is a four-year study with a complex randomised trial design [30
], with central randomisation of willing participants to intervention programmes or comparison. The trial is managed from the Institute of Public Health, University of Cambridge, following MRC guidelines. Ethical approval has been obtained from the Eastern MREC, and West Suffolk, Cambridge, Huntingdon and West Essex LRECs.
The study design and patient flows (achieved at recruitment closure, October 2003, and projected to end of study) are shown in Figure . The focus of measurement is the adult offspring of a Type 2 diabetic parent, but the focus of the intervention programme is this individual within a family context. Participants were recruited via parents with diabetes on primary care registers (20 practices), or directly through records of their family history of diabetes (seven of the 20 practices). Sedentary individuals and their families were randomised to facilitation, either 'face-to-face' or 'distance', or to a comparison arm offering a leaflet providing brief advice on the benefits of activity. Psychological, physiological, anthropometric and biochemical data were collected at baseline and one year after randomisation, with psychological data also collected at six months after randomisation.
Trial design and patient flows; Oct 2003 (recruitment closure)
The study is explanatory in design, and the quality-assured intervention programmes are delivered by carefully trained and supervised family health facilitators with experience of working in primary care or the community, and backgrounds in health promotion, dietetics and nursing.
Setting, recruitment and screening
The study is set in urban, suburban and rural Cambridgeshire, Essex and West Suffolk, England, in the homes of participants and their families. The study population consists of offspring of people with Type 2 diabetes, aged 30–50 years, without a diagnosis of diabetes, and not considered very active based on self-report at the start of the study (see below). This age range defines a group at risk of weight gain [31
]. Any individuals found at study entry to have fasting hyperglycaemia [33
] were referred to their family doctor, but retained in the trial.
Once the relevant ethical and PCT approval had been obtained, 53 practice teams in the locality were approached by letter, inviting them to take part in the study, and highlighting the reimbursement of all costs involved. Personalised letters were sent to the practice manager (who we asked to collate responses and reply using a reply slip and Freepost envelope), all partners and nursing staff. Included with each letter was a brief summary of the study and a Research Information Sheet for Practices (RISP) form [34
]. If no response was received, a follow-up phone call was made to the practice manager. A principal investigator and member of the trial team visited interested practice teams, to discuss the study in further detail. All relevant practice staff were encouraged to attend, particularly those who would be involved in the administration of proposed patient surveys. The 20 practices that agreed to take part then received a 'set-up' visit by the trial team. A 'Practice Survey Manual' was created for the practice staff, and the trial team supported the practice teams as needed throughout the survey period.
Initially participants were recruited through their parents; patients with Type 2 diabetes on the diabetes registers of 20 practices ('recruitment method 1'). Patients were written to by their general practitioner, with a description of the study, and asked to provide contact information for any offspring aged 30–50 years, living locally. Consent was also sought for the practice to pass the contact details of the offspring to the research team so that they could invite the offspring directly into the study. Piloting demonstrated feasibility and acceptability of the method, and one reminder was sent after three weeks if no reply was received.
From 20 practices, 2631 patients were approached and 2025 (77%) replied, yielding 1238 potentially eligible offspring who were invited to take part in the study. The ratio of approximately one potentially eligible offspring to two patients with diabetes was half our pilot projections, so to increase recruitment we developed a second recruitment approach ('recruitment method 2'). This approach recruited potential participants with a recorded family history of diabetes directly from practices with family history registers, and was feasible in seven of the 20 practices. General practitioners wrote to all patients aged 30–50 years with a recorded family history of diabetes, enclosing a study information sheet, and asking those willing to complete and return to the practice a questionnaire to determine which family member(s) had diabetes, and of which type. Consent was sought for this information and contact details to be passed on to the research team. Using this method, with again one reminder letter, 1340 patients were written to, and 896 (67%) responses were received, with 283 patients interested and eligible. Both recruitment approaches provided 1521 potential trial participants. Practitioners used their discretion in applying both approaches to the exclusion of patients who were physically or mentally unwell.
Study population: inclusion and exclusion criteria
Potential participants recruited by both methods were next written to by the research team with full information about the study and a screening activity questionnaire, describing occupational and leisure activity, based on published questionnaires [35
], to exclude very active individuals. Two reminder letters with questionnaires were sent at two-week intervals if necessary, giving a response rate of 74%. Respondents were excluded if they reported their occupational activity as 'heavy manual work' [35
]; or 'physical work' if their total score on the leisure questionnaire [36
] was ≥ 20; or 'sedentary' or 'standing' work if their total leisure activity score was ≥ 30. This resulted in exclusion of approximately 30% of those screened, a figure that matches well with the proportion of the UK population designated as active in prevalence surveys [37
To fulfil measurement requirements participants had to be able to walk briskly, without help, on the flat for 15 minutes. Participants also had to live within reach of the measurement centre and the Family Health Facilitators; defined as a 30-minute average travel time from the study co-ordination centre. Other exclusion criteria included individuals with serious physical or psychiatric illness limiting programme involvement; people with life issues interfering with the study; those known to be pregnant or have diabetes before baseline measurement; and those planning to move away. As shown in Figure , application of these criteria reduced the 837 'interested' responses to 465 potentially eligible individuals, who were telephoned by a trained interviewer to confirm eligibility. Eligible and interested individuals were then scheduled for baseline measurement at either the Ely Research Centre or the Addenbrooke's Hospital Wellcome Trust Clinical Research Facility, where written consent was obtained.
Eligible offspring were registered with general practitioners in the Eastern Region of the UK. Prior to both baseline measures and randomisation, these doctors were individually informed about their registered patients' intention to participate in ProActive. Brief details of the trial were sent, together with a request for feedback if the practitioner had any concerns about the offspring's participation, or about the safety of the facilitators making home visits.
Randomisation was carried out centrally by the trial statistician, using a partial minimisation procedure that dynamically adjusted the randomisation probabilities in order to balance important covariates; body mass index, sex, age, physical activity (individually calibrated heart rate monitoring, see below), family size, and behavioural intentions. Randomisation thus used baseline measures. Thirty-two pairs of siblings and two sibling-triples were cluster randomised to the same study group to avoid contamination, and the remaining 295 participants (81%) were individually randomised. Overall, 365/465 (78%) of those eligible went forward to randomisation.
Baseline measures and follow-up
At baseline and the end of the study, all participants attend the study centre at either Ely or Cambridge for questionnaires, physiological and anthropometrical measures, and venesection. At six months, psychological and self-reported physical activity data are collected by postal questionnaires. Measures relating to the intervention programme evaluation are collected by the facilitators during the intervention, and we assess reported use of self-regulatory strategies by participants to increase their activity levels at six and twelve months.
Compliance with follow-up
In similar primary care based trials we have achieved attrition rates of 30% or less [38
], and at current rates we will exceed the required 300 to complete the study (100 in each group, see Figure ).
Maximising retention is an important issue, particularly as the comparison group do not benefit from regular contact with a facilitator. At recruitment, the introductory leaflets for all three arms emphasised the importance of follow-up, irrespective of treatment group. Participants who drop out of the intervention programme are contacted by a principal investigator, and offered an opportunity to give feedback and to confirm drop out from the intervention programme only, or from trial measurement as well.
The distribution of measures across baseline, six-month and one-year follow-up are shown in Table . The principle outcome is an objective measurement of physical activity energy expenditure, the daytime physical activity ratio (dayPAR), which is the ratio of daytime energy expenditure to resting energy expenditure measured using heart rate monitoring with individual calibration for the heart rate-energy expenditure relationship [40
]. This allows more precise quantification of the relationship between energy expenditure and relevant disease end points than self-report [13
]. The method has been validated against the gold standard techniques of doubly-labelled water and whole-body calorimetry [42
]. Physical activity is also measured by a validated questionnaire covering work, recreation and domestic activity over the previous month and year [43
], and offspring report of usual physical activity patterns among family members and how they changed over the previous year.
Oxygen uptake (ml O2
/kg/body weight) is measured by indirect calorimetry during a submaximal graded treadmill exercise test, and maximal cardiorespiratory fitness (VO2max
) is estimated using predicted maximal heart rate (i.e. 220 minus age) [40
Self-report measures of well-being and quality of life include subjective health and energy (SF-36) [44
], anxiety [45
], worry about diabetes and perceived vulnerability, and EuroQol (EQ-5D) [46
The frequency and severity of physical activity related injury is assessed by study questionnaire at one year.
Psychological mediators of physical activity include intention to increase activity over the next year, and its predictors (attitude, subjective norm, perceived behavioural control). These key measures have been developed for the study following the recommendations of Ajzen [24
]. Physiological correlates of behaviour include weight measured on standard scales calibrated at three monthly intervals, body fat percentage measured by bio-electrical impedance (Bodystat, Isle of Man, UK), and systolic/diastolic blood pressure, measured using an automatic sphygmomanometer (Accutorr, UK). Biochemical correlates include fasting plasma glucose, glycosylated haemoglobin, insulin and lipids. We are storing EDTA whole blood samples for future genetic testing. Sociodemographic factors and ECG are also documented at baseline.
Cost of the intervention
The economic analysis will explore the impact of a physical activity intervention programme on NHS costs. As the study is explanatory in design, we will not conduct a full cost-effectiveness analysis, but aim to provide a cost-description of the delivery of the intervention programmes. We are measuring the costs of delivering the 'face-to-face' and 'distance' intervention programmes via family health facilitators. These costs primarily comprise the training of facilitators, educational materials, travel, and the time that facilitators spend contacting and visiting families (including cancelled visits). Travel costs and contact time are recorded by the facilitators for every trial participant. The cost of facilitator time will be based on national average salaries, employment costs, qualifications, overheads and indirect costs [47
]. Although we do not expect the ProActive
intervention programme to have an impact on health service costs in the short term, we are monitoring health service utilisation (hospital, primary and community care) in the last 20% of participants recruited to the study.
The primary safety concerns for participants in ProActive
are cardiovascular and musculoskeletal events associated with the laboratory procedures of treadmill exercise testing and injuries sustained as a consequence of increasing physical activity in everyday life. The cardiorespiratory fitness test used in this study is submaximal, and only undertaken following extensive screening procedures. If a participant exhibits a positive Rose angina questionnaire [48
], a positive physical activity readiness questionnaire [49
] or an abnormal ECG, they are referred to a clinical member of the measurement team for a more detailed medical review. If there are clinical concerns, participants are excluded from the study, and referred to their general practitioner. In over 3000 such tests undertaken by our group using this protocol, no significant adverse events have occurred. Supervising staff are trained and hold current cardio pulmonary resuscitation certificates.
Ranges for acceptable results are set for all clinical measures. If these are exceeded, the information is sent to the general practitioner, and the participant informed and advised to consult.
As the intervention programme is based on participants' own preferred activities, and emphasises small achievable goals set by the participants, the risk of excess injury is small. Group information about injury will be reported.
Participants previously unaware of their familial risk of diabetes may experience anxiety related to awareness of their increased risk status. This is considered in facilitator training, and measures of anxiety, worry about diabetes and perceived vulnerability are included (see above).
Data management, quality assurance and exclusion of bias
Physiological and anthropometric measures are made in two centres by observers unaware of individuals' group allocation. Biochemical measures are made in one laboratory with established quality assurance systems. Randomisation was undertaken by the trial statistician, independently of the trial co-ordination team, and the data entry team are unaware of study group.
The administrative database (participant information), dayPAR values and blood test results are managed in-house, with the latter being double entered. Numeric fields have limiters set so that values outside a defined range cannot be entered. Additionally, any blood results outside the 'normal range' are flagged for confirmation of value. Random checks on administrative data are performed regularly, checking the data on the database against paper records and correcting any errors found.
Double data entry of all anthropometric and questionnaire measures is undertaken by an experienced, independent agency, blind to study group (Wyman Dillon Research and Data Management, Bristol, UK). In addition, random checks are applied as described above.
Intervention (see Figure )
Intervention programme contacts
The family health facilitator contacts participants randomised to the 'face-to-face' and 'distance' interventions, and arranges a home interview including family members. At this introductory interview, personal reasons for increasing physical activity are elicited and reinforced, family participation is encouraged, and the relationships between physical activity, weight gain and prevention of Type 2 diabetes are explained and discussed.
In the 'face-to-face' arm this is followed by four visits and two brief support telephone calls over five months. During these interactions the participant and willing family members learn strategies to increase physical activity, for instance selecting activities that they enjoy doing, setting achievable goals, defining action plans, self-monitoring, self-reinforcement and relapse prevention. Pedometers are available for self-monitoring among participants who have chosen walking as their goal. A key difference between this intervention and others currently under evaluation (e.g. ACT) is that there is no absolute target for physical activity defined at the outset. Family members are encouraged to make gradual and continuous increases in their activity, as much as they feel able to, on the understanding that all increases, if maintained, are beneficial. Follow-up continues by monthly telephone calls up to one year, to discuss any difficulties in applying the strategies, and to encourage family members to increase activity further.
In the 'distance' arm, following the introductory meeting the intervention programme is delivered by six telephone calls over five months, and then monthly by post up to one year, with content similar to the 'face-to-face' arm. During the phone calls the facilitators encourage the participants to involve family members. Visits and telephone calls take approximately one hour and 45 minutes, respectively.
An arm-specific introductory leaflet is used, but otherwise materials are the same for the face-to-face and distance arms. All introductory leaflets include text to encourage retention in the trial. In the comparison arm the leaflets offer brief advice on the benefits of physical activity. Participants in the intervention programme arms are given an educational manual describing the strategies that participants are encouraged to use to increase their habitual activity in a step by step fashion.
Promotion of fidelity of intervention delivery
Various mechanisms are used to promote the fidelity of delivery of the intervention programme to the underlying psychological theories and intervention programme protocols. A detailed training manual and protocols for each contact were developed, and a Training Officer appointed. Facilitators attended a five day phased course in psychological theories, behaviour change techniques and experiential training in techniques, with six half-days initially, followed by refresher sessions at six months and continuing supervised practice by a clinical psychologist and through peer-appraisal. Facilitators complete a checklist for the introduction of and mastery of self-regulatory strategies by the participant after each contact, and monitor intervention programme attendance and drop-out for each participant.
Assessment of fidelity and evaluation of the intervention programme
An assessment of adherence by facilitators to the behaviour change techniques specified in the protocols was conducted among a random sample of 27 participants, using reliable coding frames and transcripts of the sessions. The intervention programme evaluation includes: an assessment of the frequency of meetings and telephone calls, proportion of progress reports and postcards sent and progress reports returned, satisfaction with the intervention programme, reported use of self-regulatory strategies by participants at six months and one year, and drop-outs at one year.