What this is
- This protocol outlines a 32-week randomized, controlled trial assessing the effects of dapagliflozin combined with exenatide QW in obese patients with .
- The study aims to investigate changes in and metabolic responses compared to dapagliflozin alone and a placebo.
- It addresses the need for more evidence on the synergistic effects of these glucose-lowering therapies.
Essence
- The trial will evaluate whether combining dapagliflozin with exenatide QW leads to greater reductions in compared to dapagliflozin alone in obese patients with .
Key takeaways
- The primary outcome is the adjusted mean reduction in total after 32 weeks of treatment, measured by DEXA. This will help determine the efficacy of the combination therapy.
- Secondary outcomes will assess changes in energy intake, energy expenditure, and various fat depots, providing a comprehensive view of metabolic changes.
Caveats
- The study's sample size was reduced from 120 to 110 participants due to COVID-19, which may affect the robustness of the findings.
- The trial relies on self-reported data for treatment compliance, which could introduce bias.
Definitions
- body fat mass: The total amount of fat tissue in the body, measured to assess obesity and metabolic health.
- type 2 diabetes: A chronic condition characterized by insulin resistance and high blood sugar levels, often linked to obesity.
AI simplified
Background and rationale
Type 2 diabetes (T2D) is closely related to obesity: their prevalence is rising in parallel, synergistically accelerating and increasing the severity of diabetes-related complications.1 Weight loss is therefore a primary therapeutic target in the management of patients with T2D. While some glucose-lowering treatments are associated with weight gain (eg, sulfonylureas, thiazolidinediones and insulin), two recent classes of therapeutic agents for T2D, namely, the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), are associated with weight loss, achieved via different mechanisms: increased urinary glucose loss for SGLT2i, and promotion of satiety for GLP-1 RAs.
Pharmacological inhibition of SGLT2 reduces renal glucose reabsorption in an insulin-independent mechanism promoting a daily urinary glucose excretion (UGE) of ~75 g, an energy deficit of ~300 kcal and a diuresis of ~400 mL.2 3 GLP1-RAs confer similar therapeutic benefits operating via distinct mechanisms: improving glycaemic control (by enhancing glucose-dependent insulin secretion and inhibiting hepatic glucose production)4 and reducing body weight via a central effect (promoting satiety via the hypothalamus).5 6 The glucose-lowering effects of SGLTi maybe attenuated by increased endogenous (hepatic) glucose production,7 8 partially explained by a compensatory hyperglucagonaemia.9 It is also unclear why the magnitude of weight loss with SGLT2i therapy is not commensurate with the expected weight loss based on the determined caloric loss, suggesting compensatory or adaptative changes in energy intake and energy expenditure that attenuate the energy imbalance.10 11
Overall, the limited available evidence demonstrates the additive benefits of combination therapy with a GLP-1 RA and SGLT2 inhibitor on glycaemic improvement and weight.12–14 Further studies are needed to elucidate their combined effects on metabolic and cardiovascular disease. The central hypothesis of this mechanistic study is that coadministration of exenatide once weekly (QW; a GLP-1 RA) with dapagliflozin (an SGLT2i) treatment will offset the potentially (mal)adaptive compensatory metabolic and appetitive responses occurring with dapagliflozin alone. Specifically, we anticipate that GLP-1 RAs can attenuate the increased hepatic glucose production due to hyperglucagonaemia and possible compensatory increases in appetite that arise with SGLT2i therapy (figure 1).
Potential synergy with sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.
Primary objective
The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo).
Secondary objectives
The key secondary objectives are to assess the adjusted mean change from baseline of:
In addition, this study will assess treatment compliance at 28-day intervals, based on the number of injections administered and returned tablet counts.
Exploratory endpoints
These are to be analysed and presented separately to primary and secondary outcome measures.
Safety objective
The type and frequency of adverse events will be reported for all treatment groups.
Methods and analysis
Overall design, investigational plan and study population
This is a 32-week outpatient, double-blind, parallel group, randomised placebo-controlled mechanistic study of exenatide QW (GLP1-RA) and dapagliflozin (SGLT2i) treatment. One hundred and ten participants with obesity and T2D will be recruited: male and female, aged 18–65 years, Body mass index (BMI) 30–50 kg/m2, with glycated haemoglobin (HbA1c) ≥6.5% but ≤11% (48–97 mmol/mol; see table 1 for complete criteria). Each participant will have 13 study visits. Participants will be randomised equally to each of the three treatment arms (figure 2).
Study schematic.
| INCLUSION CRITERIAEXCLUSION CRITERIAMedical History and Concurrent DiseasesMales or females, age 18–65 years.A clinical diagnosis of type 2 diabetes.Glycosylated haemoglobin (HbA1c) ≥6.5% but ≤11% (48–97 mmol/mol).Currently treated with either diet or any combination of metformin, DPP-IV inhibitors* and sulfonylureas (excluding patients treated with pioglitazone or insulin). *DPP-IV inhibitors will require wash out period of 4 weeks.BMI 30–50 kg/m.2Patients who are receiving the following medications must be on stable treatment regimen for a minimum of 2 months prior to screening:Thyroid hormone replacementAntidepressantsType 1 diabetes mellitus.History of diabetic ketoacidosis or hyperosmolar non-ketotic coma.Renal impairment: eGFR less than 60 mL/min/1.73 m.2Familial renal glucosuria.Clinically significant abnormal free T4 or patients needing initiation or adjustment of thyroid treatment according to the investigator.Severe uncontrolled hypertension ≥180 mm Hg and/or diastolic ≥110 mm Hg.Congestive heart failure class III-IV.Recent (<6 months) myocardial infarction.Known chronic liver disease (other than hepatic steatosis).Significant cardiac dysrhythmias (including pacemaker or ICD).Previous stroke.History of seizures or unexplained syncope.History of, or currently have, acute or chronic pancreatitis.History of malignancy (with the exception of basal and squamous cell carcinoma of the skin) within the last 5 years.History of medullary thyroid carcinoma or MEN2 (Multiple endocrine neoplasia type 2) or family history of medullary thyroid carcinoma or MEN2.History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study.Patient, who in the judgement of the investigator, may be at risk of dehydration or volume depletion (hypovolaemia) that may affect the patient’s safety and/or the interpretation of efficacy or safety data.Presence of any other medical condition that would, in the opinion of the investigator or their clinician, preclude safe participation in the study. This decision should be informed by dapagliflozin and exenatide precautions for use statements which will be provided to all clinicians and the research team.Alcohol consumption in excess of 21 units/week females, 28 units/week males.Current smoker (including electronic cigarettes) or having ceased smoking in the last 6 months.Any history of a pacemaker or implantable cardioverter defibrillator (ICD).Patients with a history of diabetic foot ulcers or previous (lower limb) digital amputations. | .Patients currently taking part in a structured weight loss programme such as weight watchers or slimming world (excluding those on weight management programmes as part of their diabetes care).Patients who score over 4 restraint subscale of the Dutch Eating Behaviour Questionnaire.Patients who score over 27 on the Binge Eating Scale.ALT>3×upper limit of normal (ULN).AST>3×ULN.Bilirubin>2×ULN.Haemoglobin ≤10.5 g/dL (≤105 g/L) for men; haemoglobin ≤9.5 g/dL (≤95 g/L) for women.History of unexplained microscopic or macroscopic haematuria at screening, confirmed by follow-up sample a next scheduled visit, where according to the investigator a satisfactory evaluation of haematuria has not been conducted.Weight <60 kg and >200 kg (due to DEXA limitations).BMI <30 kg/mand >50 kg/m.22Recent major change in body weight (>3 kg loss or gain in preceding month).Subjects with a history of any serious hypersensitivity reaction to GLP1-RA or SGLT2 inhibitor.Participant should have no allergies against metacresol (the preservative in insulin vial).History of anaphylaxis to food.Known food allergies or food intolerance.Known hypersensitivity to heparin.Known hypersensitivity to intravenous catheter equipment.Females of childbearing age who are not using adequate contraceptive methods or who are planning a pregnancy in the next 44 weeks (study duration plus 12 weeks).Women who are pregnant or breast feeding.Sexually active fertile men not using effective birth control if their partners are WOCBP.Diabetes treated with pioglitazone, SGLT2 inhibitors, GLP-1 analogues or insulin.Treatment with SGLT2 inhibitor, GLP1 RA or subcutaneous insulin injections 3 months before screening.Any weight loss medication (eg, orlistat) within 3 months prior to screening.Use of any drug that might affect body weight or appetite (including antipsychotics or corticosteroids) within 3 months prior to screening.Patients who are currently receiving a loop diuretic that cannot be discontinued.Active or previous substance abuse or dependence.Prisoners or subjects who are involuntarily incarcerated.Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.Dislike >25% of the study foods.Participation in other studies (within the past 30 days).Physical and Laboratory Test FindingsAllergies and Adverse Drug ReactionsSex and Reproductive StatusProhibited Treatments and/or TherapiesOther Exclusion CriteriaIn situations where the patient has a contraindication to MR scanning, they will be randomised to the study but excluded from MR scanning only. The primary outcome measurement of fat mass can be derived from DEXA |
Patient and public involvement
Patients were involved in the design and conduct of the trial. During the feasibility stage, choice of outcome measures, the number of study visits and methods of recruitment were informed through discussions with patients in the clinical setting and attendance at local diabetes education sessions. During the trial, a patient joined the independent trial steering committee (TSC). Once the trial has been published, a clear ‘plain English’ summary of the findings will be created so that they are widely available to participants and the wider patient groups. These will be presented to attendees at diabetes awareness days at the hospital and within the community.
Sample size
This trial will examine exenatide QW, a weekly GLP1-RA, added to dapagliflozin versus sham saline injection added to dapagliflozin for an intervention period, of 32 weeks compared with a control group (placebo tablet and sham injection).
The sample sizes have been calculated in order to conduct the following two comparisons:
These comparisons are selected to answer the key question of interest; although the study will not provide comparisons between arms C and A, nor will they be reported.
The original sample size calculation was carried out using Stata V.14 software (Stata Statistical Software: Release 14. College Station, Texas, USA: StataCorp LP). For both comparisons, a 1.5 kg in the change in body fat mass is considered a clinically relevant difference. From previous data, the within patient SD for the change in total body fat between baseline and 32 weeks is estimated as 1.8 kg.17 From this, a between-patient SD of 2.55 kg was computed. Using a two-group test with equal means (assuming 80% power and one-sided 5% significance level), 36 patients per treatment arm were estimated to be required in order to adequately power the planned analysis (assuming effect size of 0.59). Using these calculations and an anticipated 10% attrition and patient dropout rate, the original sample size was set at 120 participants.
As a result of the COVID-19 pandemic, however, 15 active patients were lost to follow-up and a revised sample size calculation was implemented, reducing the original sample size from 120 patients to 110 randomised patients in order to maintain meaningful results within the remaining timeframe of the study. Using the same clinically relevant difference of 1.5 kg, significance level and power, the between-patient SD would be 2.42 kg, giving an effect size of 0.62. Assuming 80% power, a minimum of 33 patients per treatment arm are required. Allowing for an anticipated 11% attrition rate/dropout rate, a total of 110 patients are required (calculated using NQuery V.8.1.2.0).
Recruitment will take place over 44 months in Liverpool University Hospital NHS Foundation Trust (Aintree site), Liverpool, UK. Participants will be recruited either from existing databases of volunteer patients, diabetes clinics in the hospital and community and by advertisement in the local press and social media.
Screening, enrolment and randomisation
After giving written informed consent, potentially eligible participants will attend a screening visit within 6 weeks prior to randomisation; this includes a medical history to confirm the participant’s eligibility to participate as determined by the inclusion/exclusion criteria (table 1), physical examination, blood tests, urinalysis and an ECG. Each participant will be informed of his/her eligibility for the trial once all results are available (usually within 1 week from obtaining consent).
The randomisation for each stratum will be performed using computer generated (Treatment Allocation Randomisation System, TARDIS) random balanced blocks to ensure approximately equal numbers of participants across the treatment arms within each stratum. Each patient will be assigned a unique study identification number. The study is set-up as a double blind trial with both the participants, doctor, site and LCTC (Liverpool Clinical Trials Centre) RESILIENT trial teams being blind to the treatment received. Unblinded members of the research staff (pharmacy and selected research nurses) will remain the same throughout the trial. A blinded confirmation email will be sent to all relevant site staff and LCTC trial team detailing the trial number and patient initials. An unblinded confirmation email will also be sent to all relevant pharmacy staff detailing the allocated treatment arm, trial number and patient initials. Only the subject number and initials will be recorded in the electronic case report form (eCRF). All other patient identifiable data will be completely anonymised. An additional validation check has been built into the eCRF (MACRO 4) for authorised trial team members only to confirm eligibility and suitability to proceed to randomisation.
Dosage and administration of study treatments
Participants will attend once a week for administration of a subcutaneous injection (exenatide QW 2 mg or sham injection) for the duration of the study (32 weeks). The exenatide QW injection and the sham injection are not identical in appearance, so to maintain the study blinding, medication dispensed will be given to a member of the unblinded research team in an opaque bag to ensure the contents cannot be seen by members of the blinded research team or the patient. No blinded staff member will be allowed in the room at the time of injection and the injection will be disposed of by unblinded staff members in line with local protocols, and in a concealed manner. Participants will also be instructed to take a tablet with water (dapagliflozin 10 mg or matching placebo) each morning for the duration of the study, while continuing with their usual medication and attending for scheduled study visits. The number and size of tablets will be identical for the investigational products (dapagliflozin 10 mg and placebo). Participants will be asked to return all unused investigational products, including any empty medication packages to the clinic at each visit. The subject’s compliance will be discussed at each study visit and assessed based on the number of injections administered and returned counts. This will be recorded in the defined CRF. To aid compliance, participants will be asked to complete a patient diary. Participants judged to be non-compliant may continue in the study, but will be counselled on the importance of taking their study medication as prescribed.
Study visits and procedures
Anthropometric measurements
Body weight and height, waist and hip circumference and whole-body bioimpedance analysis (TANITA: total body mass, fat percentage, fat mass, fat free mass and muscle mass) will be recorded. Blood pressure will be measured from the left arm after patients have been seated for 5 min. The first reading will be discarded, and the mean of three subsequent readings recorded (table 2).
| Procedure | D−42–2(including washout if necessary) | D−14–0 | D0 | W2 | W4 | W8 | W12 | W16 | W20 | W24 | W28 | W30–32 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Visit (fasting) | 0 | 1 and 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 and 12 | |
| Informed consent | X | |||||||||||
| Medical history/demographics | X | |||||||||||
| Physical examination and ECG | X | |||||||||||
| Pregnancy test | X | X | ||||||||||
| Glucometer dispensing and training | X | |||||||||||
| Urinalysis | X | |||||||||||
| Height | X | |||||||||||
| Weight | X | X | X | X | X | X | X | X | X | X | X | |
| Waist and hip measurements | X | X | X | X | X | X | X | X | X | X | ||
| Bioelectrical impedance analysis (BIA) | X | X | X | X | X | X | X | X | X | X | ||
| BP, pulse | X | X | X | X | X | X | X | X | X | X | X | |
| Blood tests | X | X | X | X | X | X | X | X | X | X | X | |
| Dapaglifozin/placebo dispensing | X | X | X | X | X | X | X | X | X | |||
| Concomitant medication check | X | X | X | X | X | X | X | X | X | X | X | |
| Compliance check | X | X | X | X | X | X | X | X | X | |||
| AE reporting | X | X | X | X | X | X | X | X | X | X | ||
| 24-hour urine | X | X | X | X | ||||||||
| 4-day food diary | X | X | X | X | ||||||||
| 4-day activity monitoring | X | X | X | X | ||||||||
| Test meal | X | X | X | X | ||||||||
| Indirect calorimetry | X | X | X | X | ||||||||
| Psychological questionnaires and VAS | X | X | X | X | ||||||||
| DEXA | X | X | ||||||||||
| MRI (full body, liver fat, pancreatic fat) | X | X | ||||||||||
| MRI cardiac | X | X | ||||||||||
| fMRI and eye-tracking | X | X | ||||||||||
| FMD | X | X | ||||||||||
| Cardiac ECHO | X | X | ||||||||||
| DLW and additional DEXA | X | X | X | X | X | |||||||
| Euglycaemic clamps | X | X |
Biochemical measurements
All patients will have a routine blood sample taken for HbA1c, fasting plasma glucose, renal profile (to include electrolytes, urea and creatinine, and eGFR), lipid profile, liver function tests (to include ALT, AST and bilirubin) and insulin. Insulin sensitivity will be measured by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).18 eGFR will be estimated using the Modification of Diet in Renal Disease (MDRD). We will measure fasting plasma glucose (FPG) and estimated glomerular filtration rate (eGFR) every 2–4 weeks. This will allow us to determine the amount of filtered glucose calculated from the product of the FPG (mg/dL) and eGFR (mL/min/1.73 m2).
Test meal visits (visits 1, 4, 7 and 11)
Test meal visits will take place at baseline and after 4, 16 and 32 weeks of treatment (tables 2 and 3). Participants will be asked to attend the investigational unit at 08:00, having had nothing to eat or drink other than water from midnight. Participants’ anthropological and biochemical measurements will be taken (see above). An explanation and demonstration of Visual Analogue Scale (VAS) questionnaires, appetite questionnaires and ventilated hood will be given. Additional measures taken during test meal days are described below.
| Time point guidelines | Procedure |
|---|---|
| Arrival 08:00* | Blood sample taken.Subjects asked to empty bladder; start of timed 24-hour urine collection.Weight, waist circumference, bioelectrical impedance analysis, pulse and blood pressure taken. |
| 08:10 | Basal metabolic rate measurement (indirect calorimetry—see below for details). |
| 08:55 (T1 VAS) | Subjects will complete a pre-breakfast, seven-component VAS questionnaire to measure hunger and other subjective variables. |
| 09:00 | Subjects will be provided with a fixed-quantity breakfast, consisting of cornflakes with milk, toast and preserve, tea/coffee and orange juice. |
| 09:20 (T2 VAS) | Subjects will complete a post-breakfast, 7-component VAS questionnaire to measure hunger and other subjective variables. |
| 10:00, 11:00, 12:00 (T3-5 VAS)hoursAdministered at hourly intervals (from pre-breakfast VAS) for 3 | Subjects will complete the same seven-component VAS questionnaire as used pre-breakfast, providing a pre-meal set of ratings. |
| 12:55 (T6 VAS) | Subjects will complete a pre-lunch, seven-component VAS questionnaire to measure hunger and other subjective variables. |
| 13:00 | Subjects will be given an ad libitum lunch. The meal consists of a multiple item buffet (mix of high-fat and low-fat savoury items) and subjects may eat ad lib, and signal when they have finished the meal. |
| 13:30 (T7 VAS) | Subjects will complete a post-lunch, seven-component VAS questionnaire to measure hunger and other subjective variables.Participants also complete a post-lunch palatability VAS. |
| 14:00, 15:00, 16:00, 17:00 (T8-11 VAS)hoursAdministered at hourly intervals (from pre-breakfast VAS) for 4 | Subjects will complete the same seven-component VAS questionnaire as used pre-breakfast, providing a post-meal set of ratings. |
Food intake and eating behaviour
Participants will be provided with a fixed load breakfast (providing 25% energy from estimated Resting metabolic rate (RMR)) followed 4 hours later by an ad libitum lunch, which they will self-serve. The ad libitum lunch will consist of a multiple item buffet (eg, high and low calorie, sweet and savoury items) to understand how the potential satiety and reward-based changes in appetite effect energy intake and modify food choice. Pen and paper VAS measures of appetite (hunger, fullness, desire to eat, prospective consumption, satisfaction, thirst and nausea) fluctuations throughout the day will also be collected with retrospective appetite and craving questionnaires at the end of the day. Taken together, these data fully characterise drug effects on appetite and eating behaviour.
A range of questionnaires assessing secondary outcomes of appetite, cravings, feelings of control and eating behaviours (including food choice) will also be completed at test meal visits. These include the Three Factor Eating Questionnaire (TFEQ)19; Power of Food Scale (PoF)20; the Craving for Sweet Foods sub-questionnaire from the Health and Tastes Attitude Scale (HTAS)21; the 7-day Control of Eating Questionnaire (COEQ)22; the external eating subscale from the Dutch Eating Behaviour Questionnaire (DEBQ)23 assessing external eating; and the Mindful Eating Scale (MES)24 describing the physical and emotional sensations associated with eating.
Indirect calorimetry
Energy expenditure and respiratory quotients will be measured on the morning of the test meal visit prior to the fixed energy breakfast using an indirect calorimeter (GEM Nutrition, Daresbury, UK) fitted with a ventilated hood and derived using the modified Weir equation.16 Participants will remain awake but motionless in a supine position for 45 min with RMR calculated from respiratory data averaged over the final 30 min of assessment. The first 15 min of each measurement will be discarded to allow for complete acclimatisation to the hood and the recumbent position.
Physical activity monitoring
Habitual physical activity will be monitored using a SenseWear mini armband (BodyMedia, Pittsburgh, Pennsylvania, USA) for a 4-day period (to include one weekend day) during weeks 0, 4, 16 and 32. Data collected from the SenseWear device include daily average step count, total energy expenditure, active energy expenditure and time spent in domains of physical activity including sleep, lying, sedentary (<1.5 metabolic equivalents, METS), light (1.5–3 METS), moderate (3–6 METS), vigorous (6–9 METS) and very vigorous (>9 METS) and is analysed using SenseWear Professional software (V.8.0).
Food diaries
Participants will be asked to complete a food diary detailing exactly what they eat and drink over the same 4 day period. Total energy consumption, carbohydrate, protein and fat content will be determined from dietary records using Nutritics (Nutrition Analysis Software for Professionals).
Baseline and end of treatment measures
Body composition
All participants will undertake a full body DEXA (Lunar IDXA, GE Healthcare, Amersham, UK) scan after an overnight fast at baseline and week 32. Body composition will be determined to quantify total and regional (trunk, limb, android and gynoid) fat mass and fat-free mass.
MRI measures of body composition, hepatic and pancreatic fat MRI eligible participants will be scanned using a 3.0 T Siemens Prisma scanner (Siemens Medical Solutions, Erlangen, Germany) at the Liverpool MRI Centre (LiMRIC). Images are obtained with the patient supine and using an integrated body coil (Siemens Medical Solutions, Erlangen, Germany).
For body composition, multiple blocks of contiguous slices using a Dixon VIBE in and out of phase sequence will be conducted to produce fat and water images from the vertex of the skull to the knees. These will be used to determine fat volumes in abdomen and neck. For hepatic fat, a multi-echo Dixon sequence with blocks of contiguous slices and breath holds on expiration will be used to image the abdomen. A single transverse slice that intersects the porta-hepatis will be positioned and a multi-echo gradient-echo image will be acquired to determine a liver fat fraction. For the assessment of pancreatic fat, circular regions of interest (~100 mm2) will be drawn in the head, body and tail of the pancreas of two representative slices, with fat fraction calculated as the average across both slices.
Exploratory outcomes
All participants will be offered the opportunity to take part in several optional study visits with a view to 20 participants completing each treatment ARM. Uptake to these optional visits will be determined by eligibility, specifically contraindications to MR scanning and patient choice.
Monitoring/dispensing visits (1, 4, 5, 6, 7, 8, 9, 10)
These visits will involve a brief consultation with the study team to review glycaemic control (self-monitored capillary blood glucose), adverse effects and compliance (tablet count), and to collect supply of medication. All injections of exenatide QW/placebo will be administered weekly by unblinded staff members at site and recorded. Unblinded members of the research team will have no role in assessment of participants outside of these specified roles as detailed in the trial delegation log.
Pharmacovigilance
All adverse events will be reported and assignment of the severity/grading (mild, moderate, severe, life-threatening, death) made by the investigator responsible for the care of the participant. The assignment of causality will be made by the investigator. All non-serious adverse events (SAEs), whether expected or not, will be recorded and updated at each study visit. All new SAEs will be reported from the point of consent until 28 days after discontinuation of the investigational medical product; this includes those thought to be associated with protocol-specified procedures. Investigators will report SAEs, serious adverse reactions (SARs) and sudden unexpected adverse reactions (SUSARs) to LCTC within 24 hours of the local site becoming aware of the event. LCTC will notify the Medicines and Healthcare products Regulatory Agency (MHRA) and main Research Ethics Committee (REC) of all SUSARs occurring during the study: fatal and life-threatening SUSARs within 7 days of notification and non-life-threatening SUSARs within 15 days. All adverse events will be followed until satisfactory resolution or until the investigator responsible for the care of the participant deems the event to be chronic or the patient to be stable.
Trial monitoring and oversight committees at LCTC
The RESILIENT study will have a Trial Management Group (TMG), Trial Steering Committee (TSC) and an Independent Safety and Data Monitoring Committee (ISDMC) to monitor study progress.
The TMG, supported by the LCTC, will be responsible for the day-to-day running and management of the trial and will consist of the protocol committee members and the trial manager. The TSC will provide oversight of the study, concentrating on progress of the study, adherence to protocol, participant’s safety and consideration of new information, making recommendations on study pathway modifications and continuation of the study. The TSC will include experienced lay members of the public, other medical experts and clinical trialists. Meetings will be held at regular intervals determined by need, but no less than once a year. The ultimate decision for the continuation of the trial lies with the TSC.
The ISDMC will be responsible for reviewing and assessing recruitment, interim monitoring of safety and effectiveness, trial conduct and external data. The ISDMC will also provide recommendations to the TSC concerning continuation of the study.
Outline of analysis
General approach
Categorical variables will be summarised as frequency (%), and continuous variables will be summarised as mean (SD) or median (IQR) depending on the distribution. Full details of the planned statistical analysis will be included in a separate statistical analysis plan to be developed in the months following trial opening and will be approved by both the ISDMC and the TSC.
Subgroup analysis
No subgroup analysis is planned for this trial.
Significance levels
For the analysis of the primary outcome, statistical significance will be tested using Hochberg’s procedure, a hierarchical analysis approach for the primary outcomes of (1) exenatide QW and dapagliflozin compared with placebo control, (2) dapagliflozin alone compared with placebo control. Here comparisons will be ordered (descending) in terms of their significance level and assessed using a p value <0.05 to determine statistical significance for the first comparison and p<0.025 for the second.
The main analysis for primary and secondary endpoints will use the full analysis set, consisting of all randomised patients, with participants analysed according to the group to which they were originally allocated, and with outcomes included irrespective of protocol adherence, in order to follow the intention-to-treat principle. The safety population, consisting of all patients who actually receive a trial intervention, according to the treatment received, will be used for analysis of toxicity and adverse events.
Missing data
Missing data are assumed to be small and analysis will be carried out on a complete case basis. If there are a significant number of missing entries on any endpoint (>20% for example), missing data shall be estimated using multiple imputation based on the method of chained equations.
Analysis
For analysis of the primary endpoint, the mean difference from baseline and week 32 will be presented with a corresponding 95% CI. Between-group differences will be analysed using linear regression techniques, analysing the week 32 values while including baseline covariate value. The effect of dapagliflozin will be estimated by contrasting (1) control arm versus dapagliflozin arm. The effect of exenatide will be estimated by comparing (2) dapagliflozin versus dapaglifozin and exenatide.
Secondary analyses
Analyses of all secondary endpoints are continuous and analysis techniques shall replicate that of primary endpoints.
Safety analysis
Information relating to adverse events (including events relating to hypoglycaemia, gastrointestinal upset, and urinary and genital tract infections) will be tabulated and summarised descriptively. Continuous laboratory values will be summarised as described above.
Ethics and dissemination
This study is being conducted in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in compliance with the European Union Directive 2001/20/EC transposed into UK law as statutory instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations 2004 and all subsequent amendments and the US Code of Federal Regulations, Title 21, Part 50 (21CFR50). The trial protocol has received the favourable opinion of the NRES North West/Liverpool Central Research Ethics Committee (14/NW/1147; protocol number UoL 001187). An appropriate patient information sheet and consent forms describing in detail the trial interventions/products, trial procedures and risks were approved by the ethical committee (IEC), and the patients are asked to read and review the document. The investigator explains the study to the patient and answer any questions posed. A contact point where further information about the trial may be obtained is provided. After being given adequate time to consider the information, the patient is asked to sign the informed consent document. A copy of the informed consent document is given to the patient for their records and a copy placed in the medical records, with the original retained in the investigator site file. The patient may withdraw from the trial at any time by revoking the informed consent. The rights and welfare of the patients are protected by emphasising to them that the quality of medical care will not be adversely affected if they decline to participate in this study.
Regulatory approval
This trial has been registered with the MHRA and has been granted a Clinical Trial Authorisation (CTA). The CTA reference is its EudraCT number: 2013-004264-60.
Publication
The results will be analysed together and published as soon as possible. The uniform requirements for manuscripts submitted to biomedical journals (http:// www.icmje.org/↗) will be respected. The ISRCTN allocated to this trial would be attached to any publications resulting from this trial.
Trial status
The trial opened for recruitment at University Hospital Aintree in Liverpool on 25 October 2017. Recruitment is ongoing at the time of publication with the anticipated trial completion (last patient last visit) in October 2021.
Supplementary Material
Acknowledgments
We would like to thank Manoj Mistry for his support with the design of patient information sheets and for his feedback on the study design.
Footnotes
Ethics statements
Patient consent for publication
Not required.