Efficacy and Safety of Teduglutide in Infants and Children With Short Bowel Syndrome Dependent on Parenteral Support.

OBJECTIVES: Our objective was to evaluate the short- and long-term safety and efficacy of teduglutide treatment in infants and children with short bowel syndrome with intestinal failure (SBS-IF). METHODS: Two open-label phase 3 studies and 1 extension study investigated the short- and long-term safety and efficacy of teduglutide (0.05 mg/kg/day) in infants and children with SBS-IF: NCT03571516, 24-week study of infants who were randomized to receive teduglutide or standard of care (SoC); NCT02980666, 24-week study of infants and children who all received teduglutide; and NCT03268811, 24-week extension study of patients who completed NCT02980666 (patients could receive up to 48 weeks of total treatment). RESULTS: Twelve infants and 8 children enrolled in the core studies, and 2 infants and 7 children in the extension study. After 24 weeks of treatment, parenteral support (PS) requirements reduced by ≥20% from baseline for 4 infants (57.1%) and 4 children (66.7%) receiving teduglutide and for 2 infants receiving SoC (50.0%). One infant (50.0%) and 4 children (80.0%) receiving teduglutide maintained the ≥20% reduction in PS at 48 weeks of treatment. Two children receiving teduglutide achieved enteral autonomy, after 12 weeks and 28 weeks of treatment, respectively. All adverse events (AEs) were in line with known impacts of SBS-IF and adverse reactions to teduglutide. Only one serious AE (abdominal pain) was considered related to teduglutide. CONCLUSIONS: Short- and long-term treatment with teduglutide resulted in clinically meaningful reductions in PS requirements for infants and children with SBS-IF. Teduglutide was well tolerated, and efficacy improved with longer-term treatment.

Efficacy, safety, and pharmacokinetics of teduglutide in adult Japanese patients with short bowel syndrome and intestinal failure: two phase III studies with an extension.

PURPOSE: The short- and long-term efficacy, safety, and pharmacokinetics of teduglutide were analyzed in adult Japanese patients with short bowel syndrome and intestinal failure (SBS-IF). METHODS: Patients received teduglutide 0.05 mg/kg/day in clinical trials (TED-C14-004, SHP633-306, and extension SHP633-307). Data were analyzed at 24 weeks and an interim data cut-off of 4.5 years. RESULTS: The parenteral support (PS) volume decreased by ≥ 20% for 9/18 patients at 24 weeks and in all 11 patients by data cut-off in SHP633-307. The mean (standard deviation) PS volume decreased from baseline at 24 weeks in TED-C14-004 (-30.1 ± 25.9%) and SHP633-306 (-25.6 ± 25.5%), and at data cut-off in SHP633-307 (-57.08 ± 28.49%). Teduglutide was absorbed quickly. The adverse events were consistent with the underlying disease and known adverse drug reactions. Anti-teduglutide antibody titers declined with long-term treatment. CONCLUSIONS: In Japanese adults with SBS-IF, teduglutide treatment was associated with clinically meaningful reductions in PS requirements, similar to findings in prior international studies. No new safety concerns specific to the Japanese SBS-IF patient population were identified with short- or long-term teduglutide treatment. Anti-teduglutide antibody titers disappeared in most Japanese adults with long-term treatment. These results constitute the longest evaluation of teduglutide treatment within clinical trials reported to date.

Lack of Increased Risk of Lymphoma with Thiopurine Therapy Regardless of Dose and Duration of Treatment in Japanese Patients with Inflammatory Bowel Diseases.

BACKGROUND: Immunomodulator therapy (e.g., thiopurines) has been linked to an increased malignancy risk, in patients with inflammatory bowel diseases (IBDs), which increases with treatment duration, based on studies mainly in Caucasian patients. However, our previous real-world study, of Japanese patients with IBDs, indicated no overall increased risk of non-Hodgkin lymphoma (NHL) with thiopurine treatment. OBJECTIVES: This subanalysis investigated the influence of thiopurine IBD treatment dose and duration, on incidence of NHL in Japanese patients. METHOD: The Medical Data Vision (MDV) claims database (17.8 million patients; April 2008-January 2018) was used to analyze incidence rate ratios (IRRs) of NHL, in eligible patients (≥1 diagnosis of ulcerative colitis or Crohn's disease) and no malignancy at diagnosis or first prescription of a thiopurine. Age- and sex-adjusted IRRs and 95% confidence interval for NHL were calculated as the incident cases compared in the subgroups versus the overall IBD population. RESULTS: Among 75,673 patients with IBDs, 103 cases of NHL were recorded. There was no overall increase in the risk of developing NHL among Japanese patients treated with thiopurines. The IRRs relative to the overall IBD population were 1.88, 1.42, and 0.38 for <1 year, 1-3 years, and ≥3 years of thiopurine treatment. There were no differences in NHL incidence when grouping patients by mean daily thiopurine dose prescribed, age, or disease subgroups. CONCLUSION: Dose or duration of thiopurine treatment did not explain a lack of increased risk of NHL with thiopurine use in Japanese patients with IBDs.

Real-world etiologies and treatments of pediatric short bowel syndrome in Japan.

BACKGROUND: Short bowel syndrome (SBS) is a rare disease that can result in intestinal failure (IF). Short bowel syndrome intestinal failure leads to stunted growth and development and high mortality rates. The primary goal of treatment is to enhance intestinal adaptation and nutrient absorption. Parenteral nutrition (PN) is used to support this process until enteral autonomy can be restored. Some patients experience prolonged partial or complete dependency on PN and face an increased risk of life-threatening catheter-related bloodstream infections and intestinal failure-associated liver disease. This study aimed to provide real-world insights into the patient characteristics and treatment dynamics of PN-dependent children with SBS-IF in Japan. METHODS: This retrospective observational study used anonymized information from a large hospital-based medical insurance database to identify pediatric patients who received PN for ≥6 months between April 2008 and January 2020. The primary endpoint was weaning from PN. Secondary endpoints included duration and complications of PN. RESULTS: Forty-eight children (mean age, 2.9 years) were eligible for inclusion. The most common causes of SBS-IF were mechanical bowel obstruction, functional bowel disorders, and Hirschsprung's disease. Twenty-two patients (45.8%) were weaned from PN during the study. The mean time to first weaning was 464.2 days and five patients (22.7%) restarted PN. The mean total duration of PN was 692.6 days in weaned patients and 1,170.9 days in unweaned patients. The most frequent complications were sepsis, catheter infections (both 79.2%), and liver dysfunction (64.6%). CONCLUSIONS: Pediatric patients with SBS-IF faced difficulties when weaning off PN and rates of life-threatening complications were high.

Etiologies and treatments of chronic intestinal failure-short bowel syndrome (SBS) in Japanese adults: a real-world observational study.

PURPOSE: Short bowel syndrome (SBS) with intestinal failure (SBS-IF) requires long-term parenteral nutrition (PN). This study investigated the real-world etiologies of SBS, treatment patterns, and PN-related outcomes among adult patients with SBS-IF in Japan. METHODS: This retrospective, observational cohort study was based on data from April, 2008 to January, 2020 from one of the largest hospital-based claim databases in Japan. Analyzed patients were aged ≥ 16 years, had received continuous PN for ≥ 6 months, and had SBS or undergone SBS-related surgery with a diagnosis of a causative disease. The primary endpoint was PN weaning. RESULTS: We analyzed data for 393 patients. The most frequent causes of SBS-IF were ileus (31.8%), Crohn's disease (20.1%), and mesenteric ischemia (16.0%). Of 144/393 (36.6%) patients who were weaned off their PN, 48 (33.3%) were subsequently restarted on PN. Of 276/393 (70.2%) patients whose PN was initiated in hospital, 156 (56.5%) transitioned to home management. The mean duration of initial PN was 450.4 and 675.5 days for patients who were able or unable to be weaned off PN, respectively. Sepsis (67.4%), catheter-related bloodstream infections (49.1%), and liver disorders (45.0%) were the most reported PN-related complications. CONCLUSIONS: Most patients with SBS-IF in Japan could not be weaned off PN and suffered life-threatening complications.

Impact of immunomodulator use on treatment persistence in patients with ulcerative colitis: A claims database analysis.

BACKGROUND AND AIM: It is unclear how adding an anti-tumor necrosis factor alpha agent to immunomodulator (IM) treatment, as a step-up strategy, affects long-term outcomes in ulcerative colitis. This retrospective study investigated persistence associated with biologic anti-tumor necrosis factor alpha agents combined with IMs versus biologic monotherapy in patients with ulcerative colitis. METHODS: This was a longitudinal cohort study of patients in the Japan Medical Data Center claims database who had been newly prescribed infliximab or adalimumab as induction (completed) and maintenance (2010-2016). Biologic persistence (i.e. no switch/discontinuation during maintenance) was compared among patients prescribed biologic monotherapy (Bio) and those prescribed a biologic combined with an IM, as step-up (Bio + prior IM) or simultaneously (Bio + IM). RESULTS: Three hundred and sixty-nine eligible patients were analyzed (233, 78, and 58 in the Bio, Bio + prior IM, and Bio + IM subgroups, respectively). Multivariate analysis showed a lower probability of nonpersistence during maintenance for infliximab-treated patients in the Bio + prior IM versus Bio subgroup (hazard ratio: 0.53; 95% confidence interval: 0.29-0.99; P = 0.045). No such effect was seen in adalimumab-treated patients (P = 0.222) or in the overall population (P = 0.398). The probability of nonpersistence during maintenance in the Bio + IM subgroup was not significantly different from that in the Bio subgroup in either the biologic subpopulation or in the overall population. CONCLUSIONS: Adding infliximab to an existing IM results in a lower probability of nonpersistence compared with infliximab monotherapy in ulcerative colitis patients. This effect is not seen in adalimumab-treated patients.

Intake of green-plant membrane with dietary oil suppresses postprandial hypertriglyceridemia in rats via promoting excretion of bile acids.

Green-plant membrane is a phytonutrient present in green leafy vegetables at high concentration. Postprandial increases in blood triglyceride levels result in insulin resistance and type 2 diabetes. Additionally, dietary life and eating order also affect postprandial hypertriglyceridemia. In this study, the effects of once-daily intake of green-plant membrane with dietary oil on postprandial hypertriglyceridemia were investigated in vitro and in vivo. In vitro, green-plant membrane bound hydrophobic bile acids but did not inhibit pancreatic lipase activity. Following the administration, green-plant membrane with dietary oil in rats, oral fat tolerance tests, increases in serum triglycerides levels were significantly reduced. Moreover, fecal total lipid and bile acid volumes were significantly increased in rats that administered 200 mg/mL green-plant membrane. These results suggest that green-plant membrane with dietary oil inhibits dietary fat absorption via promotion of bile acid excretion in feces and the effectiveness of eating green-plant membrane, such as green leafy vegetables, with meals.

Performing colonoscopy before steroid induction is associated with shorter steroid use in patients with ulcerative colitis.

BACKGROUND/AIMS: Risks of long-term steroid use in patients with ulcerative colitis (UC) outweigh the benefits, thus dosing should be tapered once a response is achieved. Colonoscopy is a key technique for assessing disease severity and optimizing treatment involving steroids. This retrospective longitudinal cohort study of patients with UC explored factors associated with the duration of systemic steroid use. METHODS: The Japan Medical Data Center database, an employer-based insurance claims database, was used to select individuals initiating prednisolone, with a prescription issued between January 1, 2010, and January 31, 2018. The study included adults with a confirmed diagnosis of UC, who had received ≥1 year of continuous treatment with 5-aminosalicylic acid, biologics, or thiopurine. Factors associated with prednisolone duration were assessed using a multivariate regression model. RESULTS: Median duration of prednisolone treatment was 98 days, and colonoscopy was performed ≤1 month before or at the first prescription of prednisolone (index date) in 32.8% of patients (607/1,853). Shorter durations of prednisolone treatment were associated with colonoscopy ≤1 month before or at the index date and higher prednisolone dose at index date, with incidence rate ratios (IRRs) of 0.776 (95% confidence interval [CI], 0.682-0.884; P<0.001) and 0.998 (95% CI, 0.996-1.000; P=0.018), respectively. Charlson Comorbidity Index scores of 1 and ≥2 predicted longer prednisolone treatment (IRR, 1.332; 95% CI, 1.174-1.511; P<0.001 and IRR, 1.599; 95% CI, 1.357-1.885; P<0.001, respectively). CONCLUSIONS: Performing colonoscopy before or at the time of initiating steroid was associated with a shorter duration of steroid use in patients with UC.

Computational Simulation Model to Predict Behavior Changes in Inflammatory Bowel Disease Patients during the COVID-19 Pandemic: Analysis of Two Regional Japanese Populations.

Managing inflammatory bowel disease (IBD) is a major challenge for physicians and patients during the COVID-19 pandemic. To understand the impact of the pandemic on patient behaviors and disruptions in medical care, we used a combination of population-based modeling, system dynamics simulation, and linear optimization. Synthetic IBD populations in Tokyo and Hokkaido were created by localizing an existing US-based synthetic IBD population using data from the Ministry of Health, Labor, and Welfare in Japan. A clinical pathway of IBD-specific disease progression was constructed and calibrated using longitudinal claims data from JMDC Inc for patients with IBD before and during the COVID-19 pandemic. Key points considered for disruptions in patient behavior (demand) and medical care (supply) were diagnosis of new patients, clinic visits for new patients seeking care and diagnosed patients receiving continuous care, number of procedures, and the interval between procedures or biologic prescriptions. COVID-19 had a large initial impact and subsequent smaller impacts on demand and supply despite higher infection rates. Our population model (Behavior Predictor) and patient treatment simulation model (Demand Simulator) represent the dynamics of clinical care demand among patients with IBD in Japan, both in recapitulating historical demand curves and simulating future demand during disruption scenarios, such as pandemic, earthquake, and economic crisis.

A Computational Platform Integrating a Mechanistic Model of Crohn's Disease for Predicting Temporal Progression of Mucosal Damage and Healing.

INTRODUCTION: Physicians are often required to make treatment decisions for patients with Crohn's disease on the basis of limited objective information about the state of the patient's gastrointestinal tissue while aiming to achieve mucosal healing. Tools to predict changes in mucosal health with treatment are needed. We evaluated a computational approach integrating a mechanistic model of Crohn's disease with a responder classifier to predict temporal changes in mucosal health. METHODS: A hybrid mechanistic-statistical platform was developed to predict biomarker and tissue health time courses in patients with Crohn's disease. Eligible patients from the VERSIFY study (n = 69) were classified into archetypical response cohorts using a decision tree based on early treatment data and baseline characteristics. A virtual patient matching algorithm assigned a digital twin to each patient from their corresponding response cohort. The digital twin was used to forecast response to treatment using the mechanistic model. RESULTS: The responder classifier predicted endoscopic remission and mucosal healing for treatment with vedolizumab over 26 weeks, with overall sensitivities of 80% and 75% and overall specificities of 69% and 70%, respectively. Predictions for changes in tissue damage over time in the validation set (n = 31), a measure of the overall performance of the platform, were considered good (at least 70% of data points matched), fair (at least 50%), and poor (less than 50%) for 71%, 23%, and 6% of patients, respectively. CONCLUSION: Hybrid computational tools including mechanistic components represent a promising form of decision support that can predict outcomes and patient progress in Crohn's disease.

Lack of Increased Risk of Lymphoma by Thiopurines or Biologics in Japanese Patients with Inflammatory Bowel Disease: A Large-Scale Administrative Database Analysis.

BACKGROUND AND AIMS: Patients with inflammatory bowel diseases may have higher incidences of non-melanoma skin cancers and non-Hodgkin lymphoma, potentially linked to underlying disease and treatments. This analysis assessed incidence rates of these malignancies in Japanese patients with ulcerative colitis or Crohn's disease, and their association with thiopurine and/or anti-tumor necrosis factor-α treatment, using data from a nationwide administrative database in Japan. METHODS: Patients diagnosed with inflammatory bowel disease without malignancy were identified from the Medical Data Vision database. Incident cases of non-melanoma skin cancers and non-Hodgkin lymphoma diagnosed after prescription of thiopurine and/or anti-tumor necrosis factor-α were identified between April 2008 and January 2018. Age- and sex-adjusted incidence rate ratios were calculated relative to the total treated patient population. RESULTS: A total of 75 673 eligible patients were identified at the index date. Thiopurine prescription with or without anti-tumor necrosis factor-α agents increased incidence rate ratios for non-melanoma skin cancers relative to the overall population (3.39 and 4.03, respectively). There were no notable differences in non-Hodgkin lymphoma incidence relative to the total population in any treatment subgroup, regardless of prescription of thiopurine and/or anti-tumor necrosis factor-α (all incidence rate ratios, ~1). CONCLUSIONS: There is no evidence for an increased incidence of non-Hodgkin lymphoma attributable to thiopurine or anti-tumor necrosis factor-α treatment in Japanese patients with inflammatory bowel disease. The impact of racial differences on non-Hodgkin lymphoma incidences should be considered. Thiopurine therapy may be a risk factor for non-melanoma skin cancers in Japanese patients.

The Effect of Heat-acid Treatment on the Formation of Resistant Starch and the Estimated Glycemic Index in Potatoes.

Potatoes are generally regarded as high glycemic index (GI) foods. Resistant starch (RS) comprises the starch fraction that is not absorbed in the small intestine, thus controlling the glucose level and improving the intestinal environment. In this study, an analysis of the formation of RS of potato starch samples under different acetic acid-thermal treatment conditions was conducted. Additionally, the relationship between the rates of starch digestion, estimated GI (eGI), and the RS content was evaluated by employing in vitro enzymatic models. Compared with control samples, the RS content in the cold-stored samples after acid-boiling was higher, whereas that of samples after heating at 120 °C with acetic acid was decreased. The eGI was negatively correlated with the RS content in potatoes. Cold store after acid-boiling was effective in increasing the RS content. Furthermore, low eGI values may have resulted from higher levels of RS in potatoes.

Resistant starch suppresses postprandial hypertriglyceridemia in rats.

Postprandial increase in blood triglyceride levels is an independent risk factor for coronary artery disease, and dietary resistant starch (RS) is increasingly being considered for its contribution to disease prevention. Specifically, RS has beneficial effects on of the glycemic index, diabetes, cholesterol levels, and weight management. However, the effects of once-daily intake of RS on postprandial hypertriglyceridemia remain poorly characterized. In this study, the effects of a single administration of cornstarch-derived RS on postprandial increases in blood triglyceride levels were investigated in rats using oral fat tolerance/loading tests. Following the administration of lipid meals, increases in serum triglycerides levels were significantly reduced in rats fed corn oil containing 500mg/mL RS. Moreover, fecal lipid volumes and wet weights following lipid meals were significantly greater in rats fed corn oil containing 500mg/mL RS than in the corn oil only group, confirming the inhibition of dietary fat absorption. Finally, a significant positive correlation was observed between fecal lipid contents and wet weights in rats administered RS. These results suggest that RS intake with dietary fats induces defecation and confirm results of recent reports on the health-promoting potential of once-daily RS intake.