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Introduction In 2015, 603.7 million adults globally were estimated to be obese, with more than 70 countries showing a doubling in prevalence of obesity since 1980.1 Little long term success has been found in treating established obesity through lifestyle change,2 perhaps because of the substantial, permanent changes in diet and physical activity required to achieve and sustain weight loss. An alternative strategy is to focus on prevention of weight gain, but evidence evaluating the effectiveness of interventions for weight gain prevention is limited.3 4 Reports from longitudinal weight tracking studies show that each year on average the population gains a small amount of weight (0.4-1 kg),5 but that weight is gained more rapidly during particular periods, such as the Christmas holiday season.6 7 A narrative review of weight gain during the holiday season reported consistent increases in weight of 0.4 kg to 0.9 kg across several studies.8 Furthermore, these weight gains were not fully lost in the months following the holiday event. Although these gains are small, over 10 years they would lead to a 5-10 kg increase in body weight, which is sufficient to drive the obesity epidemic.

onsistent increases in weight of 0.4 kg to 0.9 kg across several studies.8 Furthermore, these weight gains were not fully lost in the months following the holiday event. Although these gains are small, over 10 years they would lead to a 5-10 kg increase in body weight, which is sufficient to drive the obesity epidemic. People gain weight at Christmas for several reasons. The festive season coincides with public holidays in the United Kingdom and many other countries, providing an opportunity for prolonged over-consumption and sedentary behaviour. On Christmas Day alone an individual might consume 6000 calories (25 104 kJ)9; three times the recommended daily allowance. Characteristically people enjoy a more relaxed lifestyle and participate in more social events during the Christmas holiday period, which presents situations for increased energy intake. This could be through the availability of a greater variety of foods (many of which are energy dense),10 11 increased alcohol intake,12 larger portion sizes,13 and relaxed eating with friends and family.14 People have also reported that family celebrations provide the greatest challenge for eating restraint.15 Given that Christmas is likely to tax even the most experienced weight controller,16 effective interventions to prevent weight gain are needed to promote the restraint of eating and drinking during these high risk periods. A systematic review of weight gain prevention interventions identified the potentially useful role of low intensity interventions incorporating diet, physical activity, and self regulation strategies.3

ions to prevent weight gain are needed to promote the restraint of eating and drinking during these high risk periods. A systematic review of weight gain prevention interventions identified the potentially useful role of low intensity interventions incorporating diet, physical activity, and self regulation strategies.3 We conducted the Winter Weight Watch Study, a randomised controlled trial to evaluate the effectiveness of a brief behavioural intervention encouraging restraint of eating and drinking over the Christmas holiday period to prevent weight gain. Methods The study was a two group double blinded randomised controlled trial designed to test the effectiveness of a brief behavioural intervention comprising encouragement to regularly self weigh, tips for weight management, and information on the physical activity calorie equivalent (PACE) of festive foods and drinks to prevent weight gain over the Christmas period. Participants were individually randomised to trial groups.

ss of a brief behavioural intervention comprising encouragement to regularly self weigh, tips for weight management, and information on the physical activity calorie equivalent (PACE) of festive foods and drinks to prevent weight gain over the Christmas period. Participants were individually randomised to trial groups. Participants Participants were recruited from local workplaces, social media, and local schools (parents) through flyers and posters. We engaged with workplaces through human resources departments and company communication officers. Staff at schools that had previously taken part in research at the university were asked to distribute posters to parents. Researchers screened potential participants who contacted the research team. Participants were eligible for inclusion if they were aged 18 years or more and had a body mass index (BMI) of 20 or more. We excluded pregnant or breastfeeding women and those with insufficient English to provide written informed consent.

ts. Researchers screened potential participants who contacted the research team. Participants were eligible for inclusion if they were aged 18 years or more and had a body mass index (BMI) of 20 or more. We excluded pregnant or breastfeeding women and those with insufficient English to provide written informed consent. Data collection Collection of baseline data took place pre-Christmas 2016 and 2017 (November and December) with follow-up post-Christmas 2017 and 2018 (January and February), respectively. Eligible participants were asked to attend two appointments (baseline and follow-up) with a researcher, either at the participant’s home or at a convenient location (workplace, community venue, university). Baseline and follow-up appointments were arranged concurrently. To reduce the possibility of missed appointments, we sent reminder letters to participants one week before their appointments. We also collected data relating to personal characteristics and lifestyle behaviours through a questionnaire booklet distributed to participants at baseline and follow-up. To assess generalisability of the intervention we collected data on whether participants had access to weighing scales at home.

their appointments. We also collected data relating to personal characteristics and lifestyle behaviours through a questionnaire booklet distributed to participants at baseline and follow-up. To assess generalisability of the intervention we collected data on whether participants had access to weighing scales at home. Interventions The multicomponent intervention was informed by self regulation theory17 and the habit formation model18 and aimed to promote restraint of energy consumption. The intervention comprised three components: encouragement to self monitor and record weight at least twice weekly (ideally daily), and instruction to reflect on weight trajectory; 10 tips for weight management; and pictorial information about the physical activity calorie equivalent (PACE) of festive foods and drinks (see supplementary file S1).

hree components: encouragement to self monitor and record weight at least twice weekly (ideally daily), and instruction to reflect on weight trajectory; 10 tips for weight management; and pictorial information about the physical activity calorie equivalent (PACE) of festive foods and drinks (see supplementary file S1). The goal of the intervention was for participants to gain no more than 0.5 kg (about 1lb) of their baseline weight. We set this target (referred to as the participants’ “maximum weight”) to allow for some flexibility related to the natural variation in weight throughout the day. Participants were informed of their maximum weight during the baseline appointment (pre-Christmas), which was written on their weight record card (see supplementary file S1). We asked participants to weigh themselves at the same time each day while wearing similar amounts, or no, clothing. The potential effectiveness of self weighing is based on the principles of self regulation theory17 and habit formation (developing habits around regular self weighing).18 Self monitoring in the context of self weighing might show people how their behaviour affects their weight and allow them to make adjustments. Regular weighing and recording of weight to check progress against a target (self monitoring) has been shown to be an effective behavioural intervention within weight management programmes.19 20 21 22

context of self weighing might show people how their behaviour affects their weight and allow them to make adjustments. Regular weighing and recording of weight to check progress against a target (self monitoring) has been shown to be an effective behavioural intervention within weight management programmes.19 20 21 22 To help with weight management, intervention participants were provided with 10 tips, based on the previously piloted 10 Top Tips (10TT), which has been shown to result in weight loss in overweight adults.23 24 We amended the 10TT for seasonal appropriateness (see supplementary file S1). To highlight the high energy content of popular Christmas food and drinks, we also provided participants with PACE information—for example, to expend the calories in one mince pie requires 21 minutes of running and from a small glass of mulled wine requires 32 minutes of walking (see supplementary file S1). PACE labelling has been shown to reduce the energy intake of adults and encourage physical activity.25 26 The comparator group received a brief information leaflet, amended from general public health information, about leading a healthy lifestyle.27 No dietary advice was included (see supplementary file S2).

To help with weight management, intervention participants were provided with 10 tips, based on the previously piloted 10 Top Tips (10TT), which has been shown to result in weight loss in overweight adults.23 24 We amended the 10TT for seasonal appropriateness (see supplementary file S1). To highlight the high energy content of popular Christmas food and drinks, we also provided participants with PACE information—for example, to expend the calories in one mince pie requires 21 minutes of running and from a small glass of mulled wine requires 32 minutes of walking (see supplementary file S1). PACE labelling has been shown to reduce the energy intake of adults and encourage physical activity.25 26 The comparator group received a brief information leaflet, amended from general public health information, about leading a healthy lifestyle.27 No dietary advice was included (see supplementary file S2). Outcomes The primary outcome was weight at follow-up. We compared weight between study groups at follow-up, adjusted for baseline weight and attendance at a commercial weight loss programme. We compared several secondary outcomes between the trial groups at follow-up: weight gain of 0.5 kg or less, self reported frequency of self weighing (at least twice weekly versus less than twice weekly), percentage body fat, and cognitive restraint of eating, emotional eating, and uncontrolled eating.

loss programme. We compared several secondary outcomes between the trial groups at follow-up: weight gain of 0.5 kg or less, self reported frequency of self weighing (at least twice weekly versus less than twice weekly), percentage body fat, and cognitive restraint of eating, emotional eating, and uncontrolled eating. Trained researchers used standardised protocols to take anthropometric measures. Weight was measured to the nearest 0.1 kg, with participants clothed but without shoes or socks, using a calibrated automated digital scale (TANITA T6360; Tanita, Tokyo, Japan). Simultaneously the same scale was used to measure percentage body fat. Height was measured at baseline using a portable stadiometer (seca 213; seca, Birmingham, UK). The three factor eating questionnaire was used to measure cognitive restraint, emotional eating, and uncontrolled eating, and a score was derived for each of these outcomes.28 We hypothesised that the intervention would prevent weight gain by increasing cognitive restraint of eating and drinking.28

ca, Birmingham, UK). The three factor eating questionnaire was used to measure cognitive restraint, emotional eating, and uncontrolled eating, and a score was derived for each of these outcomes.28 We hypothesised that the intervention would prevent weight gain by increasing cognitive restraint of eating and drinking.28 Sample size The relation between overweight and mortality is linear (30% increase per 5 kg/m2)29 therefore the prevention of even small amounts of weight gain sustained over the lifetime can have important health benefits.30 We proposed a sample size based on an effect size of 0.75 kg difference in weight between the groups at follow-up. We chose this pragmatically as an effect size that we could realistically expect to achieve from a brief intervention over a short period. A total of 226 participants would provide 80% power to detect 0.75 kg (SD 2.0)30 difference in weight between the groups, with 5% significance. With allowance for 20% loss to follow-up, the required sample size was 284. Randomisation and masking A researcher individually randomised participants at the baseline visit. An independent statistician generated the random allocation sequence with random block sizes of 4, 6, and 8 using STATA software (version 14.2, StataCorp, College Station, TX).

Sample size The relation between overweight and mortality is linear (30% increase per 5 kg/m2)29 therefore the prevention of even small amounts of weight gain sustained over the lifetime can have important health benefits.30 We proposed a sample size based on an effect size of 0.75 kg difference in weight between the groups at follow-up. We chose this pragmatically as an effect size that we could realistically expect to achieve from a brief intervention over a short period. A total of 226 participants would provide 80% power to detect 0.75 kg (SD 2.0)30 difference in weight between the groups, with 5% significance. With allowance for 20% loss to follow-up, the required sample size was 284. Randomisation and masking A researcher individually randomised participants at the baseline visit. An independent statistician generated the random allocation sequence with random block sizes of 4, 6, and 8 using STATA software (version 14.2, StataCorp, College Station, TX). Randomisation was stratified by participant attendance at a commercial weight loss programme at baseline. This stratification variable was chosen because commercial weight loss programmes have been shown to be effective interventions for weight loss.31 Data on attendance at these programmes were collected at baseline. Participants were then randomised, and allocation was concealed using opaque, sequentially numbered, sealed envelopes. Participants were blinded to the aim of the trial (we said the study was about weight gain in winter) and their allocation until the end of the study. Researchers were blinded to group allocation and baseline weight during follow-up appointments. The sealed envelope with this information was opened after follow-up body weights had been measured. To maintain blinding of the researcher to assignment groups, we requested that participants did not reveal the information given to them at baseline.

o group allocation and baseline weight during follow-up appointments. The sealed envelope with this information was opened after follow-up body weights had been measured. To maintain blinding of the researcher to assignment groups, we requested that participants did not reveal the information given to them at baseline. Statistical analysis A prespecified statistical analysis plan was made available before analyses. The primary analysis was by modified intention to treat—including all randomly assigned participants for whom data on the primary endpoint were available. We used linear regression modelling to assess the primary outcome, with weight at follow-up as the outcome variable, trial arm as the explanatory variable of interest, and baseline weight and the stratification variable (attendance at a weight loss programme) as covariates. The difference in weight between the intervention group and comparator group is presented as an adjusted mean with corresponding 95% confidence interval and P value. The unadjusted change in weight between baseline and follow-up for both groups is also presented. The primary outcome analysis was repeated with additional covariates (BMI and time (days) between baseline and follow-up). We analysed other continuous outcomes (percentage body fat, cognitive restraint, emotional eating, and uncontrolled eating) as the primary outcome (adjusted for baseline measures and the stratification variable) and repeated with the additional covariates.

ovariates (BMI and time (days) between baseline and follow-up). We analysed other continuous outcomes (percentage body fat, cognitive restraint, emotional eating, and uncontrolled eating) as the primary outcome (adjusted for baseline measures and the stratification variable) and repeated with the additional covariates. To estimate the odds ratio (comparing intervention group with comparator group) for gaining 0.5 kg or less of baseline weight at follow-up and frequency of self weighing (at least twice weekly), we used logistic regression models, adjusting only for the stratification variable (and baseline for the self weighing outcome) and then including the additional covariates. These results are presented as adjusted odds ratios with corresponding 95% confidence intervals and P values. Patient and public involvement Before commencement of the trial, patient and public involvement representatives provided feedback on the research question, study design, study concept, and content of the study materials. We used these responses to refine and inform specific elements of the trial. Results A total of 272 adults were randomised (n=93 in 2016 and n=179 in 2017). Figure 1 shows the flow of participants through the study. Six participants (2%) failed to provide follow-up data for the primary outcome. Fig 1 Flow of participants through study

Patient and public involvement Before commencement of the trial, patient and public involvement representatives provided feedback on the research question, study design, study concept, and content of the study materials. We used these responses to refine and inform specific elements of the trial. Results A total of 272 adults were randomised (n=93 in 2016 and n=179 in 2017). Figure 1 shows the flow of participants through the study. Six participants (2%) failed to provide follow-up data for the primary outcome. Fig 1 Flow of participants through study The participants were predominantly women (n=213 (78%)) and of white ethnicity (n=201 (78%); table 1). The mean age was 43.9 (SD 11.7) years, and 25% (n=67) of participants were from areas of high deprivation. Mean length of time in the study was 45.3 (SD 5.7) days. Participants’ baseline characteristics were generally well balanced across the two study groups (see table 1 and supplementary file S3). Supplementary file S4 shows the mean time in study for each randomisation group per year. Table 1 Baseline characteristics of participants and time in study by randomisation group. Values are numbers (percentages) unless stated otherwise

The participants were predominantly women (n=213 (78%)) and of white ethnicity (n=201 (78%); table 1). The mean age was 43.9 (SD 11.7) years, and 25% (n=67) of participants were from areas of high deprivation. Mean length of time in the study was 45.3 (SD 5.7) days. Participants’ baseline characteristics were generally well balanced across the two study groups (see table 1 and supplementary file S3). Supplementary file S4 shows the mean time in study for each randomisation group per year. Table 1 Baseline characteristics of participants and time in study by randomisation group. Values are numbers (percentages) unless stated otherwise Characteristics All participants (n=272) Comparator group (n=136) Intervention group (n=136) Mean (SD) age (years) 43.9 (11.7) 43.4 (11.9) 44.4 (11.6) Women 213 (78) 106 (78) 107 (79) Ethnicity: White 206 (78) 101 (78) 105 (79) South Asian 34 (13) 17 (13) 17 (13) Black Caribbean 10 (4) 5 (4) 5 (4) Black African 1 (0.4) 1 (1) 0 (0) Mixed 8 (3) 4 (3) 4 (3) Other Asian 4 (1) 2 (1) 2 (1) Deprivation fourth*: 1 (most deprived) 67 (25) 31 (23) 36 (26) 2 62 (23) 34 (25) 28 (21) 3 52 (19) 23 (17) 29 (21) 4 (least deprived) 91 (33) 48 (35) 43 (32) Mean (SD) weight (kg) 80.0 (19.1) 79.7 (19.0) 80.3 (19.5) Median (interquartile range) weight (kg) 75.6 (65.9-88.6) 75.6 (67.5-86.9) 76.1 (65-90.5) BMI category: 20-24.9 87 (32) 44 (32) 43 (32) 25-29.9 100 (37) 52 (38) 48 (35) 30-34.9 43 (16) 20 (15) 23 (17) 35-39.9 23 (8) 11 (8) 12 (9) ≥40 19 (7) 9 (7) 10 (7) Mean (SD) BMI 28.8 (6.6) 28.7 (6.7) 28.8 (6.5) Median (interquartile range) BMI 27.1 (24.2-31.4) 27 (24.3-30.8) 27.4 (24.2-32.4) Employment status: In paid employment 207 (79) 104 (80) 103 (77) Self employed 20 (8) 9 (7) 11 (8) Unemployed 2 (1) 1 (1) 1 (1) Student 5 (2) 2 (1.5) 3 (2) Other 29 (11) 14 (11) 15 (11) Marital status: Married 147 (56) 70 (54) 77 (58) Single 116 (44) 60 (46) 56 (42) Mean (SD) time in study (days) 45.3 (5.7) 45.9 (5.8) 44.7 (5.6) BMI=body mass index.

oyment 207 (79) 104 (80) 103 (77) Self employed 20 (8) 9 (7) 11 (8) Unemployed 2 (1) 1 (1) 1 (1) Student 5 (2) 2 (1.5) 3 (2) Other 29 (11) 14 (11) 15 (11) Marital status: Married 147 (56) 70 (54) 77 (58) Single 116 (44) 60 (46) 56 (42) Mean (SD) time in study (days) 45.3 (5.7) 45.9 (5.8) 44.7 (5.6) BMI=body mass index. * Index of multiple deprivation. Primary outcome The unadjusted mean weight change (follow-up−baseline) was −0.13 kg (95% confidence interval −0.4 to 0.15) in the intervention group and 0.37 kg (0.12 to 0.62) in the comparator group. The adjusted mean difference in follow-up weight between groups (intervention−comparator) after adjustment for baseline weight and attendance at a commercial weight loss programme was −0.49 kg (95% confidence interval −0.85 to −0.13, P=0.008)—that is, follow-up weight was lower in the intervention group than comparator group. The result was similar when further adjusting for baseline BMI and the time participants were in the study (−0.48 kg, −0.84 to −0.12; P=0.01; table 2). Table 2 Adjusted differences in primary and secondary outcomes between intervention and comparator group at follow-up Outcomes Baseline Follow-up Primary model* Further adjusted model† Comparator group Intervention group Comparator group Intervention group No Mean (SD) No Mean (SD) No Mean (SD) No Mean (SD) Mean difference (95% CI) P value Mean difference (95% CI) P value Primary outcome Weight at follow-up 136 79.72 (19.01) 136 80.29 (19.45) 134 80.16 (18.77) 132 79.95 (18.96) −0.49 (−0.85 to −0.13) 0.008 −0.48 (−0.84 to −0.12) 0.01 Secondary outcomes

Outcomes Baseline Follow-up Primary model* Further adjusted model† Comparator group Intervention group Comparator group Intervention group No Mean (SD) No Mean (SD) No Mean (SD) No Mean (SD) Mean difference (95% CI) P value Mean difference (95% CI) P value Primary outcome Weight at follow-up 136 79.72 (19.01) 136 80.29 (19.45) 134 80.16 (18.77) 132 79.95 (18.96) −0.49 (−0.85 to −0.13) 0.008 −0.48 (−0.84 to −0.12) 0.01 Secondary outcomes Percentage body fat 136 33.99 (8.78) 134 34.23 (9.42) 133 34.14 (8.99) 128 34.37 (9.17) −0.02 (−0.51 to 0.48) 0.95 −0.03 (−0.53 to 0.47) 0.91 Cognitive restraint 129 14.01 (3.16) 131 13.05 (3.05) 124 14.10 (2.92) 121 14.22 (2.98) 0.64 (0.08 to 1.20) 0.03 0.62 (0.06 to 1.19) 0.03 Emotional eating 129 7.54 (2.67) 133 7.94 (2.99) 126 7.56 (2.66) 128 7.63 (2.82) −0.06 (−0.43 to 0.30) 0.73 −0.05 (−0.42 to 0.32) 0.80 Uncontrolled eating 128 19.83 (5.12) 128 20.46 (5.90) 124 19.91 (5.03) 122 19.84 (5.09) −0.49 (−1.25 to 0.26) 0.20 −0.42 (−1.18 to 0.34) 0.28 Weight gain <0.5 kg - - - - 134 79 (58.96) 132 84 (63.64) 1.22 (0.74 to 2.00)‡ 0.44 1.23 (0.75 to 2.04)‡ 0.41 Self weighing at least twice weekly 130 30 (23.08)§ 131 37 (28.24)§ 126 25 (19.84)§ 128 109 (85.16)§ 55.93 (22.15 to 141.24)‡ <0.001 64.96 (24.48 to 172.39)‡ <0.001 * Adjusted for baseline value of outcome variable and attendance at commercial weight loss programme (stratification variable). † Further adjusted for baseline body mass index and time of follow-up. ‡ Odds ratio (95% confidence interval). § Number (percentage).

Percentage body fat 136 33.99 (8.78) 134 34.23 (9.42) 133 34.14 (8.99) 128 34.37 (9.17) −0.02 (−0.51 to 0.48) 0.95 −0.03 (−0.53 to 0.47) 0.91 Cognitive restraint 129 14.01 (3.16) 131 13.05 (3.05) 124 14.10 (2.92) 121 14.22 (2.98) 0.64 (0.08 to 1.20) 0.03 0.62 (0.06 to 1.19) 0.03 Emotional eating 129 7.54 (2.67) 133 7.94 (2.99) 126 7.56 (2.66) 128 7.63 (2.82) −0.06 (−0.43 to 0.30) 0.73 −0.05 (−0.42 to 0.32) 0.80 Uncontrolled eating 128 19.83 (5.12) 128 20.46 (5.90) 124 19.91 (5.03) 122 19.84 (5.09) −0.49 (−1.25 to 0.26) 0.20 −0.42 (−1.18 to 0.34) 0.28 Weight gain <0.5 kg - - - - 134 79 (58.96) 132 84 (63.64) 1.22 (0.74 to 2.00)‡ 0.44 1.23 (0.75 to 2.04)‡ 0.41 Self weighing at least twice weekly 130 30 (23.08)§ 131 37 (28.24)§ 126 25 (19.84)§ 128 109 (85.16)§ 55.93 (22.15 to 141.24)‡ <0.001 64.96 (24.48 to 172.39)‡ <0.001 * Adjusted for baseline value of outcome variable and attendance at commercial weight loss programme (stratification variable). † Further adjusted for baseline body mass index and time of follow-up. ‡ Odds ratio (95% confidence interval). § Number (percentage). Secondary outcomes The estimated reduction in percentage body fat in the intervention group compared with comparator group was small and non-significant (−0.03%, 95% confidence interval −0.53% to 0.47%, P=0.91 in the further adjusted model). The model adjusted only for baseline percentage body fat, and the stratification variable provided a similar result. The odds of gaining no more than 0.5 kg weight was higher for those in the intervention group than comparator group, but this was non-significant (1.23, 95% confidence interval 0.75 to 2.04, P=0.41). Those in the intervention group had increased odds of self weighing at least twice weekly (64.96, 95% confidence interval 24.48, 172.39, P<0.001).

e than 0.5 kg weight was higher for those in the intervention group than comparator group, but this was non-significant (1.23, 95% confidence interval 0.75 to 2.04, P=0.41). Those in the intervention group had increased odds of self weighing at least twice weekly (64.96, 95% confidence interval 24.48, 172.39, P<0.001). Cognitive restraint scores increased significantly for the intervention group compared with comparator group at follow-up (mean difference in further adjusted model: 0.62, 95% confidence interval 0.06 to 1.19, P=0.03). Estimated differences in emotional eating and uncontrolled eating scores were non-significant (table 2).

Cognitive restraint scores increased significantly for the intervention group compared with comparator group at follow-up (mean difference in further adjusted model: 0.62, 95% confidence interval 0.06 to 1.19, P=0.03). Estimated differences in emotional eating and uncontrolled eating scores were non-significant (table 2). Discussion In this randomised controlled study, a brief behavioural intervention that encouraged adults to weigh themselves regularly, offering advice for weight management and information about the physical activity calorie equivalents (PACE) of popular festive food and drinks prevented weight gain over the Christmas period. Although the difference in weight we detected was marginally smaller than the estimate of effect size used in our sample size calculation, it is still important29 given that the relation between weight and mortality is linear and any weight gain prevented will have a positive impact on health outcomes. Our secondary outcome of reducing the proportion of participants gaining at least 0.5 kg was not statistically significant, but the trial was not powered to detect a difference in this outcome. The null finding for percentage body fat might result from the difficulty in detecting small changes in adiposity using bioelectrical impedance.32 In line with the aims of the intervention, participants in the intervention group were more likely to weigh themselves at least twice weekly than their comparators. We hypothesised that the intervention would work by encouraging participants to reflect on their food and drink consumption and take action if their weight began to increase; we found evidence that this occurred in participants in the intervention group, who showed statistically significantly higher cognitive restraint of eating scores post-intervention than participants in the comparator group. Alcohol consumption seemed to be marginally higher in the comparator group at baseline (consumed alcohol in past week? Yes: 70% comparator v 61% intervention. See supplementary table S3). As alcohol can contribute considerably to energy intake, interventions to prevent weight gain at Christmas could be enhanced by an increased focus on reducing the consumption of alcoholic drinks.

rator group at baseline (consumed alcohol in past week? Yes: 70% comparator v 61% intervention. See supplementary table S3). As alcohol can contribute considerably to energy intake, interventions to prevent weight gain at Christmas could be enhanced by an increased focus on reducing the consumption of alcoholic drinks. Studies have shown that weight increases significantly during holiday occasions (0.4-0.9 kg)8 and accounts for most of annual weight gain.5 6 Low intensity interventions targeting high risk periods such as Christmas could be an important contributor to obesity prevention efforts in the population.

rator group at baseline (consumed alcohol in past week? Yes: 70% comparator v 61% intervention. See supplementary table S3). As alcohol can contribute considerably to energy intake, interventions to prevent weight gain at Christmas could be enhanced by an increased focus on reducing the consumption of alcoholic drinks. Studies have shown that weight increases significantly during holiday occasions (0.4-0.9 kg)8 and accounts for most of annual weight gain.5 6 Low intensity interventions targeting high risk periods such as Christmas could be an important contributor to obesity prevention efforts in the population. Comparison with existing literature Few trials have tested interventions for weight gain prevention in adults. One systematic review reported that only nine randomised controlled trials have been published in 10 years.3 Furthermore, no trial has tested brief (<10 weeks) interventions. Most have reported interventions that result in small to modest changes in weight between groups at follow-up. Several studies have reported a statistically significant difference in weight between intervention and comparator group of 1.0 kg and 3.5 kg.33 34 35 36 37 38 All successful interventions were multifactorial and intensive, consisting of dietary, behavioural, and physical activity elements and with regular contact and support. Interventions varied in duration, and the substantial heterogeneity of interventions made comparisons difficult. The review authors concluded that the less intensive interventions incorporating self monitoring of weight in addition to general dietary advice, physical activity recommendations, and behaviour change components could be more successful at preventing the small gains in weight observed in populations over time and that studies to test this were required. We found that a brief intervention of between four to eight weeks that prompted participants to restrain their eating and drinking during a high risk period for weight gain, can be effective.

uccessful at preventing the small gains in weight observed in populations over time and that studies to test this were required. We found that a brief intervention of between four to eight weeks that prompted participants to restrain their eating and drinking during a high risk period for weight gain, can be effective. Although this intervention was successful in preventing weight gain, it was multicomponent and therefore not possible to determine the effectiveness of the individual factors, although we did find that participants in the intervention group were more likely to weigh themselves at least twice weekly than those in the comparator group. Additionally, evidence from other studies suggests that each of the intervention components can be effective in facilitating weight management. Previous prevention trials that included self weighing reported associations between frequent self weighing and weight change.3 In one study, however, self weighing was not found to be associated with weight change,34 which could have been the result of the low level of adherence to self weighing and which was not the case in our study.

n trials that included self weighing reported associations between frequent self weighing and weight change.3 In one study, however, self weighing was not found to be associated with weight change,34 which could have been the result of the low level of adherence to self weighing and which was not the case in our study. To promote restraint of eating and drinking, we gave participants 10 Top Tips (10TT) for good weight management and information of the amount of physical activity required to expend the calories in food and drinks consumed. The 10TT23 24 were developed as a simple weight loss intervention on the basis of a set of everyday eating and physical activity behaviours. The tips incorporate advice on the repetition of eating and physical activity behaviours consistent with the habit formation model.39 10TT can result in weight loss, showing that brief habit based information can be useful in facilitating weight management.23 24

set of everyday eating and physical activity behaviours. The tips incorporate advice on the repetition of eating and physical activity behaviours consistent with the habit formation model.39 10TT can result in weight loss, showing that brief habit based information can be useful in facilitating weight management.23 24 In addition to offering participants tips for good weight management we considered it important to highlight the calorie content and demands of popular food and drinks. This is because studies have shown that people often underestimate the energy content of foods40 41 or do not understand the amount of physical activity required to expend energy dense foods42; foods that are more often consumed at Christmas.43 By highlighting this information, we hypothesised that participants would show restraint of eating and drinking. Studies have shown the provision of PACE information to be associated with lower energy meals being chosen from menus and therefore consumed at meal times, with encouragement to be more physically active.44 45 Collectively, although PACE information and labelling seems promising in helping people to understand the energy costs of foods and drinks, particularly at high risk times such as Christmas, further research is required to investigate the effectiveness of such an approach.

couragement to be more physically active.44 45 Collectively, although PACE information and labelling seems promising in helping people to understand the energy costs of foods and drinks, particularly at high risk times such as Christmas, further research is required to investigate the effectiveness of such an approach. Strengths and limitations of this study The intervention was novel and designed to be easily implemented if effective. Loss to follow-up was low (2%), reducing the potential for bias. With the larger sample size, it was possible to detect a smaller effect than we had used in planning the study. The power calculation was also conservative as it did not allow for the adjustment of baseline weight in the analysis. This high follow-up rate could be because participants engaged well with the study or because the follow-up period was short. We also reimbursed participants for their time when they provided data at the follow-up time point (£10 high street shopping voucher). People were recruited from a range of ethnic groups and with varied BMI and deprivation status, which increases the generalisability of the findings and has the potential to reduce health inequalities. The PACE information on Christmas foods and drinks used in the study was tailored to the local cultural context but could easily be adapted for use in other settings with different types of foods and drink consumed during festive periods. In our study, 83% (n=230) of participants had access to weighing scales at home. This supports the ease of implementation of our intervention. Men can be difficult to recruit to weight management trials,46 but a relatively high proportion (22%) participated in our study. Participants were blinded to the aim of the study and the researchers who collected outcome data at follow-up were also blinded to group allocation until after weight had been measured.

tion. Men can be difficult to recruit to weight management trials,46 but a relatively high proportion (22%) participated in our study. Participants were blinded to the aim of the study and the researchers who collected outcome data at follow-up were also blinded to group allocation until after weight had been measured. Our study has several limitations. A longer period of follow-up would have been useful to determine if the weight gain prevented persisted over time. The amount of weight gain prevented by the intervention might be considered relatively small (about 0.5 kg), but the intervention was brief, and at a population level if the weight loss was maintained the benefits to health would be important.30 Although we blinded participants to the main outcome of the study and did not explicitly state its intention, our recruitment materials requested volunteers for a study to prevent weight gain during winter. It is possible we recruited people with better health awareness although we were able to recruit people with a range of BMI status. Participants were mostly women in the healthy or overweight BMI categories and although these are important target groups, this could limit the generalisability of our findings.

ng winter. It is possible we recruited people with better health awareness although we were able to recruit people with a range of BMI status. Participants were mostly women in the healthy or overweight BMI categories and although these are important target groups, this could limit the generalisability of our findings. Conclusion and policy implications A brief intervention underpinned by self regulation theory,17 consisting of encouragement to regularly self weigh, tips for weight management, and PACE information prevented weight gain in adults over the Christmas period. Cognitive restraint of eating was increased in the intervention group. These results should be considered by health policy makers to prevent weight gain in the population during high risk periods such as holidays. What is already known on this topic Each year people gain a small amount of weight Holidays such as at Christmas are responsible for most of this annual weight gain Studies have shown that weight gained during holiday periods is not lost What this study adds A brief intervention to increase restraint of eating and drinking through self weighing, information on physical activity calorie equivalents of popular foods and drinks, and tips for weight management prevented weight gain over the Christmas period Cognitive restraint of eating was increased in the intervention group We thank the participants and researchers (Sue Clifford, Christina Kerin, Ryan Griffin, Janice Gunnell) for making this trial possible and the schools, workplaces, and social media groups for supporting recruitment to this trial.

What this study adds A brief intervention to increase restraint of eating and drinking through self weighing, information on physical activity calorie equivalents of popular foods and drinks, and tips for weight management prevented weight gain over the Christmas period Cognitive restraint of eating was increased in the intervention group We thank the participants and researchers (Sue Clifford, Christina Kerin, Ryan Griffin, Janice Gunnell) for making this trial possible and the schools, workplaces, and social media groups for supporting recruitment to this trial. Web extra Extra material supplied by authors Supplementary information: additional material Contributors: AJD conceived the study with input from AF. AJD wrote the protocol with contributions from AF and FM. FM wrote the first version of the manuscript with input from coauthors. FM, AJD, AF, and MP wrote the statistical analysis plan with input from AS and CE. CE conducted the statistical analyses with support from AS. All authors had full access to the data, take responsibility for the integrity of the data and the accuracy of the data analysis, contributed to the interpretation of the results, and reviewed and approved the final manuscript. AJD is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

ntegrity of the data and the accuracy of the data analysis, contributed to the interpretation of the results, and reviewed and approved the final manuscript. AJD is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Funding: This work was independent research as part of a PhD studentship funded by the School of Medical and Dental Sciences at the University of Birmingham. This paper presents independent research supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the NIHR Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. AF reports grants from Ethicon (Johnson and Johnson), researcher led, outside the submitted work. Ethical approval: This study was approved by the University of Birmingham Science, Technology, Engineering and Mathematics ethical review committee (ERN_16-0673). All participants provided written informed consent.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. AF reports grants from Ethicon (Johnson and Johnson), researcher led, outside the submitted work. Ethical approval: This study was approved by the University of Birmingham Science, Technology, Engineering and Mathematics ethical review committee (ERN_16-0673). All participants provided written informed consent. Data sharing: Data from the Winter Weight Watch study or the study materials are available from the corresponding author at a.c.farley@bham.ac.uk. All individual participant data will be available on request one year after publication of trial outcomes. The study protocol is available on request. All requests for data access will need to specify the planned use of data and will require approval from the trial investigator team prior to release. Transparency: The guarantor (AJD) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. The manuscript follows the CONSORT guidelines for the reporting of clinical trials.

n who received an extended course of treatment. Estimates of treatment effects are presented with 95% confidence intervals. P values are two tailed with a P value less than 0.05 considered statistically significant. Analyses were carried out using SAS version 9.4 (Cary, NC) or Stata 14 (StataCorp, College Station, TX). Patient and public involvement The trial protocol was reviewed by representatives of the UK Nephrotic Syndrome Trust (NeST) and the UK Renal Patient Support Group, who provided valuable input about trial design, acceptability of trial visit frequency, and adverse event monitoring. A NeST representative participated on the trial steering committee. After publication, the trial results will be disseminated to all study collaborators. The plain English summary of the study results will be sent to the participants and/or their parents through their responsible clinician. The summary will also be available on the NeST website and the PREDNOS study website (www.birmingham.ac.uk/prednos).

he trial results will be disseminated to all study collaborators. The plain English summary of the study results will be sent to the participants and/or their parents through their responsible clinician. The summary will also be available on the NeST website and the PREDNOS study website (www.birmingham.ac.uk/prednos). Results Participants Overall, 237 participants aged 1-14 years were recruited from 86 centres between July 2011 and October 2014; 119 were randomised to an extended course of treatment and 118 to a standard course of treatment. Fourteen (five in the extended course group and nine in the standard course group) were withdrawn early after randomisation because of loss of corticosteroid sensitivity, leaving an intention to treat analysis population of 223 (114 in the extended course group and 109 in the standard course group). Figure 1 shows the patient flow through the trial. When participants withdrew consent or were lost to follow-up, data collected up until that point were included in the analysis. Fig 1 CONSORT diagram of participant flow through trial

Introduction Idiopathic nephrotic syndrome is the commonest childhood glomerular disorder, with an annual incidence of two per 100 000 children in the United Kingdom. Children present with the disease at a median age of 2-3 years, and it is twice as common in boys and four to six times more common in people of South Asian origin.1 2 3 4 More than 90% of children who present with idiopathic nephrotic syndrome respond to a course of high dose corticosteroid treatment, and current practice is to treat most patients empirically with prednisolone.5 6 Children who respond to treatment are given a diagnostic label of steroid sensitive nephrotic syndrome and generally have a good prognosis with a low incidence of end stage renal disease. After initial successful treatment, around 80% of children with steroid sensitive nephrotic syndrome have disease relapses requiring further courses of high dose prednisolone. About 50% develop frequently relapsing nephrotic syndrome (two or more relapses within six months of presentation or four relapses within any 12 months) or steroid dependent nephrotic syndrome (relapse while receiving prednisolone or within 14 days of stopping the drug).7 Relapses and further high dose prednisolone treatment are associated with substantial morbidity.8 When complications develop or are anticipated after repeated courses of corticosteroids, alternative immunosuppressive treatment is indicated, such as levamisole, cyclophosphamide, ciclosporin, tacrolimus, mycophenolate mofetil, or rituximab.

high dose prednisolone treatment are associated with substantial morbidity.8 When complications develop or are anticipated after repeated courses of corticosteroids, alternative immunosuppressive treatment is indicated, such as levamisole, cyclophosphamide, ciclosporin, tacrolimus, mycophenolate mofetil, or rituximab. The best initial prednisolone regimen for children presenting with steroid sensitive nephrotic syndrome remains unknown. The eight week course first described in the 1960s by the International Study of Kidney Disease in Children (prednisolone 60 mg/m2 for four weeks then 40 mg/m2 on alternate days for four weeks) continues to be used in most UK centres and in many other countries. However, systematic review data suggest that a more intensive initial treatment course improves clinical outcomes.9 When the prednisolone in nephrotic syndrome (PREDNOS) trial started, six randomised controlled trials had compared the eight week course with a range of different prednisolone regimens of three months or longer.10 11 12 13 14 15 A 2005 Cochrane review concluded that prednisolone treatment of three months or longer statistically significantly reduced the rate of relapse at 12-24 months and the rate of frequently relapsing nephrotic syndrome.16 The Kidney Disease: Improving Global Outcomes guidelines published in 2012 supported the conclusions of this Cochrane review. These guidelines recommended daily prednisolone treatment of 60 mg/m2 or 2 mg/kg for four to six weeks followed by 40 mg/m2 or 1.5 mg/kg on alternate days and continued for two to five months, with tapering of the dose.17 Despite these recommendations, several methodological concerns relating to these six studies have resulted in the continued use of the eight week course in the UK and elsewhere.

g for four to six weeks followed by 40 mg/m2 or 1.5 mg/kg on alternate days and continued for two to five months, with tapering of the dose.17 Despite these recommendations, several methodological concerns relating to these six studies have resulted in the continued use of the eight week course in the UK and elsewhere. We conducted the PREDNOS trial to compare this eight week course with a longer 16 week course in UK children. The study design was optimised to overcome the methodological concerns relating to previous studies. We first performed an external pilot study over a year that included 55 participants. This pilot study helped us to develop the design of the main trial and found that participants of different ethnicities could be recruited in district hospitals and tertiary nephrology centres. The primary objective of the main trial was to determine whether an initial 16 week extended course of prednisolone treatment increased the time to first relapse in children with steroid sensitive nephrotic syndrome compared with the eight week standard course. Secondary objectives were to determine whether the extended course reduced the relapse rate, the proportion of participants who developed frequently relapsing nephrotic syndrome or steroid dependent nephrotic syndrome, and the requirement for second and third line immunosuppressive agents. Additionally, we considered whether the extended course was associated with an increased incidence of corticosteroid related adverse events, including behavioural problems. We also performed a cost effectiveness analysis by comparing costs and quality adjusted life years for the two regimens, and the methods and results are reported in supplementary appendices 1, 3, and 4.

was associated with an increased incidence of corticosteroid related adverse events, including behavioural problems. We also performed a cost effectiveness analysis by comparing costs and quality adjusted life years for the two regimens, and the methods and results are reported in supplementary appendices 1, 3, and 4. Methods Participants We performed this double blind, placebo controlled, randomised controlled trial across 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. Children aged 1-14 years with a first episode of idiopathic nephrotic syndrome were eligible to participate if they had a first morning urine protein to creatinine ratio or albumin to creatinine ratio greater than 200 mg/mmol; had a serum or plasma albumin level less than 25 g/L; had not previously received treatment with corticosteroids, immunosuppressive or cytotoxic drugs for any form of renal disease; and had no evidence of underlying systemic disorder or use of drugs known to be associated with nephrotic syndrome. We excluded children with histological changes other than minimal change glomerulonephritis (when renal biopsy had been performed), history of poor adherence to treatment, or a known allergy to prednisolone.

had no evidence of underlying systemic disorder or use of drugs known to be associated with nephrotic syndrome. We excluded children with histological changes other than minimal change glomerulonephritis (when renal biopsy had been performed), history of poor adherence to treatment, or a known allergy to prednisolone. Interventions and randomisation Potential participants started prednisolone 60 mg/m2 daily for four weeks in accordance with routine clinical practice. Trial recruitment and randomisation took place when the children were thought to be corticosteroid sensitive (three consecutive days of zero or trace proteinuria on Albustix test; generally between 14 and 21 days after start of prednisolone treatment). We obtained fully informed written consent from the parents or guardians and assent from children when age appropriate. We then performed randomisation online through a secure 24 hour internet based randomisation service or by a telephone call to the Birmingham Clinical Trials Unit. Participants were randomised in a 1:1 ratio to either an extended course of treatment or a standard course of treatment by using a minimisation algorithm to ensure balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). The extended treatment group received prednisolone 60 mg/m2 daily (maximum 80 mg) for four weeks followed by 12 weeks of prednisolone treatment on alternate days, starting at 60 mg/m2 (maximum 80 mg) and tapering by 10 mg/m2 every two weeks (total dose 3150 mg/m2). The standard treatment group received prednisolone 60 mg/m2 daily (maximum 80 mg) for four weeks followed by 40 mg/m2 (maximum 60 mg) on alternate days for four weeks (total dose 2240 mg/m2). In both groups, treatment in the first four weeks was open label and then it was blinded in the following 12 week phase, with matching placebo in the standard course (control) group. A central pharmacy dispensed the entire course of blinded trial drugs in crushable tablet form in blister packs, delivered by courier to the family home.

treatment in the first four weeks was open label and then it was blinded in the following 12 week phase, with matching placebo in the standard course (control) group. A central pharmacy dispensed the entire course of blinded trial drugs in crushable tablet form in blister packs, delivered by courier to the family home. In accordance with routine clinical practice, children’s first morning urine was tested for proteinuria (Albustix). We provided parents with a diary so that they could record urine test results and the drugs administered on a daily basis. Parents also used the diary to record illnesses and consultations with healthcare professionals (such as general practitioners, nurses, or hospital emergency department clinicians), and details of drugs prescribed or purchased over the counter. Families contacted their local trial site if the child had a relapse (urine analysis showed three consecutive days of 3+ proteinuria or generalised oedema in association with 3+ proteinuria) so that treatment could be prescribed. We also instructed families to call their local site if they had any other concerns—for example, if their child had developed new adverse events or they had questions about urine analysis results.

ive days of 3+ proteinuria or generalised oedema in association with 3+ proteinuria) so that treatment could be prescribed. We also instructed families to call their local site if they had any other concerns—for example, if their child had developed new adverse events or they had questions about urine analysis results. Trial assessments and data collection We performed trial visits at 4, 8, 12, and 16 weeks, and then at 5, 6, 8, 10, 12, 18, 24, 30, 36, 42, and 48 months after the children started treatment with open label prednisolone. They were followed up for a minimum of 24 months and up to a maximum of 48 months. The trial finished when the last participant had completed 24 months of follow-up. At each trial visit, we recorded information on relapses, adherence to trial treatment, other drug treatments, adverse events, and use of healthcare resources. A full clinical assessment was performed, including height, weight, and blood pressure measurements. Any event that resulted in death, was life threatening, required admission to hospital or prolonged an existing hospital admission, caused persistent or major disability or incapacity, or resulted in a congenital anomaly or birth defect was considered a serious adverse event. These events were reported using specific forms.

vent that resulted in death, was life threatening, required admission to hospital or prolonged an existing hospital admission, caused persistent or major disability or incapacity, or resulted in a congenital anomaly or birth defect was considered a serious adverse event. These events were reported using specific forms. Data recorded on case report forms were generally not the source data for clinical information. However, when self reported patient information on relapses and drug changes was taken from diaries and entered onto case report forms, these forms were considered to be the source data. We did not verify source data taken from diaries because the diaries were not retained. Parents completed three questionnaires at 4 and 16 weeks, and then at 12, 24, 36, and 48 months: the Achenbach child behaviour checklist was used to assess behavioural change in eight categories (anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behaviour, and aggressive behaviour), and the paediatric quality of life inventory and the child health utility 9 dimension were used to assess quality of life.18 19 20

e in eight categories (anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behaviour, and aggressive behaviour), and the paediatric quality of life inventory and the child health utility 9 dimension were used to assess quality of life.18 19 20 Sample size The primary analysis was based on a log rank test of time to relapse. We expected a relapse rate of 60% at one year in the standard course group. To detect an absolute difference of 20% (considered a clinically meaningful difference by the paediatric nephrologists on the study team) in the relapse rate, from 60% in the standard course group to 40% in the extended course group, with 80% power and α=0.05, we needed 200 participants. Allowing for a dropout rate of 15%, the total number of participants required was 236 (118 in each group).

difference by the paediatric nephrologists on the study team) in the relapse rate, from 60% in the standard course group to 40% in the extended course group, with 80% power and α=0.05, we needed 200 participants. Allowing for a dropout rate of 15%, the total number of participants required was 236 (118 in each group). Statistical analysis The primary outcome measure was the time from starting open label prednisolone treatment to first relapse. We used Kaplan-Meier survival curves to visually present the time to first relapse. We compared the primary analysis of time to first relapse between groups using a log rank test. A Cox proportional hazard model was fitted to obtain a hazard ratio and 95% confidence intervals. As a secondary analysis, we also fitted a Cox proportional hazard model, which was adjusted for the minimisation variables of ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). It is unlikely that a child will have a relapse while taking corticosteroids; however, it is possible for children in the standard course group to experience an early relapse in weeks 9-16 when receiving placebo, which could bias the results in favour of the extended course group. Corticosteroid dependency could also differ between the groups (defined as relapsing while receiving corticosteroid treatment or within 14 days of stopping the drug). To avoid the potential for bias in these situations, we set the relapse time to 18 weeks in children who had a relapse before 18 weeks. We also performed a secondary analysis of time to first relapse using the actual relapse date. Two a priori subgroup analyses were carried out for the primary outcome for the minimisation variables of ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). We included a treatment group by subgroup interaction parameter in the Cox proportional hazard model to assess whether there were any differences in the treatment effect across the different stratums.

for the minimisation variables of ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). We included a treatment group by subgroup interaction parameter in the Cox proportional hazard model to assess whether there were any differences in the treatment effect across the different stratums. Secondary outcomes were relapse rate, incidence of frequently relapsing nephrotic syndrome and of steroid dependent nephrotic syndrome, use of second line immunosuppressive drugs, rates of adverse events and serious adverse events, behavioural change using the Achenbach child behaviour checklist, and quality adjusted life years. We compared relapse rates (number for each child) using a negative binomial model to obtain an incident rate ratio. Categorical data items (eg, frequently relapsing nephrotic syndrome, steroid dependent nephrotic syndrome) were analysed using a χ2 test, and relative risks were produced. We reported adverse event data on a Likert scale (none, mild, moderate, or severe). These data were dichotomised according to whether the participant experienced the adverse event or not, and relative risks were reported. The number of children who reported a serious adverse event was reported. The Achenbach child behaviour checklist was analysed using repeated measures methods. We converted the exploratory outcomes height, weight, body mass index, and blood pressure values to standard deviation scores and presented them graphically using longitudinal plots, with no statistical analysis planned.

was reported. The Achenbach child behaviour checklist was analysed using repeated measures methods. We converted the exploratory outcomes height, weight, body mass index, and blood pressure values to standard deviation scores and presented them graphically using longitudinal plots, with no statistical analysis planned. We included participants in the analysis according to their initial randomised treatment allocation. We excluded participants who were found to be corticosteroid resistant after randomisation. This is not expected to introduce bias because most of the dropouts occurred before the start of randomised treatment, and clinicians were unaware of the treatment assigned to their patients. We describe this analysis as intention to treat. A hazard ratio or relative risk less than 1 favoured the children who received an extended course of treatment. Estimates of treatment effects are presented with 95% confidence intervals. P values are two tailed with a P value less than 0.05 considered statistically significant. Analyses were carried out using SAS version 9.4 (Cary, NC) or Stata 14 (StataCorp, College Station, TX).

Results Participants Overall, 237 participants aged 1-14 years were recruited from 86 centres between July 2011 and October 2014; 119 were randomised to an extended course of treatment and 118 to a standard course of treatment. Fourteen (five in the extended course group and nine in the standard course group) were withdrawn early after randomisation because of loss of corticosteroid sensitivity, leaving an intention to treat analysis population of 223 (114 in the extended course group and 109 in the standard course group). Figure 1 shows the patient flow through the trial. When participants withdrew consent or were lost to follow-up, data collected up until that point were included in the analysis. Fig 1 CONSORT diagram of participant flow through trial Baseline characteristics did not differ between the extended course and standard course groups (table 1). Most of the intention to treat population were boys (65%, n=146), 65% (n=145) were aged less than 6 years, and 20% (n=44) were of South Asian origin. Eighty six (39%) did not complete their course of trial drugs. This was more common in the standard course group (extended course 32/114 (28%) v standard course 54/109 (50%); P=0.001) and the main reason was relapse while double blind trial drugs were being administered. Adherence to trial drugs was high; 13% (n=29) reported missed doses and most of these patients reported missing only one or two doses. Attendance rates for follow-up trial visits were high, as were submission rates of clinical data and participant questionnaires (>90% of expected data received at each time point).

red. Adherence to trial drugs was high; 13% (n=29) reported missed doses and most of these patients reported missing only one or two doses. Attendance rates for follow-up trial visits were high, as were submission rates of clinical data and participant questionnaires (>90% of expected data received at each time point). Table 1 Baseline characteristics of intention to treat population. Values are numbers (percentages) unless stated otherwise Characteristics Extended course group (n=119) Standard course group (n=118) Total (n=237) No of corticosteroid sensitive participants 114 109 223 Mean (SD) age (years) 5.1 (3.2) 4.7 (2.9) 4.9 (3.1) Age (years): 1-2 28 (25) 29 (27) 57 (26) 3-5 45 (39) 43 (39) 88 (39) 6-11 35 (31) 34 (31) 69 (31) 12-17* 6 (5) 3 (3) 9 (4) Age (years)†: ≤5 73 (64) 72 (66) 145 (65) ≥6 41 (36) 37 (34) 78 (35) Boys 68 (60) 78 (72) 146 (65) Ethnicity†: South Asian 23 (20) 21 (19) 44 (20) White 75 (66) 73 (67) 148 (66) Other or not stated 16 (14) 15 (14) 31 (14) Median (interquartile range) body mass index centile 90.0 (69.5-97.5) 85.3 (66.3-97.3) 87.5 (66.6-97.3) Body mass index centile: Underweight (<5th) 0 (0) 2 (2) 2 (1) Healthy (5th-84th) 48 (42) 52 (48) 100 (45) Overweight (85th-95th) 24 (21) 19 (17) 43 (19) Obese (≥95th) 42 (37) 36 (33) 78 (35) Mean (SD) open label daily prednisolone dose (mg/m2) 58.0 (6.8) 58.5 (5.9) 58.2 (6.4) * Participants were eligible for the trial if they were aged 1-14 years at time of diagnosis. † Minimisation variable.

Characteristics Extended course group (n=119) Standard course group (n=118) Total (n=237) No of corticosteroid sensitive participants 114 109 223 Mean (SD) age (years) 5.1 (3.2) 4.7 (2.9) 4.9 (3.1) Age (years): 1-2 28 (25) 29 (27) 57 (26) 3-5 45 (39) 43 (39) 88 (39) 6-11 35 (31) 34 (31) 69 (31) 12-17* 6 (5) 3 (3) 9 (4) Age (years)†: ≤5 73 (64) 72 (66) 145 (65) ≥6 41 (36) 37 (34) 78 (35) Boys 68 (60) 78 (72) 146 (65) Ethnicity†: South Asian 23 (20) 21 (19) 44 (20) White 75 (66) 73 (67) 148 (66) Other or not stated 16 (14) 15 (14) 31 (14) Median (interquartile range) body mass index centile 90.0 (69.5-97.5) 85.3 (66.3-97.3) 87.5 (66.6-97.3) Body mass index centile: Underweight (<5th) 0 (0) 2 (2) 2 (1) Healthy (5th-84th) 48 (42) 52 (48) 100 (45) Overweight (85th-95th) 24 (21) 19 (17) 43 (19) Obese (≥95th) 42 (37) 36 (33) 78 (35) Mean (SD) open label daily prednisolone dose (mg/m2) 58.0 (6.8) 58.5 (5.9) 58.2 (6.4) * Participants were eligible for the trial if they were aged 1-14 years at time of diagnosis. † Minimisation variable. Primary outcome No statistically significant difference was found in the primary outcome measure of time to first relapse between the extended course and standard course groups (fig 2; hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log rank P=0.28). The median time to first relapse was 139 (interquartile range 90-179) days for the extended course group versus 87 (64.5-134) days for the standard course group. Eighty per cent (n=179) of participants reported a relapse during trial follow-up (extended course 91/114 (80%) v standard course 88/109 (81%); difference −1%, 95% confidence interval −11% to 10%; table 2).

uartile range 90-179) days for the extended course group versus 87 (64.5-134) days for the standard course group. Eighty per cent (n=179) of participants reported a relapse during trial follow-up (extended course 91/114 (80%) v standard course 88/109 (81%); difference −1%, 95% confidence interval −11% to 10%; table 2). Fig 2 Time to first relapse in participants receiving extended or standard course of prednisolone treatment Table 2 Secondary outcome measures in extended course and standard course groups. Values are numbers (percentages) unless stated otherwise Secondary outcome measures Extended course group Standard course group Estimate (extended v short course) (95% CI) P value Relapse n=114 n=109 No of relapses 454 394 — No of participants who had a relapse 91 (80) 88 (81) 0.87* (0.65 to 1.17) 0.28 Mean (SD) No of relapses for each participant 3.98 (3.30) 3.61 (3.25) 1.09† (0.86 to 1.39) 0.46 No of participants who had FRNS 60 (53) 55 (50) 1.04‡ (0.81 to 1.35) 0.75 No of participants who had SDNS 48 (42) 48 (44) 0.96‡ (0.71 to 1.29) 0.77 Second line immunosuppressive drugs No of participants who received immunosuppressant drugs 62 (54) 61 (56) 0.97† (0.77 to 1.23) 0.81 Type of immunosuppressant drug: Ciclosporin 4 (4) 6 (6) — Tacrolimus 18 (16) 8 (7) — Levamisole 34 (30) 35 (32) — Cyclophosphamide 29 (25) 31 (28) — Mycophenolate mofetil 15 (13) 13 (12) — Rituximab 1 (1) 5 (5) — Corticosteroid dose n=94 n=90 —

No of participants who received immunosuppressant drugs 62 (54) 61 (56) 0.97† (0.77 to 1.23) 0.81 Type of immunosuppressant drug: Ciclosporin 4 (4) 6 (6) — Tacrolimus 18 (16) 8 (7) — Levamisole 34 (30) 35 (32) — Cyclophosphamide 29 (25) 31 (28) — Mycophenolate mofetil 15 (13) 13 (12) — Rituximab 1 (1) 5 (5) — Corticosteroid dose n=94 n=90 — Mean (SD) total prednisolone dose (mg)‡ 6674.1 (4998.2) 5474.6 (3697.3) Mean difference=1199.5 (−83.8 to 2482.8) 0.07 A ratio less than 1, and a negative mean difference, favours the extended course group. FRNS=frequently relapsing nephrotic syndrome; SDNS=steroid dependent nephrotic syndrome. * Hazard ratio. † Incident rate ratio. ‡ Relative risk. ‡ Total dose received during trial (after completion of trial drug). Prespecified subgroup analyses for the primary outcome for ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more) showed no clear evidence to suggest that the treatment effect differed between the participant subgroups. We found some evidence (P for interaction=0.08) that time to first relapse was increased in participants in the extended course group aged 5 years or less (hazard ratio 0.72, 95% confidence interval 0.50 to 1.05) compared with participants aged 6 years or more. In participants aged 6 years or more, time to first relapse was increased in those in the standard course group (1.26, 0.77 to 2.07).

was increased in participants in the extended course group aged 5 years or less (hazard ratio 0.72, 95% confidence interval 0.50 to 1.05) compared with participants aged 6 years or more. In participants aged 6 years or more, time to first relapse was increased in those in the standard course group (1.26, 0.77 to 2.07). Secondary outcomes The total number of relapses in each participant ranged from zero to 15; nine participants in the extended course group and eight in the standard course group had 10 or more relapses. We found no differences in the mean number of relapses, the proportion developing frequently relapsing or steroid dependent nephrotic syndrome, or the number requiring alternative immunosuppressive treatment. The total dose of prednisolone received during the trial (after completing the course of trial drugs) was not statistically significantly different between the two treatment groups (table 2). Adverse events and behaviour Table 3 shows the cumulative incidence of adverse events over the 24 months of follow-up. We found no differences between the two groups for any of these adverse events except for poor behaviour reported by parents (yes or no), which was more common in the standard course group. However, when we analysed the detailed quantitative behavioural data collected using the Achenbach child behaviour checklist we found no differences in behaviour score (P=0.28) or the proportion of participants reporting normal checklist scores at any time point during the trial.

re common in the standard course group. However, when we analysed the detailed quantitative behavioural data collected using the Achenbach child behaviour checklist we found no differences in behaviour score (P=0.28) or the proportion of participants reporting normal checklist scores at any time point during the trial. Table 3 Cumulative incidence of adverse events over 24 months of follow-up. Values are numbers (percentages) unless stated otherwise Adverse event Extended course group (n=114) Standard course group (n=109) Relative risk (95% CI) Cushingoid facies 83 (73) 78 (72) 1.02 (0.88 to 1.19) Striae 14 (12) 7 (6) 1.92 (0.81 to 4.54) Hypertrichosis 45 (39) 41 (38) 1.05 (0.77 to 1.45) Acne 12 (11) 7 (6) 1.64 (0.68 to 3.99) Increased appetite 106 (93) 103 (94) 1.00 (0.94 to 1.07) Poor behaviour 94 (82) 101 (93) 0.90 (0.82 to 0.98) Glycosuria 19 (17) 14 (13) 1.34 (0.72 to 2.48) Cataract 1 (1) 1 (1) 0.96 (0.06 to 15.00) Abdominal pain 49 (43) 51 (47) 0.91 (0.69 to 1.20) Serious adverse events Forty six participants reported 67 serious adverse events (extended course 19/114 (17%) v standard course 27/109 (25%); P=0.13). Serious adverse events most commonly related to admission for disease relapse or bacterial infection. We considered six serious adverse events in the extended course group and five in the standard course group to be drug related, although none resulted in discontinuation of the trial drug. The one death due to unintentional injury was unrelated to the trial.

ated to admission for disease relapse or bacterial infection. We considered six serious adverse events in the extended course group and five in the standard course group to be drug related, although none resulted in discontinuation of the trial drug. The one death due to unintentional injury was unrelated to the trial. Exploratory outcomes The mean height, weight, and body mass index z scores did not differ between the two treatment groups at any time point throughout the trial period. We found a progressive increase in height z score and decrease in body mass index z score over the trial period (supplementary figs 1 and 2). No differences were found in mean systolic and diastolic blood pressure between the two treatment groups at any time point throughout the trial, with a trend to reduction in z score with increasing time after presentation (supplementary fig 3). Cost effectiveness analysis Supplementary appendices 1, 3, and 4 report full details of the economic evaluation. In brief, we found the extended course of treatment to be cheaper than the standard course after allowing for all primary care, secondary care, and prescription costs over 24 months. Furthermore, the extended course produced a small incremental gain in quality of life compared with the standard course. These findings mean that the extended course was a cost effective use of healthcare resources when conventional rules of cost effectiveness were applied.

care, and prescription costs over 24 months. Furthermore, the extended course produced a small incremental gain in quality of life compared with the standard course. These findings mean that the extended course was a cost effective use of healthcare resources when conventional rules of cost effectiveness were applied. Discussion The PREDNOS trial recruited UK children with steroid sensitive nephrotic syndrome and compared an initial extended 16 week course of prednisolone treatment with the standard eight week course described by the International Study of Kidney Disease in Children. The results did not show any clinical benefit on key primary and secondary clinical endpoints. We found no statistically significant difference between the two treatment groups in the outcome measures: time to first relapse of nephrotic syndrome; incidence of any relapse or the number of relapses experienced; the proportion of participants who went on to develop frequently relapsing or steroid dependent nephrotic syndrome; or the requirement for alternative non-corticosteroid immunosuppressive treatment. Confidence intervals for the incidence of any relapse excluded clinically important benefit. Subgroup analyses showed no clear evidence that the treatment effect differed according to ethnicity or age, although the trial was not powered to detect differences in subgroups.

non-corticosteroid immunosuppressive treatment. Confidence intervals for the incidence of any relapse excluded clinically important benefit. Subgroup analyses showed no clear evidence that the treatment effect differed according to ethnicity or age, although the trial was not powered to detect differences in subgroups. Although there is no evidence that an extended course of prednisolone treatment statistically significantly reduces clinical endpoints, the direction of the effect was to delay the time to relapse. We found some evidence that an extended course of prednisolone reduced healthcare resource use in the first two years and resulted in a small improvement in quality of life. Combined in a cost effectiveness analysis, these findings provide evidence that an extended course of treatment is a cost effective use of healthcare resources.

evidence that an extended course of prednisolone reduced healthcare resource use in the first two years and resulted in a small improvement in quality of life. Combined in a cost effectiveness analysis, these findings provide evidence that an extended course of treatment is a cost effective use of healthcare resources. Strengths and weaknesses of this study The randomised, double blind, placebo controlled trial design ensured a low risk of selection, performance, detection, and selective reporting bias. The unselected trial population with broad inclusion criteria that was recruited from 86 centres across the UK included 44 (20%) participants from the South Asian community. The trial was therefore representative of UK children presenting with steroid sensitive nephrotic syndrome. The inclusion of a substantial proportion of participants of South Asian origin is of particular importance because of the increased incidence of the disease in this group. In addition, the UK South Asian population is generally under-represented in clinical trials, with recruitment posing several challenges.21

ndrome. The inclusion of a substantial proportion of participants of South Asian origin is of particular importance because of the increased incidence of the disease in this group. In addition, the UK South Asian population is generally under-represented in clinical trials, with recruitment posing several challenges.21 We managed to recruit around one third of all UK children who presented with steroid sensitive nephrotic syndrome over the trial period, which indicates a high level of acceptance of the trial among patients and clinicians. We used internationally recognised definitions of disease outcomes from the International Study of Kidney Disease in Children. We also chose a primary outcome measure that was believed to be of great clinical importance by clinicians and patient advisors and was consistent with the outcome measures used in many other studies. We systematically produced data on adverse effects related to corticosteroid treatment; these data are clinically relevant and of great importance to families but are often ignored. Baseline features were well balanced and the dropout rate was low and rate of completion of visits high.

sures used in many other studies. We systematically produced data on adverse effects related to corticosteroid treatment; these data are clinically relevant and of great importance to families but are often ignored. Baseline features were well balanced and the dropout rate was low and rate of completion of visits high. Possible weaknesses include the potential exclusion of young children who were unable to take the trial drug, which was provided as a crushable tablet, rather than a suspension or in soluble or dispersible form. We found 14 participants to be steroid resistant after randomisation but before any difference in treatment regimen started, and we withdrew these children from the trial. In practice, these patients would not receive the extended or standard course of treatment, and so the intention to treat analysis was not compromised. The mean age of participants was 4.9 years, which is higher than the median age of presentation in the International Study of Kidney Disease in Children (3 years). The mean age in our trial is, however, comparable to the median ages of 4.2-6.7 years in the three most recent randomised controlled trials of corticosteroid treatment in children with steroid sensitive nephrotic syndrome.

he median age of presentation in the International Study of Kidney Disease in Children (3 years). The mean age in our trial is, however, comparable to the median ages of 4.2-6.7 years in the three most recent randomised controlled trials of corticosteroid treatment in children with steroid sensitive nephrotic syndrome. Comparison with other studies The Kidney Disease: Improving Global Outcomes 2012 treatment recommendations were based on six trials that were reported before the start of the PREDNOS trial, but they all had methodological deficiencies.10 11 12 13 14 15 None was adequately blinded and there were additional concerns about selection, performance, detection, and attrition biases. While we conducted the PREDNOS trial, two randomised controlled trials were reported that compared shorter and longer corticosteroid regimens. One of these trials was a high quality Japanese study that compared eight weeks of prednisolone treatment with six months of treatment.22 23 Similar to PREDNOS, the findings showed no benefit of treatment extension.

two randomised controlled trials were reported that compared shorter and longer corticosteroid regimens. One of these trials was a high quality Japanese study that compared eight weeks of prednisolone treatment with six months of treatment.22 23 Similar to PREDNOS, the findings showed no benefit of treatment extension. Our outcome data are similar to those reported in previous studies; in particular the overall proportion of participants who had a relapse and the rate of frequently relapsing nephrotic syndrome. Previous studies have been inconsistent in the monitoring and reporting of adverse events associated with using corticosteroids. However, meta-analyses have consistently shown no difference in risk of adverse events between an eight week course of prednisolone treatment and longer duration regimens. Similar to these findings, we found no differences in adverse events between the extended course and standard course groups in PREDNOS; one exception was poor behaviour reported by parents, which was more common in the standard course group. However, despite this difference in reported behaviour, when parents completed the Achenbach child behaviour checklist, no statistically significant differences in behaviour scores were detected that might indicate a clinical concern. Consistent with current UK clinical practice, in this trial we did not routinely perform formal slit lamp ophthalmic assessment, regular blood tests, or dual energy x ray absorptiometry scans to assess bone mineral density. These tests have been included in the protocols of other recent high quality randomised controlled trials; the overall incidence of cataract, major persistent biochemical abnormality, and bone mineral density abnormality was low.

lar blood tests, or dual energy x ray absorptiometry scans to assess bone mineral density. These tests have been included in the protocols of other recent high quality randomised controlled trials; the overall incidence of cataract, major persistent biochemical abnormality, and bone mineral density abnormality was low. Our data suggest a possible advantage of an extended course of prednisolone treatment in children younger than 6 years, although the trial was not powered to detect differences in subgroups. This advantage has also been identified in other randomised controlled trials23 and warrants further investigation. We suggest an individual patient data meta-analysis, particularly as several studies have shown that children aged less than 6 years generally have a higher risk of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome.11 23 24 25 The shift of evidence away from the use of an extended course of treatment back to a standard course of treatment raises the problem of whether further studies should investigate if corticosteroid courses can be reduced further in steroid sensitive nephrotic syndrome. This subject has been dealt with in an early randomised controlled trial, which showed the relapse rate and incidence of frequently relapsing nephrotic syndrome were higher in children who received a shorter course of treatment rather than a standard course of treatment.26 However, in common with many of the earlier studies in this disease group, the trial was at risk of several biases.

ial, which showed the relapse rate and incidence of frequently relapsing nephrotic syndrome were higher in children who received a shorter course of treatment rather than a standard course of treatment.26 However, in common with many of the earlier studies in this disease group, the trial was at risk of several biases. The supplementary material reports the economic evaluation, which shows the extended course of treatment to be cost effective. We found healthcare costs in the extended course group were reduced because of fewer primary care visits and hospital admissions, lower costs of some drugs, and increased quality of life measured at various time points. These economic observations are compatible with the clinical outcomes because they act in the same direction as the increase in time to relapse with the extended course of treatment. Cost effectiveness analyses focus on the combined ratio of costs and outcomes. In our analysis, the extended course was cheaper and produced a gain in quality of life, therefore it offered a cost effective use of resources. Conclusions and policy implications The PREDNOS trial provides evidence that an extended 16 week course of prednisolone treatment will not improve important clinical endpoints compared with the standard eight week course of treatment. However, depending on the decision making criteria, extended course treatment could offer a cost effective use of healthcare resources. Concerns about adverse events from extended prednisolone treatment were not supported.

t improve important clinical endpoints compared with the standard eight week course of treatment. However, depending on the decision making criteria, extended course treatment could offer a cost effective use of healthcare resources. Concerns about adverse events from extended prednisolone treatment were not supported. What is already known on this topic More than 90% of children who present with idiopathic nephrotic syndrome respond to a course of high dose oral corticosteroid, and current practice is to treat most patients with prednisolone The Kidney Disease: Improving Global Outcomes 2012 treatment guidelines recommended that prednisolone be administered daily for four to six weeks followed by alternate daily for two to five months—this recommendation was based on six trials that were reported before the start of the PREDNOS trial, although all had methodological problems Most UK centres and many other countries continue to use the standard eight week course of prednisolone first described by the International Study of Kidney Disease in Children in the 1960s What this study adds An extended initial 16 week course of prednisolone treatment in UK children with steroid sensitive nephrotic syndrome did not improve the pattern of disease relapse compared with those who received the standard eight week course Extended course prednisolone treatment reduced healthcare resource use in the first two years and made a small improvement in quality of life Concerns about adverse events from exposing children to extended prednisolone treatment were not supported

What this study adds An extended initial 16 week course of prednisolone treatment in UK children with steroid sensitive nephrotic syndrome did not improve the pattern of disease relapse compared with those who received the standard eight week course Extended course prednisolone treatment reduced healthcare resource use in the first two years and made a small improvement in quality of life Concerns about adverse events from exposing children to extended prednisolone treatment were not supported We thank the National Institute for Health Research (NIHR) Health Technology Assessment for funding this trial; Kidney Research UK and Kid’s Kidney Research for funding the pilot trial; the participants and their parents; the NIHR Clinical Research Network: Children for support with the trial set-up and recruitment; the clinical trials pharmacy at Birmingham Children’s Hospital for dispensing and distributing the trial drug; Elisabeth Hodson and Jonathan Craig of the Cochrane Kidney and Transplant Group; the service users group from the UK Nephrotic Syndrome Trust and the renal patient support group, in particular Wendy Cook, Samantha Davies-Abbott, and Shahid Muhammad for help with trial design and conduct and review of the English summary; the British Association for Paediatric Nephrology; and the Royal College of Paediatrics and Child Health. See supplementary file for the detailed list of PREDNOS contributors.

We thank the National Institute for Health Research (NIHR) Health Technology Assessment for funding this trial; Kidney Research UK and Kid’s Kidney Research for funding the pilot trial; the participants and their parents; the NIHR Clinical Research Network: Children for support with the trial set-up and recruitment; the clinical trials pharmacy at Birmingham Children’s Hospital for dispensing and distributing the trial drug; Elisabeth Hodson and Jonathan Craig of the Cochrane Kidney and Transplant Group; the service users group from the UK Nephrotic Syndrome Trust and the renal patient support group, in particular Wendy Cook, Samantha Davies-Abbott, and Shahid Muhammad for help with trial design and conduct and review of the English summary; the British Association for Paediatric Nephrology; and the Royal College of Paediatrics and Child Health. See supplementary file for the detailed list of PREDNOS contributors. The PREDNOS study will be published in full as Webb NJA, Woolley RL, Lambe T, et al. Sixteen week versus standard eight week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT. Health Technol Assess 2019;23 (www.birmingham.ac.uk/prednos). Web extra Extra material supplied by authors Supplementary information: appendices 1-5 Supplementary information: detailed list of PREDNOS contributors

The PREDNOS study will be published in full as Webb NJA, Woolley RL, Lambe T, et al. Sixteen week versus standard eight week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT. Health Technol Assess 2019;23 (www.birmingham.ac.uk/prednos). Web extra Extra material supplied by authors Supplementary information: appendices 1-5 Supplementary information: detailed list of PREDNOS contributors Contributors: NJAW was the chief investigator, developed and ran the pilot study and the main study, led protocol development, recruited participants, interpreted study findings, and led the drafting of the paper. RLW undertook statistical analysis, interpreted study findings, contributed to writing the paper, and commented on the paper. TL performed cost effectiveness analyses and wrote the health economic content. EF developed the economic evaluation protocol, supervised economic analyses, contributed to writing the economic content, and commented on the paper. EAB oversaw the coordination and management of the study, had major input in developing the protocol, managed the delivery and execution of the study, contributed to writing the paper, and commented on the paper. ENB oversaw the coordination of the study from set-up to final report, had substantial input into the study set-up and management, and commented on the paper. RST was the original chief investigator, contributed to study design and management, and commented on the paper. CC was the statistical lead for the pilot study, designed the main study, helped with protocol development, interpreted study findings, and commented on the paper. JJD reviewed the statistical and economic analyses and results of the study, assisted in interpreting study findings, contributed to writing the paper, and commented on the paper. KW designed the study, interpreted study findings, and commented on the paper. NJI was responsible for the statistical aspects of the study, contributed to protocol development, supervised statistical analyses, interpreted study findings, contributed to writing the paper, and commented on the paper. NJAW is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

tributed to protocol development, supervised statistical analyses, interpreted study findings, contributed to writing the paper, and commented on the paper. NJAW is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Funding: The PREDNOS study was funded by an investigator led grant from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (HTA grant reference No 08/53/31). This report presents independent research commissioned by the NIHR. The views and opinions expressed by the authors in this publication are those of the authors and do not necessarily reflect those of the UK National Health Service, the Medical Research Council, the NIHR Central Commissioning Facility, Evaluation, Trials and Studies Coordinating Centre, the HTA programme, or the Department of Health. The researchers in the PREDNOS study are independent of the funders. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

re, the HTA programme, or the Department of Health. The researchers in the PREDNOS study are independent of the funders. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: NJAW has served on advisory boards within the past five years for Abbvie, Alexion, AMAG, Astellas, Raptor, Takeda, and UCB. These related to the design and conduct of early phase trials in childhood kidney disease. None related to the treatment of corticosteroid sensitive nephrotic syndrome.Ethical approval: This study was approved by the North West 7 Research Ethics Committee (10/H1008/122). The trial was carried out under a clinical trial authorisation in accordance with the Medicines for Human Use (Clinical Trials) Regulations (21761/0255/001-0001) and conducted in accordance with the Declaration of Helsinki. Data sharing: Requests for access to data from the PREDNOS study should be addressed to the corresponding author at nicholas.webb@mft.nhs.uk. The individual participant data collected during the trial (including the data dictionary) will be available, after deidentification, when the article has been published with no end date. All proposals requesting data access will need to specify how the data will be used, and all proposals will need the approval of the trial coinvestigator team before data release.

g the trial (including the data dictionary) will be available, after deidentification, when the article has been published with no end date. All proposals requesting data access will need to specify how the data will be used, and all proposals will need the approval of the trial coinvestigator team before data release. Transparency: The lead author (NJAW) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.