Doctor Referral of Overweight People to Low Energy total diet replacement Treatment (DROPLET): pragmatic randomised controlled trial

Abstract Objective To test the effectiveness and safety of a total diet replacement (TDR) programme for routine treatment of obesity in a primary care setting. Design Pragmatic, two arm, parallel group, open label, individually randomised controlled trial. Setting 10 primary care practices in Oxfordshire, UK. Participants 278 adults who were obese and seeking support to lose weight: 138 were assigned to the TDR programme and 140 to usual care. 73% of participants were re-measured at 12 months. Interventions The TDR programme comprised weekly behavioural support for 12 weeks and monthly support for three months, with formula food products providing 810 kcal/day (3389 kJ/day) as the sole food during the first eight weeks followed by reintroduction of food. Usual care comprised behavioural support for weight loss from a practice nurse and a diet programme with modest energy restriction. Main outcome measures The primary outcome was weight change at 12 months analysed as intention to treat with mixed effects models. Secondary outcomes included biomarkers of cardiovascular and metabolic risk. Adverse events were recorded. Results Participants in the TDR group lost more weight (−10.7 kg) than those in the usual care group (−3.1 kg): adjusted mean difference −7.2 kg (95% confidence interval −9.4 to −4.9 kg). 45% of participants in the TDR group and 15% in the usual care group experienced weight losses of 10% or more. The TDR group showed greater improvements in biomarkers of cardiovascular and metabolic risk than the usual care group. 11% of participants in the TDR group and 12% in the usual care group experienced adverse events of moderate or greater severity. Conclusions Compared with regular weight loss support from a practice nurse, a programme of weekly behavioural support and total diet replacement providing 810 kcal/day seems to be tolerable, and leads to substantially greater weight loss and greater improvements in the risk of cardiometabolic disease. Trial registration International Standard Randomised Controlled Trials No ISRCTN75092026.


Table of Contents:
Full Inclusion and Exclusion criteria 2 Medication adjustment guidelines 3 Figure S1: Treatment effect by sub-group 4 Table S1: Typical Nutritional Composition of meal replacements used in TDR 5 Table S2: Adjusted treatment effects under different missing data approaches 6 Figure S2: Pattern mixture modelling 7 Table S3: Adverse events analysis 8 Table S6: 12 month outcomes for participants with a baseline diagnosis of type 2 diabetes 9

Full list of Inclusion and Exclusion criteria Inclusion:
Participants were included in the study if the met the following criteria:  Participant is willing and able to give informed consent for participation in the study.  Aged 18 years or above.  Body Mass Index ≥30 kg/m 2 .  Likely to benefit from weight loss in the Primary Care physician's opinion.

Exclusion:
The following criteria were used to exclude individuals for whom weight loss might not be safe, those who may have difficulty adhering to TDR intervention, or those with medical conditions that were a contraindication to the TDR programme.
 Currently or recently (within 3 months of study entry) attended a weight management programme or currently participating in another weight loss study.
 Had bariatric surgery, or scheduled bariatric surgery.
• Pregnant, breastfeeding, or planning to become pregnant during the course of the study.
• Receiving insulin therapy • Heart attack or stroke within the last 3 months • Heart failure of grade II New York Heart Association and more severe • Angina, arrhythmia, including atrial fibrillation or prolonged QT syndrome • Taking MAOI medication • Taking anticoagulant medication (e.g. warfarin) • Taking varenicline (smoking cessation medication) • Chronic renal failure of stage 4 or 5 • Active liver disease (except NAFLD) a past history of hepatoma or within 6 months of onset of acute hepatitis. • People having active treatment for cancer other than skin cancer treated with curative intent by local treatment only or people taking hormonal or other long-term secondary prevention treatment after initial cancer treatment. • Active treatment or investigation for possible or confirmed gastric or duodenal ulcer.
Maintenance treatment with acid-suppression is not a contra-indication. • Porphyria • Scheduled for surgery within 12 months • A member of household is already enrolled in the study • Unwilling to provide blood samples • Patients that the Primary Care physician judges not able to meet the demands of either treatment programme or measurement schedule. This may include severe medical problems not listed above or severe psychiatric problems including substance misuse that make following the treatment programme or adhering to the protocol unlikely.

Medication adjustment guidelines
4 Figure S1: Treatment effect by sub-groups *IMD decile is an indicator of deprivation, with decile 1 being most deprived, and decile 10 the least deprived. IMD groups were compared using median split. IMD was not a pre-specified sub-group analysis, and was added after the statistical analysis plan was written, but before the primary analysis was conducted.