ISRCTN 51125379

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ISRCTN 51125379 www.dtu.ox.ac.uk/4-T
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4-T Design

• Collaborative academic and pharmaceutical study
• Three-year, multi-centre trial of addition of
  anlogue insulin to oral hypoglycaemic agents in
  700 patients with Type 2 diabetes
• Open-label, three arm comparison of
• Basal insulin, given once (or twice) daily
• Prandial insulin, given three times daily
• Biphasic insulin, given twice daily
• 50 secondary-care based UK clinical centres
• Funded by Novo Nordisk

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4-T Trial Organisation
Steering Committee Overall responsibility for
scientific, professionaland operational conduct
of the study
Diabetes Trials Unit Study Design
Protocol Co-ordinating Centre Web-based data
collection Clinical queries Statistical
analyses Publication
Novo Nordisk Study Design Protocol Site
initiation monitoring Investigator
agreements Ethical regulatory aspects Study
medication SAE reporting
DTU CentralLaboratory
Clinical Centres
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Steering Committee Remit

• Main decision-making body of the Study
• Responsible for protocol design
• Ensure overall scientific, professional and
  operational conduct
• Review performance of clinical centres,
  co-ordinating centre, central laboratory and
  centre monitors on a monthly basis

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Steering Committee Membership

• Professor Rury Holman (Chair)
• Dr Jonathan Levy (Co-chair)
• Dr Andrew Farmer (Academic GP)
• Ms Joanne Keenan (DTU Project Manager)
• Dr Melanie Davies (Independent Diabetologist)
• Mr George Nelson (Patient Representative)
• Dr Alan McDougall (Novo Nordisk)
• Dr Henrik Schou (Novo Nordisk)
• Dr Mari-Anne Gall (Novo Nordisk)

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Three Way Randomisation
Glycaemic target HbA1c 6.5
Add once (or twice) daily basal insulin
700 T2DMon OAD
Add twice daily biphasic insulin
Add thrice daily prandial insulin
Randomisationvisit
Oneyear
progress to more intensive insulin regimen only
if clinically necessary stop sulphonylurea if
taken
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4-T Main Study Objectives

• Impact of adding a single insulin preparation to
  OHAAbility of the three different analogue
  insulin preparations to achieve good glycaemic
  control, defined as HbA1C levels 6.5 ,
  evaluated over 12 months
• Need for more complex insulin regimensLonger
  term efficacy and durability of the three insulin
  preparations, as well as the need for a second
  analogue insulin preparation to be added in order
  to achieve good glycaemic control, evaluated in
  the second and third years of the study
• Insulin dose calculatorStudy data will be used
  to derive algorithms that estimate individual
  insulin requirements, starting doses and
  titration steps

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Major Inclusion Criteria

• Aged 18 years, male and female
• Type 2 diabetes for at least 12 months
• On maximal tolerated doses of metformin and
  sulphonylurea for at least four months
• Body mass index 40 kg/m2
• HbA1c 7.0 to 10.0 inclusive
• Written informed consent

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Major Exclusion Criteria

• Taking insulin therapy
• Taking oral antidiabetic therapy other than
  sulphonylurea and/or metformin
• Plasma creatinine gt130 µmol/L
• ALT 2x upper limit of normal
• Life threatening cardiovascular disease
• Participation in a clinical drug trialwithin the
  last three months
• Lactating or potentially pregnant females

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Primary Outcome and Sample Size

• The primary objective is to compare the HbA1c
  levels achieved by the three insulin regimens
• Formal analyses will be performed at one year and
  at three years, without adjustment for multiple
  comparisons, as the two phases of the study are
  regarded as separate experiments
• 4-T has 95 power to show equivalence between
  groups at the 5 level of significance if 233
  patients per group are randomised, assuming an
  HbA1c standard deviation of 1.1 and a dropout
  rate that does not exceed 15

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Three-level Hypoglycaemia Classification
Plasma glucose 3.1 mmol/L,(56 mg/dl)or not
measured
Grade 1Symptomsonly
Treated bysubject alone
Hypoglycaemicepisode
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Safety Assessments

• Incidence of major hypoglycaemic episodes
• Incidence of unexpected and/orserious adverse
  events (SAEs)
• Plasma ALT, creatinine and lipid levels
• Stop metformin if plasma creatinine 150 µmol/L
• Blood pressure

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Schedule

• The study commenced 1st November 2004
• 50 UK centres have been enrolled
• 18 patients per centre will be recruited
• One year results expected in 2007
• Three year results expected in 2009

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Co-ordinating Centre

• First point of contact/triage for all queries
• Email 4-T_at_dtu.ox.ac.uk
• Phone [phone]
• Fax [phone]
• Web site www.dtu.ox.ac.uk/4-T