Transcript Slides - Diabetes Trials Unit : Home page

ISRCTN 51125379
www.dtu.ox.ac.uk/4-T
…in an academic collaboration with
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
4-T Trial Organisation
Steering Committee
Overall responsibility for scientific, professional
and operational conduct of the study
Diabetes Trials Unit
Study Design & Protocol
Co-ordinating Centre
Web-based data collection
Clinical queries
Statistical analyses
Publication
DTU Central
Laboratory
Novo Nordisk
Study Design & Protocol
Site initiation & monitoring
Investigator agreements
Ethical & regulatory aspects
Study medication
SAE reporting
Clinical Centres
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
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)
Three Way Randomisation
Glycaemic target: HbA1c ≤6.5%
700 T2DM
on OAD
R
Add once (or twice)
daily basal insulin*
Add prandial insulin
if glycaemic target not met†
Add twice daily
biphasic insulin*
Add midday prandial insulin
if glycaemic target not met†
Add thrice daily
prandial insulin*
Add basal insulin
if glycaemic target not met†
Randomisation
visit
One
year
Two
years
* progress to more intensive insulin regimen only if clinically necessary
† stop sulphonylurea if taken
Three
years
4-T Main Study Objectives
Impact of adding a single insulin preparation to OHA
Ability 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 regimens
Longer 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 calculator
Study data will be used to derive algorithms that estimate
individual insulin requirements, starting doses and
titration steps
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
Major Exclusion Criteria
 Taking insulin therapy
 Taking oral antidiabetic therapy other than
sulphonylurea and/or metformin
 Plasma creatinine >130 µmol/L
 ALT ≥2x upper limit of normal
 Life threatening cardiovascular disease
 Participation in a clinical drug trial
within the last three months
 Lactating or potentially pregnant females
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%
Three-level Hypoglycaemia Classification
Treated by
subject alone
Plasma glucose
≥3.1 mmol/L,
(≥56 mg/dl)
or not measured
Plasma glucose
<3.1 mmol/L
(<56 mg/dl)
Hypoglycaemic
episode
Assistance
required
Grade 1:
Symptoms
only
Grade 2:
Minor
episode
Grade 3:
Major
episode
Safety Assessments
 Incidence of major hypoglycaemic episodes
 Incidence of unexpected and/or
serious adverse events (SAEs)
 Plasma ALT, creatinine and lipid levels
 Stop metformin if plasma creatinine ≥150 µmol/L
 Blood pressure
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
Co-ordinating Centre
First point of contact/triage for all queries
 Email:
[email protected]
 Phone:
01865 857 239
 Fax:
01865 857 248
 Web site:
www.dtu.ox.ac.uk/4-T