Open Access Protocol Microvascular Outcomes after ...Microvascular Outcomes after Metabolic Surgery (MOMS) is a randomised, two-arm (with allocation ratio 1:1), controlled, single-centre

Microvascular Outcomes afterMetabolic Surgery (MOMS) in patientswith type 2 diabetes mellitus and class Iobesity: rationale and design for arandomised controlled trial

Ricardo Vitor Cohen,1 Tiago Veiga Pereira,2 Cristina Mamédio Aboud,3

Pedro Paulo de Paris Caravatto,1 Tarissa Beatrice Zanata Petry,1

José Luis Lopes Correa,1 Carlos Aurélio Schiavon,4 Mariangela Correa,3

Carlos Eduardo Pompílio,1 Fernando Nogueira Quirino Pechy,1 Carel le Roux,5

on behalf of MOMS Study Investigators

To cite: Cohen RV,Pereira TV, Aboud CM, et al.Microvascular Outcomes afterMetabolic Surgery (MOMS)in patients with type 2diabetes mellitus and class Iobesity: rationale and designfor a randomised controlledtrial. BMJ Open 2017;7:e013574. doi:10.1136/bmjopen-2016-013574

▸ Prepublication history forthis paper is available online.To view these files pleasevisit the journal online(http://dx.doi.org/10.1136/bmjopen-2016-013574).

Received 21 July 2016Revised 22 September 2016Accepted 15 November 2016

For numbered affiliations seeend of article.

Correspondence toDr Ricardo Vitor Cohen;[email protected]

ABSTRACTIntroduction: There are several randomised controlledtrials (RCTs) that have already shown that metabolic/bariatric surgery achieves short-term and long-termglycaemic control while there are no level 1A ofevidence data regarding the effects of surgery on themicrovascular complications of type 2 diabetes mellitus(T2DM).Purpose: The aim of this trial is to investigate thelong-term efficacy and safety of the Roux-en-Y gastricbypass (RYGB) plus the best medical treatment (BMT)versus the BMT alone to improve microvascularoutcomes in patients with T2DM with a body massindex (BMI) of 30–34.9 kg/m2.Methods and analysis: This study design includes aunicentric randomised unblinded controlled trial. 100patients (BMI from 30 to 34.9 kg/m2) will be randomlyallocated to receive either RYGB plus BMT or BMTalone. The primary outcome is the change in the urinealbumin-to-creatinine ratio (uACR) captured as theproportion of patients who achieved nephropathyremission (uACR<30 mg/g of albumin/mg of creatinine)in an isolated urine sample over 12, 24 and60 months.Ethics and dissemination: The study was approvedby the local Institutional Review Board. This studyrepresents the first RCT comparing RYGB plus BMTversus BMT alone for patients with T2DM with a BMIbelow 35 kg/m2.Trial registration number: NCT01821508;Pre-results.

INTRODUCTIONType 2 diabetes mellitus (T2DM) is one ofthe leading causes of morbidity and mortalityworldwide. Six randomised controlled trials(RCTs) have shown that short-term and

long-term glycaemic control after metabolicsurgery is superior to the best medical carewithout surgery.1–7 Metabolic surgery add-itionally improves dyslipidaemia, inflamma-tion and blood pressure.8–10 Mortality wasalso reduced after surgery, especially in thosepatients with T2DM,11–15 although baselinebody mass index (BMI) did not predictbenefit; rather, non-anthropometric para-meters such as fasting insulin did predict car-diovascular events and mortality.16–21

The risk of developing microvascular com-plications depends on both the duration andseverity of hyperglycaemia and the othercomponents of metabolic syndrome,22 andfor any treatment modality to be successful,

Strengths and limitations of this study

▪ This is a randomised controlled trial designed tocompare the effects of Roux-en-Y gastric bypass(RYGB) plus best medical treatment (BMT) andBMT alone on patients with type 2 diabetes mel-litus (T2DM) with microvascular complicationsand with body mass index (BMI) from 30 to35 kg/m2, the most prevalent BMI range ofT2DM.

▪ The long-term follow-up will allow to assess thedurability of the metabolic effect after RYGB, anissue never tested in this BMI population.

▪ The study was designed to be performed usingoptimised methodological resources in order toprevent systematic bias.

▪ The study cannot be blinded as one of the inter-ventions is RYGB.

▪ The level of physical activity was not measuredin a systematic manner in study participants.

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more than glycaemia needs to be addressed.23 24 Thesubgroup of patients with diabetes and chronic kidneydisease (CKD), regardless of their BMI, as manifested byalbuminuria, impaired glomerular filtration rate or bothhave the highest mortality, while it also is the leadingcause for renal replacement therapy.25 26 Those withoutCKD have a much lower risk of morbidity and mortality.In spite of the importance to avoid or treat microvascu-lar T2DM complications, the vast majority of metabolicsurgery studies have focused on glycaemic control, whileinsufficient attention has been directed to complicationsof T2DM.27–30

The main legacy of this study is to provide data sup-porting that metabolic surgery associated with the bestmedical treatment (BMT) might be superior to theBMT alone to treat microvascular complications in theBMI range where T2DM is more prevalent.

ObjectivesThe aim of this trial is to investigate the long-term effi-cacy and safety of the Roux-en-Y gastric bypass (RYGB)plus the BMT versus the BMT alone to improve micro-vascular outcomes in patients with T2DM with a BMI of30–34.9 kg/m2.

Trial designMicrovascular Outcomes after Metabolic Surgery(MOMS) is a randomised, two-arm (with allocation ratio1:1), controlled, single-centre phase III clinical trial(figure 1). The primary end point is the change in theurine albumin:creatinine ratio (uACR) captured as the

proportion of patients who achieved nephropathy remis-sion (uACR<30 mg/g of albumin/mg of creatinine) inan isolated urine sample (morning) over 12, 24 and60 months. Patient recruitment occurred from April2013 to March 2016. All surgical procedures were com-pleted by April 2016. The trial was prospectively regis-tered in ClinicalTrials.gov (NCT01821508). Intermediate(preliminary) analyses will also be performed at prespe-cified follow-up periods of 12 and 24 months. The lastpatient final visit is scheduled for April 2021(60 months’ follow-up).The study centre developed some strategies to guaran-

tee the quality and completeness of data and procedures(use of checklists and workflow). An independent pro-fessional will enter study acquired information on a web-based data entry system (Medscale). This method wasparameterised to generate automatic queries and tomaximise the collection of consistent and valid data. Amonitor (dedicated and designed specifically for thisprotocol) will audit the overall quality and completenessof the data entered on the electronic case report form(eCRF), examine source documents, compliance of allstudy team with Good Clinical Practice, the integrity ofthe regulatory binder and communication with theInstitutional Review Board (IRB).

METHODSStudy settingThe study is conducted in a diabetes and obesity carecentre affiliated with a 400-bed private tertiary care hos-pital in São Paulo, Brazil.

Figure 1 Simplified MOMS

algorithm. BMT, best medical

treatment; HbA1c, glycated

haemoglobin; MOMS,

Microvascular Outcomes after

Metabolic Surgery; RYGB,

Roux-en-Y gastric bypass.

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Eligibility criteriaInclusion criteriaPatients with diabetic kidney disease as defined by albu-minuria and an estimated glomerular filtration rate>30 mL/min treated within a specialist diabetes servicehad to comply with all of the following criteria atrandomisation:1. Age: 18–65 years;2. BMI: 30–34.9 kg/m2;3. <15 years of history of T2DM;4. Negative glutamic acid decarboxylase autoantibodies

test;5. Fasting C peptide over 1 ng/mL;6. Appropriate postprandial C peptide response after a

500 kcal mixed meal challenge.

Exclusion criteria1. Autoimmune diabetes or type 1 diabetes;2. Previous abdominal operations that would compli-

cate an RYGB;3. Pregnancy or women of childbearing age without

an effective contraceptive;4. Alcoholism or illicit drug use;5. Severe hepatic disease that may complicate RYGB;6. Inflammatory bowel disease or malabsorptive

syndrome;7. Major cardiovascular event in the past 6 months;8. Current angina;9. Severe psychiatric disorders that would complicate

follow-up after RYGB;10. Use of immunosuppressive drugs, chemotherapy

and/or radiotherapy;11. Uncontrolled coagulopathy;12. Advanced proliferative retinopathy with or without

amaurosis;13. CKD stage 4 or 5 waiting for renal replacement

therapy;14. Stage 3 peripheral neuropathy;15. Pulmonary embolism in the past 2 years.

InterventionsAfter randomisation, patients were allocated in a 1:1ratio to RYGB plus BMT or BMT only (figure 2).

Best medical treatment‘BMT’ is defined as the use of current best clinical treat-ment available (table 1). T2DM medication titration wasand will be performed by the investigators and will bebased on home-checked glycaemia and blood test resultsordered during follow-up visits.

RYGB plus BMTPatients allocated to RYGB will receive a similar BMTcompared with the control group. All operations werecompleted by a single experienced surgeon and the lastprocedure was performed in early April 2016. On theday before the procedure, patients received a liquid diet,continued their medication, except if otherwise

suggested by the attending investigator. Patients wereadmitted to the hospital 12 hours before the operationand started fasting 8–10 hours before surgery. Afteradmission, patients underwent a preanaesthetic visit.Laparoscopic RYGB was performed under general

anaesthesia and consisted of the creation of the gastricpouch (20–30 mL), a biliary limb of 80 cm and alimen-tary limb of 150 cm, with a side-to-side jejunojejunost-omy and a linear stapler gastrojejunostomy (figure 3).Concomitant cholecystectomy was performed in patientswith preoperative cholelithiasis. Deep vein thrombosisprophylaxis included compression stockings and inter-mittent pneumatic compressors. Cefazolin 2 g was admi-nistered during anaesthesia induction and 8 hours afterthe end of the operation. The surgical arm received andwill keep receiving during follow-up the same amount ofnutritional counselling and included information onfood consistency and progression to solids. All medica-tions are managed by the endocrinology team. First,insulin will be titrated and may be withdrawn, followedby liraglutide, linagliptin and empagliflozin. Metforminwill be maintained throughout the trial. The parametersof full medication withdrawal in the RYGB+BMT arefasting glucose below 100 mg/dL and glycated haemo-globin (HbA1c) <6.0%. ACE inhibitor and angiotensinII receptor blockers are continued in all groups, even inpatients with negative albuminuria. Simvastatin is alsoprescribed and maintained.

Drug titrationDrugs with a beneficial effect on microvascular andmacrovascular will be continued even if uACRs normal-ise. Antidiabetic medications, including insulin, mayhave their dose reduced to avoid hypoglycaemia.Metformin will be continued in all cases, but the dosesmay be reduced if HbA1c was below 5.7% and fastingplasma glucose (FPG) below 100 mg/dL. On the basisof our previous experience in metabolic surgery inpatients with T2DM who have BMI<35 kg/m2 (30) after8–10 years of follow-up, we can associate less T2DMrecurrence when metformin is not discontinued(unpublished data). The insulin sensitiser drug mayhave its dose decreased when HbA1c is lower than 5.7%and even discontinued if hypoglycaemia is detected.

Concomitant care: nutritional evaluation and physicalactivityAs part of a multidisciplinary team approach, all patientswill be advised by a dietitian to reduce food intake andto increase physical activity. Patients also completed24 hours daily dietary intake.

Concomitant care: management of other comorbiditiesAll other conditions such as hypertension and hyperlip-idaemia are evaluated and treated according to standardrecommendations and guidelines. Compliance is alsoregistered during follow-up visits.

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OutcomesPrimary outcomeThe main outcome is the change in the uACR(intention-to-treat (ITT) analysis) captured as the pro-portion of patients who achieved nephropathy remission(uACR<30 mg/g of albumin/mg of creatinine) in anisolated urine sample (morning) over 12, 24 and60 months.

Secondary outcomesThe secondary outcomes are changes in diabetic retin-opathy, changes in diabetic neuropathy, use of antidia-betic medication, glycaemic control (defined asFPG<100 mg/dL and HbA1c <6.0% with or withoutmedication), blood pressure control (defined as systolicblood pressure <130 mm Hg and diastolic <80 mm Hg),lipid control (defined as low-density lipoprotein <100and <70 mg/dL in patients with previous cardiovascular

events; high-density lipoprotein >50 mg/dL and trigly-cerides <150 mg/dL, hepatic fibrosis assessed throughintraoperative liver biopsy and control evaluated by post-operative liver elastography, fatal and non-fatal cardiovas-cular events, quality of life (36-item Short Form HealthSurvey, SF-36) and diabetic urinary bladder dysfunction(assessed through a questionnaire).

Participant timelineScreening visitThe screening visit was performed by one of the medicalinvestigators with the help of a research nurse.Information about the study design, procedures,follow-up visits and all risks involved in both arms of thetrial was explained. Then a checklist containing theinclusion and exclusion criteria was completed. Allpatients provided written informed consent previously toall study procedures. Those patients not using optimal

Figure 2 CONSORT 2010 standard RCT flow diagram for MOMS trial. BMT, best medical treatment; CONSORT, Consolidated

Standards of Reporting Trials; GAD, glutamic acid decarboxylase; RYGB, Roux-en-Y gastric bypass.

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drugs for glycaemic control, blood pressure or dyslipi-daemia were started on the appropriate medication. Alleligible patients had coloured retinography, angiofluor-esceinography and eye refraction examinations. Baselineblood and imaging tests (echocardiogram, X-ray, abdom-inal ultrasound and ECG) were ordered.

Randomisation visitA comprehensive clinical evaluation was undertaken toconfirm eligibility 4–6 weeks after screening. After eligi-bility confirmation, patients received an identificationnumber that was used in all documentation. During thisvisit, an assessment to evaluate neuropathy was per-formed through vibratory and pinprick sensation tests.Patients randomised to the RYGB+BMT arm were

further assessed with upper digestive endoscopy andelastography ultrasound. Two weeks after the randomisa-tion visit, all the tests were reviewed to ensure that allpatients were eligible to proceed. Both groups were seenby a dietitian who also took anthropometric

measurements. The dietitian reinforced the benefits ofintense lifestyle modifications.

Follow-upPatients in the RYGB+BMT arm were seen after 1 and4 weeks from the index procedure by the medical inves-tigators and the dietitian. All adverse events (AEs) werecaptured. Changes were made to diet, physical activityand medications as appropriate to optimise T2DMcontrol. After the first month, patients from both armshad and will have their follow-up consultations at thesame intervals. A physical examination will be per-formed on all visits and samples will be collected untilthe end of the study (table 2).

Sample sizeThe study was designed to show a difference in the pro-portion of participants achieving a healthy uACR (remis-sion) at the time point of 60 months (primary end pointdefined a binary outcome). The proportion of patientsexpected to achieve remission was sourced from previ-ous publications,30 31 empirical data from a surgeon(RVC) with extensive experience in bariatric surgery aswell as a consensus and expert opinion of a panel ofseven specialists in obesity/diabetes (RC, ClR, PPdPC,TBZP, JLLC, CAS, FNQP).Remission was estimated to occur in 50% of partici-

pants in the RYGB+BMT arm and 10% of participants inthe BMT-only arm. To accommodate two prespecified(preliminary) analyses at follow-up times of 12 and24 months, the significance level was set at the 1.7% αlevel for the primary outcome (Bonferroni adjustment).Thus, to detect the expected difference in the propor-tion of participants achieving remission and anticipatinga potential 5-year 20% loss of follow-up rate, a samplesize of 100 patients (50 participants in each group) willgive a ≥90% statistical power at an α level of 1.7%.

Recruitment strategyAdvertisementsRecruitment started in April 2013. Initially, candidateswere referred from several private and public healthcareproviders from the city of Sao Paulo, Brazil. Then apress release with an overview of the trial, goals and eli-gibility criteria was published in a major Brazilian

Table 1 List of medications prescribed in both groups

T2DM medication ARBs/ACE inhibitors Statins Others

Metformin 2 g/day Losartan 25 mg Simvastatin 20 mg Thioctic acid 600 mg

Pioglitazone 30 mg Enalapril 5 mg Antihypertensive agents

Linagliptine 5 mg Na+ proton pump inhibitors

Liraglutide 1.8 mg od

Glargine insulin

Glulisine insulin

Empaglifozin 10 mg

ARB, angiotensin II receptor blocker; od, once daily; T2DM, type 2 diabetes mellitus.

Figure 3 Laparoscopic RYGB. RYGB, Roux-en-Y gastric

bypass.

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Table 2 Schedule of visits, examinations and procedures

Year 1 Year 2 Year 3 Year 4 Year 5

Assessments Screen Random Surgery*

First until third

PO

W

1

W

4

M

3

M

6

M

9

M

12

M

15

M

18

M

21

M

24

M

28

M

32

M

36

M

40

M

44

M

48

M

52

M

56

M

60

Informed consent X

Medical history X

Physical examination X X X X X X X X X X X X X X

Medical assessment X X X X X* X X X X X X X X X X X X X X X X X X

Concomitant medication X X X X X X X X X X X X X X X X X X X X X X

Inclusion/exclusion criteria X X

Randomisation X

Adverse events X X X X X X X X X X X X X X X X X X X X X X

Nerve conduction studies X X X X X X X X X X X X X X

Nutritional assessment X X X X X X X X X X X X X X X X X

SF-36, IPSS and OAB-Qsf X X X X X X

Urinary diary X X X X X X X X

Serum pregnancy test X

CBC X X X X X X X

AST/ALT X X X X X X

Amylase X X† X† X X X

Sodium and potassium X

Urea and creatinine X X X X X X X X X X X X X X X

PT and aPPT X

Lipids X X X X X X X X X X X

Fasting plasma glucose X X* X X X X X X X X X X X X X X

HbA1c X X X X X X X X X X X X X X X X X X

Microalbumin and

creatinine

X X X X X X X X X X X

Iron and ferritin X X X X X X X

Calcium, PTH and vitamin

D

X X X X X X X X

Folic acid X X X X X X

Vitamin A, B1 and B12 X X X X X X X

Anti-GAD X

PSA X

PCR X X* X* X* X* X* X* X* X* X* X* X*

HIV test X

MMTT X X X X X X X X X X X

Urine sample (DNA) X X X X X X X

Urinalysis X X X X* X X

Chest X-ray X

Abdominal ultrasound X

ECG X

Echocardiogram X X

Continued

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newspaper and disseminated through major online newswebsites. Finally, several posts were published in socialmedia applications.After reaching a dedicated trial ‘hotsite’, the candi-

dates completed an online form with general informa-tion on their BMI, time of diagnosis of T2DM andhistory of microvascular complications. The informationwas sent to a dedicated hospital’s email address. Eligiblecandidates were invited to a screening visit at theOswaldo Cruz German Hospital Health Research Unitwhere written informed consent was obtained.

Assignment of interventionsSequence generationRandomisation was carried out by an independent inves-tigator not involved in patient enrolment, treatment orfollow-up (central randomisation). Computer-generatedrandom numbers (Stata V.14.0, StataCorp, CollegeStation, Texas, USA) were used to assign randomly, in a1:1 ratio, patients either to RYGB+BMT or BMT onlyusing a permuted stratified block randomisation proced-ure with random block sizes of 2, 4 and6. Randomisation was stratified by gender and blocksizes were kept confidential to avoid prediction of futurepatients’ allocation.

Concealment mechanismRandomisation codes were released only after patientshad been formally recruited into the trial. The random-isation sequence was prepared in advance by the studybiostatistician and was concealed from all research inves-tigators at all times. Participants, staff members andresearchers could not foresee assignment because ofcentral allocation. All patients who gave consent for par-ticipation were pseudoanonymised (personal informa-tion was removed and replaced with a coded identifier),and this list was supplied to the central allocation, whichrandomly allocated patients into the BMT+RYGB arm orBMT-only arm.

BlindingBlinding was not possible because of the nature of theintervention. However, investigators in charge of the stat-istical analysis and laboratory personnel will be blindedto the allocation status of each participant in the trial.

Data managementSeveral procedures are performed to assure data quality,including missing data, permitted/non-permitted valueranges and logic checks. To get high-quality data andkeep the number of errors and missing data as little aspossible, several checklists and standard operational pro-cedures were created and adopted to ensure that datawere complete and reliable. The training and consist-ency of process were straightforward since this is asingle-centre study. The study team was trained beforethe beginning of the study and received an individualdelegation from the principal investigator, according to

Table

2Co

ntinued

Year1

Year2

Year3

Year4

Year5

Assessments

Screen

Random

Surgery*

Firstuntilthird

PO

W 1

W 4

M 3

M 6

M 9

M 12

M 15

M 18

M 21

M 24

M 28

M 32

M 36

M 40

M 44

M 48

M 52

M 56

M 60

Upperdigestiveendoscopy

X

Elastrographyultrasound

XX

XX

XX

Detailedeyeexamination

XX

XX

X

Vitalsigns

XX

XX

X*

XX

XX

XX

XX

XX

XX

XX

XX

XX

Weight

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

X

Height

X

Dispensingdrugs

XX

XX*

XX

XX

XX

XX

XX

XX

XX

XX

X

RYGB

X

Glucosemonitoring

X*

XX

XX

XX

XX

XX

XX

XX

XX

XX

*Procedure

exclusiveforsurgicalarm

.†Procedure

exclusiveforclinicalarm

.ALT,serum

glutamic-pyruvic

transaminase;aPPT,activatedpartialthromboplastintime;CBC,complete

bloodcount;GAD,glutamic

acid

decarboxylase;HbA1c,glycatedhaemoglobin;IPSS,

nternationalProstate

Symptom

Score;MMTT,MixedMealToleranceTest;OAB-Q

sf,OveractiveBladderQuestionnaireShortForm

;PO,orally;PT,prothrombin

time;PSA,prostate-specific

antigen;PTH,parathyroid

horm

one;RYGB,Roux-en-Y

gastric

bypass;SF-36,36-item

ShortForm

HealthSurvey.

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his professional expertise. Each participant received anumerical code to ensure his confidentiality and track-ing. Source documents (paper) and original study formshave been kept at the site (in a secure and accessibleplace). Storage follows the numerical code while theaccess is limited to the study team.A case report form was designed, and an eCRF was

created (Medscale). The site study team is responsiblefor eCRF entry data. Each study staff member receivedtraining and a login/password to access eCRF, and thetype of activity that may be undertaken is regulated bythe privileges associated with each login. The MedscaleeCRF system was parametrised to perform data valida-tion and discrepancy management.A dedicated monitor (dedicated and designed specif-

ically for this protocol) is responsible for source dataverification and the creation of queries and/or dataclarification forms for all participants’ source docu-ments. Quality assurance and control will be assured bythis dedicated monitor, and a statistician will be respon-sible for final data validation and database analysisthroughout the duration of the study.

RetentionWe anticipated a 15–20% 5-year loss to follow-up rateand planned our sample size accordingly. However, afterrandomisation, trial coordinators will make every doableeffort to follow participants for the entire trial period.Strategies involving actual contact (phone calls, emailsand standard mail) will be developed and implementedto achieve the highest possible level of follow-up.

Participant withdrawalsIndividuals who decide to withdraw from the trial will beasked to provide continued monitoring and further datacollection after their withdrawal. Participants who werelost to follow-up despite several attempts to reach themwill have their data imputed.

Statistical methodsAll analyses will be based on the ITT principle. An over-view of methods of analysis is presented in table 3. Wewill compare the proportion of participants achievingthe primary outcome between RYGB+BMT versus BMTgroups using an unconditional logistic regression model.We will also investigate both the occurrence and timingof albumin:creatinine ratio normalisation throughoutthe 5-year follow-up period by using a Cox proportionalhazards model. The proportional hazards assumptionwill be confirmed by testing the interaction with log(time) as well as graphically via plots of Schoenfeld resi-duals. Both in the logistic and Cox proportional hazardmodels, we will include as covariates baseline albumin:creatinine ratio, BMI, age, diabetes medication use,glucose and HbA1c levels as well as the duration ofT2DM. Continuous outcomes will be analysed bymixed-effects generalised linear models adjusting for thebaseline version of the response variable. Missing data

will be handled using multiple imputation methodsassuming that data are missing at random. Demographicand clinical characteristics of participants will be com-pared between groups (RYGB+BMT vs BMT) using theunpaired Student’s t-test for continuous variables,whereas dichotomous variables will be tested usingFisher’s exact test and its generalisations for 2xk tables(when necessary). Data will be expressed as mean±SD,median (IQR) or counts (percentage) when appropri-ate. Whenever feasible, variables with asymmetric distri-butions will be transformed using standardmathematical functions (eg, logarithm, square root,etc). Statistical significance will be set at the 1.7% level(two-sided) for the primary outcome and 5% for second-ary outcomes. Main conclusions will be based on theITT principle and on the logistic regression model. Alldata analyses will be performed using the Stata package(V.13.0, Stata Corp, College Station, Texas, USA).

Additional analysesPrimary analyses will be carried out on an ITT basis, butsubsequent studies may be conducted on a per protocolbasis. Primary analyses will also be performed with mul-tiple imputation methods. However, we will also provideresults from analyses restricted to complete cases, forcomparison with results from the multiple imputationprocesses.

Adjusted analysisAll statistical models will be run with appropriate adjust-ment for baseline characteristics.

Analysis population and missing dataIn the case of missing data, we will perform and reportthe multiple imputation analysis according to the recom-mendations of White et al.32 Missing data will behandled using multiple imputation methods assumingthat data are missing at random. Specifically, we will usea combination of predictive mean matching andregression-based methods to impute missing data. Atotal of 100 data sets will be created to reduce samplingvariability. A burn-in period of 500 iterations will beused. Imputation will be performed in Stata V.14.0(StataCorp, College Station, Texas, USA).

MonitoringAdverse eventsAEs were defined as any untoward medical event or clin-ical investigation that a patient underwent even if it didnot have a causal relation to the medical or surgicalinterventions. AEs were also defined as any unfavourableand unintended clinical manifestation or disease tem-porally associated with the surgical or medical treatment.Serious AEs (SAEs) are AEs that pose risk to life, resultin hospital admission, increase hospital stays or may bedebilitating or disabling. AEs and SAEs must be reportedwithin 24 hours through detailed documentation andforwarded to the IRB. Follow-up of AEs/SAEs should be

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Table 3 Variable, measures and methods of analysis

Variable/outcome Hypothesis Outcome measure Methods of analysis

Primary outcome

Remission (uACR<30 µg

of albumin/mg of creatinine)

The proportion of remission is higher at 12,

24 and 60 months in the RYGB+BMT arm

compared with the BMT-only arm.

Number of participants achieving remission Logistic regression (primary

analysis) and Cox proportional

hazards model (exploratory analysis)

Secondary outcome

Glycaemic control Reduction is higher in the RYGB+BMT arm

compared with the BMT-only arm.

Fast glucose in mg/dL Mixed-effects generalised linear

models

HbA1c Reduction is higher in the RYGB+BMT arm

compared to the BMT-only arm.

HbA1c levels (in %) Mixed-effects generalised linear

models

Blood pressure control The proportion of patients with blood

pressure control is higher in the RYGB

+BMT arm compared with the BMT-only

arm.

Number of participants achieving systolic blood

pressure <130 mm Hg and diastolic <80 mm Hg

Mixed-effects generalised linear

models

Lipid control The proportion of patients with lipid control

is higher in the RYGB+BMT arm compared

with the BMT-only arm.

Number of participants with LDL<100 or <70 mg/dL

in patients with previous cardiovascular events;

HDL>50 mg/dL and triglycerides <150 mg/dL

Logistic regression

Retinopathy Resolution of retinopathy Number of patients achieving resolution or

reduction in the degree of retinopathy and/or

macular oedema (severity scale)

Logistic regression

Neuropathy New development or worsening of

neuropathy

Number of patients with new or worsening of

neuropathy

Logistic regression

Medical treatment Reduction of medication for T2DM Number of medications necessary for targeting

euglycaemia

Linear regression

Hepatic fibrosis Improvement of fibrosis Reduction of hepatic elastographic resistance Logistic regression

Voiding dysfunction Improvement of voiding dysfunction Reduction in the degree of voiding dysfunction

symptoms

Logistic regression

Quality of life (SF-36) Quality of life is higher in the RYGB+BMT

arm compared with the BMT-only arm.

Quality of life questionnaire Mixed-effects generalised linear

models

Clinical and sociodemographic variables

Age There is no difference between the RYGB

+BMT arm compared with the BMT-only

arm at baseline.

Years Student’s t-testBMI kg/m2 Student’s t-testWeight kg Student’s t-testGender 1=male, 0=female Fisher’s exact test

Waist circumference cm Student’s t-testUrinary albumin g/dL Student’s t-testCreatinine mg/dL Student’s t-testFasting blood glucose mg/dL Student’s t-testTotal, HDL and LDL cholesterol mg/dL Student’s t-testTriglycerides mg/dL Student’s t-testDiastolic and systolic blood

pressure

mm Hg Student’s t-test

BMT, best medical treatment; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; RYGB, Roux-en-Y gastric bypass; SF-36, 36-item Short Form HealthSurvey; T2DM, type 2 diabetes mellitus; uACR, urine albumin-to-creatinine ratio.

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continued until resolution or stabilisation of thepatients.

AuditingAuditing will be carried out throughout the duration ofthe study by a dedicated monitor. It will include key indi-cators and will be carried out in all source documents/participants. These key indicators are informed consentform (ICF) and process, eligibility criteria, enrolment,allocation of study groups, scheduled and missed testsand procedures, policies to protect participants, con-comitant and prohibited medications, dispensing medi-cation procedures, identification and reporting of AEsand SAEs, deviation report, regulatory documents andcommunication with local IRB, following InternationalConference on Harmonisation-Good Clinical Practice(ICH-GCP) and regulatory agency guidelines.

Ethics and disseminationResearch ethics approvalProtocol, ICF and recruitment materials were reviewedand approved by our local IRB. The initial approval wasreceived on 25 February 2013 and since then they havebeen notified of the progress of the study on a regularbasis.

Protocol amendmentsAll changes needed after the initial IRB approval will besubmitted to the IRB for approval. Amendment to theclinical protocol ought to be implemented after aformal IRB approval and an updated informed consentsigned by the patients and the investigators.Protocols amendments/ICF changes were submitted

to the IRB and approved before implementation. Thehistory of changes is available and can be tracked byversion and date changes.

ConsentPatients identified as possible participants receivedgeneral information about the study from an investigator(medical doctor). Then they received the ICF and weregiven an opportunity to read and discuss with their rela-tives/friends. Then a formal discussion was performedbetween the investigator and the patient. During thisprocess, the patient had the opportunity to ask questionsand clarify all doubts. At the end, the patient whoexpressed willingness to make part of the study signedthe ICF (as well as the investigator) and then became astudy participant. Assent form and ancillary studiesconsent were not necessary for this study.

ConfidentialityAll medical information derived from the study is confi-dential, and no third party disclosure was allowed.Source data/information will be handled by the desig-nated personnel, and the information will be stored inpassword-protected computers and in coded patientnotes to protect confidentiality.

Declaration of interestsThe lead author (RVC) has received an honorarium as amember of the Speaker’s panel of Johnson & Johnson.

Study sponsorship and access to dataData will be available for authorised investigators only.Third parties may have access to data with expresswritten permission from the lead investigator (RVC).However, sponsors will not participate in data analysisnor will have access to data (either in full or in part).

Ancillary and post-trial careThe Oswaldo Cruz German Hospital has an insurancepolicy (specific for the MOMS protocol) to cover non-negligent harm associated with the protocol, whichcovers additional healthcare, compensation or damageswhether awarded voluntarily by the MOMS study or byclaims pursued through the courts.

Dissemination policyAfter the publication of the trial protocol, the investiga-tors plan to publish all the listed end points, as this RCTis the first trial on BMT combined with metabolicsurgery versus the best medical care without surgery forpatients with T2DM with a BMI below 35 kg/m2. Theresults of this trial will be published in peer-reviewed sci-entific journals and presented at major conferences,regardless of the magnitude or direction of the observedeffect.

Trial organisation and managementThe study investigators were responsible for completingall pertinent information using the clinical report forms,the accuracy of data and maintaining the confidentialityof patients’ data. Only the investigators had access to thefinal data set. All documentation will be kept readilyavailable for 5 years after the study termination in case ithad to be monitored, audited or inspected by thesponsor or regulatory authorities.

Author affiliations1The Center for Obesity and Diabetes, Oswaldo Cruz German Hospital, SãoPaulo, Brazil2Health Technology Assessment Unit, Oswaldo Cruz German Hospital, SãoPaulo, Brazil3Health Research Unit, Oswaldo Cruz German Hospital, São Paulo, Brazil4Research Institute Hcor, Heart Hospital, São Paulo, Brazil5Diabetes Complication Research Centre, UCD Conway Institute, School ofMedicine and Medical Science, University College Dublin, Dublin, Ireland

Acknowledgements The authors would like to thank the staff of the HealthResearch Unit, Oswaldo Cruz German Hospital for the full assistance for theMOMS trial.

Contributors RVC, TVP, CMA, ClR and CMA conceived and designed thestudy and participated in logistical planning of the study, and were involved inthe drafting of the article. TVP provided the statistical support for the samplesize estimates and the design of the statistical analysis. TBZP and CEP wereinvolved in the screening and randomisation process and are involved in thepatient’s follow-up. RVC, CAS, PPdPC, JLLC and FNQP performed alloperations.

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Funding The study is supported by a research grant from Johnson &Johnson Medical Brazil and Oswaldo Cruz German Hospital.

Competing interests None declared.

Ethics approval Local Institutional Review Board (IRB; Ethical ResearchCommittee from Oswaldo Cruz German Hospital—#201681).

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement The authors shall make data available to thescientific community with as few restrictions as feasible, ensuringanonymisation, while retaining exclusive use until the publication of majoroutputs.

Open Access This is an Open Access article distributed in accordance withthe Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, providedthe original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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1BMJ Open 2017;7:e013574corr1. doi:10.1136/bmjopen-2016-013574corr1

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Correction

Cohen RV, Pereira TV, Aboud CM on behalf of MOMS Study Investigators, et al. Microvascular Outcomes after Metabolic Surgery (MOMS) in patients with type 2 diabetes mellitus and class I obesity: rationale and design for a randomised controlled trial. BMJ Open 2017;7:e013574. doi: 10.1136/bmjopen-2016-013574

The author Carel le Roux should be listed as Carel W le Roux. His ORCID number is 0000000155215445.

Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/

BMJ Open 2017;7:e013574corr1. doi:10.1136/bmjopen-2016-013574corr1

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