Scott D. Lee

Vedolizumab as induction and maintenance therapy for Crohn's disease

BACKGROUND The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohns disease is unknown. METHODS In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohns disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohns Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS Vedolizumab-treated patients with active Crohns disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease.

BACKGROUND & AIMS Some women with inflammatory bowel disease require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus via the placenta and then cleared, or whether structurally different TNF antagonists have different rates of transfer. METHODS We studied 31 pregnant women with inflammatory bowel disease receiving infliximab (IFX, n = 11), adalimumab (ADA, n = 10), or certolizumab (CZP, n = 10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. RESULTS Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were less than 2 μg/mL. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. CONCLUSIONS The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohns disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohns Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohns disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

Certolizumab pegol in patients with moderate to severe Crohn's disease and secondary failure to infliximab.

BACKGROUND & AIMS Patients with moderate to severe Crohns disease who receive infliximab may experience secondary failure (loss of response and/or hypersensitivity). Data on the utility of switching to certolizumab pegol in these patients are limited. METHODS A total of 539 patients with active Crohns disease and secondary failure to infliximab were enrolled in a 26-week trial. Patients received open-label induction with subcutaneous certolizumab pegol 400 mg at weeks 0, 2, and 4. Those in clinical response at week 6 were randomized to certolizumab pegol 400 mg every 2 or every 4 weeks through week 24. The primary end point was response at week 6. Secondary end points included remission at week 6 and response and remission at week 26. RESULTS At week 6, 334 of 539 patients (62.0%) achieved response and 212 of 539 (39.3%) achieved remission. A total of 329 patients were randomized and received maintenance therapy. At week 26, 39.9% (67 of 168) and 36.6% (59 of 161) of patients in the every-4-weeks and every-2-weeks groups were in clinical response, respectively (P = .55). Corresponding remission rates at week 26 were 29.2% and 30.4%, respectively (P = .81). Serious infections occurred in 9 of 539 (1.7%) and 12 of 373 (3.2%) of patients during induction and maintenance, respectively. A single malignancy (skin carcinoma) occurred in a patient receiving every-4-weeks maintenance therapy. CONCLUSIONS Response to open-label induction therapy with certolizumab pegol was achieved by 62% of patients with moderate to severely active Crohns disease and secondary failure to infliximab. Among these patients, certolizumab pegol 400 mg every 4 weeks showed similar efficacy to every-2-weeks dosing for maintenance of response and remission.

Prevalence of and risk factors for vitamin B12 deficiency in patients with Crohn's disease

Background: Crohns disease (CD) can commonly involve the terminal ileum, which is the site of B12 absorption. The aim of this study was to define the prevalence of vitamin B12 abnormalities in a population with CD and to identify risk factors associated with B12 abnormalities in CD. Methods: The medical records of 201 patients with CD evaluated at a tertiary care center were retrospectively reviewed to determine the prevalence of B12 deficiency and to evaluate factors associated with B12 deficiency. The prevalence of B12 deficiency in a control population of 40 patients with ulcerative colitis was also assessed. Results: The prevalence of an abnormal serum B12 concentration in patients with CD was 18.4% (95% confidence interval [CI] 13.1–23.8%) compared with 5% (95% CI, 0–11.8%) (P = 0.035) in ulcerative colitis controls. Risk factors for B12 deficiency in patients with CD included prior ileal (odds ratio [OR], 7.22; 95% CI, 1.97–26.51) or ileocolonic (OR, 5.81; 95% CI, 2.09–16.12) resection and the need for ongoing medical therapy (OR, 2.59; 95% CI, 1.03–6.47). Neither disease location nor duration was independently associated with the risk of B12 deficiency. Conclusions: Vitamin B12 abnormalities are common in patients with CD and patients with a prior ileal or ileocolonic resection are at particular risk. Routine screening for B12 deficiency in patients with CD is warranted.

Long‐term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7‐year results from the PRECiSE 3 study

The efficacy and safety of certolizumab pegol (CZP) in moderate‐to‐severe Crohns disease were demonstrated in two 26‐week double‐blind studies (PRECiSE 1 & 2).

A randomized controlled trial of gastric lavage prior to endoscopy for acute upper gastrointestinal bleeding

Goals: We hypothesized that large volume gastric lavage prior to endoscopy for acute upper gastrointestinal bleeding would improve the quality of endoscopic examination. Background: Blood retained in the stomach can impair visualization during esophagogastroduodenoscopy. Patients with acute upper gastrointestinal bleeding and a retained gastric fundic pool during endoscopy may have worse outcomes than patients without a retained fundic pool. No trials to date have evaluated if large volume gastric lavage prior to endoscopy improves visualization during acute upper gastrointestinal bleeding. Study Methods: Patients with acute upper gastrointestinal bleeding were randomized to esophagogastroduodenoscopy alone or large volume tap water gastric lavage prior to esophagogastroduodenoscopy. The quality of endoscopic visualization was assessed using a 5-point scale. Clinical outcomes were compared for lavaged and nonlavaged patients. Results: A total of 39 patients were randomized. In 1 patient, lavage was unsuccessful. The quality of visualization was not significantly different between groups for the esophagus, gastric antrum, or duodenum but was significantly better for the gastric fundus for patients randomized to lavage (P = 0.02). There was no significant difference between groups for ability to define a bleeding source, achieve hemostasis, recurrent bleeding, need for repeat endoscopy, and length of stay or death. There were no complications. Conclusions: Large volume gastric lavage prior to esophagogastroduodenoscopy for acute upper gastrointestinal bleeding is safe and provides better visualization of the gastric fundus.

Briakinumab for treatment of Crohn's disease: Results of a randomized trial

Background:This study assessed the efficacy and safety of briakinumab, a human anti-IL-12/23p40 monoclonal antibody, compared with placebo for the induction and maintenance of remission in patients with moderately to severely active Crohns disease. Methods:In this phase 2b, multicenter, double-blind, parallel group study, 246 patients stratified by prior tumor necrosis factor–antagonist use and response, were randomized (1:1:1:3) to 4 intravenous induction regimens: placebo, 200, 400, or 700 mg briakinumab, at weeks 0/4/8. At week 12, responders in the placebo or 400-mg induction groups entered the maintenance phase with the same regimen, whereas responders in the 700-mg induction group were rerandomized (1:1:1) to receive placebo, 200, or 700 mg briakinumab at weeks 12/16/20. At week 24, patients in remission stopped receiving study drug (withdrawal phase) until relapse. Patients experiencing relapse, nonresponders, and nonremitters could enter the open-label phase. Results:The primary end point of clinical remission at week 6 was not met. There were numerically greater rates of remission and response at 6, 12, or 24 weeks in patients treated with briakinumab. The safety and tolerability profile of briakinumab was similar in the induction and maintenance phases of the trial. Conclusions:Briakinumab showed a similar safety and tolerability profile to placebo in the induction and maintenance phases, and comparable rates of serious adverse events, adverse events leading to discontinuation, and malignancy. These data provide support for the potential efficacy of briakinumab and other IL-12/23 inhibitors in the treatment of moderate-to-severe Crohns disease.

O-001 A Multicenter, Double-Blind, Placebo-Controlled Phase3 Study of Ustekinumab, a Human IL-12/23P40 mAB, in Moderate-Service Crohn's Disease Refractory to Anti-TFNα: UNITI-1

Background:Interleukins 12&23 are implicated in the pathophysiology of Crohns disease (CD). These pro-inflammatory cytokines are blocked by ustekinumab (UST). In a previous Phase 2b study (CERTIFI),1 UST IV induction followed by SC maintenance was shown effective in moderate-severe CD refractory to anti-TNF therapy. This Phase 3 study examined the efficacy and safety of IV UST induction in these patients. Methods:Patients with moderate-severely active CD (CDAI 220–450) who previously failed or were intolerant to at least 1 TNF-antagonist were randomized (1:1:1) at Week (Wk) 0 to a single dose of IV placebo (PBO), UST 130 mg, or weight-based tiered UST dosing approximating 6 mg/kg (260mg [weight ⩽55 kg], 390mg [weight >55 kg and ⩽85 kg], 520mg [weight >85 kg]). The primary endpoint was clinical response at Wk6, defined as reduction from baseline in the CDAI score of >100 points; patients with baseline CDAI score >220 to <248 points were considered in clinical response if a CDAI score of <150 was present. At Wk8, patients either transitioned to the IM-UNITI maintenance study or were followed to Wk20. Results:The 741 randomized patients had a history of TNF-antagonist failure, with baseline median CDAI of 317, CRP of 9.9 mg/L, and prior disease duration of 10.1 years. Of these, 51% had previously failed ≥2 anti-TNFs with 29.1%, 69.4%, and 36.4% of patients, respectively, satisfying protocol criteria for primary non-response, secondary non-response, or intolerance to at least one TNF antagonist. Statistical significance was demonstrated for the primary and all 4 major secondary endpoints at both IV doses. Clinical response at Wk6 (primary endpoint) was observed in 33.7% of the ∼6 mg/kg and 34.3% of the 130 mg UST groups versus 21.5% in PBO (P = 0.003 and 0.002, respectively). Clinical remission (CDAI <150) at Wk8 was observed in 20.9% of the ∼6 mg/kg group and 15.9% of the 130 mg UST group versus 7.3% on PBO (P < 0.001, P = 0.003, respectively). Clinical response at Wk8 was seen in 37.8% of the ∼6 mg/kg and 33.5% of the 130 mg UST groups, versus 20.2% on PBO (each P ⩽ 0.001). Proportion of patients with 70pt CDAI response at Wk6 was 43.8% of the ∼6 mg/kg and 46.1% of the 130 mg UST groups versus 30.4% in PBO (P = 0.002 and <0.001, respectively) and at the first post-baseline Wk3 visit, 40.6% in ∼6 mg/kg and 38.4% in the 130 mg UST groups versus 27.1% in PBO (P = 0.001 and P = 0.009, respectively), the final major secondary endpoint. Both IV UST induction doses additionally resulted in significant improvements in CDAI, IBDQ, CRP, fecal lactoferrin and calprotectin versus IV PBO. Proportions of patients with AEs, SAEs, and infections were similar in the UST and PBO groups. One opportunistic infection (listeria meningitis) was reported in the ∼6 mg/kg UST group. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST-treated patients through Wk20. Conclusions:In a population of moderate-severe CD patients refractory to one or more prior TNF-antagonists, IV UST induced clinical response and remission and was well-tolerated throughout induction, confirming the previous positive induction data from the Phase 2b CERTIFI study.

Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines

Background: The goal of this study was to assess the natural history of low‐grade dysplasia (LGD) and its risk of progression in ulcerative colitis (UC) patients by prospective endoscopic surveillance. Methods: Forty‐two UC patients with LGD were followed prospectively using a uniform approach to surveillance colonoscopy with an average of 43 biopsies per exam. The interval between colonoscopies ranged from 3–12 months. Progression was defined as development of high‐grade dysplasia (HGD) or cancer at subsequent colonoscopy or at colectomy. Univariate and multivariate analysis were performed to identify risk factors associated with progression. Results: Patients were followed for an average of 3.9 years (range 1–13). Over that period 19% (8/42) of patients progressed to advanced neoplasia (two cancer, six HGD) while 17% (7/42) had persistent LGD and 64% (27/42) had indefinite dysplasia or no dysplasia at the end of follow‐up. Multivariate analysis demonstrated that the number of biopsies with LGD at baseline was associated with an increased risk of progression to advanced neoplasia (relative risk [RR] 5.8, 95% confidence interval [CI]: (1.29–26.04). Among the 15 patients who underwent colectomy, four were found to have higher‐grade neoplasia on their colectomy specimen than their preoperative colonoscopy, and these patients were more likely to be nonadherent with recommendations for colectomy. Conclusions: The majority (81%) of UC patients with LGD did not progress to higher grades of dysplasia during a 4‐year follow‐up. Patients with three or more biopsies demonstrating LGD at a single colonoscopy were at increased risk for progression to advanced neoplasia. (Inflamm Bowel Dis 2012;)