BACKGROUND:Recent studies have shown increased duodenal mucosal permeability as a possible key player in the pathophysiology of functional dyspepsia (FD). Adverse reaction to nutrients is an important candidate underlying mechanism. Intragastric infusion of fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) induced symptoms reminiscent of FD with a rapid onset. OBJECTIVE:We evaluated the effect of a low FODMAP diet (LFD) and individual FODMAP-triggers on symptom severity and duodenal mucosal permeability in FD. DESIGN:Patients with FD followed a 6-week LFD and filled out the validated Leuven Postprandial Distress Syndrome (LPDS) daily diary, Short Form-Nepean Dyspepsia Index (SF-NDI) Questionnaire, patient assessment of upper gastrointestinal symptoms (PAGI-SYM) and Patient Health Questionnaire (PHQ). Patients underwent an endoscopy with duodenal biopsies to define mucosal integrity by quantifying transepithelial electrical resistance (TEER) and dextran flux. LFD was followed by a blinded reintroduction during which patients were challenged by 7 powders (fructans, fructose, galacto-oligosaccharides (GOS), lactose, mannitol, sorbitol, glucose). RESULTS:36 FD patients entered the study. LPDS improved significantly at the end of the LFD in 73%. In addition, SF-NDI, PAGI-SYM and PHQ improved significantly. Dextran flux and TEER were not significantly different, but delta TEER correlated positively with delta LPDS. A large variety of FODMAP powders was able to induce recurrence with mannitol as the most prevalent triggering FODMAP (23%). Surprisingly, 27% showed higher LPDS scores during intake of glucose. CONCLUSIONS:A LFD significantly improved PDS symptoms, but this was not associated with altered mucosal integrity. Powder reintroduction identified a large variety in individual FODMAPs and glucose as triggers.

BACKGROUND & AIMS:The efficacy of a low fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in irritable bowel syndrome (IBS) is well established. After the elimination period, a reintroduction phase aims to identify triggers. We studied the impact of a blinded reintroduction using FODMAP powders to objectively identify triggers and evaluated the effect on symptoms, quality of life, and psychosocial comorbidities. METHODS:Responders to a 6-week low FODMAP diet, defined by a drop in IBS symptom severity score (IBS-SSS) compared with baseline, entered a 9-week blinded randomized reintroduction phase with 6 FODMAP powders (fructans, fructose, galacto-oligosaccharides, lactose, mannitol, sorbitol) or control (glucose). A rise in IBS-SSS (≥50 points) defined a FODMAP trigger. Patients completed daily symptom diaries and questionnaires for quality of life and psychosocial comorbidities. RESULTS:In 117 recruited patients with IBS, IBS-SSS improved significantly after the elimination period compared with baseline (150 ± 116 vs 301 ± 97, P < .0001, 80% responders). Symptom recurrence was triggered in 85% of the FODMAP powders, by an average of 2.5 ± 2 FODMAPs/patient. The most prevalent triggers were fructans (56%) and mannitol (54%), followed by galacto-oligosaccharides, lactose, fructose, sorbitol, and glucose (respectively 35%, 28%, 27%, 23%, and 26%) with a significant increase in abdominal pain at day 1 for sorbitol/mannitol, day 2 for fructans/galacto-oligosaccharides, and day 3 for lactose. CONCLUSION:We confirmed the significant benefit of the low FODMAP diet in tertiary-care IBS. A blinded reintroduction revealed a personalized pattern of symptom recurrence, with fructans and mannitol as the most prevalent, and allows the most objective identification of individual FODMAP triggers. Ethical commission University hospital of Leuven reference number: s63629; Clinicaltrials.gov number: NCT04373304.

Background and objectives: To investigate the effect of carbohydrate intake before laparoscopic Roux-en-Y gastric bypass (LRYGB) on body weight, body composition and glycaemic status after surgery. Methods: In a tertiary centre cohort study, dietary habits, body composition and glycaemic status were evaluated before and 3, 6 and 12 months after LRYGB. Detailed dietary food records were processed by specialized dietitians on the basis of a standard protocol. The study population was subdivided according to relative carbohydrate intake before surgery. Results: Before surgery, 30 patients had a moderate relative carbohydrate intake (26%-45%, M-CHO), a mean body mass index (BMI) of 40.4 ± 3.9 kg/m² and a mean glycated haemoglobin A1c (A1C) of 6.5 ± 1.2% compared to 20 patients with a high relative carbohydrate intake (> 45%, H-CHO), mean BMI of 40.9 ± 3.7 kg/m² (non-significant, NS) and a mean A1C of 6.2% (NS). One year after surgery, body weight, body composition and glycaemic status were similar in the M-CHO (n = 25) and H-CHO groups (n = 16), despite less caloric intake in the H-CHO group (1317 ± 285 g vs. 1646 ± 345 g in M-CHO, p < 0.01). Their relative carbohydrate intake converged to 46% in both groups, but the H-CHO group reduced the absolute total carbohydrate consumption more than the M-CHO group (190 ± 50 g in M-CHO vs. 153 ± 39 g in H-CHO, p < 0.05), and this was especially pronounced for the mono- and disaccharides (86 ± 30 g in M-CHO vs. 65 ± 27 g in H-CHO, p < 0.05). Conclusion: A high relative carbohydrate intake before LRYGB, did not influence the change in body composition or diabetes status after surgery, despite a significantly lower total energy intake and less mono- and disaccharide consumption after surgery.

Rationale: The understanding of gastrointestinal physiology is scarce. Therefore, the aim of the study was to examine the effect of food intake on gastrointestinal transit, pH and pressure in participants with normal-weight and obesity.

Parenteral nutrition (PN) is recommended in patients nutritionally at risk and unable to receive oral or enteral nutrition. A standardized electronic PN order format could enhance appropriate PN prescribing. We developed the OLIVE TREE (Offering guidance and Learning to prescribers to Initiate PN using a Validated Electronic decision TREE), embedded in our electronic health record. We aimed to evaluate its validity and impact on physicians’ prescribing behavior. A non-randomized before-after study was carried out in a tertiary care center. The OLIVE TREE comprises 120 individual items. A process validation was performed to determine interrater agreement between a pharmacist and the treating physician. To estimate the proportion of patients for whom the OLIVE TREE had an effective and potential impact on physicians’ prescribing behavior, a proof of concept study was conducted. The proportion of patients for whom PN was averted and the proportion of decisions not in line with the recommendation were also calculated. The process validation in 20 patients resulted in an interrater agreement of 95.0%. The proof of concept in 73 patients resulted in an effective and potential impact on prescribing behavior in 50.7% and 79.5% of these patients, respectively. Initiation of PN was not averted and recommendations of the OLIVE TREE were overruled in 42.5% of the patients. Our newly developed OLIVE TREE has a good process validity. A substantial impact on prescribing behavior was observed, although initiation of PN was not avoided. In the next phase, the decision tree will be implemented hospital-wide.

Introduction: Obesity is a global health challenge, and pharmacologic options are emerging. Once daily subcutaneous administration of 3 mg liraglutide, a glucagon like peptide-1 analogue, has been shown to induce weight loss in clinical trials, but real-world effectiveness data are scarce. Methods: It is a single-centre retrospective cohort study of patients who were prescribed liraglutide on top of lifestyle adaptations after multidisciplinary evaluation. In Belgium, liraglutide is only indicated for weight management if the BMI is >30 kg/m2 or ≥27 kg/m2 with comorbidities such as dysglycaemia, dyslipidaemia, hypertension, or obstructive sleep apnoea. No indication is covered by the compulsory health care insurance. Liraglutide was started at 0.6 mg/day and uptitrated weekly until 3 mg/day or the maximum tolerated dose. Treatment status and body weight were evaluated at the 4-month routine visit. Results: Between June 2016 and January 2020, liraglutide was prescribed to 115 patients (77% female), with a median age of 47 (IQR 37.7–54.0) years, a median body weight of 98.4 (IQR 90.0–112.2) kg, a BMI of 34.8 (IQR 32.2–37.4) kg/m2, and an HbA1c level of 5.6%. Five (4%) patients did not actually initiate treatment, 9 (8%) stopped treatment, and 8 (7%) were lost to follow-up. At the 4-month visit, the median body weight had decreased significantly by 9.2% to 90.8 (IQR 82.0–103.5) kg (p < 0.001). Patients using 3.0 mg/day (n = 60) had lost 8.0 (IQR 5.8–10.4) kg. The weight loss was similar (p = 0.9622) in patients that used a lower daily dose because of intolerance: 7.4 (IQR 6.2–9.6) kg for 1.2 mg (n = 3), 7.8 (IQR 4.1–7.8) kg for 1.8 mg (n = 16), and 9.0 (IQR 4.8–10.7) kg for 2.4 mg/day (n = 14). Weight loss was minimal if liraglutide treatment was not started or stopped prematurely (median 3.0 [IQR 0.3–4.8] kg, p < 0.001, vs. on treatment). Further analysis showed an additional weight reduction of 1.8 kg in the patients that had started metformin <3 months before the start of liraglutide (p < 0.001). The main reasons for liraglutide discontinuation were gastrointestinal complaints (n = 5/9) and drug cost (n = 2/9). Conclusion: In this selected group of patients, the majority complied with liraglutide treatment over the initial 4-month period and achieved a significant weight loss, irrespective of the maximally tolerated maintenance dose. Addition of metformin induced a small but significant additional weight loss.

Background: Despite the increasing prevalence and medical burden of obesity, the understanding of gastrointestinal physiology in obesity is scarce, which hampers drug development. Aim: To investigate the effect of obesity and food intake on gastrointestinal transit, pressure and pH. Material and methods: An exploratory cross-sectional study using a wireless motility capsule (SmartPill (c)) was performed in 11 participants with obesity and 11 age- and gender-matched participants with normal weight (group) in fasted and fed state (visit). During the first visit, the capsule was ingested after an overnight fast. During a second visit, the capsule was ingested after a nutritional drink to simulate fed state. Linear mixed models were constructed to compare segmental gastrointestinal transit, pressure and pH between groups (obesity or control) and within every group (fasted or fed). Results: Food intake slowed gastric emptying in both groups (both P < 0.0001), though food-induced gastric contractility was higher in participants with obesity compared to controls (P = 0.02). In the small intestine, a higher contractility (P = 0.001), shorter transit (P = 0.04) and lower median pH (P = 0.002) was observed in participants with obesity compared to controls. No differences were observed for colonic measurements. Conclusion: Obesity has a profound impact on gastrointestinal physiology, which should be taken into account for drug development.

BACKGROUND:The reported prevalences and effects of nutritional risk vary widely in the literature because of both methodological differences (e.g., screening tools and statistical analyses) and different patient populations.OBJECTIVE:In this study the authors analyzed in-hospital mortality, 30-d mortality, readmission within 4 mo, and justified length of stay (jLoS) (determined by governmental assessment to justify financial compensation) in hospitalized patients nutritionally at risk compared with hospitalized patients not at risk.DESIGN:This was a multicenter retrospective cohort study in 6 Belgian hospitals among inpatients in 2018. Propensity score matching was applied, including comorbidity score and exact matching for hospital, age group, sex, type of admission, living situation, and medical specialty.RESULTS:In total, 73,843 of 85,677 patients were screened at admission, with 16,141 found to have nutritional risk (prevalence of 21.9%). Oncology patients had the highest risk prevalence of 38.3%, whereas patients receiving plastic or reconstructive surgery had a prevalence of 5.2%. Patients nutritionally at risk had higher odds of dying in the hospital (5.1% compared with 3.3%; OR: 1.56; 95% CI: 1.37, 1.76), dying within 30 d of admission (6.8% compared with 4.3%; OR: 1.62; 95% CI: 1.45, 1.81) and being readmitted within 4 mo after discharge (35.5% compared with 32.9%; OR: 1.12; 95% CI: 1.07, 1.18). These differences were consistent across hospitals. The association between being nutritionally at risk and jLoS was ambiguous.CONCLUSIONS:One out of 5 patients included in this study was nutritionally at risk. Using propensity score matching, higher odds of in-hospital mortality, readmission, and 30-d mortality were observed. In contrast to oft-reported increased length of stay with poor nutrition, propensity matched data for jLoS suggested that this association was less pronounced in this cohort.

Rationale: International guidelines state that clinical decision support enhances appropriate prescribing of parenteral nutrition (PN), leading to increased quality of care and cost savings. We aimed to develop, validate and analyse an electronic PN decision tree (ePNDT) embedded in our electronic health record.

To retrospectively analyse data obtained from the multi-domain assessment of hospitalized COVID-19 patients, to describe their health status at discharge, and to investigate whether subgroups of patients, more specific ICU patients and older adults (> 70 years), had more (or less) risk to experience specific impairments. The results of the assessment show that physical, functional, cognitive, nutritional, and psychological impairments are highly prevalent in the group of COVID-19 patients, both in ICU and non-ICU patients, adults and older adults. The high prevalence of physical, cognitive, psychological, and functional impairments in hospitalized COVID-19 patients, both ICU and non-ICU patients, indicates that assessment of impairments is imperative. To retrospectively analyse data obtained from the multi-domain assessment of hospitalized COVID-19 patients, to describe their health status at discharge, and to investigate whether subgroups of patients, more specific ICU patients and older adults (> 70 years), had more (or less) risk to experience specific impairments. Retrospective case series in the University Hospitals Leuven, Belgium of confirmed COVID-19 patients 'after surviving an ICU-stay', 'aged ≥ 70 years', or 'aged < 70 years with a length of hospitalization > 7 days'. Exclusion criteria were 'unwilling to cooperate', 'medically unstable', or 'palliative care policy'. Following tests were used: 'Five Times Sit To Stand Test', 'hand grip dynamometry', 'Barthel index', 'Swallowing screening', 'Montreal Cognitive Assessment', 'Hospital Anxiety and Depression Scale', and 'Nutritional Risk Screening 2002'. One or more tests were obtained in 135/163 patients (83.3%). Physical impairments were present in 43.2–82.8% of the patients. Median BI was 10/20 indicating limited self-dependency. Swallow impairments were present in 3/53 (5.7%) and 24/76 (31.6%) had risk of malnutrition. Impaired memory was seen in 26/43 (60.5%) and 22/47 (46.8%) had elevated anxiety/depression scores. Older adults had more physical, functional, and cognitive impairments. ICU patients had a lower hand grip force. The high prevalence of physical, cognitive, psychological, and functional impairments in hospitalized COVID-19 patients, both ICU and non-ICU patients, indicates that assessment of impairments is imperative. These results imply that rehabilitation and follow-up is essential for these patients. This paper proposes a short, workable assessment composed with known outcome measures to assess different domains of COVID-19 patients.

Roux-en-Y gastric bypass (RYGB) is thought to reduce calcium absorption from the gut. Here, we report the case of a patient with a RYGB, who developed primary hypoparathyroidism after a total thyroidectomy, leading to recalcitrant hypocalcaemia. Despite aggressive oral calcium and calcitriol supplementation, she remained hypocalcaemic and required intravenous (IV) calcium supplementation to control her symptoms, and to keep calcium serum levels within an acceptable range. Teriparatide treatment improved calcium levels marginally. This treatment, however, was poorly tolerated and ultimately stopped by the patient. As a last resort, reversal of RYGB was performed to improve calcium absorption from the gut. Unfortunately, IV calcium supplementation remained necessary. This case illustrates that the reversal of RYGB is not always a guarantee for success in managing recalcitrant hypocalcaemia.

Abstract The increasing worldwide prevalence of obesity is a major public health concern, which has led to the development of surgical treatment strategies that achieve long-term sustainable weight loss and improvement of comorbidities and quality of life. However, nonsurgical complications can occur which sometimes necessitate hospital readmission depending on the severity. Current literature about hospital admission for nonsurgical complications after bariatric surgery is especially sparse. We performed a 5-year retrospective analysis of patients admitted for nonsurgical complications after bariatric surgery at the Department of Endocrinology, University Hospitals Leuven (Belgium). Patient and readmission characteristics were described by type of first bariatric surgery performed, time after first surgery, amount of bariatric surgeries in total, reason for hospitalization (nutritional, functional, psychological, metabolic and medical), need for parenteral and enteral feeding during hospitalization and duration of hospitalization. In a period of five years, there were 152 hospitalizations of 107 patients (86% females). The majority of patients (53%) underwent Roux-en-Y gastric bypass (RYGB) and had in total 1 (1–2) bariatric procedures. The median BMI before the first bariatric procedure was 40.7 (37.9–46.7) kg/m2. Patients were admitted 7.6 (3.4–13.1) years after surgery at an average age of 49 ± 12 years. Nutritional (66.4%), functional (37.5%) and co-presenting nutritional-functional (25.0%) problems were the most important reasons for hospitalization. In regard to the nutritional complications, the most important reasons for hospital admission were dumping syndrome (19.7%), macro- and micronutrient deficiencies (16.4%), bad compliance to prescribed nutritional guidelines (14.5%), anorexia (11.2%), extensive weight loss (10.5%) and failure to thrive (9.2%). During hospitalization, parenteral and enteral feeding was started in 19.1% and 9.9% of hospitalizations, respectively. The median duration of all hospitalizations was 8 (4–13) days. To conclude, the majority of hospitalized patients underwent RYGB and was female. Most patients were admitted late after surgery and nutritional problems were the most common complication. Nonsurgical complications after bariatric surgery are a clear illustration of the double-edged sword of surgical obesity management. The exact gastrointestinal anatomical and physiological changes provide the intended effect of weight loss, but may also elicit unintended imbalances of excessive losses of nutrients that compromise the outcome. Our findings demonstrate the need for lifelong multidisciplinary follow-up of lifestyle behavior and education on diet both before and after bariatric surgery.

Background Bone loss and increased fracture risk following bariatric surgery has been reported. We investigated whether the two most commonly performed surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), lead to bone loss. In addition, we examined whether fortification of the diet with calcium citrate prevents bone loss. Methods We used mouse models for SG and RYGB and compared bone loss with a group of sham mice with similar weight loss. All groups were switched at the time of surgery to a low-fat diet (LFD). We also examined whether fortification of the diet with calcium citrate and vitamin D was able to prevent bone loss. Results At 2 weeks we observed no major bone effects. However, at 8 weeks, both trabecular and cortical bone were lost to the same extent after SG and RYGB, despite increased calcium absorption and adequate serum levels of calcium, vitamin D, and parathyroid hormone (PTH). Diet fortification with calcium citrate and vitamin D was able to partially prevent bone loss. Conclusions Both SG and RYGB lead to excess bone loss, despite intestinal adaptations to increase calcium absorption. Fortifying the diet with calcium citrate and vitamin D partly prevented the observed bone loss. This finding emphasizes the importance of nutritional support strategies after bariatric surgery, but also affirms that the exact mechanisms leading to bone loss after bariatric surgery remain elusive and thus warrant further research.

3062 Background: MET kinase is a therapeutic target in a range of cancer indications; it is a primary oncogenic driver and a mechanism of therapy resistance. OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2). Methods: This study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary activity of OMO-1 in patients (pts) with advanced malignancies (NCT03138083). Module 1 data, evaluating ascending doses of OMO-1 monotherapy, are reported here. Results: As of January 16, 2019, 34 pts were enrolled at 5 twice-daily (BD) dose levels of OMO-1: 100, 200, 250, 350, and 400 mg, including 10 with MET gene amplified or mutated tumours. OMO-1 was generally well tolerated between 100 - 250 mg BD; pts were in the study for an average of 94 days (range: 15-291 days) and 20/34 pts discontinued due to disease progression. Most frequently-reported AEs were nausea (17/34), vomiting (14/34) and fatigue (14/34), mainly G1-2. Notably, no peripheral oedema, cardiovascular events or non-malignancy related LFT abnormalities were observed. A total of 36 SAEs were reported: 17 in 11 subjects were considered related to OMO-1, and included nausea (3/17), vomiting (4/17), chills, diarrhoea, influenza-like illness (2/17), increased blood bilirubin, blood creatinine (3/17) and neutrophil count, and sepsis. A dose of 250 mg BD was determined as the recommended Phase 2 dose (RP2D); doses ≥350mg BD were not in keeping with optimum long-term dosing: at 400 mg BD, 2/3 subjects experienced influenza-like illness (G2 and G3) and at 350 mg BD 2/5 subjects had G2 fatigue and nausea/vomiting. OMO-1 has a half-life of 2.5-3 hrs and plasma exposure is dose-proportional without accumulation. Elevated creatinine was observed across all dose levels, consistent with OCT2 inhibition. IHC analysis on paired tumour biopsies from a MET-mutated NSCLC pt dosed at 200 mg BD showed near-complete inhibition of phosphorylated MET, without affecting total MET. Conclusions: OMO-1 has a favourable safety profile at a RP2D of 250mg BD. Expansion cohorts for MET mutated/amplified tumour types are enrolling. Clinical trial information: NCT03138083.

e14674 Background: The MET kinase is an established therapeutic target in a range of cancer indications, being a primary oncogenic and therapy resistance driver. Methods: OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2) that is currently being explored in a Phase I/II study (NCT03138083). Results: Pre-clinical data for OMO-1 indicates that anti-tumor efficacy against MET driven tumor models does not require 24/7 exposure in the plasma. PK/PD assessments indicate that OMO-1 efficacy is AUC driven. Exposures above a trough concentration of ~600ng/ml for a period of 6-8hr and an AUC of 3000ng.h/ml result in complete target inhibition sufficient to induce regression or stasis of MET driven in-vivo models. Dosing of OMO-1 at 12.5mg/kg BD 4hr apart, or split over 4 doses 2hr apart, with a dosing-free period of 18-20hr was sufficient to obtain the effects preclinically. The ongoing Phase I/II study in patients with solid tumours utilised learnings from the pre-clinical and FIH study (NCT01964872) where ascending single doses and multiple doses were evaluated. The selected starting dose for the patient study (100mg BD, 4 hr apart) achieved exposures above the predicted MBAD. Paired tumor biopsies were obtained from a higher dose level (200mg BD). A MET exon 14 skipping mutation NSCLC patient at this dosed demonstrated near-complete inhibition of phospho MET accompanied by signs of clinical benefit and lesion shrinkage, thereby matching the preclinical data. Certain ‘class effect’ adverse events, such as edema, were not observed. Conclusions: OMO-1 is an oral, potent MET TKI with a novel dosing regime, identified during preclinical optimization (BD 4hr apart), that demonstrates encouraging signs of clinical activity without certain ‘class-specific’ adverse events. Further evaluation of this differentiated and efficacious agent is warranted and ongoing.

Bariatric surgery has proven to be a valuable treatment option for morbid obesity. However, these procedures can lead to impaired intestinal absorption of calcium and vitamin D, thereby challenging calcium homeostasis and possibly contributing to bone loss leading to an increased fracture risk. Besides calcium and vitamin D malabsorption, hormonal changes occurring after surgery can also be the source of observed bone loss. In this review, first, a case report will be discussed, highlighting the relevance of this topic. Afterwards, changes in bone density and fracture risk, after the two most performed types of bariatric surgery, Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB) will be discussed. In addition, we discuss the putative underlying mechanisms leading to bone changes based on both preclinical and clinical observations. Nonetheless, it is clear further research is needed to further elucidate the exact mechanisms of bone loss following bariatric surgery and subsequently identify potential treatment options for bone preservation.

BACKGROUND:Achieving weight loss is the cornerstone of the treatment of the metabolic consequences of obesity, in particular of glucose intolerance. OBJECTIVE:To determine whether improvement in glucose control depends on dietary macronutrient composition of the diet at identical weight loss. MATERIALS AND METHODS:Twenty-two weeks old diet-induced obese C57BL/6 mice lost weight through caloric restriction on normal chow (R-NC) or high fat diet (R-HF). Control mice were fed normal chow (LEAN) or high fat diet (OBESE) ad libitum. Body weight and composition were assessed after 8 weeks of dietary intervention. Glucose homeostasis was evaluated by intraperitoneal glucose tolerance tests (IPGTT). Epididymal white adipose (eWAT) and hepatic tissues were analyzed by immunohistochemistry and RT-qPCR. RESULTS:By 30 weeks of age, the body weight of the mice on R-NC (31.6±1.7g, mean±SEM) and R-HF (32.3±0.9g) was similar to LEAN mice (31.9±1.4g), while OBESE mice weighed 51.7±2.4g. Glucose tolerance in R-NC was better than in LEAN mice (69% AUC IPGTT, P 0.0168) whereas R-HF mice remained significantly less glucose tolerant (125% AUC IPGTT, P 0.0279 vs LEAN), despite identical weight loss. The eWAT pads and adipocyte size were similar in LEAN and R-NC mice, while the eWAT pad size of R-HF was 180% of R-NC (P < 0.0001) and the average adipocyte size of R-HF mice was 134% of R-NC fed mice (P 0.0285). No LEAN or R-NC mice had hepatic steatosis, in contrast to 28.6% of R-HF mice. Compared to OBESE mice, inflammatory markers were lower in eWAT and liver tissue of R-NC, but not in R-HF mice. Measures of visceral adiposity correlated well with glucose tolerance parameters. CONCLUSIONS:In mice, caloric restriction on a normal chow diet improved glucose tolerance significantly more when identical weight loss was achieved on a high fat diet.

TPS2614 Background: OMO-1, a highly selective, oral, small molecule MET kinase/OCT2 inhibitor, demonstrated single agent cellular and in vivo anti-tumour activity, including regression in MET driven xenograft models. Preclinical studies to identify optimal drug combinations Predicted efficacious exposures of OMO-1 were reached without clinically relevant adverse events in healthy volunteers, data from this study expedited the ongoing patient study. Methods: This novel study design consists of distinct study modules, each investigating a different hypothesis. Module 1, investigating OMO-1 monotherapy, commenced in Aug 2017. It consists of Part A (dose finding) and an optional Part B (cohort expansions in relevant clinical indications eg MET amplification or exon 14 skipping mutation). Part A is a traditional 3 + 3 dose escalation design. Part B expansions are powered to compare response rates to historical data. The option to start Part B and add further modules will be based on emerging data, a substantial protocol amendment being put in place before starting a new module. The dosing schedule/sequence of OMO-1 in each module may be adapted in response to emerging data. The maximum tolerated dose of OMO-1 for individual modules may differ based on the emerging safety profile for each combination. For all modules, Part A cohorts may be expanded by up to 12 additional patients, mandatory serial tumour biopsies will be taken and assessed for relevant PD biomarkers. This design allows one protocol to respond to emerging data, supporting studies in both monotherapy and multiple combinations, reducing the time to ‘first subject in study’ compared with multiple individual studies. It also allows investigators to pre-empt emerging data and changes to the treatment landscape. These challenges emphasize the need for flexible designs as the landscape of drug development continues to quickly evolve. Clinical trial information: NCT03138083.