direct-protocol

STUDY PROTOCOL Open Access
The Diabetes Remission Clinical Trial
(DiRECT): protocol for a cluster randomised
trial
Wilma S. Leslie1*
, Ian Ford1
, Naveed Sattar1
, Kieren G. Hollingsworth2
, Ashley Adamson2
, Falko F. Sniehotta2
,
Louise McCombie3
, Naomi Brosnahan1
, Hazel Ross3
, John C. Mathers2
, Carl Peters2
, George Thom1
, Alison Barnes2
,
Sharon Kean1
, Yvonne McIlvenna1
, Angela Rodrigues2
, Lucia Rehackova2
, Sviatlana Zhyzhneuskaya2
, Roy Taylor2
and Mike E. J. Lean1
Abstract
Background: Despite improving evidence-based practice following clinical guidelines to optimise drug therapy,
Type 2 diabetes (T2DM) still exerts a devastating toll from vascular complications and premature death. Biochemical
remission of T2DM has been demonstrated with weight loss around 15kg following bariatric surgery and in several
small studies of non-surgical energy-restriction treatments. The non-surgical Counterweight-Plus programme, running
in Primary Care where obesity and T2DM are routinely managed, produces >15 kg weight loss in 33 % of all enrolled
patients. The Diabetes UK-funded Counterpoint study suggested that this should be sufficient to reverse T2DM by
removing ectopic fat in liver and pancreas, restoring first-phase insulin secretion.
The Diabetes Remission Clinical Trial (DiRECT) was designed to determine whether a structured, intensive, weight
management programme, delivered in a routine Primary Care setting, is a viable treatment for achieving durable
normoglycaemia. Other aims are to understand the mechanistic basis of remission and to identify psychological
predictors of response.
Methods/Design: Cluster-randomised design with GP practice as the unit of randomisation: 280 participants
from around 30 practices in Scotland and England will be allocated either to continue usual guideline-based care
or to add the Counterweight-Plus weight management programme, which includes primary care nurse or dietitian
delivery of 12-20weeks low calorie diet replacement, food reintroduction, and long-term weight loss maintenance.
Main inclusion criteria: men and women aged 20-65years, all ethnicities, T2DM 0-6years duration, BMI 27-45 kg/m2
.
Tyneside participants will undergo Magnetic Resonance (MR) studies of pancreatic and hepatic fat, and metabolic
studies to determine mechanisms underlying T2DM remission. Co-primary endpoints: weight reduction ≥ 15 kg and
HbA1c <48 mmol/mol at one year. Further follow-up at 2 years.
Discussion: This study will establish whether a structured weight management programme, delivered in Primary Care
by practice nurses or dietitians, is a viable treatment to achieve T2DM remission. Results, available from 2018 onwards,
will inform future service strategy.
Trial registration: Current Controlled Trials ISRCTN03267836. Date of Registration 20/12/2013
Keywords: Type 2 diabetes, Weight management, Total diet replacement, Primary care
* Correspondence: Wilma.Leslie@glasgow.ac.uk
Roy Taylor and Mike EJ Lean are joint PIs and senior authors for this work.
1
University of Glasgow, University Avenue, Glasgow G12 8QQ, UK
Full list of author information is available at the end of the article
© 2016 Leslie et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Leslie et al. BMC Family Practice (2016) 17:20
DOI 10.1186/s12875-016-0406-2

Background
T2DM is closely linked to obesity, particularly adult
weight gain, and is the main contributor to rising health-
care costs of obesity [1, 2]. Whilst it seldom develops
with BMI <21 kg/m2
, most people with T2DM have a
BMI >25 kg/m2
and around 50 % have a BMI >30 kg/m
[2–4]. With BMI >35 kg/m2
, 20 % of all men and 11 %
of women have known diabetes [5].
There is consistent evidence that modest sustained
weight loss, using a variety of diet and lifestyle ap-
proaches to achieve 5–10 % weight loss, will prevent the
onset of most new cases of T2DM in those with pre-
diabetes [6, 7],
, and that it improves all aspects of dia-
betes control (glycaemia, blood pressure, lipids and
microvascular damage [8] with reductions in drug
doses,
[9, 10]. Advice to lose and maintain 5–10 % weight
loss, by diet and exercise is included in most clinical
guidelines [11, 12]. However, most T2DM patients in the
UK are now managed in primary care, many do not re-
ceive the necessary specialist lifestyle advice and support,
from trained staff, to achieve 5 % weight loss. Financial
incentives are provided only for diagnosis and for pre-
scribing anti-diabetic drugs [13].
Recognising changes in obesity prevalence, and also
recent evidence for the benefits of more aggressive inter-
ventions including surgery, the 2010 SIGN Obesity
guideline set a new weight loss/ maintenance target of
>15–20 % for those with BMI >35 kg/m, or >30 kg/m2
with serious medical complications such as T2DM [11].
This degree of weight loss most reliably led to diabetes
remission in a randomised trial of bariatric surgery [14]
and several studies have suggested that similar weight
loss is necessary to normalize blood glucose and insulin
[15, 16]. There is also indirect evidence that such weight
loss might normalise life expectancy in those with
T2DM [4]. However, routine NHS diabetes care seldom
aims for weight loss of >15 kg (commonly equivalent on
average to >15 %: most studies have average weight close
to 100 kg in obese individuals with T2DM) and vanish-
ingly few obese people with T2DM achieve this goal.
Bariatric surgery can reverse the metabolic abnormal-
ities of T2DM, at least in patients up to 6 years after
diagnosis [17] and the proportion of individuals achiev-
ing normal blood glucose is determined primarily, by the
extent of weight loss [18]. However the Counterpoint
study [16] demonstrated that a broadly similar benefit
can be reproduced by negative energy balance alone.
Eleven people with T2DM (nine male and two female,
BMI 33.6 ± 1.2 kg/m2) were studied before and after 1, 4
and 8 weeks of a 2.5 MJ (600 kcal)/day liquid diet. Re-
sults showed a mean weight loss of 15.3 kg and a rapid
return of fasting blood glucose to normal, which per-
sisted for up to 3 months after return to normal diet.
The underlying changes in liver and pancreas fat were
consistent with the Twin Cycle Hypothesis [19]. Publica-
tion of the Counterpoint study, demonstrating remission
of T2DM and normalization of first-phase insulin re-
sponse following weight loss of about 15 kg, prompted a
massive response from people with T2DM who wanted
to try to reverse their disease by weight loss. Evaluation
of 77 reported experiences of self-directed weight loss
indicated diabetes remission in 61 % overall: 80 % with
>20 kg weight loss; 63 % with 10-20 kg weight loss; and
53 % with <10 kg weight loss [20]. These data, while
self-reported and from self-selected motivated patients,
indicate both a desire amongst those with T2DM to re-
verse their diagnosis, and that well-maintained weight
loss leading to sustained remission of T2DM is achiev-
able in a community setting.
The feasibility of a non-surgical approach for weight
management has been demonstrated within routine
NHS primary care. That feasibility study, mainly in non-
diabetic patients (n = 91, mean BMI >48 kg/m2)
found
that an 810 kcal/d Total Diet Replacement (TDR),
followed by structured food reintroduction and then a
long-term weight-maintenance programme, was accept-
able to both staff and patients. This programme resulted
in a mean loss of about 17 kg in 12 weeks [21]. At
12 months, at least 30 (33 %) of the 91 enrolled patients
remained >15 kg lighter than at baseline. These observa-
tions indicate that it is possible to achieve, and maintain,
substantial weight loss for many individuals by non-surgical
methods. A recent systematic review of controlled studies
evaluating very low energy diets (800 kcal/d), in individuals
diagnosed with T2DM, found that these interventions led
to greater weight losses at 3–6 months than minimal inter-
vention or standard care [22]. However a longer and larger
study is needed to determine whether i) this is a viable
treatment for putting T2DM into remission, and ii) this ap-
proach is potentially transferable to a larger scale as part of
routine GP care. The latter is particularly important be-
cause most overweight people with T2DM in the UK are
managed in primary care rather than in specialist hospital
clinics.
It is also important to extend our understanding of the
mechanisms, which underlie the development of T2DM
in susceptible individuals, and those responsible for
achieving and maintaining remission. Over an eight-
week study period, the Counterpoint study [16] showed
a return to near-normal first-phase insulin secretion,
concurrent with a loss of abnormal ectopic fat accumu-
lation in liver and pancreas. The subsequent Counterbal-
ance study [23] found that this dramatic reversal of
T2DM occurs most reliably in patients with diabetes
duration under 6 years since diagnosis. There is always
some uncertainty about the duration of a diabetic state
prior to diagnosis, but with known duration over 8 years
since diagnosis, remission was much less likely.
Leslie et al. BMC Family Practice (2016) 17:20 Page 2 of 10

Study Objectives: (as set out in application & Ethics
submission)
To determine whether a programme designed to
achieve remission of T2DM to normal glucose
tolerance by substantial weight loss can be
effectively delivered, within the routine Primary
Care setting where T2DM is normally managed
To evaluate potential prospective metabolic and
psychological markers for a good response to the
proposed treatment programme
To define the mechanisms of long-term remission of
diabetes, in particular examining the relationships of
VLDL-triglyceride production rates to both pancreas
fat content and beta cell function.
To evaluate the barriers to successful reversal of
T2DM at both the individual and service level
Data will be collected for possible future health eco-
nomics analyses
Co-primary endpoints:
Reduction in weight of 15 kg (assumed equal on
average to 15 %) or more at one year;
Remission of diabetes (HbA1c 48 mmol/mol) at
1 year.
Secondary endpoints:
Quality of life
Physical Activity
Serum Lipids, Liver function tests, Urea
Electrolytes, plasma glucose
Programme acceptability
Methods/Design
The study will use a cluster-randomised controlled de-
sign, with GP practice the unit of randomisation. Ran-
domisation at a practice level will avoid contamination
between groups and allow consistent advice from prac-
tice nurses/dietitians.
Randomisation of practices will be conducted centrally
and independently of the research team, by the Robert-
son Centre for Bio-Statistics, University of Glasgow.
Practices will be allocated using a minimisation method
to maintain the required balance across intervention
groups within each study region (Scotland or England)
and practice list size (5700 or ≤ 5700).
Funding was awarded by Diabetes UK following exten-
sive peer review. Ethical approval was obtained from the
West of Scotland Research Ethics Committee (reference
number: 13/WS/0314).
Recruitment
General practices
Recruitment of general practices will be undertaken in mul-
tiple Health Board areas in Scotland and in the Newcastle
-upon-Tyne NHS Foundation Trust area in the North East
of England. Practices will be invited to participate by the
Primary Care Research Network (PCRN). Practices express-
ing interest in participation will be contacted by the re-
search team and recruited to the study.
Participant recruitment
Two hundred and eighty participants (140 per arm) will
be recruited to the study from general practice (Fig. 1).
Potential participants will be identified by a compu-
terised search of GP records, undertaken by staff from
PCRN. Lists generated by the search will be reviewed by
GP’s to remove individuals likely to be ineligible, or un-
suitable to approach because of co-morbidity or other
practical or medical obstacles to participation identified
by the GP. Reasons for exclusions will be recorded. Po-
tential participants will be sent an invitation to partici-
pate on behalf of their GP. The invitation includes a
written information sheet providing details of the treat-
ment arm to which their GP practice is randomised.
Patients are asked to indicate whether, or not, they are
interested in participating, using reply-paid envelopes.
Applying adaptive trial principles in response to early
process evaluation which revealed low uptake by eligible
patients, under substantial amendments the invitation
letter was re-formatted as a coloured leaflet. A single re-
minder letter will be posted, after one month, to patients
who do not respond to the initial invitation. Telephone
calls will be made to those patients who are eligible and
to those who had previously joined a register to indicate
their willingness to be approached for clinical trials.
Posters in primary care waiting rooms will also remind
patients, and encourage those interested to respond if
they had received an invitation.
Patients who respond as interested in participating will
be contacted by a member of the research team and in-
vited to attend for a screening appointment where the
study will be fully explained and discussed. Informed
consent will be secured from all participants, for 2-years
on the trial protocol and for indefinite long-term data
collection from their medical records and through na-
tional records linkages.
Inclusion criteria
Written informed consent
Men and women aged 20–65 years
T2DM of duration 0–6 years (diagnosis based on 2
recorded diagnostic-level tests, HbA1c and/or blood
glucose)

HbA1c ≥ 48 mmol/mol at the last routine clinical
check, within last 12 months if on diet alone
HbA1c ≥ 43 mmol/mol if on treatment with oral
hypoglycaemic agents
Body Mass Index (BMI) 27 kg/m2
and 45 kg/m2
Exclusion criteria
Current insulin use
Recent routine HbA1c ≥108 mmol/mol
Weight loss of 5 kg within the last 6 months
Recent eGFR 30 mls/min/1.73 m2
Substance abuse
Known cancer
Myocardial infarction within previous 6 months
Severe heart failure defined as equivalent to the New
York Heart Association grade 3 (NYHA)
Learning difficulties
Current treatment with anti-obesity drugs
Diagnosed eating disorder or purging
Pregnant/ considering pregnancy
Patients who have required hospitalisation for
depression or are on antipsychotic drugs
People currently participating in another clinical
research trial
People with contraindications for MR scanning
Trial procedures
Practices randomised to control will continue to deliver
usual diabetes and obesity management as per current clin-
ical guidelines. Detailed information on usual care path-
ways will be recorded in each area. Participants recruited
in these practices will be followed up for 2 years and seen
on 3 occasions by the study research dietitians, for study
outcome data collection (Additional file 1: Table 1).
Practices randomised to intervention will continue
usual guideline-based care and also deliver Counter-
weight Plus, which includes a Total Diet Replacement
(TDR) phase followed by structured food reintroduction
(FR) and a structured support programme for long term
Fig. 1 Study flow chart

weight loss maintenance. The intervention will be deliv-
ered to each participant individually, at their general prac-
tice, by either a practice nurse or local dietitian, depending
on practice preference and availability of dietetic support.
Participants will attend for 35 appointments over the
2-year intervention period (Additional file 1: Table 1).
Training (8 h) for the practice nurses/dietitians in de-
livery of Counterweight Plus and study protocol will be
provided by the study research dietitians who are trained
in the package developed for, and improved following,
the Counterweight feasibility study in primary care [21].
A detailed description of the practical dietetic input will
be published separately.
TDR phase (0-12wks)
A commercial micronutrient-replete 825–853 kcal/d li-
quid formula diet (soups and shakes) will be provided
(Cambridge Weight Plan) to replace usual foods, with
ample fluids (2.25 L), for 12 weeks. Oral hypoglycaemic
agents (OHA), antihypertensive and diuretic drugs will
be withdrawn on commencement of TDR, and reintro-
duced (as per study protocols) if T2DM or hypertension
returns. Aspirin will be continued if prescribed because
of a previous MI (prior to the previous 6 months), but
discontinued if prescribed solely because of T2DM.
Beta-blockers prescribed for the management of angina
will be continued. A soluble fibre supplement (Fybogel
2 × 3.5 g/day) will be prescribed to reduce constipation.
Participants will return for review one week after com-
mencement on the TDR and at 2 weekly intervals there-
after until the commencement of the FR stage (Fig. 1).
To allow some flexibility for patients whose commit-
ments, or life events, prevent achievement of 15 kg at
12 weeks, or if individuals wish to achieve more weight
loss, the TDR phase may continue up to 20 weeks. If
BMI falls below 23 kg/m2
during the TDR phase, partici-
pants will be moved forward to the FR and weight loss
maintenance phases.
Food reintroduction phase (weeks 12–18)
The FR phase includes a stepped transition to a food-
based diet based on the “Eatwell” guidelines [24] while
reducing TDR. To allow flexibility for participants whose
confidence varies, the FR phase can be varied between
protocol-defined limits of 2–8 weeks before switching to
full food-based weight loss maintenance. Participants
will monitor weight on a weekly basis and compare this
with caloric intake and activity levels. Participants will
return for review at 2 weekly intervals throughout the
FR phase.
Weight loss maintenance phase (weeks 19–104)
Participants will be advised to follow a food based diet
and will be provided with an individually tailored energy
prescription, to support weight stabilisation and prevent
weight regain. The option of using one sachet of formula
diet per day for the duration of weight loss maintenance
will also be available to participants. Review appoint-
ments will be at monthly intervals.
All participants allocated to the intervention will be
provided with printed support materials describing the
management plan and support for each phase of the
intervention. Those who are physically capable will be
advised to increase daily physical activity. Step-counters
will be provided with the recommendation to aim to
reach and maintain their individual sustainable max-
imum, up to 15,000 steps/day [25, 26].
Relapse management for weight regain or re-emergence
of diabetes
If weight regain occurs, or if diabetes is found to have
returned (HbA1c ≥48 mmol/mol) at any time during the
18-month weight loss maintenance stage, ‘rescue plans’
to reverse weight gain will be offered.
1) Weight regain of 2 kg: offer the use of TDR to
replace one or two main-meal per day for 4 weeks,
offer orlistat 120 mg tid, with each meal.
2) Weight gain of 4 kg, or to 15 kg below starting
weight or if diabetes recurs: offer 4 weeks TDR with
fortnightly practice nurse/dietitian review and then a
2–4 week FR (as described above). Individualised
dietary advice, based on the Eatwell guidelines [24],
and physical activity targets will be reinforced for
weight loss maintenance. Orlistat treatment, as
above, will be offered for the remainder of the
weight loss maintenance period, with repeat advice
to restrict dietary fat.
Relapse management will include an exploration of the
reasons for weight regain, and anticipatory support to
prevent recurrence.
Patient safety
Intervention participants will be closely monitored
throughout the study (Additional file 1: Table 1). Blood
pressure, postural symptoms and capillary blood glucose
will be monitored at each appointment. Anti-hypertensive
therapy or oral hypoglycaemic agents will be reintroduced
if necessary according to a defined proforma (Appendix 1:
Protocols for management of blood pressure inadequate
glucose control). All observations/results which may pose
a risk to health will be discussed with the participant and
their GP. Enquiry at each study visit will identify the
occurrence of adverse events which will be recorded.
Protocol delivery fidelity
A standard training protocol has been developed to min-
imise variability and maintain intervention protocol

fidelity across all practices. Practitioner mentoring
(nurse or dietitian) will be carried out, by the study re-
search dietitians, during each stage of the intervention,
and feedback provided to practitioners as required. Vari-
ability in primary outcome assessments (body weight,
T2DM status) will be minimised by using calibrated
equipment and quality-controlled assays of blood glu-
cose and HbA1c.
Measurements
The measurements taken at each stage of the DiRECT
study are detailed in Additional file 1: Table 1.
Height will be measured to the nearest mm, with the
Frankfort plane horizontal, using a portable stadiometer
(Chasmors Ltd, London). Body weight will be measured
to the nearest 100 g in light clothing without shoes using
Class 111 approved calibrated scales (Marsden Group
UK). Waist circumference will be measured halfway be-
tween the point of the lowest rib and the iliac crest. Hip
circumference will be measured at the maximum cir-
cumference around the buttocks. Blood pressure will be
measured with patients seated, at rest, with legs
uncrossed for at least 5 min.
Blood will be collected to measure: serum urea and
electrolytes, liver function tests, serum total cholesterol,
HDL cholesterol and triglycerides, HbA1c, plasma glu-
cose, metabolomic profiling and other novel metabolic/
protein markers. Urine will be collect for: assessment of
microalbuminuria and for proteomics.
Objectively measured health behaviours
Physical activity will be assessed in all participants at
baseline, 12 and 24 month follow-up, using GENEAc-
tiv accelerometers, a fully waterproof wrist-worn tri-
axial, raw data accelerometer, for activity and sleep
tracking in free living studies (http://www.geneacti-
v.org/actigraphy/geneactiv-original). The device will be
worn by participants for 9 days at each data collec-
tion time point.
Mechanistic studies (Tyneside)
Tyneside participants (intervention (68); control (20))
will participate in mechanistic studies to define the
physiological mechanisms underlying the long term
remission of T2DM (Additional file 1: Table 1). Liver
and pancreas fat will be quantified using 3-point
Dixon MR scanning [16]. VLDL1 secretion rates will
be measured by plasma accumulation during inhib-
ition of clearance [27]. Beta-cell function will be
assessed using the stepped insulin secretion test with
arginine [16]. Indirect calorimetry, using a Quark
RMR indirect calorimeter (COSMED, Rome, Italy),
will estimate rates of whole body lipid oxidation as
part of the assessment of lipid dynamics. Whole body
glucose oxidation will also be measured [28].
Programme acceptability, process evaluation and Quality of
Life
Participants At least 10 intervention and 10 control
participants in both Scotland and Tyneside will be in-
vited to participate in semi-structured face-to-face or
telephone interviews focusing on experiences, barriers,
facilitators and behaviour strategies for self-regulation.
The exact number of patients recruited will follow
standard guidelines for data saturation in qualitative re-
search [29]. Intervention participants will be inter-
viewed on four occasions during the TDR phase using
semi-structured theory domain [30] interviews, before/
at the commencement of TDR, 6–8 weeks afterwards,
and at months 1 and 12 of the weight maintenance
phase. Control group participants will be interviewed
twice, at the commencement (parallel to TDR phase)
and at the end of their participation in the study (paral-
lel to month 12 of the weight maintenance phase). In-
terviews will be carried out at the participant’s GP
practice, at the University premises, or by telephone.
Secondary trial outcomes for Quality of Life (EQ-5D-
3 L) will be measured at baseline, 12 and 24 months.
Psychological process measures (intention, perceived
control and satisfaction with treatment) will be quanti-
fied using questionnaires developed specifically for the
study in both intervention and control groups. Ques-
tionnaires will be administered, by the study research
dietitians, at baseline and 12 months for all participants.
Intervention participants will complete an additional
questionnaire at the end of the TDR period.
Ecological Momentary Assessment (EMA)
All interviewed participants (20 in intervention group
and 20 in control group) will be invited to complete an
Ecological Momentary Assessment (EMA) for 12 weeks
from the baseline interview and for 8 weeks (weeks 3–
10 inclusive) during the weight maintenance phase.
EMA will prompt participants to record experiences
by responding to a set of daily questions measuring ad-
herence to the dietary prescription as well as other mea-
sures associated with adherence. For participants who
do not wish to complete the EMA via mobile phone,
procedures will be provided for on-line or paper- and-
pencil-based completion.
Healthcare professionals
A purposive convenience sample of 10–15 health care
professionals (nurses dietitians) involved in delivering
the intervention will be invited for interview and the bar-
riers and facilitators to implementation, and ease of en-
gagement with the intervention, will be evaluated using

semi-structured theory domain interviews. Standard
guidelines for qualitative research will be used to achieve
data saturation [29]. Interviews will be conducted either
face-to-face at the health professionals place of work, or
by telephone if preferred by the health professional.
Statistical analysis
Primary outcome measures will be analysed in a hier-
archical fashion, first analysing reduction in weight of
15 kg or more as a binary outcome with significance
assessed at the 5 % significance level, followed, if the first
test is significant, by test of remission of diabetes status
as a binary outcome also at the 5 % level of significance.
The overall type I error will not exceed 5 % because of
the hierarchical nature of the testing.
Data will be analysed initially on an intention-to-treat
(ITT) basis at the 12 month time point. For participants
who discontinue the formal weight management
programme the follow-up weights (from routine atten-
dances) and the end of study diabetes status will be used.
Secondary analyses will include fasting blood glucose at
6 months in those maintaining weight loss of 15 kg or
more; a secondary per protocol ‘completer’s analyses’ of
those who complete the intended management (irre-
spective of their dietary adherence or weight -change);
analysis of BP and blood lipid outcomes; mechanistic pa-
rameters analysed according to blood glucose outcomes.
Participants reporting drug intolerance, diet intolerance
or poor-compliance will be recorded and these partici-
pants will be included in the ITT analysis.
Non-responders
Anonymised data (age, sex, BMI and duration of dia-
betes) for all patients identified as satisfying the recruit-
ment criteria and invited to participate will be recorded.
Data for non-responders will be compared with the
same data from those who agree to participate in the
study. This will permit identification of any recruitment
bias, determine the representativeness of study partici-
pants, and help establish generalisability of the trial
findings.
Participant withdrawal
Participants who withdraw from the intervention proto-
col, or who fail to return for follow-up assessments, will
continue to have data collected from their routine dia-
betic clinic/GP visits, unless they specifically withdraw
consent for this. Data analysis will use best available
follow-up weights (closest within a window of ±3 months
from routine attendances) and end of study diabetes
status for participants who discontinue the formal
weight management programme. Drug intolerance, diet
intolerance or poor-compliance will be recorded: these
patients will be included in ITT analysis.
Sample size
Power calculations have assumed diabetes remission in
22 % of intervention participants at one year compared
with 5 % in the control group. An interclass correlation
coefficient of 0.05 for weight change has been assumed
to account for cluster randomisation. Allowing for an es-
timated 25 % individual participant drop-out within
12 months, we will recruit a total of 280 participants.
Recruitment of at least 10 participants per practice for
25 practices will provide over 80 % power at alpha =0.05.
Recruitment of 30–35 practices will allow for possible GP
practice dropouts. In the event that lower numbers volun-
teer per practice, the power calculation will be revised, to
re-set the recruitment plan.
Discussion
In the UK, as in the rest of the world, the prevalence of
diabetes (of which approximately 90 % is T2DM), con-
tinues to rise. This is a particularly serious problem for
younger people with more extreme levels of obesity with
potentially many years of future hyperglycaemia and
other weight-related features of Metabolic Syndrome. In
the past, T2DM was commonly referred to as ‘mild dia-
betes’. It is now recognised as a devastating progressive
disease, which causes accelerated aging macrovascular
complications affecting heart, legs and brain, plus micro-
vascular damage to eyes, kidneys and nervous system.
These sequelae have lessened to some extent with mod-
ern evidence-based treatments under clinical guidelines.
However, T2DM still reduces life-expectancy signifi-
cantly [31, 32] and is now a very major cause of pro-
longed disability, and a growing burden on healthcare
services and on health budgets [33] . Remission of
T2DM can be achieved by substantial weight loss follow-
ing either bariatric surgery [17] or hypocaloric diet [16].
While current clinical guidelines recommend bariatric
surgery for obese T2DM patients, there is little realistic
prospect of this being offered to most people because of
surgical and follow-up resource limitations, and personal
preference to avoid surgery. The DiRECT study has been
designed to establish the feasibility and durability of a
primary care-based dietary intervention, which, if effect-
ive could be offered routinely as soon as possible after
diagnosis of T2DM.
To assess the efficacy and safety of the DiRECT inter-
vention, and the additional burden to patients and to
staff, outcomes will be compared with those from a non-
intervention control sample of similar participants with
T2DM, using random allocation. Recognising the un-
doubted value of current clinical evidence-based guide-
lines, it was considered essential that both groups
should continue to be managed under current UK
guidelines from NICE and SIGN [11, 12], and that any

new guidelines, emerging during the course of the trial,
should be applied equally to all participants.
This trial is designed to be as ‘realistic’ as possible, so
that the results can be assessed in the context of conven-
tional chronic disease management, and to allow maximal
transferability into routine healthcare. In the UK, most pa-
tients with T2DM are now managed in NHS primary care
at least in the earlier stages of the disease before serious
vascular complications have developed. The setting for
DiRECT is therefore routine NHS primary care, with the
intervention being delivered by existing staff following
training, and then interactive support and on-the-job
mentoring being provided by the experienced research
team dietitians, until practitioners are confident and
competent. This is the same model as evaluated in
the UK feasibility study of the Counterweight-Plus
weight management programme [21], which is now
being offered in some health boards as part of routine
NHS primary care.
A cluster randomised intervention was chosen to avoid
contamination, which would be inevitable with random-
isation at an individual level within GP practices, and to
avoid the conflict which would arise for the dietitian or
nurse if asked to offer a radically different intensive man-
agement only to randomly selected patients from their
practice. The training and mentoring of practice staff de-
livering the programme was designed to ensure fidelity in
programme delivery, necessary when interventions are de-
livered in more than one centre, but there always remains
a possibility that differences will remain between centres.
We therefore applied a conservative inter-class correlation
of 0.05, which requires a 25 % increase in numbers re-
cruited into the study. In our experience, the ICC (inter-
class cluster effect) is likely to be smaller than this. In our
Counterweight feasibility study, using the same interven-
tion in 22 General Practices, there was no evidence of a
cluster effect. If this applies to the present study, it is likely
to be modestly over-powered.
A key principle behind the methodology of both DiR-
ECT and the earlier Counterweight Plus feasibility study
[21] is the aim to assess the impacts from maximising
weight losses and long-term maintenance for the max-
imum number of people. This is subtly different from an
evaluation of a specific treatment, such as a drug which is
given in fixed dose. Optimising weight control entails
complicated behavioural modifications in the context of
busy lives and often conflicting personal knowledge and
attitudes, within a wide variety of changeable social
and domestic situations. It would certainly have been
possible to have tested a rigid diet and lifestyle pre-
scription, but an ‘off-the-shelf’ intervention could re-
sult in a very wide range of weight losses between
individuals, with resulting wide range of secondary
metabolic changes. The Counterweight feasibility
study indicated that while about 25 % of patients
followed the TDR fully for 12 weeks, the remainder
had adhered only partially to the plan. The final out-
comes of those patients varied, but many did achieve
the intended 15 kg weight loss, and feedback indi-
cated that they valued some flexibility which could
accommodate individual circumstances and prefer-
ences in order to maximize weight losses. A fixed
diet and lifestyle prescription cannot deliver a fixed
weight-loss over a fixed time-period in a real-life set-
ting. The decision was therefore taken that the DiR-
ECT study would adopt a protocol which included
flexibility (within pre-defined ranges) for the dur-
ation of the different phases of the intervention.
Thus, it was planned that each participant should
aim to lose at least 15 kg, (more if possible), but
allow some to cease TDR early (if they were finding
it difficult) and move on to FR, and others to extend
TDR if there has been interruptions to protocol ad-
herence, or they wished to continue longer. Defined
windows of flexibility were incorporated into the
protocol for each phase of weight-management, in-
cluding pre-planned relapse-management plans for
those whose weights begin to rise, or whose T2DM
returned, during the maintenance phase. In a real-
life, routine setting, these would be normal and ex-
pected components of care.
The aim of DiRECT is to achieve remission of dia-
betes, which was hypothesised would follow substantial
weight loss, of the order of 15 kg. To achieve this, the
duration of the weight loss intervention for DiRECT had
to be at least 3 months, followed by a longer period to
establish and optimise weight loss maintenance. Most
clinical guidelines require evidence over 12-months or
longer. The feasibility study [21] had evaluated the
Counterweight-Plus programme at 12 months, but not
longer. For this reason, for the power estimations, the
co-primary outcome measures were 12-month changes:
weight loss 15 kg and HbA1c 48 mmol/mol) analysed
as binary outcomes.
The choice of HbA1c cut-off for the co-primary out-
come measure was between 48 mmol/mmol (the diagnos-
tic threshold for T2DM) and 42mmo/mmol (diagnostic
threshold for IGT/pre-diabetes). There is existing evidence
that weight loss of 5-10 kg (mean 4 kg at 4 years) will
prevent the development of T2DM for 58 % of patients
with IGT/pre-diabetes, and that ~55 % will revert to
a completely normal HbA1c of 42 mmol/mmol [34].
The aim of DiRECT being to achieve remission of
established T2DM, it was considered most appropriate to
adopt the cut-off 48 mmol/mmol for the primary outcome
measure, with 42 mmol/mmol as a secondary outcome
measure.

Conclusion
The DiRECT study, whose results will be available from
2018, aims to provide evidence to inform and guide future
strategy to enhance the management of T2DM. It evalu-
ates an existing, but not yet recommended, approach for
routine weight management. The experimental protocol is
patient-centered, and flexible within defined limits, in
order to optimize weight loss and maintenance for the
maximum number of patients. Its aims are to reverse the
diagnosis of T2DM and normalise other associated meta-
bolic features for substantial proportion of participants.
With effective long-term weight loss maintenance, this
should allow freedom for patients from the limitations
which diabetes places on everyday life, occupation, insur-
ance etc. In addition, it might potentially reduce morbidity
from diabetic complications, but the present study is not
powered for this purpose.
Appendix 1: Protocols for management of blood
pressure inadequate glucose control
Blood pressure
Background
Antihypertensive and diuretic drugs will be stopped on
the day the total diet replacement is commenced. This is
a safety measure, because blood pressure is likely to fall
on the diet. This protocol lays out the standard approach
to be followed to allow clear description of the research
findings. Individual clinical decisions may be necessary
for a person’s best interest. The level of 140 mmHg is
chosen to allow safe decisions during the weight loss
period. After the Food Reintroduction period follow
usual guidelines for management of hypertension. To
simplify decision making, systolic pressure only is used
as a guide to therapy even though both systolic and dia-
stolic are relevant to long term benefit.
Protocol
When antihyperensive drugs are stopped,
re-emphasise the importance of avoiding
sodium (salt)
1. In the first 2 weeks after stopping antihypertensives
and diuretics:
If systolic BP over 165 mmHg on repeated measurement
- restart one drug, as below.
2. Thereafter, if systolic BP is 140 mmHg - restart
one drug as below.
3. Increase dose weekly to achieve target.
4. If systolic BP remains 140 mmHg on the first drug
- add a second drug, as below.
5. Increase dose weekly to achieve target.
6. Repeat as necessary with third, fourth or more
drugs (increasing each to maximum dose).
Order of reintroduction of previously used drugs
1. ACE inhibitors (ramipril. lisinopril, perindropril,
etc.)
2. Angiotensin receptor blockers (irbesartan,
candesartan etc.)
3. Thiazide type (bendroflumethazide, indapamide
etc.)
4. Spironolactone
5. Calcium channel blocker (nifedipine, amlodipine
etc.)
6. Beta blocker (atenolol, labetolol etc.)
7. Alpha blocker (doxazosin, prazosin)
8. All others
Glucose control
Background
All anti-diabetic drugs will be stopped on the day Total
Diet Replacement (TDR) is commenced. This is a safety
measure because blood glucose levels fall rapidly on the
diet.
Protocol
1. After 2 weeks of TDR if osmotic symptoms (thirst,
polyuria) are troublesome or if random capillary
glucose is over 20 mmol, check HBA1c and that
weight loss is as anticipated.
2. If it is not, discuss whether any other help would be
helpful with following the low calorie liquid diet.
3. If weight loss is satisfactory but control is still
inadequate, consider introducing an oral hypoglycaemic
agent.
4. Start at the lowest dose and increase gradually.
5. Subsequently, if control remains poor, add further
agents
6. Urge further weight loss at each visit
Order for reintroduction of anti-diabetic medications
1. Reintroduce metformin (500 mg bd). If this has
previously caused GI upset for the individual, use
the slow release preparation.
2. Increase metformin to a usual maximum of 1 g BD
over 2–4 weeks
3. If a second agent is required, add sitagliptin 100 mg
od.
4. If, after 4 weeks, control is still inadequate, add
gliclazide 80 mg od (or other sulphonylurea if
previously used, or if preferred).
5. Increase sulphonylurea dose gradually until glucose
control is adequate
6. Use current diabetes guidelines if glucose control
remains inadequate

Additional file
Additional file 1: Table 1. DiRECT schedule of assessments. (DOCX 26.4 kb)
Competing interests
ML and NB have received funding from Cambridge Weight Plan for
conference attendance and for other departmental research. At the time of
study commencement, NB, HR LMcC were shareholders and employees of
Counterweight Ltd.
Authors’ contributions
ML RT conceived the study and are the principal investigators. WL, IF, NS,
KH, AA, FS, NB, LMcC, HR, JM, CP, GT, AB, SK, Y McI, LR SZ and AR have
contributed to the design of the study. WL drafted the manuscript. All
authors critically reviewed the manuscript, and have read and approved the
final version.
Funding
The DiRECT study is funded as a Strategic Research Initiative by Diabetes UK.
Formula diet delivered is donated by Cambridge Weight Plan.
Author details
1
University of Glasgow, University Avenue, Glasgow G12 8QQ, UK. 2
Newcastle
University, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK.
3
Counterweight Ltd, Edinburgh, UK.
Received: 27 December 2015 Accepted: 21 January 2016
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