Protocol

Overview

1. The main objectives are: In year one; to determine the degree to which the randomised addition to existing oral therapies of
   1. long-acting analogue insulin once-daily (or twice if needed)
   2. prandial rapid-acting analogue insulin thrice-daily
   3. pre-mixed long and rapid acting (biphasic) analogue insulin twice-daily

can achieve HbA1c values less than 6.5%.

2. In years two and three; to determine the degree to which HbA1c values less than 6.5% can be achieved when existing sulphonylurea therapy is replaced by a second insulin preparation.
3. To derive algorithms that predict likely starting and adjustment doses of insulin for Type 2 diabetic patients with inadequate glycaemic control on oral agents.

Background

Diabetes is serious disease which can shorten life by 5-10 years and has major complications such as loss of sight, kidney failure and amputations. The UK Prospective Diabetes Study (UKPDS) has shown that improved glycaemic control can substantially reduce the risk of complications. This is difficult to achieve in practice as progressive loss of pancreatic insulin secretory ability means that oral treatments become less effective with time. Despite the increasing need for insulin therapy in people with Type 2 diabetes, there remains considerable uncertainty as to how best to start or to adjust insulin doses. The situation is different to Type 1 diabetes because substantially larger doses of insulin are needed as many patients are obese and also have insulin resistance associated with Type 2 diabetes.

Managing Type 2 diabetes in primary, rather than secondary care, means that Practices are for the first time being required to initiate and adjust insulin therapy in large numbers of patients without clear guidance as to when to commence insulin, whether to give it in addition to or instead of existing oral agents, or how to optimise doses without causing hypoglycaemia. The 4-T study is designed to provide evidence based advice to assist primary care practitioners:

• Choose an appropriate insulin regimen when treatment with standard oral agents (sulphonylurea and/or metformin) become insufficient
• Determine appropriate starting doses for individuals with Type 2 diabetes (often 2-3 times higher than in Type 1 diabetes)
• Manage the transition to a second insulin preparation when disease progression renders sulphonylurea therapy inadequate

4-T is testing the approach used successfully in the UKPDS whereby insulin is added to existing oral therapy. This simple approach has no risk of sudden deterioration in glycaemic control and requires less intensive monitoring. Patients will be recruited mainly from primary care but the study will mostly be run via secondary care sites to ensure that centres have sufficient patients to provide adequate experience with each of the analogue insulin regimens being tested. The trial strategies, however, are designed with primary care practice in mind so that the study results can be transferred directly to a primary care setting in due course. Health economic,  behavioural and quality of life issues are being examined in detail in order that the trial results can be implemented most appropriately.

Methods

This multi-centre, open-label, randomised, parallel-group trial has been designed with the help of physicians working in primary and secondary care and includes a patient representative on its Steering Committee. It will compare three different analogue insulin strategies in subjects with Type 2 diabetes who are inadequately controlled on their existing metformin and sulphonylurea therapy (or one of these agents if the other is not tolerated). A treat-to-target approach (HbA_1c less than 6.5 %) will be used to ensure that all participants achieve their best possible glucose control and to allow the analogue insulin regimens to be compared in terms of ease of use, acceptability, weight effects, risk of hypoglycaemia and impact on microalbuminuria.  Subjects will be randomised in equal numbers to:

• Analogue basal insulin (Levemir®) once-daily (twice if needed)
• Analogue biphasic insulin (NovoMix30®) twice-daily or
• Analogue rapid-acting insulin (NovoRapid®) thrice-daily with meals

In year one, subjects will remain on their existing oral agents and their randomly allocated single insulin formulation unless they have unacceptable hyperglycaemia, in which case their sulphonylurea (if taken) will be stopped and a second insulin formulation added. In years two and three, sulphonylurea therapy (if taken) will be stopped and a second insulin formulation added routinely if glycaemic targets are not met. Those allocated basal insulin will add rapid acting insulin thrice-daily with meals, those allocated biphasic insulin will add rapid acting insulin at lunchtime (midday) and those allocated meal time rapid acting insulin will add basal insulin once-daily (twice if needed).  

The basal and rapid acting insulin arms are being compared with biphasic insulin as this is used most often at present in the UK. The HbA_1c target of less than 6.5% is that recommended by current European (EASD), International (IDF) and American (AACE) diabetic guidelines. Insulin dose titration throughout the trial will be based on self-measured capillary glucose (SMCG) values, aiming to maintain plasma glucose values pre-meal between 4.0 and 5.5 mmol/l and two-hour post-meal between 5.0 and 7.0 mmol/l. All groups will be asked to increase their insulin doses, as necessary, by encouraging both subjects and clinical investigators to adhere to the treat-to-target approach. It is anticipated that in years two and three some 40% of subjects will require a second insulin to be added. The protocol driven discontinuation of sulphonylurea therapy in subjects commencing a second insulin formulation offers a unique opportunity to examine the indicators in clinical practice for deciding when a sulphonylurea is no longer making a significant contribution and additional insulin therapy needs to be substituted. Metformin will be continued throughout the trial (where tolerated), given that it confers cardioprotection as well as lowering glucose.

Main Inclusion Criteria

• Males and females, aged 18 years or more with Type 2 diabetes for 12 months or more

• Insulin naïve, although short term insulin treatment (7 days or less at any one time) is allowed

• On maximum tolerated dose of metformin and/or sulphonylurea (or at least half maximum recommended dose for the last 4 months prior to inclusion).  The dose should be unchanged for the last 4 weeks prior to inclusion

• Body mass index 40.0 kg/m2 or less

• HbA_1c 7.0 % to 10.0% inclusive

• Able and willing to use insulin injections and perform self-monitoring of plasma glucose

• Provided written informed consent before any trial related activities commence

Main Exclusion Criteria

• Taking oral anti-diabetic therapies other than sulphonylurea or metformin

• Life threatening cardiovascular disease

• Plasma creatinine above 130 µmol/l or ALT more than twice upper limit of normal

• Known sight-threatening retinopathy

• Hypoglycaemia unawareness or recurrent major hypoglycaemia

• Anticipated changes in concomitant medication which may interfere with glucose regulation

• Uncontrolled hypertension (blood pressure 180/105 mm Hg or above)

• Known or suspected allergy to trial products or related products

• Any condition that the Investigator or Sponsor feel would interfere with trial participation or evaluation of results

• Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation

• Pregnant or planning to become pregnant within the next 12 months, breast-feeding, or judged to be using inadequate contraceptive methods

• Receipt of any investigational trial drug within 3 months prior to participation in 4-T

• Subjects previously screened for participation or already participated in 4-T

Outcome Measures

Primary

In year 1, to compare the ability of three different single insulin analogue regimens to achieve HbA_1c values less than 6.5 % when added to existing oral anti-diabetic treatment.

In years 2 & 3, to determine longer term efficacy and durability of the insulin regimens and assess the need for a second insulin formulation to achieve HbA_1c values less than 6.5 %.

To derive algorithms to estimate starting and adjustment insulindose requirements in Type 2 diabetes.

 Secondary

Study Management

The 4-T trial has been designed and developed by the University of Oxford Diabetes Trials Unit (DTU) in an academic collaboration with Novo Nordisk.  The data arising from the trial will be owned, analysed and reported by the Diabetes Trials Unit. Novo Nordisk will primarily be responsible for some of the operational aspects of the trial, particularly with respect to contracting with clinical centres, regulatory issues, routine on-site monitoring and drug accountability.

Funding

The trial is funded by an unrestricted educational grant from Novo Nordisk.

4-T Office, Diabetes Trials Unit, OCDEM, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ
Tel: +44 (0)1865 857239     Fax: +44 (0)1865 857248    Email: 4-T@dtu.ox.ac.uk

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