Ethics statement
The Newcastle and North Tyneside NHS Research Ethics Committee approved the study protocol and all participants gave informed, written consent before the start of the study.
Study design, randomisation and end points
We conducted a Randomised Controlled Trial (RCT) with one Intervention and one Control arm. Participants were randomly allocated either to intensive behavioural interventions to promote dietary modification and increased physical activity or to a minimal intervention Control group. The planned maximum follow-up for any individual was five years.
Recruitment was by referral from primary care physicians who identified eligible people likely to be at risk of impaired glucose regulation (using the criteria: aged over 40 and overweight (BMI > 25 kgm-2)) from their primary care databases and invited them to participate.
Oral glucose tolerance tests (OGTT) were conducted in the Clinical Research Facility, Royal Victoria Infirmary Newcastle upon Tyne. Eligible participants (with IGT) were randomly allocated to the Intervention (I) or Control (C) group using randomisation lists, prepared independently by the EDIPS co-ordinating centre in Helsinki. Randomisation was stratified by sex and by two hour plasma glucose value (derived from the mean of two standard oral glucose tolerance tests (OGTTs) - stratum 1: 7.8 to 9.4 mmol/l; stratum 2: 9.5 to 11.1 mmol/l). Blinding of participants and intervention staff was not possible. Data collection staff were blinded to the extent that this was possible given participants' knowledge of their allocation.
Outcomes
1. Development of T2D, diagnosed on the basis of two OGTTs conducted with 1-12 weeks of each other, assessed annually from baseline, was the primary study end point.
2. Other end points were myocardial infarction or sudden cardiac death, intermittent claudication, stroke or death from other causes.
3. Secondary outcomes were changes in BMI (kgm-2), intakes of carbohydrate and fat (as percentages of total energy intake) and dietary fibre (g), and participation in physical activity (minutes of moderate aerobic physical activity per day).
Inclusion and exclusion criteria
We included people aged over 40 years with BMI > 25 kgm-2 and with established IGT defined as a mean 2-hour plasma glucose value ≥ 7.8 mmol/l and < 11.1 mmol/l from two consecutive standard OGTTs (glucose load 75 g) conducted between one and 12 weeks apart (World Health Organisation 1999 classification)[11]. If the 2-h OGTT value was just over the diabetes threshold (11.1-11.5 mmol/l) or under the IGT threshold (7.3-7.7 mmol/l), a second OGTT was performed within 1-12 weeks. If the mean of the 2-h values from the two OGTTs was ≥ 7.8 and <11.1 mmol/l the individual was eligible for inclusion. A diabetic value in the second OGTT was an exclusion criterion, even if the mean value was in the IGT range. People with previous diagnosis of diabetes, or with chronic illness that would make participation in moderate physical activity impossible, or on a special diet for medical reasons were excluded.
Measurements
All participants received a clinical assessment prior to randomisation and annually thereafter, including an OGTT, anthropometric and blood biochemistry measurements. Additionally they were asked to complete a health status questionnaire (RAND-36),[12] the WHO cardiovascular questionnaire[13] and annual three-day (two week days and one weekend day) diet and physical activity diaries.
Assessments were conducted in the Clinical Research Facility, Royal Victoria Infirmary in Newcastle upon Tyne.
Body weight was measured to the nearest 0.1 kg in light indoor clothing using SECA 770 electronic scales (Alpha Model 770, SECA Limited, Birmingham, UK). Height was measured to the nearest half centimetre using a SECA 225 stadiometer (SECA Limited, Birmingham, UK). Waist circumference was measured to the nearest centimetre at the midpoint between the iliac crest and the lower rib margin. Percentage body fat was measured by bioelectrical impedance, using a BODYSTAT 1500 (BODYSTAT Ltd, Douglas, Isle of Man, UK).
Blood was collected from the antecubital vein with the participant in a sitting position using a needle to insert a cannula. If a tourniquet was used it was opened immediately after the needle had entered the vein. Glucose was measured in venous plasma, using a Yellow Springs glucose analyser (Yellow Springs Instrument co Inc, Ohio, USA.). Food portion sizes were validated by the study dietician using a photographic food atlas [14] and nutrient composition was analysed using Microdiet software (Downlee Systems, Salford, UK). The activity diary covered the whole 24 hour period on all three days. Participants were asked to record activity for each 30 minute period throughout the day starting from midnight (midnight to 00.30, 00.30 to 1.00, 1.00 to 1.30 etc.) using an integer scoring system based on MET scores. For example, lying down was scored 1 and brisk walking was scored 6. A 24-hour activity score of 80 would be achieved by lying down for eight hours and sitting for the rest of the day. Thirty minutes of brisk walking would add four to a participant's score on any day.
Interventions
Behavioural interventions consisted of regular individual advice from a dietician and physiotherapist trained in motivational interviewing [15]. Intervention participants were also invited to some group sessions, notably 'cook and eat' events. They also received a regular quarterly newsletter. The newsletter contained: healthy eating recipes, nutritional information, suggestions for local walks, and exercise options. The dietary intervention provided advice and counselling to develop an individual plan for behaviour change, with the aim of achieving: >50% total dietary energy intake from carbohydrate, reduced total and saturated fat intake with <30% total dietary energy from fat, increased fibre intake, and weight loss to achieve BMI <25 kgm-2[16]. Analysis of participants' three day food diaries, collected quarterly, and regular weight and waist measurements were used to tailor individual dietary advice. The physical activity intervention was designed to encourage participation in increased physical activity equivalent to accumulating 30 minutes of moderate aerobic physical activity per day. Analysis of participants' three day activity diaries, collected quarterly, was used in motivational feedback and to tailor goals for increasing physical activity, which were negotiated at each visit.
Participants in the Intervention group were seen by the intervention team (dietician and physiotherapist) for approximately 30 minutes per session, immediately following randomisation and two weeks later, then monthly for the first three months and every three months thereafter up to five years. In addition to individual and group activities, participants received an information pack detailing facilities and opportunities for physical activity in Newcastle upon Tyne, a City Card (a discount scheme run by Newcastle Leisure Services offering up to 80% discount on access to physical activity facilities) and the opportunity to meet with a trainer at a local leisure centre and take part in an induction session. Information generated from earlier studies in Newcastle was used to tailor the intervention to the local conditions [17–19]
Control condition
Both Intervention and Control groups were offered standard health promotion advice including widely available contemporary written leaflets on healthy eating and physical activity. Control group participants were otherwise offered 'usual care' by their primary care physician.
Sample size
EDIPS-Newcastle was designed to contribute to the European study. We aimed for a sample size of 100 participants (50 in each arm), contributing to a planned total of 750 participants across Europe.
Analysis
The Statistical Package for Social Scientists (SPSS inc. version 15) was used for analyses. We used independent t-tests to compare continuous variables and Chi-squared tests to compare categorical variables in the Intervention and Control groups at baseline. Pragmatic (intention-to-treat) analysis of the primary endpoint was conducted using Kaplan-Meier survival analysis to determine the difference in relative risk of cumulative incidence of diabetes between the Intervention and Control groups.
For secondary outcomes we used independent t-tests to compare the Intervention and Control group means of continuous variables at baseline and in each year of the study.
For the explanatory analyses of secondary outcomes, we pooled the Intervention and Control groups and considered each secondary outcome measure in turn. For these outcomes we used a scoring system whereby any individual's beneficial change from their baseline value in an outcome measure was scored 1 for each year of beneficial change (cut off change values were 0.01 for beneficial increase or -0.01 for beneficial reduction) and all other values (no change or detrimental change) were scored 0. The scores for each participant were totalled across study years and the participants were divided into two groups (for each measure separately): a 'sustained change' group with a score of two or more, indicating beneficial change in the parameter for at least two years; and a 'no sustained change' group with a score less than 2, indicating less than two years beneficial change, no change or detrimental change. These groups were then compared using Kaplan-Meier survival analysis for progression to T2D. We also used independent t-tests to compare the 'sustained change' and 'no sustained change' group means and the difference between the groups for each of the secondary outcomes at baseline and in each year of the study. Two years of sustained change was chosen as the criterion for explanatory analysis groups after consideration of other possibilities (e.g. one year or three years) and with reference to the findings of our qualitative study linked to this trial[20].
The baseline characteristics, weight, height, BMI, waist circumference, hip circumference, body fat %, plasma glucose (fasting, 30 minute, 60 minute and 120 minute), plasma insulin (fasting, 30 minute and 120 minute), age, sex, socioeconomic status and working capacity of the 'sustained change' and 'no sustained change' groups for each secondary outcome were compared for equality with t-tests or Chi-squared tests as appropriate.
