The ADDITION Study. Intensive Treatment in People With Screen Detected Diabetes in Primary Care.
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      The ADDITION study comprise 2 parts: screening for Type 2 diabetes and intensive treatment
      compared to standard treatment.

        1. In the screening study, the feasibility and results of country specific models to
           identify undiagnosed individuals with Type 2 diabetes will be evaluated.

        2. In the treatment study the effects of routine care in general practice according to
           local and national guidelines will be compared with an intensive ADDITION protocol,
           including structured lifestyle education (dietary modification, increased physical
           activity and smoking cessation) and intensive treatment of blood glucose, blood pressure
           and lipids, and prophylactic aspirin with or without motivational interviewing, on
           mortality, macrovascular and microvascular disease. Furthermore the impact of treatment
           on health status, treatment satisfaction and health service costs will also be assessed.
    

Detailed description: 
      Aims:

        -  To develop and evaluate strategies for early detection of type 2 diabetes in different
           countries and different populations.

        -  To study whether a multifactorial treatment strategy can reduce CVD-mortality and reduce
           the incidence of macro- and microvascular complications. The treatment strategy consists
           of motivational interviewing, encouraging behavioural changes (dietary advises, physical
           activity, smoking cessation) and intensive pharmacological treatment of blood pressure,
           blood glucose, and serum lipids

        -  To identify genetic markers predicting development of diabetic complications

        -  To evaluate health economical consequences of screening and early intervention for type
           2 diabetes

      Design and methods:

      The study is an investigator initiated and designed study, initiated in Denmark by the two
      principal investigators, planned and conducted in collaboration between the four centers in
      Denmark, UK and the Netherlands. The study has two elements: a screening study and a
      subsequent intervention study.

      In the screening study, the feasibility and results of country specific models to identify
      undiagnosed individuals with Type 2 diabetes will be evaluated.

      In the treatment study the effects of routine care in general practice according to local and
      national guidelines will be compared with an intensive ADDITION protocol, including
      structured lifestyle education (dietary modification, increased physical activity and smoking
      cessation) and intensive treatment of blood glucose, blood pressure and lipids, and
      prophylactic aspirin with or without motivational interviewing, on mortality, macrovascular
      and microvascular disease. Furthermore the impact of treatment on health status, treatment
      satisfaction and health service costs will also be assessed.

      Methodology - Screening study:

      In Denmark > 300 primary care physicians from 5 different counties (Copenhagen, Aarhus,
      Ringkøbing, Ribe and Sønderjylland) participate in the study. Diabetes-related information is
      sent to all individuals aged 40-69 years enrolled in their practice. A questionnaire
      (diabetes risk score29) including age, gender, family history of type 2 diabetes; obesity;
      physical activity and previously diagnosed hypertension was used. Individuals scoring high on
      the questionnaire are encouraged to contact their physician for an examination of random
      blood glucose (RGB) and HbA1c. A step-wise strategy based on RBG, HbA1c, FPG and OGTT is used
      to diagnose diabetes In the Netherlands all people aged 50-69 years and listed with the
      participating primary care physicians is invited to fill in a diabetes risk questionnaire
      based on the same risk factors as in Denmark. Those at high risk of having type 2 diabetes
      are requested to come for a screening visit at a centre set up near the general practice. A
      stepwise screening strategy based on RBG, FPG and OGTT is used to diagnose diabetes In UK,
      different strategies are used in Cambridgeshire and Leicester. In Cambridgeshire a search of
      computerised general practice records is performed, using a simple validated risk score,
      based on routine general practice data (age, gender, prescribed medication and body mass
      index), to identify people in the age of 40-69 years at high risk of having undiagnosed
      diabetes30. Those with a high score undergo a stepwise screening strategy based on RBG, FPG
      and OGTT is used to diagnose diabetes In Leicester all white European subjects aged 40-75
      years and Asian, black or Chinese subjects aged 25-75 years are invited in a restricted
      geographical region within Leicester. All attendant undergo an OGTT as the first screening
      step (unless FPG > 7.0 mmol/l)

      Diagnostic procedures:

      The diagnostic procedure includes a stepwise procedure minimizing the work-load on the
      general practitioner and includes the questionnaire, random capillary blood glucose and HbA1c
      as screening instruments followed by fasting capillary blood glucose (FCBG) and an oral
      glucose tolerance test in everyone with marginally elevated FCBG. The diagnostic criteria
      follow the most recent World Health Organization guidelines (31) and are based on two
      diagnostic glucose values measured on independent days.

      Exclusion criteria:

      Participants are excluded if they already have diabetes, are pregnant or lactating or have a
      severe psychotic illness, are house bound or have an illness with a likely survival of less
      than one year.

      Outcome measures:

      Outcome measures from the screening study include measures of the efficacy of the screening
      campaign, the objective health status of patients newly identified by the campaign,
      feasibility as reported by the primary care physician, and the economic impact or benefit of
      the a programme. Furthermore a substudy explores the psycho-social and ethical aspects of the
      screening programme.

      Methodology - Intervention study:

      All patients diagnosed as part of the screening programme are invited to enter the
      ADDITION-study. The study will include a minimum of 3000 patients with screen detected
      diabetes. The general practices are randomised to the routine care group (standard care as
      given by the GP) or to the intervention group which features a target driven, intensive
      multifactorial approach to treatment. The study is an open, multicentre, parallel group trial
      with randomisation of general practices. Patients are screened and recruited during the
      period January 1st 2000 and June 30th 2006. The end of follow up is by July 1st 2009.
      Participation is based on informed consent in accordance with the Declaration of Helsinki.

      Intensive Treatment strategy:

      The intensive multifactorial treatment includes lifestyle advices (concerning diet, physical
      activity, medication adherence and tobacco cessation), prescription of aspirin and stepwise
      increases in pharmacological treatment of blood glucose, blood pressure and lipids, according
      to strict targets (appendix 1). The treatment targets are as follows:

        -  HbA1c < 7.0

        -  Total cholesterol < 5.0 mmol/l (4.5 mmol/l if CVD present)but statin to everyone with
           total cholesterol > 3.5 mmol/l

        -  Blood pressure < 135/85

        -  Aspirin 75- 150 mg/day to everyone on antihypertensive treatment Behavioural advices
           include

        -  Smoking cessation

        -  Physical activity 30 min./day

        -  Healthy diet (low fat, 600g of fruit and vegetables/day)

      The treatment targets may be intensified during the study according to the results of other
      clinical trials published during the study period, as the aim is to strive for treatment
      targets based on the most intensive guidelines available.

      Within the intensive group a further randomisation allocates 50% of the patients to country
      specific interventions concerned with improving adherence to lifestyle changes and
      medication. This intervention, including the use of motivational interviewing) is delivered
      either by a trained facilitator (UK and The Netherlands) or through training of practitioners
      (Denmark), and is based on a client-centred non-directive counseling style to help patients
      explore and resolve ambivalence and stimulate lifestyle changes, appropriate diabetes
      self-care and adherence to medical treatment 32,33.

      Pharmacological treatment:

      The decision on which pharmaceutical drug to use for the individual patients with is made by
      the clinician as the study is target driven and not a trial comparing different specific
      drugs. The clinician is provided with recommendations for a treatment strategy (appendix 1),
      which should be based on balancing treatment effect, side-effects and cost. The main priority
      is achievement of treatment targets with a flexible lifestyle and low rates of side effects
      such as hypoglycaemia and weight gain.

      Therapies are adjusted at 2 to 4-weekly intervals until targets are reached, thereafter every
      3 months. HbA1c is taken every third month, in between antidiabetic drugs are adjusted
      according to blood glucose measurements in the interim.

      Outcome measures: see other section.

      Sample size and statistical power:

      Based on levels of risk in the conservative-treatment arm of the UKPDS, the expected event
      rate is 3% per year for the combined endpoint (all-cause mortality, nonfatal myocardial
      infarction, stroke, revascularisation or amputation). With a sample size of 1350 patients in
      each arm (standard versus intensive treatment) the study will allow the detection of a 30%
      risk reduction in the intervention group at a significance level of 5% with a mean duration
      of follow-up of 5 years.

      Timescale:

      The screening study began in late 2000 and will end by June 30th 2006. Patients are enrolled
      into the treatment study following diagnosis in the screening study: thus the treatment study
      proceeds along with the evaluation phase of the screening study. The follow-up will continue
      until July 1st 2009.

      Ethics and safety:

      The Scientific Ethics Committee in the involved counties in Denmark and the Multipractice
      Study Committee have accepted the project, and the study has been approved by the ethical
      committees in UK and the Netherlands.

      A data safety and monitoring committee will have access to all end point data (unblinded)
      after 1, 3 and 5 years, and the study will be terminated if the composite end point
      (including: Cardiovascular death, non-fatal MI, non-fatal stroke, revascularisation and
      amputation) should demonstrate a clear advantage of intensive versus standard treatment
      (p<0.001) or a clear advantage of the standard versus intensive treatment (p<0.01).

      Perspectives of the trial:

      The results of the study will be of immediate national and international relevance to policy
      decisions about screening for diabetes, and subsequent intensive treatment. If the study
      shows that screening and early intervention markedly reduces the risk of developing premature
      CVD, then the study will have potential important impact at the individual patient level as
      well as on the societal level. If the study fails to show an effect of screening and early
      intensive treatment then this would have direct impact on future recommendations for
      screening and treatment regimens, and the study could lead to significant savings if it shows
      that strict treatment targets are not essential in the early phase of the disease. The
      results of the sub-study will inform approaches to health promotion to the management of
      chronic disease and risk, and to strategies to support adherence applicable not only to
      diabetes but also to other chronic diseases.

      References and Appendix 1 on www.addition.au.dk
    

Intervention name(s): optimised treatment
Intervention type(s): Procedure
Intervention description(s): The intervention targeted individual patients and the Primary Care Team. Practitioners were trained in a target driven, intensive multifactorial approach including lifestyle advice (smoking cessation, physical activity 30 min./day and healthy diet) and pharmacological treatment with the aim of reducing the complications of diabetes as described in protocol.
The training included meetings, practice visiting, written feed back reports and reminders on controls.
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Type 2 diabetes; Screening; Intensive treatment; Polypharmacy; Primary care