This proof-of-concept study explores how interventions repositioning lower-energy options to be more prominent influence food choices in a simulated food delivery platform and if these interventions can help to reduce the amount of energy selected. | PMC10197857 | |
Methods | PMC10197857 | |||
Design | This was a five-arm randomised controlled trial. Participants were recruited to obtain a UK representative sample, with specific quotas set for age, gender, location, and income. Quotas were set based on data from the UK Office for National Statistics [ | PMC10197857 | ||
Interventions | This study was conducted using ‘Take a BITe’, a simulated food delivery platform created and hosted by the Behavioural Insights Team. The platform has a similar design to real-world food delivery platforms such as Deliveroo, UberEats, and JustEat. There were 21 restaurants and 570 food or drink items, each in three different portions (i.e. 1710 individual food options in total). Data were used from research on the nutritional content of takeaway food options [
Screenshots of the 'Take a BITe’ online platform, showing (The five study conditions (shown illustratively in Fig.
Control (C): restaurants and foods positioned in a random order. Food items were randomly ordered within food categories, but the order in which food categories appear was not randomised (e.g. starters presented first, followed by mains, etc.).Foods only (F): all food items listed in ascending order of energy content within each restaurant and food category (e.g. starters, mains), with restaurants ordered at random.Restaurants only (R): restaurants listed in ascending order of average energy content per main meal, with foods listed at random within restaurant menus.Foods and restaurants (FR): a combination of interventions 1 and 2, where foods were listed in ascending order of energy content in menus and restaurants were listed in ascending order of average energy content per main meal.Foods and restaurants plus price (FRP): restaurants and foods were repositioned as in intervention 3, but this time using a kcal-price index. For the restaurant order, the index was calculated by dividing the average energy content of mains by the average price of mains for each restaurant. For the food order within food categories of restaurant menus, the index was calculated by dividing the energy of a dish by the price. This meant that lower energy but higher price options were positioned at the top. The FRP trial arm primarily sought to test for proof-of-concept if positioning based on consideration for both health and profits, with price here used as a proxy for profits, could impact energy purchased while remaining sensitive to financial constraints of industry.
Illustrative concept diagrams of the study conditions showing ( | PMC10197857 | ||
Participant recruitment | Participants were required to be users of a food delivery platform and adults (18 years or older) living in the UK. Our study aimed to collect data from 9,000 participants in order to be powered to detect a 65 kcal reduction in total energy, with a standard deviation estimated at 550 kcal, 80% power, 5% significance level, and corrections for multiple comparisons. 65 kcal was determined based on findings from a previously conducted study [ | PMC10197857 | ||
Ethics | Ethics approval was granted for the study protocol by the Central University Research Ethics Committee (Ref: R65010/007). The protocol was pre-registered on the Open Science Framework ( | PMC10197857 | ||
Results | The study was run from February to March 2022. 15,051 entrants were assessed for eligibility to participate. 5,148 were excluded for failing to meet inclusion criteria or failing attention checks. 9,293 completed the study task, but 290 were excluded from analysis because their hypothetical order baskets contained either more than 4,000 or fewer than 150 kcals (see CONSORT Flow Diagram, Fig.
1819 in the control group,1858 in the foods only repositioning intervention (F),1812 in the restaurants only repositioning intervention (R),1749 in the foods and restaurants repositioning intervention (FR), and.1765 in the foods and restaurants repositioning based on energy content and price (FRP).
CONSORT flow diagramAcross all conditions, participants ordered on average 1269 kcal with a value of £14.63 (see Supplementary Tables Compared to the control, repositioning both foods and restaurants purely based on the energy content of options resulted in the greatest effect (-209 kcal; 95% CIs: -248, -168), followed by repositioning restaurants (-161 kcal; 95% CIs: -201, -121), repositioning restaurants and foods based on a kcal/price index (-117kcals; 95% CI: -158, -74) and repositioning foods based on their energy content (-88kcals; 95% CI: -130, -45) (Fig.
Mean energy from foods selected in the control group and the four intervention groups (foods repositioning, restaurants repositioning, and foods and restaurants repositioning, foods and restaurants plus price repositioning). Bar ranges represent 95% confidence interval, and ** indicates adjusted p < 0.01In a comparison of estimated marginal means for total energy in participants’ baskets, all interventions led to baskets with significantly lower energy contents than the control. All intervention groups significantly differed from each other in terms of their effect on the energy content of participants baskets, with the exception of interventions F (foods repositioning) and FRP (foods and restaurant plus price repositioning), which did not significantly differ (Table
Estimated percentage change between all study groups for total energy from foods selected. The reference group is the first group listed*Confidence intervals are calculated using HC3 heteroscedasticity-robust standard errorsThe average energy content of mains and the energy density of a standardised serving was also lower in all interventions when compared to the control (Supplementary Tables The total basket price at checkout varied between interventions. All interventions repositioning options purely based on the energy content of items reduced the basket price at checkout. However, the interventions that repositioned options to give more prominence to lower-energy but higher-price foods and restaurants (FRP) reduced the energy content of participants’ baskets whilst increasing the basket price (Fig.
Mean money spent (£) in the control and four intervention groups. Bar ranges represent 95% confidence interval, and ** indicates adjusted p < 0.01Subgroup analysis found there was a greater impact among people of higher versus medium SEP of the FRP intervention (147 fewer kcal ordered, 95% CI: 53–241, p-value: 0.022) (Fig.
Marginal mean plots for average energy (in kcals) placed in basket by (The study task could be undertaken from a desktop or mobile device. There was a greater impact of the intervention among people using a mobile device compared to desktop in the study conditions that involved repositioning restaurants purely based on energy content (199 fewer kcal ordered, p-value: 0.003 for study arm R;139 fewer kcal ordered, p-value: 0.046 for study arm FR) (Fig. There was a greater intervention effect among participants that used a delivery platform more than once a week compared to those that used it less than once a week for the intervention repositioning restaurants based on the energy content of their mains (133 fewer kcal selected, p-value: 0.021 for study group R) (Fig. All other subgroup analyses and interactions tested were not significant. | PMC10197857 | ||
Discussion | All the interventions tested in this study reduced the energy content of participants’ baskets, showing as a proof-of-concept that these approaches might have the potential to lower energy purchased from food delivery platforms. The greatest decrease was in the intervention that repositioned both foods and restaurants purely based on energy content. All interventions repositioning options purely based on energy content led to a decrease in total basket price, which may represent an implementation barrier for industry. An intervention designed to mitigate the potential reduction in revenue was successful in its aim, but less effective or no different in reducing the energy content of foods selected than the other price-agnostic interventions.One of the strengths of this study is its relevance to real food purchasing platforms. The sample was large and broadly representative of the UK population and participants were free to choose a meal from a virtual site that closely mimicked online delivery platforms. The energy purchased in this study was comparable to energy content for takeaway food reported previously (medians for five takeaway food types of 1125–1820 kcal per meal) [As a proof-of-concept, this study shows the potential impact of repositioning options in food delivery platforms to promote health outcomes and explores strategies to promote health outcomes whilst protecting the bottom line of restaurants and delivery platforms. Voluntary implementation in real-world settings may be challenging, as was previously seen when voluntary food reformulation targets resulted in limited changes [This study focused on prominent positioning of items at the top of the page, based on evidence from previous research that primacy effects are a critical factor in boosting selection in online settings [It has been suggested that interventions focusing on changing the choice architecture in people’s environments may reduce disparities due to the universal application of interventions [Post hoc we observed two other factors which may warrant further exploration. First, interventions that altered the restaurant position were more effective when participants accessed the study on a mobile phone compared to a desktop computer. This seems plausible since mobile device users may need to scroll further to see the same numbers of restaurants as on a desktop or laptop, and therefore be more likely to click on restaurants nearer the top. Second, the effect of interventions was smaller in the restaurants only repositioning conditions among participants who used food delivery platforms more often. One possible explanation for this is that frequent users may know more about how these platforms work, and more quickly search for what they want to select, rather than browsing. | PMC10197857 | ||
Conclusions | Repositioning of products and restaurants to make lower energy options more prominent in a simulated online delivery platform effectively reduced the amount of energy in recipients’ baskets. Although all interventions were effective, changing the order of both the foods and the restaurants was more effective than altering either alone. Further research is needed to better consider how to optimise these interventions and expand upon these proof-of-concept findings, but results indicate they could be implemented in a sustainable business model. | PMC10197857 | ||
Acknowledgements | Not applicable. | PMC10197857 | ||
Authors’ contributions | RP, FM | FB, LB, JB, SK, JF, JL, AM, FM, RP, HH, and SAJ contributed to the study design. ML and SK, JF, FM analysed data and performed statistical analysis. ML wrote the manuscript. All authors made critical revisions and approved the final version of the manuscript. | PMC10197857 | |
Funding | Obesity, RP | OBESITY | This research was funded by NESTA. RP is funded by a Royal Society and Wellcome Trust Sir Henry Dale fellowship (222566/Z/21/Z). SAJ, ML and LB are funded by NIHR Applied Research Collaborations Oxford. SAJ is also funded by the National Institute of Health Research Oxford Biomedical Research Centre (BRC) Obesity, Diet and Lifestyle Theme. The funders NIHR and Wellcome Trust had no role in the study design, data collection, analysis or interpretation. NESTA employees were involved in the study design, data collection, and creating code for analysis, as well as manuscript editing. ML ran analyses independent from NESTA. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. | PMC10197857 |
Data Availability | Data will be made available upon request. | PMC10197857 | ||
Declarations | PMC10197857 | |||
Ethics approval and consent to participate | Ethics approval was granted for the study protocol by the Central University Research Ethics Committee (Ref: R65010/007). The protocol was pre-registered on the Open Science Framework ( | PMC10197857 | ||
Consent for publication | Not applicable. | PMC10197857 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10197857 | ||
List of Abbreviations | Socioeconomic positionBody mass index | PMC10197857 | ||
References | PMC10197857 | |||
Background | pituitary hormone deficiencies, GHD | GROWTH HORMONE DEFICIENCY, SHORT STATURE, GHD | Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. | PMC10440873 |
Methods/design | GHD | EARLY PUBERTY, SECONDARY, GHD | Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. | PMC10440873 |
Discussion | ADVERSE EFFECTS | If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8–4.6 million (€2.05–5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects. | PMC10440873 | |
Trial registration | EudraCT number: 2020-001006-39 | PMC10440873 | ||
Keywords | PMC10440873 | |||
Background | idiopathic, GHD | EARLY PUBERTY, GROWTH HORMONE DEFICIENCY, GHD | Around 500 children are diagnosed with growth hormone deficiency (GHD) every year in the UK, of whom 75% have idiopathic, isolated GHD (I-GHD) [To make the diagnosis of I-GHD in a short child, the National Institute for Health and Care Excellence (NICE) recommends at least two GH stimulation tests. These tests measure the peak GH concentration in the blood following an injection with a stimulating substance such as glucagon or insulin, and I-GHD is diagnosed if both show a peak GH < 6.7 μg/L [formerly 20 mU/L] [A number of studies have shown that sex steroid priming improves the response to provocative testing [Although I-GHD is known to reverse in many children, traditional practice is to continue treatment with daily injections of GH until FH is achieved. Establishing normal GH status in early puberty would relieve patients from the diagnostic uncertainty of GHD persistence and may allow patients to stop GH therapy earlier whilst still reaching a normal FH. This would relieve them of the unpleasant and inconvenient burden of daily injections of an unnecessary medication and considerably reduce health care cost [This phase III, international, multi-centre, open label, randomised, controlled, non-inferiority trial will assess the safety, efficacy, health-related quality of life, cost effectiveness, biochemical and bone health effects of discontinuing GH therapy in children who have a normal GH re-test in established puberty. The acceptability of the trial and treatment pathways to patients, parents and staff will be explored via a qualitative research sub-study. | PMC10440873 |
Methods/design | PMC10440873 | |||
Aim | GHD | SECONDARY, GHD |
To assess whether children in established puberty with early GHD reversal who stop growth hormone therapy (GH −) achieve no worse near final height standard deviation scores (FH SDS) (primary outcome), target height (TH) minus near final height (FH), health-related quality of life (HRQoL), bone health index and lipid profiles (secondary outcomes) than those continuing growth hormone (GH +).To determine the cost-effectiveness of GH − in the early re-testing scenario and the cost-effectiveness of the new care pathway (early re-testing) compared to traditional care (late re-testing).To assess staff, parent and patient perspectives of the trial pathways and reasons for declining to participate or dropping out of the trial. | PMC10440873 |
Study design | The study design is as follows: phase III, international, multicentre, open-label, randomised controlled non-inferiority trial, including an internal pilot study, qualitative sub-study and within-trial cost analysis. The duration of the trial will be 90 months, including a 12-month pilot phase. | PMC10440873 | ||
Sub-studies | PMC10440873 | |||
Health economics | A health economic analysis will be conducted in UK patients to determine the cost-effectiveness of GH discontinuation in the early re-testing scenario in the UK National Health Service (NHS) setting by estimating the cost per percentage of children achieving TH of GH − compared to GH + and the cost-effectiveness of the new care pathway (early re-testing) compared to traditional care (late re-testing). | PMC10440873 | ||
Qualitative research | GHD, ’ | RECRUITMENT, GHD | We will conduct qualitative research with UK carers, children and staff participating in the internal pilot study. The main aim of the qualitative research is to ensure the feasibility and acceptability of the trial for patients, carers and clinicians, with a particular focus on recruitment processes. These data will provide useful insights into carers’ and children’s preferences for treatment and help optimise the main trial processes. This research will explore carers’ and children’s perceptions in relation to re-testing normal (i.e. GHD reversal), reasons for agreeing to or declining trial participation, reactions to treatment allocation and associated recruitment and retention during the internal pilot. Data collection will include audio-recordings of recruitment consultations and interviews with carers, children and staff.We will consent staff at UK recruiting sites and potential trial participants (children and carers) to audio-record recruitment consultations. Recording recruitment consultations will provide valuable data concerning how the trial and treatment groups are presented by staff and how this is received by potential participants and their carers. Following consent, semi-structured interviews will be conducted with a sample of carers and children participating in both arms of the pilot study (Children recruited to the pilot and their carers will be interviewed at two time points: T1—approximately 2 weeks after randomisation—and T2—approximately 6 months following randomisation. Where possible, interviews will be conducted at a time and place preferred by participants. Separate interviews will be conducted with the carers and the children themselves, unless children wish to be interviewed whilst their carers are present.T1 and decliner interviews will focus on the recruitment process, children’s motivations for taking part or not in the trial and specific barriers and facilitators to patient participation. In addition, T1 and decliner interviews will also explore children’s and carers’ experiences of GHD and its impact on their daily lives, their understanding and expectations of GHD testing and treatment options and their expectations for the trial. T2 interviews will explore children’s and their carers’ experience of the trial and treatment options and of related trial processes and procedures.Data collection and analysis will proceed iteratively until the research team judge that the data and sample size have sufficient depth and breadth [ | PMC10440873 |
Consent and recruitment | GHD, PIS | GHD | Children with I-GHD reversal under the care of a paediatric endocrinologist and/or a general paediatrician will be recruited from 12 UK and 5 Austrian centres. Administration of GH medication will be stopped for a minimum of 6 weeks prior to a GH re-test being performed in line with local protocols. If the patient is thought to be eligible after GH retesting, the clinical team will send the participant information sheet (PIS) to the patients’ parent/guardian, and they will be invited into clinic to discuss potential participation in the trial. It will be the responsibility of the principal investigator (PI) or their delegate to ensure written informed consent is obtained for each participant and/or parent/guardian prior to performing any trial-related procedures. The responsibility for obtaining consent may be delegated by the PI to another clinician as captured on the GHD Reversal Trial site signature and delegation log. If the potential participant and/or parent/guardian are willing to take part in the trial (and meet all of the eligibility criteria), they will be asked to sign and date the latest version of the GHD Reversal Trial informed consent form (ICF) and Assent Form if appropriate and the child will be randomised to one of the study arms. The participant and/or parent/guardian will give explicit consent for the regulatory authorities, members of the research team and or representatives of the sponsor to be given direct access to the participant’s medical records as required. This will be specified on the ICF.We will request consent for review of participants’ medical records and for the collection of blood samples to assess serum IGF-1 and lipid profiles (fasting lipids − serum triglyceride and serum total cholesterol) and peak stimulated GH. | PMC10440873 |
Inclusion and exclusion criteria | PMC10440873 | |||
Inclusion criteria | re-testingAbility | INSULIN TOLERANCE, EVENT |
Children aged 8–15 years of age (inclusive) for females and 9–17 years of age (inclusive) for males with reversed I-GHD (peak GH ≥ 6.7 μg/L using arginine or insulin tolerance test and a serum IGF-1 within normal reference range for sex and age), normal brain MRI (including small anterior pituitary) and in established puberty (Tanner stages B2/3 in girls and 6–12 ml testes* in boys (as measured by orchidometer**)The initial diagnosis of I-GHD will have been made by either two GH stimulation tests (peak GH < 6.7 μg/L) or one stimulation test (peak GH < 6.7 μg/L) with IGF-1 below normal range for sex and age (< -2SDS) irrespective of sex-hormone priming for GH stimulation testsChildren will have discontinued GH treatment for a minimum of 6 weeks prior to re-testingAbility to tolerate the administration of GH therapyAbility to comply with trial schedule and follow-upWritten informed consent obtained from the patient’s parent/guardian and written assent obtained from patient (where age appropriate). In the UK, patients aged 16 years or older will provide their own written informed consent.*In the event of discrepancy between the size of an individual’s testicles, the larger testicle should be used.**In the event that the size of a patient’s testicle falls between the measuring beads of the orchidometer and it is not clear which bead the testicle is most similar to, the larger bead should be used. | PMC10440873 |
Exclusion criteria | congenital mid-brain malformations, pituitary hormone deficiency, GHD | TUMOURS, HYPOPITUITARISM, SEPTO-OPTIC DYSPLASIA, GHD |
Multiple pituitary hormone deficiency (hypopituitarism) with or without additional pituitary hormone supplementationKnown genetic cause of I-GHDOrganic GHD (mid-brain tumours, congenital mid-brain malformations, septo-optic dysplasia; radiotherapy to the total body or brain)Ectopic posterior pituitaryOther indications for GH therapyReceiving GH treatment at any time between the (minimum 6-week) GH discontinuation period prior to retesting and randomisationReceiving prednisolone or dexamethasone at any time during the (minimum 6-week) GH discontinuation periodKnown history of persistent non-compliance with prescribed medication regimensPregnant or lactatingAny malignancyCurrently participating in another Clinical Trial of an Investigational Medicinal Product (CTIMP) | PMC10440873 |
Randomisation | Following confirmation of patient eligibility, receipt of informed consent and completion of all questions and data items on the randomisation form, the patient will be randomised at the level of the individual in a 1:1 ratio to either continue (GH +) or discontinue (GH −) growth hormone therapy. Randomisation will be provided by a secure online randomisation system at Birmingham Clinical Trials Unit (BCTU). A minimisation algorithm will be used within the online randomisation system to ensure balance in the treatment allocation over the following variables:Tanner stage (B2 (females) or 6– < 9 ml testicular volume of the largest testicle (males) vs B3 (females) or 9–12 ml testicular volume (males).Sex (male vs female).Participating centre.Following randomisation, a confirmatory e-mail will be sent to the responsible clinician including the child’s trial number and treatment allocation. | PMC10440873 | ||
Planned interventions | Participants in the control arm (GH +) will resume receiving their GH treatment at a dosing level determined by their clinical care team (following the minimum 6-week discontinuation period required prior to randomisation). Participants in the experimental arm (GH −) will not resume GH treatment. Both arms will be followed up at 6 monthly intervals until near FH or the 36-month follow-up (whichever is soonest).All currently available GH treatment preparations with the active ingredient Somatropin are allowed, as detailed in the British National Formulary for Children (BNFc) in the UK and Kindermedika in Austria ( | PMC10440873 | ||
Trial schema (Fig. | Trial schemaGHD Reversal Trial schedule of assessments. Three asterisks (***) indicate the following: patients will be followed up until ‘Near FH (growth rate < 2 cm/year and bone age of 14 and 16 for males and females respectively). Given the usual duration of pubertal growth until FH is reached, 3 years follow-up has been allowed for; however, if patients do not reach near FH by 3 years, this may be longer | PMC10440873 | ||
Study procedures | GHD | ADVERSE EVENT, GHD | Routine retesting in established puberty is routine clinical practice in all trial sites. Children with GHD persistence at retesting will restart GH; those with GHD reversal will be offered study participation. Following consent, participants will be randomised to GH + (25–35 µg/kg/day) and GH − groups and followed in routine endocrine clinics until ‘Near FH’ (growth rate < 2 cm/year) is reached. In the GH − group, any unexpected decrease in IGF-1 concentrations below − 2 SD (lower limit of normal) at 6 months would trigger a repeat GH stimulation test and recommencement of GH if deficient.The baseline visit for all patients will include confirmation of inclusion and exclusion criteria, informed consent/assent, randomisation and allocation of trial number, prescription of growth hormone (if randomised to continue treatment), a record of the preparation and dose prescribed, a record of concomitant medication and relevant medical history. Height, weight and Tanner stage will also be measured at baseline. All patients will have 6-monthly visits to measure height, weight, Tanner stage, serum IGF-1 (at 6 months and annually thereafter) as well as checking compliance with GH therapy and any concomitant medication and adverse event reporting. HRQoL will be measured using the CHU9D questionnaire at baseline and at each 6-monthly visit. A left hand X-ray will be conducted at enrolment and near FH, for central analysis using the BoneXpert software. Fasting lipids will be measured at baseline and near FH.At near FH, all subjects will have a GH stimulation test to reconfirm GH status. Given the usual duration of pubertal growth until near FH is achieved, we have allowed for 3 years follow-up.The information captured at the randomisation and subsequent visits are shown in Fig. | PMC10440873 |
Sample size and power calculation | Diabetes | DIABETES | Determination of non-inferiority margin was carefully considered, following extensive consultation. A questionnaire was sent to all investigators, British Society for Paediatric Endocrinology and Diabetes clinical study group members, and a patient support group representative (Whilst the percentage of children reaching mid-parental TH [For the primary outcome measure of near FH-SDS with a non-inferiority design comparing means and assuming equal variance, a non-inferiority margin of 0.55 near FH-SDS, a one-sided test with alpha = 0.025 and 90% power, a group size of 57 (total | PMC10440873 |
Outcome measures | PMC10440873 | |||
Primary outcome | The primary outcome is as follows: near final height in standard deviation score (FH SDS). | PMC10440873 | ||
Secondary outcomes | Growth related:The proportion of children reaching normal adult height (− 2SD)The proportion reaching mid-parental target height (− 2SD)Difference in child’s target height minus near final height (TH-FH, in SDS and centimetres)Bone related:Bone age delay at near final heightBone age acceleration between enrolment and near final heightBone health index at near final heightBiochemistry:Serum IGF-1 and lipid profiles (fasting lipids − serum triglyceride and total serum cholesterol) at final heightPeak stimulated GH at final height | PMC10440873 | ||
Adverse events | ADVERSE EVENTS | Number of adverse events in each arm.Health economics.Cost per percentage of children in each arm achieving target heightCost per quality-adjusted life year gainedQualitative research:Trial acceptability (parents, patients and recruiting site staff)Reasons for declining participation in the trialParent and patient experience of the trial and treatment pathways | PMC10440873 | |
Data management | GHD | GHD | All processes are detailed in the study protocol and in the GHD Reversal Trial data management plan. | PMC10440873 |
Statistical analysis | SECONDARY | A separate statistical analysis plan (SAP) has been produced which provides a more comprehensive description of the planned statistical analyses which is available from the corresponding author on request. The primary comparison groups will be composed of those treated with GH (25–35 μg/kg/day) versus those not treated with GH. Non-inferiority outcomes will be analysed using both intention-to-treat (ITT) (i.e. all participants will be analysed in the treatment group to which they were randomised, irrespective of compliance or other protocol deviation) and per-protocol analyses (i.e. those participants who are considered adherent to their allocated intervention, as defined in the SAP). This is because an ITT analysis alone may bias results in favour of non-inferiority. Superiority outcomes will be analysed using ITT analyses only. For all primary and secondary outcome measures, summary statistics and differences between groups will be presented with 95% confidence intervals. Outcomes will be adjusted for the minimisation variables and baseline values where appropriate. No adjustment for multiple comparisons will be made. | PMC10440873 | |
Primary outcome measure | The primary outcome measure is near FH-SDS (using the WHO Growth Charts [ | PMC10440873 | ||
Secondary outcome measures | REGRESSION, SECONDARY, ADVERSE EVENT | Growth and bone-related secondary outcomes will be considered non-inferiority outcomes and so will be analysed as per the primary outcome using both ITT and per-protocol analyses. Biochemistry and adverse event outcomes will be considered superiority outcomes and so will be analysed using ITT analyses only. Continuous outcomes will be analysed using linear regression models, adjusting for minimisation variables and baseline response (where applicable). Adjusted mean differences will be presented alongside 95% confidence intervals. Binary outcomes will be analysed using log binomial regression models, adjusting for minimisation variables, with both a log and identity link to obtain risk ratios and risk differences, respectively. | PMC10440873 | |
Subgroup analyses | REGRESSION | Subgroup analyses will be limited to minimisation variables: sex and Tanner stage, for the primary outcome only. Tests for statistical heterogeneity (e.g. by including the treatment group by subgroup interaction parameter in the regression model) will be performed prior to any examination of effect estimate within subgroups. The results of subgroup analyses will be treated with caution and will be used for the purposes of hypothesis generation only. | PMC10440873 | |
Missing data and sensitivity analyses | EVENT | Every attempt will be made to collect full follow-up data on all trial participants; it is thus anticipated that missing data will be minimal. Participants with missing primary outcome data will not be included in the primary analysis in the first instance. This presents a risk of bias, and sensitivity analyses will be undertaken to assess the effect of any missing data. In brief, this will include a multiple imputation approach, using important variables to predict the near FH SDS and a last observation carried forward (LOCF) approach, which assumes no change from the previous assessment.A further sensitivity analysis will be conducted to assess the impact of participants who have not reached near FH by the end of the study. For the primary analysis, all participants will be included and for any participants who have not reached near FH, their height recorded at the end of study follow-up visit will be used. Although we anticipate this to be a rare event, we will conduct a sensitivity analysis (for the primary outcome only) which excludes any participants who have not reached near FH by the end of the study. Full details are included in the SAP. | PMC10440873 | |
Internal pilot and stopping rules | GHD reversers, GHD | RECRUITMENT, GHD | To ensure the success of the trial, screening data will be kept on the GHD Reversal Trial database on the number of early re-tests, GHD reversers and recruits. No patient identifiable information will be collected at this stage. These data will be analysed and presented as part of the progress report for the trial steering committee (TSC). According to published standards, Amber and Red ‘Stop/Go’ criteria have been agreed with the Funder. Time points are calculated from first centre opening. Three Stop–Go criteria measurable in the first 12 months of the trial were identified as critical steps for the trial’s successful recruitment (see Table GHD Reversal Trial Stop/Go criteria | PMC10440873 |
Planned interim analysis | SECONDARY | Interim analyses of safety and efficacy for presentation to the independent DMC will take place during the trial. The committee will meet prior to trial commencement to agree the manner and timing of such analyses but this is likely to include the analysis of the primary and major secondary outcomes and full assessment of safety (SAEs) at least at annual intervals. Criteria for stopping or modifying the trial based on this information will be ratified by the DMC. Details of the agreed plan will be written into the SAP. | PMC10440873 | |
Planned final analyses | The primary analysis for the trial will occur once all participants have either fulfilled the near FH definition (growth rate of < 2 cm/year and have reached a bone age of 14 years (females) or 16 years (males)), have completed the 36-month assessment or have withdrawn from the study or been lost to follow-up and corresponding outcome data have been entered onto the trial database and validated as being ready for analysis. All other outcome measure analyses will be undertaken when the final participant (as defined above) reaches their 36-month assessment. | PMC10440873 | ||
Health economics analysis | GHD | SECONDARY, GHD | The health economics analysis has two specific aims. The first is to assess the cost-effectiveness of GH discontinuation in the early re-testing scenario by estimating the cost per percentage of children achieving TH of GH − compared to GH + over a 12-month period, and the second is to assess the cost-effectiveness of the new care pathway (early re-testing) compared to traditional care (late re-testing).To assess the cost-effectiveness of no GH therapy (GH −) compared to GH therapy (GH +) in patients with GHD reversal, a cost-consequence analysis will initially be reported, describing all the important results relating to resource use, costs and consequences. Subsequently a trial-based cost-effectiveness analysis will be undertaken from an NHS/personal social services (PSS) perspective to determine the cost per percentage achieving TH of GH − compared to GH + over a 12-month period.Resource use information will be obtained on all healthcare utilisation (primary care and secondary care) and will be obtained mainly from participant questionnaires. Unit costs will be obtained from standard sources and healthcare providers including the British National Formulary (BNF), PSSRU publication on Unit Costs of Health and Social Care and NHS Reference costs.Mean costs and outcomes will be estimated for both the no GH therapy (GH −) and GH therapy (GH +) arms. Cost data are likely to be skewed; therefore, non-parametric comparison of means (e.g. bootstrapping) will be undertaken. Multiple imputation techniques will be used to deal with missing costs, in order to ensure that all eligible trial participants are included in the analysis.Incremental cost-effectiveness ratios (ICERs) will be calculated, and cost-effectiveness acceptability curves will be presented to estimate the probability that GH − is cost-effective for different willingness to pay thresholds.The second objective of the health economics analysis is to determine the cost-effectiveness of the new care pathway (early re-testing) compared to traditional care (late re-testing) using a decision analytic modelling approach. The model will determine the cost per percentage achieving TH and cost per additional quality-adjusted life year (QALY) gained for the intervention (early re-testing) and usual care arm (late re-testing).Data from the main trial and other published sources will be used to populate the model. An incremental cost-effectiveness analysis will determine the cost per percentage achieving TH and an incremental cost-utility analysis will be undertaken to estimate the cost per QALY gained. Both analyses will be conducted from an NHS perspective. Deterministic sensitivity analysis will be undertaken to assess the impact of changing the values of key parameters. Uncertainty in the confidence to be placed on the results of the economic analysis will be explored by conducting a probabilistic sensitivity analysis to estimate cost-effectiveness acceptability curves. | PMC10440873 |
Reporting guidelines | The SPIRIT reporting guidelines have been used in this publication [ | PMC10440873 | ||
Ethical considerations | RECRUITMENT | In the UK, ethical approval, MHRA approval (Clinical Trial Authorisation), HRA approval and local capacity and capability assessments will be obtained prior to the start of recruitment. In Austria, CTIS ethical approval and BASG approvals (Clinical Trial Authorisation) has been obtained. The study will be conducted in accordance with the principles of GCP and comply with all legislation. This process will be managed by the BCTU trials management team in conjunction with UCL as sponsor (the sponsor played no part in the study design; collection, management, analysis and interpretation of data; writing of the report; and the decision to submit the report for publication). An independent DMC will ensure the safety and dignity of the study participants as well as the reliability of the results obtained. Information will be provided to parents and patients verbally and through parent and participant information sheets. The information sheets will clearly explain that participation in the trial is entirely voluntary with the option of withdrawing from the trial at any stage and that participation or non-participation will not affect the participant’s usual care which, for children who had ever been on GH would include monitoring to FH. Though all trials involving children require careful ethical consideration, we do not anticipate any specific ethical issues beyond those in randomised controlled trials within the paediatric population. There are no major concerns surrounding the withdrawal of GH in study patients with reversed I-GHD. | PMC10440873 | |
Reporting of adverse events | ADVERSE EVENTS, RSI | The collection and reporting of adverse events (AEs) will be in accordance with Regulation (EU) No. 536/2014 (Clinical Trial Safety Reporting requirements), the Medicines for Human Use Clinical Trials Regulations (2004) and its subsequent amendments, the UK Policy Framework for Health and Social Care (2017), and the requirements of the Health Research Authority (HRA).As per routine practice AEs will be recorded in the patient’s medical notes including the documentation of the assessment of severity, seriousness and causality (relatedness) in relation to the intervention(s) in accordance with the protocol. The assessment of causality should be made with regard to the Reference Safety Information (RSI) for the GH + arm.The reporting timeframe for adverse events will be from the date of randomisation until the participant reaches near final height or otherwise exits the study. The reporting timeframe for serious adverse events will be from the date of randomisation until the GH stimulation test is conducted at near FH. This will provide a minimum 6-week wash out period for any participants that have been receiving GH therapy. | PMC10440873 | |
Auditing | Investigators will permit trial-related monitoring, audits, ethical review, and regulatory inspection(s) at their site, providing direct access to source data/documents. Investigators will comply with these visits and any required follow | PMC10440873 | ||
Protocol amendment communication | Important protocol modifications will be communicated to relevant parties in accordance with BCTU’s quality management system. | PMC10440873 | ||
Dissemination | GHD | SECONDARY, GHD | The GHD Reversal Trial protocol will be made publicly available via both the GHD Reversal Trial webpage hosted by the Trial Office and subsequently published in an appropriate journal, in advance of the final data set. Upon completion of the trial and analysis of the final dataset, a Final Report to the Funder will be prepared. The results of this trial will be submitted for publication in a peer reviewed journal. The manuscript will be prepared by the co-investigators and authorship will be determined by the BCTU trial publication policy. Any secondary publications and presentations prepared by Investigators must be reviewed and approved by the TMG prior to submission. Manuscripts must be submitted to the TMG in a timely fashion to allow time for review and resolution of any outstanding issues. Authors must acknowledge that the trial was performed with the support of BCTU/UoB, UCL, and JKU. The results of the trial will be disseminated by the trials unit to participating clinical centres, who will be asked to distribute this to the participants and the wider clinical community. | PMC10440873 |
Monitoring | PMC10440873 | |||
Trial Steering Committee (TSC) | TSC, GHD | GHD | The TSC for the GHD Reversal Trial will meet at least annually and as required depending on the needs of the trial. The TSC includes members who are independent of the investigators, their employing organisations, funders and sponsors.Membership and duties/responsibilities are outlined in the TSC Charter. In summary, the TSC will provide overall oversight of the trial, including the practical aspects of the study, as well as ensure that the study is ran in a way which is both safe for the participants and provides appropriate feasibility data to the sponsor and investigators. The TSC will consider and act, as appropriate, upon the recommendations of the DMC or equivalent and ultimately carries the responsibility for deciding whether a trial needs to be stopped on grounds of safety or efficacy. | PMC10440873 |
Independent Data Monitoring Committee (DMC) | GHD | ADVERSE EVENTS, RECRUITMENT, GHD | Data analyses will be supplied in confidence to an independent DMC, which will be asked to give advice on whether the accumulated data from the trial, together with the results from other relevant research, justifies the continuing recruitment of further participants. The DMC includes members who are independent of the trial, the trial investigators, their employing organisations, funders, and sponsors. The DMC have no competing interests. The DMC will operate in accordance with a trial specific charter based upon the template created by the Damocles Group. The role of the DMC is to safeguard the interests of trial participants; assess the safety and efficacy of the interventions during the trial; ensure the trial collects the necessary information to address the trial question; and monitor the overall conduct of the clinical trial. The DMC will receive and review the progress, the accruing data and details of all serious adverse events of this trial and provide advice on the conduct of the trial to the trial steering committee (TSC). The DMC is composed of a chair based on previous experience of serving on DMCs and chairing meetings, an expert DMC statistician and two clinicians with experience in GHD and clinical trials methodology. The DMC will meet at least annually as agreed by the committee and documented in the charter, unless there is a specific reason (e.g. safety phase) to amend the schedule.Additional meetings may be called if recruitment is much faster than anticipated and the DMC may, at their discretion, request to meet more frequently or continue to meet following completion of recruitment. An emergency meeting may also be convened if a safety issue is identified. The DMC will report directly to the TSC, who will convey the findings of the DMC to the funder, sponsor and MHRA as relevant. The DMC may consider recommending the discontinuation of the trial if the recruitment rate or data quality are unacceptable or if any issues are identified which may compromise participant safety. The trial will stop early if the interim analyses showed differences between treatments that were deemed to be convincing to the clinical community. | PMC10440873 |
Data access | During the period of the study, only the data monitoring committee (DMC) will have access to the full trial dataset in order to ensure participant safety. Following publication of the findings, an aggregated, anonymised final trial dataset will be made available to external researchers upon approval from the sponsor, the TMG and the BCTU data sharing committee in line with standard data sharing practices for clinical trial data sets. | PMC10440873 |
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