Search

Introduction Lubiprostone capsules are approved for managing three different chronic constipation conditions. A “sprinkle” formulation may facilitate use in individuals with difficulty swallowing capsules. Our objective was to evaluate the bioequivalence, pharmacokinetics (PK), and bioavailability of lubiprostone sprinkles vs lubiprostone capsules, compared with placebo. Methods A 1-week randomized, placebo-controlled, double-blinded, bioequivalence study (study 302) and a single-dose PK and bioavailability crossover study (study 304) were conducted. In study 302, 522 subjects with chronic constipation were randomized to lubiprostone sprinkle 24 μg twice daily (BID), lubiprostone capsule 24 μg BID, or placebo. The primary efficacy endpoint was observed spontaneous bowel movement (SBM) counts (equivalence defined as showing the 90% confidence interval [CI] of the “between-group SBM ratio” to be contained within 0.8–1.25). Study 304 included two cohorts of healthy volunteers randomized to a single 48-μg lubiprostone dose, sprinkle, or capsule (n = 35) or to a single 48-μg sprinkle dose, in fed or fasted state (n = 14). Results Both lubiprostone formulations significantly improved SBM count (sprinkle, 4.82 ± 3.66, P = 0.002; capsule, 5.74 ± 3.79, P

Many patients with chronic idiopathic constipation (CIC) remain unsatisfied with their treatment options. Plecanatide is a pH-sensitive uroguanylin analog that increases fluid and ion movement into the gastrointestinal lumen, softening stools and encouraging motility, while limiting the risk of diarrhea. The objective of this phase 2 study is to evaluate the safety and efficacy of once-daily oral plecanatide in patients with CIC and identify the most effective dose. A 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was conducted in patients aged 18–75 years and diagnosed with CIC based on modified Rome III criteria (

Background This randomized, open-label phase 2a study investigated the safety/tolerability, pharmacokinetics, and efficacy of olorinab—a highly selective, peripherally acting, full agonist of the cannabinoid receptor 2—in patients with Crohn’s disease (CD) experiencing abdominal pain. Methods Eligible subjects 18–80 years of age with quiescent to mildly active CD were randomized to receive olorinab 25 or 100 mg three times daily for 8 weeks. The primary objective was to assess safety/tolerability. Results Fourteen subjects received olorinab 25 mg (N = 6) or 100 mg (N = 8). Ten subjects [4 (67%) in the 25-mg group and 6 (75%) in the 100-mg group] reported a total of 34 treatment-emergent adverse events (TEAEs; 32 grade 1/2, not serious events; 2 grade 3, serious, not treatment-related events). No dose reductions or discontinuations due to TEAEs or deaths were reported. Dose-proportional increases in olorinab exposure from 25 to 100 mg were observed, with minimal accumulation at both doses. At week 8, the mean (SD) change from baseline in average abdominal pain score at peak olorinab plasma concentrations was −4.61 (1.77) in the 25-mg group (P = 0.0043) and −4.57 (2.17) in the 100-mg group (P = 0.0036). The change from baseline at week 8 in the mean (SD) number of pain-free days per week was +1.60 (2.61) in the 25-mg group and +2.33 (3.62) in the 100-mg group. No subject required pain medication on study. Conclusions Patients with quiescent to mildly active CD receiving olorinab experienced mild-to-moderate adverse events and an improvement in abdominal pain scores in this study.

This multi-center, fixed-dose, open-label study evaluated the long-term safety and tolerability of once-daily oral plecanatide for the treatment of adults with chronic idiopathic constipation (CIC).Eligible patients completed a phase 2b or phase 3 double-blind study of plecanatide, or had not previously been treated with plecanatide. Enrolled patients received plecanatide (3 or 6 mg) for up to 72 weeks. Safety and tolerability were assessed by the incidence, nature, and severity of spontaneously reported treatment-emergent adverse events (TEAEs). Patients also completed Patient Global Assessment questionnaires, which included measures of treatment satisfaction and the desire to continue treatment.There were 2370 patient exposures in this study, with the vast majority (90.5%) receiving treatment with plecanatide 6 mg. At the time of study closure, 1932 (81.5%) had completed or were still receiving study drug. TEAEs were qualitatively and quantitatively similar to those observed in prior double-blind studies. The most common TEAEs were diarrhea (7.1%) and urinary tract infection (2.2%). TEAEs leading to discontinuation occurred in 5.3% of patients, with diarrhea leading to discontinuation in 3.1%. Most TEAEs were mild/moderate in severity and were generally considered not related to plecanatide treatment. At the end of treatment, the median score for treatment satisfaction was 4.0 (quite satisfied), and the median score for treatment continuation was 4.0 (quite likely).Long-term treatment of adults with CIC demonstrated that plecanatide was safe and well tolerated, with low TEAE and discontinuation rates. Patients indicated satisfaction and a desire to continue with plecanatide treatment.

Objective: This open-label, multi-center, fixed-dose study (NCT02706483) evaluated the long-term safety and tolerability of plecanatide for the treatment of adults with irritable bowel syndrome wit...

Summary Background A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet. Methods We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18–70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 μg, 90 μg, or 150 μg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 μg or 300 μg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence, and biopsy cohorts had a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. Findings Participants were enrolled from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. In the three-dose study, nine participants were randomly allocated to Nexvax2 60 μg and three to placebo (first cohort), nine were allocated to Nexvax2 90 μg and four to placebo (second cohort), eight were allocated to Nexvax2 150 μg and four to placebo (third cohort), and three were allocated to Nexvax2 150 μg and three to placebo (biopsy cohort). In the 16-dose study, eight participants were randomly allocated to Nexvax2 150 μg and four to placebo (first cohort), ten were allocated to Nexvax2 300 μg and three to placebo (second cohort), and seven were allocated to Nexvax2 150 μg and seven to placebo (biopsy cohort). The MTD for Nexvax2 was 150 μg because of transient, acute gastrointestinal adverse events with onset 2–5 h after initial doses of the vaccine, similar to those caused by gluten ingestion. In the ascending dose cohorts in the three-dose study, six (55%) of 11 placebo recipients, five (56%) of nine who received Nexvax2 60 μg, seven (78%) of nine who received Nexvax2 90 μg, and five (63%) of eight who received Nexvax2 150 μg had at least one treatment-emergent adverse event, as did all three (100%) placebo recipients and one (33%) of three Nexvax2 150 μg recipients in the biopsy cohort. In the ascending dose cohorts of the 16-dose study, five (71%) of seven placebo-treated participants, six (75%) of eight who received Nexvax2 150 μg, and all ten (100%) who received Nexvax2 300 μg had at least one treatment-emergent adverse event, as did six (86%) of seven placebo recipients and five (71%) of seven Nexvax2 150 μg recipients in the biopsy cohort. Vomiting, nausea, and headache were the only treatment-emergent adverse events that occurred in at least 5% of participants in either study. Among participants given the MTD, eight gastrointestinal treatment-emergent adverse events occurred in four (50%) of eight participants in the third cohort and none (0%) of three participants in the biopsy cohort in the three-dose study, and five events occurred in five (63%) of eight participants in the first cohort and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Median villous height to crypt depth ratio in distal duodenal biopsies was not significantly different between those who received the vaccine at the MTD on either schedule and those who received placebo. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative (responders to treatment) in two (22%) of nine placebo-treated participants in the three-dose study versus two (33%) of six who received Nexvax2 60 μg, five (63%) of eight who received Nexvax2 90 μg, and six (100%) of six who received Nexvax2 150 μg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 μg (p=0·021). Interpretation The MTD of Nexvax2 was 150 μg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides without deterioration in duodenal histology. The gastrointestinal symptoms that followed the first intradermal administration of the vaccine resembled those associated with oral gluten challenge. These findings support continued clinical development of this potential therapeutic vaccine for coeliac disease. Funding ImmusanT.

Iron deficiency anemia (IDA) is a common finding in patients after bariatric surgery. The cause is multifactorial including reduced oral iron intake and malabsorption. While many patients can be managed with oral supplements, parenteral iron may be needed to restore and maintain iron stores. Subjects who had previous bariatric surgery and had participated in phase 3 industry-sponsored clinical trials designed to assess the safety and/or efficacy of intravenous (IV) ferric carboxymaltose (FCM) were retrospectively selected from the databases of each of these studies. Demographic data, efficacy measures [hemoglobin, ferritin, and transferrin saturation (TSAT)], and adverse events were compared between FCM and other agents utilized as comparators in the trials. Two hundred eighty-one subjects from the intention to treat (ITT) population were included (mean age 49 years, BMI 33 kg/m2, including 253 females). FCM had similar or improved efficacy (p

David C Ford,1 Naomi V Dahl,2 William E Strauss,2 Charles F Barish,3 David J Hetzel,4 Kristine Bernard,2 Zhu Li,2 Lee F Allen,2 1Toronto Digestive Disease Associates, Inc, Vaughan Endoscopy Clinic, Vaughan, ON, Canada; 2AMAG Pharmaceuticals, Inc, Waltham, MA, 3Wake Gastroenterology, Wake Research Associates, Raleigh, NC, USA; 4Department of Gastroenterology, Royal Adelaide Hospital, Adelaide, SA, Australia Introduction: Iron deficiency anemia (IDA) is common in patients with gastrointestinal (GI) disorders and can adversely affect quality of life. Oral iron is poorly tolerated in many patients with GI disorders. Ferumoxytol is approved for the intravenous treatment of IDA in patients with chronic kidney disease. This study aimed to evaluate the efficacy and safety of ferumoxytol in patients with IDA and concomitant GI disorders. Patients and methods: This analysis included 231 patients with IDA and GI disorders from a Phase III, randomized, double-blind, placebo-controlled trial evaluating ferumoxytol (510 mg ×2) versus placebo in patients who had failed or were intolerant of oral iron therapy. The primary study end point was the proportion of patients achieving a ≥20 g/L increase in hemoglobin (Hgb) from baseline to Week 5. Other end points included mean change in Hgb, proportion of patients achieving Hgb ≥120 g/L, mean change in transferrin saturation, and patient-reported outcomes (PROs). Results: Significantly more patients with IDA receiving ferumoxytol achieved a ≥20 g/L increase in Hgb versus placebo (82.1% vs 1.7%, respectively; P

Remimazolam is an ultrashort-acting benzodiazepine.We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (the randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 μg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator's discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and ≤5 doses of remimazolam or placebo in any 15-minute interval (≤3 doses of midazolam in any 12-minute interval in the open-label midazolam arm).There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P .0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge earlier, and felt back to normal sooner than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam, and hypoxia occurred in 1% of patients with remimazolam or midazolam. There were no treatment-emergent serious adverse events.Remimazolam can be administered safely under the supervision of endoscopists for outpatient colonoscopy, and it allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. (Clinical trial registration number: NCT02290873.).

The aim of this study is to assess the efficacy and safety of lubiprostone in adults with chronic constipation.This multicenter, parallel-group trial enrolled 237 patients with chronic constipation and randomized them to 4 weeks of double-blind treatment with oral lubiprostone 24 mcg or placebo twice daily. The primary efficacy endpoint was the number of spontaneous bowel movements (SBMs) after 1 week of treatment. Secondary evaluations included SBMs at weeks 2, 3, and 4; percentage of patients with a SBM within 24 h of first study dose; stool consistency; degree of straining; constipation severity; abdominal bloating and discomfort; global treatment effectiveness; and safety assessments.Lubiprostone-treated patients experienced greater mean numbers of SBMs at week 1 compared with placebo (5.89 versus 3.99, P = 0.0001), with significantly greater percentages having SBMs within 24 h of the first dose (61.3% versus 31.4%, P0.0001). At each assessment, SBM frequency and percentages of full responders (or =4 SBM per week) were significantly greater among lubiprostone-treated patients compared with placebo (Por = 0.0171). Lubiprostone-treated patients reported significant improvements in stool consistency, straining, and constipation severity at all weeks, and in abdominal bloating at week 1. Patient assessments of treatment effectiveness were significantly greater with lubiprostone compared with placebo at all weeks (P0.0004). Gastrointestinal-related disorders were the most common adverse events in both treatment groups.In patients with chronic constipation, lubiprostone produced a bowel movement in the majority of individuals within 24 h of initial dosing, with sustained improvement in frequency as well as other constipation symptoms over 4 weeks of treatment.

Background: Interleukin-11 is a mesenchymally derived cytokine with pleiotropic activities. A pilot study suggested therapeutic benefit of recombinant human interleukin-11 (rhIL-11) in patients with Crohn's disease. Aim: To determine the safety and preliminary estimate of efficacy of rhIL-11 in treating active Crohn's disease. Methods: Patients with mild to moderately active Crohn's disease, defined as a Crohn's disease activity index (CDAI) ≥ 220 and ≤ 450, were enrolled in a multicentre trial. Stable doses of 5-aminosalicylates, antibiotics, 6-mercaptopurine or azathioprine were permitted with appropriate wash-in periods. Oral, intravenous or rectally administered corticosteroids were not allowed. Patients were randomized to 6 weeks of subcutaneous injection with rhIL-11 15 μg/kg or placebo weekly, or rhIL-11 7.5 μg/kg or placebo twice weekly. The primary end-point was per cent change in CDAI at week 6; the major secondary end-point was the proportion of patients in remission, defined as a 100 point decrease in CDAI and absolute CDAI ≤ 150. Results: Baseline characteristics were similar among the 148 evaluated patients (49 placebo, 49 rhIL-11 15 μg/kg once weekly, 50 rhIL-11 7.5 μg/kg twice weekly). Treatment was well-tolerated, with mild injection site reactions occurring more frequently among patients treated with rhIL-11. Headache, oedema, and increased platelet count occurred significantly more often in the rhIL-11 7.5 μg/kg twice weekly group, but not the 15 μg/kg once weekly group. There was a trend toward decreased mean per cent change in CDAI in the rhIL-11 15 μg/kg once weekly group vs. placebo (–31.5% vs. – 18.5%, 95% confidence interval for the difference – 27.9–1.6%). A significantly greater proportion of patients receiving rhIL-11 15 μg/kg once weekly achieved remission compared to placebo (36.7% vs. 16.3%, 95% confidence interval for the difference 3.4–37.4%; 16.4% for rhIL-11 7.5 μg/kg, N.S.). Conclusions: Weekly subcutaneous injection with rhIL-11 15 μg/kg is safe and effective in inducing remission in a subset of patients with active Crohn's disease.

Background Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. Methods In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14–18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. Results A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of −7.0 mm in favor of NTG 0.4% (95% CI −13.6, –0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. Conclusions This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. Trial registration ClinicalTrials.gov, NCT00522041

Background. Iron deficiency anemia (IDA) is a common hematological complication with potentially serious clinical consequences that may require intravenous iron therapy. Ferric carboxymaltose (FCM) is a stable, nondextran iron formulation administered intravenously in large single doses to treat IDA.Objective. Two open-label, randomized, placebo-controlled trials evaluated safety of multiple or single 750 mg FCM doses compared to standard medical care (SMC) in IDA patients. Secondary endpoints were improvements in hemoglobin and iron indices.Design and Patients. Adults with hemoglobin ≤12 g/dL, ferritin ≤100 or ≤300 ng/mL with transferrin saturation ≤30% were randomized to receive single (n=366) or weekly (n=343) FCM or SMC (n=360andn=366).Results. Significantly greater (P≤0.001) increases in hemoglobin and iron indices occurred in FCM groups versus SMC. In the multidose study, up to two infusions of FCM were needed to reach target iron levels versus 3–5 of intravenous iron comparators. FCM and SMC groups had similar incidences and types of adverse events and serious adverse events. Transient hypophosphatemia not associated with adverse events or clinical sequelae occurred in the FCM groups.Conclusion. Intravenous FCM is safe, well tolerated, and associated with improvements in hemoglobin and iron indices comparable to SMC when administered in single doses of up to 750 mg at a rate of 100 mg/min. Fewer FCM infusions were required to reach target iron levels compared to other intravenous iron preparations.

Background: Natalizumab, a humanized monoclonal IgG4 antibody to α4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied. Methods: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score ≥ 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment. Results: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (−37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug–drug interactions were noted. Conclusions: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone. (Inflamm Bowel Dis 2007;13:2–11)

A residue-free sodium phosphate tablet (RF-NaP) was formulated that lacks microcrystalline cellulose, which can appear as a whitish residue in the colon. A multicenter, randomized, investigator-blinded study was conducted to compare the colon-cleansing efficacy of 40 or 32 tablets of RF-NaP with the marketed 40-tablet NaP treatment regimen.Eight hundred sixteen patients were randomized prior to colonoscopy to receive either 40 tablets (60 g) of NaP or RF-NaP or 32 tablets (48 g) of RF-NaP. Colon cleansing was assessed using a 4-point scale based on retained "colonic contents." The primary end point was overall colon-cleansing response rate to treatment (score of excellent/good) versus nonresponse (fair/inadequate).Seven hundred four patients were included in the efficacy analysis. The overall colon-cleansing response rates were comparable among treatment arms (94.5%, 97.0%, and 95.3% for NaP, RF-NaP 40, and RF-NaP 32 tablets, respectively). Ascending colon-cleansing response rates for RF-NaP 40 (95.7%) and 32 tablets (93.6%) were significantly better than for NaP tablets (88.5%, p0.03 for both). Patients treated with RF-NaP 32 tablets experienced less pronounced changes in electrolyte levels and fewer adverse events (138/239, 58%) compared with patients receiving NaP (161/238, 68%, p= 0.07) and RF-NaP 40 tablets (156/236, 66%, p= 0.03). The most common adverse events reported were abdominal distention, nausea, abdominal pain, and vomiting.Based on the safety, efficacy, and patient preferences, the 32-tablet RF-NaP regimen was superior to the 40-tablet RF-NaP and NaP regimen for colon cleansing prior to colonoscopy.

Background: Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease. Materials and Methods: We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity. Results: STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42% - 82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI

Current understanding of inflammatory bowel disease (IBD) has resulted in the development of new treatments that antagonise the pathological pathways associated with T lymphocytes and inflammatory cytokines. Intercellular adhesion molecules (ICAMs) contribute to leukocyte adhesion and migration, local lymphocyte stimulation, and are responsible for T lymphocyte trafficking in the intestine. ICAMs are constitutively expressed by enterocytes and are upregulated in the presence of inflammation. Mobile T lymphocytes in the circulatory system are key to the deleterious inflammatory response resulting in IBD. Alicaforsen, a human ICAM-1 antisense oligonucleotide, blocks ICAM-1 production by disabling target RNA molecules and blocking the translation of protein. This alters the local inflammatory reaction in the intestinal wall. Alicaforsen has been evaluated in both Crohn's disease and ulcerative colitis. The role of the immune system in IBD is reviewed and the responses to treatment with alicaforsen are discussed.

BACKGROUND: An estimated 220,000 bariatric surgeries are performed in the US yearly. Malabsorption of nutrients after bariatric surgery is common and may lead to IDA, with incidence rates of up to 49%. OBJECTIVE: To evaluate the economic, MRU, clinical outcomes, and treatment of IDA in adult bariatric surgery patients with commercial insurance coverage. METHODS: Using Truven Health MarketScan® claims data, bariatric surgery patients were identified by ICD-9-CM and CPT codes then classified by surgery and IDA diagnosis within two years of initial surgery. Intravenous (IV) iron treatment was determined by HCPCS codes, prescription oral iron by NDC codes, and blood transfusions by CPT and ICD-9CM codes. Clinical, MRU, and economic outcomes for all-cause health services were compared between IDA and non-IDA patients. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, controlling for demographic and clinical characteristics on outcomes of complications and hospitalization. RESULTS: Of the 24,382 bariatric surgery patients analyzed, 11.7% received an IDA diagnosis 2 years post-surgery (avg days to diagnosis=279). Most (98.7%) of the IDA group developed anemia post surgery. Most IDA patients received a test for iron in the post-index period; only 9.3% received IV iron treatment, with iron dextran (3.8%) and iron sucrose (3.4%) being the most common (avg days to IV iron treatment=403 days). Prescription oral iron was found in 4.8% of all IDA patients (avg days to oral iron treatment=477). Approximately 9% of IDA patients received a blood transfusion (avg days to transfusion=306). Average age was 46 years with a higher percentage of females (83.8% IDA, 78.8% non-IDA). Most clinical characteristics were similar, except heart disease (1.3% IDA vs 0.8% non-IDA; P=0.003) and gallbladder disease (0.0% IDA vs 0.2% non-IDA; P=0.037).More IDA patients had post-surgery complications (40.4% vs 27.7%; P

Background Estimates show there are approximately 220,000 cases of bariatric surgery performed in the United States (US) each year. Malabsorption of nutrients, including vitamins and minerals following bariatric surgery is common and may lead to iron deficiency anemia (IDA), with some studies showing incidence rates up to 49% of bariatric surgery patients. Objective The purpose of this study was to evaluate the economic, medical resource use (MRU), and clinical outcomes of IDA in adult bariatric surgery patients having commercial insurance coverage, and to further evaluate the treatment of IDA in this population. Methods This study was based on the Truven Health MarketScan® claims databases. Bariatric surgery patients were identified by ICD-9-CM and CPT procedure codes for restrictive, malabsorptive, and combined restrictive/malabsorptive bariatric surgeries; and further classified as an IDA patient if an IDA diagnosis was identified within two years of initial surgery. Intravenous (IV) iron treatment was determined by HCPCS codes. Prescription oral iron treatment was determined by NDC codes. Blood transfusions were determined by CPT and ICD-9-CM procedure codes. Clinical, MRU, and economic outcomes, including hospitalization, bariatric surgery complications, MRU and payer reimbursement for all-cause health services were evaluated over a two-year period following surgery and compared between patients with and without IDA. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, controlling for demographic and clinical characteristics (including post-surgery IDA status, diabetes, cancer, sleep apnea, heart disease, stroke, hypertension, dyslipidemia, gallbladder disease, osteoarthritis, and chronic back pain) on the outcomes of bariatric surgery complications and hospitalization in the post-surgery period. Results A total of 24,382 bariatric surgery patients were analyzed, and 2,845 (11.7%) patients were diagnosed with IDA in the two-year period following surgery (average days to IDA diagnosis = 279 days). Of the patients with IDA, nearly all (98.7%) developed their anemia following surgery. Most IDA patients received a test for iron in the post-index period, but only 9.3% of all IDA patients received IV iron treatement with either iron dextran (3.8%) and iron sucrose (3.4%) being the most common treatments (average days until IV iron treatment = 403 days). Prescription oral iron was found in 4.8% of all IDA patients (average days to oral iron treatment = 477 days). Approximately 9.0% of all IDA patients received a blood transfusion (average days until blood transfusion = 306 days). Average age was 46 years for patients with and without IDA and more females were found in each group (83.8% in patients with IDA, 78.8% in patients without IDA). Clinical characteristics were similar between groups with the exception of heart disease (1.3% patients with IDA vs 0.8% patients without IDA; P = 0.003) and gallbladder disease (0.0% patients with IDA vs 0.2% patients without IDA; P = 0.037). More IDA patients were associated with a bariatric surgery complication than patients without IDA (40.4% vs 27.7%; P < 0.001) with most complications attributable to other and unspecified postsurgical complications: nonabsorption (22.4% vs 16.5%; P < 0.001), digestive system complications (15.6% vs 10.2%; P < 0.001), and gastrojejunal ulcer (7.6% vs 2.0%; P < 0.001). Multivariate results showed IDA patients were more likely to have a bariatric surgical complication as compared to patients without IDA [OR (95 % CI) = 1.372 (1.262, 1.492)]. IDA patients were hospitalized more often than patients without IDA (42.9% vs 20.9%; P < 0.001) and adjusted results showed IDA patients to be more than twice as likely to be hospitalized [OR (95% CI) = 2.574 (2.370, 2.796)]. Total costs were twice as much among IDA patients as compared to those without IDA ($38,025 vs $19,245; P < 0.001) (Figure 1). Conclusions Bariatric surgery patients that develop IDA may be associated with higher complication rates as well as higher MRU and direct medical costs. Although most bariatric surgery patients that develop IDA are tested for their iron, most are not treated with IV iron, oral iron, and most do not receive blood transfusions. Further research is warranted to determine if IDA is a result of bariatric surgery complications or a predictor of increased MRU and costs. Disclosures: Knight: Covance: Consultancy. D'Sylva:American Regent Inc.: Employment. Moore:Covance: Consultancy. Barish:Wake Gastroenterology/Wake Research Associates: Honoraria.

Currently available IV iron agents pose substantial safety and practical challenges to effective management of iron deficiency anemia. Iron dextran administration requires a test dose and carries the risk of anaphylaxis. Non-dextran-containing IV iron agents (iron sucrose and ferric gluconate) do not require a test dose nor have this safety issue, but pose some practical challenges. These agents are FDA approved only for chronic kidney disease indications and require repeated administration of small doses (125 mg of iron as ferric gluconate over 10 minutes, 200 mg of iron as iron sucrose over 2–5 minutes, or 300–400 mg of iron as iron sucrose over 1.5 to 2.5 h). Accordingly, in a multicenter, randomized, blinded, placebo-controlled, crossover trial we assessed the safety of iron carboxymaltose, a new, investigational non-dextran IV iron complex that allows for rapid administration of high doses of iron. Five-hundred and eighty four (584) iron deficiency anemia patients received either a blinded dose of IV iron carboxymaltose (15 mg/kg up to a maximum of 1000 mg in NS) or placebo over 15 minutes on Day 0. On Day 7, patients were crossed over to receive either placebo or iron carboxymaltose utilizing the same dosing as Day 0. We recorded all adverse events and classified as an adverse drug event (ADE) any that was considered by the investigator as being possibly or probably related to study drug. The mean dose of iron carboxymaltose administered was 962 (+ 88) mg. No CTC Grade 4 or 5 or serious ADE were reported and no subject discontinued from study drug due to an ADE. No clinically important differences in vital signs or physical exams were noted between subjects treated with iron carboxymaltose and placebo. During the post dose 24-h and 7-d treatment period, ADEs reported by >1% of patients in either treatment were higher in patients after receiving iron carboxymaltose than in patients after receiving placebo. The 24-h period events included nausea (2.1% iron carboxymaltose vs. 1.1% placebo), headache (2.0% vs. 1.3%), and dizziness (1.3% vs. 0.2%). The 7-d period events included nausea (2.5% iron carboxymaltose vs. 1.1% placebo), ALT increased (1.3% vs. 0.2%), AST increased (1.3% vs. 0%), headache (2.9% vs. 1.4%), dizziness (1.6% vs.0.2%) and rash (1.1% vs. 0.2%). The majority of the ADEs were classified by the investigator as mild to moderate. No ADE consistent with a hypersensitivity reaction was reported. One patient experienced a transient, asymptomatic, CTC Grade 1 decrease in BP (from 132/85 to 95/68 mmHg) which resolved spontaneously. CTC Grade 3 ADEs were reported in 4 patients after receiving iron carboxymaltose (headache and asymptomatic decrease in serum phosphate) and 5 patients (rash, creatinine increase and asymptomatic decrease in serum phosphate) after receiving placebo. We conclude that rapid administration of high dose iron carboxymaltose (15 mg/kg for maximum of a 1,000 mg over 15 minutes) is well tolerated and associated with minimal risk of ADE in a large cohort of patients with iron deficiency anemia.

Many cases of recurrent noncardiac chest pain are considered to be of esophageal origin. The mechanism of this pain is poorly understood and only rarely appears related to abnormal esophageal contractions observed during manometry. We studied the response to intraesophageal balloon distention in 30 patients with noncardiac chest pain (mean age 52 yr) and 30 controls (mean age 41 yr). A polyvinyl balloon (length 30 mm; maximum diameter after 10-ml distention, 25 mm) was positioned 10 cm above the lower esophageal sphincter and inflated with progressively larger volumes of air (each increase = 1 ml). Chest pain was correlated with balloon volumes and pressures, esophageal contractions 5 cm above the balloon, and electrocardiogram changes. Results were as follows: 18 of 30 (60%) patients and 6 of 30 (20%) controls (p less than 0.005) experienced chest pain. Electrocardiogram changes of ischemia were not seen. Neither balloon pressures nor esophageal contractions above the balloon differed significantly during pain in the controls or patients. As assessed by pressure-volume curves, esophageal tone was also similar in all subjects regardless of pain production. Patients were more sensitive to smaller volumes of balloon distention; 15 of 18 patients had chest pain at less than or equal to 8 ml volume while controls only noted chest pain at greater than or equal to 9 ml volume. We therefore arrived at the following conclusions: esophageal balloon distention may provide a nonpharmacologic provocative test for esophageal chest pain; and the mechanism of chest pain in these patients may be related to lower pain threshold to balloon distention, which is independent of esophageal contractions.

The evaluation of suspected esophageal chest pain is frustrating because of difficulty in clearly implicating the esophagus. Balloon distention was considered as a new provocative test in the esophagus because it has been shown to safely produce pain in other hollow gastrointestinal organs. Studies were performed in 50 chest pain patients (mean age 50 years) with negative coronary arteriograms and 30 healthy volunteers (mean age 41 years). A polyvinyl balloon (length 30 mm; maximum diameter after 10 cc distention 25 mm) was positioned 10 cm above the lower esophageal sphincter and inflated with 1-cc increments of air to a total volume of 10 cc. Using a placebo-controlled design, pain response was recorded along with associated balloon volumes. Pain occurred in 28/50 (56%) patients and 6/30 (20%) volunteers (P less than 0.005). Symptoms were unassociated with ECG changes, and resolved immediately with decompression of the balloon. Most patients (24/28) experienced their typical chest pain at less than or equal to 8 cc distention, while all volunteers with pain noted it at greater than or equal to 9 cc distention. For this reason, 8 cc was considered a diagnostic cutoff. Chest pain patients were also studied with two other commonly used provocative tests: intraesophageal acid perfusion and intravenous edrophonium (80 micrograms/kg). These tests reproduced pain in only 12 (24%) patients. Positive balloon studies occurred in 11 of these patients and identified an additional 13 patients, thus increasing the diagnostic yield from 24% to 48%. Only one of 22 (4%) balloon-negative patients had a positive acid-perfusion or edrophonium test.

We report two patients with systemic lupus erythematosus (SLE) who were found to have complete (acidotic) distal renal tubular acidosis (DRTA). One patient had nephrocalcinosis and renal magnesium wasting with tetany; the other patient had nephrolithiasis and nephrotic syndrome secondary to membranous glomerulopathy. Both patients had decreased urinary citrate excretion but neither had hypercalciuria. We discuss the association of DRTA with immunologic disorders and the possible role of hypocitraturia in promoting renal calcification in these patients. We suggest that patients with renal calcification be evaluated for DRTA, and that patients found to have DRTA be further evaluated for signs, symptoms, and laboratory evidence of immunologic disorders.

• Gastroesophageal reflux (GER) and its many manifestations are extremely common problems. The pulmonary manifestations are the least well understood and are often unrecognized. We reviewed the available literature on the subject of respiratory tract symptoms secondary to chronic GER in an attempt to promote wider recognition of this relationship. We hope that this review will call attention to the potential importance of GER in those patients in whom such a mechanism might be responsible for pulmonary symptoms. ( Arch Intern Med 1985;145:1882-1888)

• Venous thrombosis, resulting in superior vena cava syndrome, developed in a patient with two permanent transvenous pacemaker wires. Therapy with streptokinase resulted in prompt relief of the obstruction, with no complications. In properly selected patients, streptokinase may be the treatment of choice for this potentially life-threatening problem. ( Arch Intern Med 1983;143:1050-1052)