Randomised clinical trial: a phase 1b study of GB004, an oral HIF-1α stabiliser, for treatment of ulcerative colitis.

BACKGROUND: Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut. AIMS: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC. METHODS: This double-blind, placebo-controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3-12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5-aminosalicylates, corticosteroids or immunosuppressants. RESULTS: Thirty-four patients were randomised. GB004 120 mg for 28 days was generally well-tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment-related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo. CONCLUSION: Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.

Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study.

BACKGROUND: Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease. METHODS: STEPSTONE was a phase 2, uncontrolled, multicentre trial in adults with moderately to severely active Crohn's disease recruited at 28 hospital and community research centres in Canada, the USA, Hungary, Poland, and Ukraine. All patients began treatment with a 7-day dose escalation (4 days on ozanimod 0·25 mg daily followed by 3 days at 0·5 mg daily). Patients then received ozanimod 1·0 mg oral capsule daily for a further 11 weeks, for a 12-week induction period, followed by a 100-week extension. The primary endpoint was change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 12, as determined by a blinded central reader. Data are reported for the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02531113 and EudraCT, number 2015-002025-19, and is completed. FINDINGS: 69 patients were enrolled between Nov 17, 2015, and Aug 18, 2016. At week 12, the mean change from baseline in SES-CD was -2·2 (SD 6·0); 16 (23·2%, 95% CI 13·9-34·9) patients experienced endoscopic response. A reduction from baseline in Crohn's Disease Activity Index (CDAI) score also was observed (mean change -130·4 [SD 103·9]). Clinical remission (CDAI <150 points) was shown in 27 (39·1%, 95% CI 27·6-51·6) patients and response (CDAI decrease from baseline ≥100) in 39 (56·5%, 95% CI 44·0-68·4) of patients. The mean change from baseline in two-item patient-reported outcome (PRO2, stool frequency, abdominal pain scores) score was -66·1 (SD 65·4). Mean change from baseline in Geboes Histology Activity Score (GHAS) was -5·9 (SD 11·0) and in Robart's Histopathology Index (RHI) -10·6 (25·1). Adverse events were most frequently those attributed to Crohn's disease, most commonly Crohn's disease (flare) in 18 (26%) patients. The most commonly reported serious treatment-related adverse events were Crohn's disease (six [9%]) and abdominal abscess (two [3%]). INTERPRETATION: Endoscopic, histological, and clinical improvements were seen within 12 weeks of initiating ozanimod therapy in patients with moderately to severely active Crohn's disease. Phase 3 placebo-controlled trials have been initiated. FUNDING: Celgene Corporation.

Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial.

OBJECTIVE: We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment. DESIGN: Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo. RESULTS: Inter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608-0.649). CONCLUSION: All four existing histological indices were similarly reliable and responsive based on this dataset.

A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score.

BACKGROUND: Combining clinical, endoscopic, and histological data associated with ulcerative colitis disease activity in a composite index could be a more sensitive way to detect efficacy in small numbers of patients during early drug development. Our aim was to derive and externally validate a novel index for this purpose. METHODS: Index development was done with data from a phase 2 placebo-controlled trial of ozanimod in patients with moderate-to-severe ulcerative colitis (n=179). Multivariable logistic regression modelling determined associations between candidate index items and absence of rectal bleeding (Mayo Clinic rectal bleeding subscore of 0), with items with a p value of less than 0·10 being taken forward into the final model. Model fit was internally validated and then externally validated in an independent phase 2 clinical trial dataset (MLN02, n=146) by measuring the area under the curve of the receiver operating characteristic (AUROC). FINDINGS: In the derivation cohort, multivariable analysis indicated that the Mayo Clinic stool frequency subscore (odds ratio [OR] 0·43, 95% CI 0·30-0·61; p<0·0001) and the Robarts histopathology index (0·97, 0·93-1·01; p=0·09) were associated with absence of rectal bleeding. Although the Mayo Clinic endoscopic subscore was not significantly associated with rectal bleeding in multivariable analysis (0·74, 0·43-1·27; p=0·27), it was entered into the final model on the basis of the established diagnostic and prognostic significance of endoscopic findings. With these parameters, we established the composite UC-100 score (1 + 16 × Mayo Clinic stool frequency subscore [0 to 3] + 6 × Mayo Clinic endoscopic subscore [0 to 3] + 1 × Robarts histopathology index score [0 to 33]), which ranges from 1 (no disease activity) to 100 (severe disease activity). The UC-100 score strongly discriminated absence of rectal bleeding in both the development (AUROC 0·82, 95% CI 0·75-0·88) and validation cohorts (0·86, 0·80-0·92). A UC-100 score of 25 or less corresponds to a 95% probability of absence of rectal bleeding. INTERPRETATION: We have developed and validated a novel composite disease activity index (the UC-100 score) with good discriminative performance that could used in early phase trials of ulcerative colitis. FUNDING: None.

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. CONCLUSIONS: In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2-sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10-millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

The sphingosine-1-phosphate 1 receptor (S1P1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation.

Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.

BACKGROUND: Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. METHODS: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks. RESULTS: The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache. CONCLUSIONS: In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.).

Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients with multiple sclerosis but has potential safety concerns. We assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis. METHODS: RADIANCE is a combined phase 2/3 trial. Patients with relapsing multiple sclerosis were recruited from 55 academic and private multiple sclerosis clinics in 13 countries across Europe and the USA. Eligible participants were aged 18-55 years, had an Expanded Disability Status Scale (EDSS) score of 0-5·0, and had either one or more relapses in the previous 12 months, or one or more relapses in the past 24 months and one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening. Participants were assigned by a computer-generated randomisation sequence in a 1:1:1 ratio to ozanimod (0·5 mg or 1 mg) or matching placebo once daily for 24 weeks by an independent, unmasked, statistical team. Trial participants, study site personnel, MRI assessors, steering committee members, and the study statistician were masked to treatment assignment. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0·25 mg to 0·5 mg or 1 mg over 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions measured by an independent MRI analysis centre at weeks 12-24 after treatment initiation. Analysis was by intention to treat. Here, we report results from the 24-week phase 2 trial. This trial is registered with ClinicalTrials.gov, number NCT01628393. The 2-year phase 3 trial is ongoing. FINDINGS: The first patient was randomised on Oct 18, 2012, and the final visit of the last randomised patient was on May 11, 2014. The intention-to-treat and safety population consisted of 258 participants, 88 were assigned placebo, 87 ozanimod 0·5 mg, and 83 ozanimod 1 mg; 252 (98%) patients completed the assigned treatment. The mean cumulative number of gadolinium-enhancing lesions at weeks 12-24 was 11·1 (SD 29·9) with placebo compared with 1·5 (3·7) with ozanimod 0·5 mg (odds ratio 0·16, 95% CI 0·08-0·30; p<0·0001) and 1·5 (3·4) with ozanimod 1 mg (odds ratio 0·11, 95% CI 0·06-0·21; p<0·0001). Three serious adverse events unrelated to treatment were reported in patients assigned ozanimod 0·5 mg: optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related). No serious infectious or cardiac adverse events were reported, and no cases of macular oedema arose. The most common adverse events in the ozanimod 0·5 mg and 1 mg groups compared with placebo were nasopharyngitis (11 and five vs 12), headache (five and three vs eight), and urinary-tract infections (six and two vs two). The maximum reduction in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, with no patient having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod. INTERPRETATION: Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing. FUNDING: Receptos, Inc.

Haemodynamic effects, safety, and pharmacokinetics of human stresscopin in heart failure with reduced ejection fraction.

AIMS: Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤ 35% and cardiac index (CI) ≤ 2.5 L/min/m(2). METHODS AND RESULTS: Sixty-two patients with HF and LVEF ≤ 35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen. CONCLUSION: In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP. TRIAL REGISTRATION: NCT01120210.

Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab.

BACKGROUND & AIMS: The efficacy of infliximab for treating patients with ulcerative colitis has been established. METHODS: The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan-Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo. RESULTS: Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy. CONCLUSIONS: Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

Infliximab therapy in children with concurrent perianal Crohn disease: observations from REACH.

OBJECTIVE: Post hoc analyses evaluated the effect of infliximab upon concurrent perianal Crohn disease (CD) in a subpopulation of 31 patients from REACH, a randomized trial of 112 children with moderately to severely active luminal CD. MATERIALS AND METHODS: The Pediatric Crohn Disease Activity Index perirectal subscore was used to assess perianal symptom activity and therapeutic response. Patients with no symptoms or asymptomatic tags received a score of 0; those with "1-2 indolent fistula, scant drainage, no tenderness" received a score of 5; and those with "active fistula, drainage, tenderness or abscess" received a score of 10. Initial perirectal subscores of 10 or 5 decreasing to 0 were considered complete response. Subscores of 10 decreasing to 5 were considered partial response. All patients were followed for efficacy and safety through week 54. RESULTS: Twenty-two patients with baseline perianal disease were randomized at week 10 following a 3-dose infliximab induction regimen. At week 2, 40.9% (9/22) of patients with signs and symptoms of perianal disease at baseline attained response (4 partial and 5 complete). At week 54, 72.7% (16/22) of patients with signs and symptoms of perianal disease attained response (1 partial and 15 complete). Nine patients developed perianal signs and symptoms during treatment; 7 had complete response and 2 had no response at week 54. The incidence of adverse events for patients with perianal symptoms at baseline and for those in the overall REACH population was similar (95.7% vs 94.6%). CONCLUSIONS: Infliximab rapidly reduced concurrent perianal disease signs and symptoms in this REACH cohort.

Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn's disease: results of the REACH study.

BACKGROUND & AIMS: Crohn's disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy. METHODS: One hundred twelve subjects ages 6-17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy. Serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), urine C-telopeptide of collagen cross-links (CTX-1), and deoxypyrodinoline (DPD) were collected at baseline and 10 weeks. PCDAI and height z-scores were assessed at baseline and at 10 and 54 weeks. RESULTS: Models were adjusted for bone age, gender, height, and steroid use. Baseline BSAP and P1NP levels were negatively associated with PCDAI (both P = .01). BSAP and P1NP increased during induction (both P < .001) and were associated with 54-week increases in height z-score (P < .05 and P < .001, respectively). Improvements in P1NP were associated with 54-week decreases in PCDAI (P = .01). CTX-1 and DPD also increased during induction (P < .001 and P = .01, respectively) but were not associated with changes in PCDAI. Changes in CTX-1 were associated with improvements in height z-score (P < .002). CONCLUSIONS: Infliximab therapy is associated with dramatic increases in BSAP and P1NP, consistent with inhibition of tumor necrosis factor-alpha effects on osteoblasts. The increases in CTX-1 and DPD likely reflect coupling of bone formation and resorption and increases in linear growth.

Response and remission are associated with improved quality of life, employment and disability status, hours worked, and productivity of patients with ulcerative colitis.

BACKGROUND: Impairment of health-related quality of life, employment, and productivity has been documented in patients with moderate to severe ulcerative colitis. METHODS: Using prospectively collected data from the Active Ulcerative Colitis Trials 1 and 2, we examined the impact of clinical response or remission, as defined using the Mayo score, on health-related quality of life, employment, disability, productivity, and hours worked per week. These analyses were based on observed data and included all 728 patients, regardless of their randomized treatment group (i.e., placebo and infliximab patients were grouped for analysis). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form (SF-36) scores among nonresponders, responders, and patients in remission were compared. In addition, changes in employment, disability status, productivity, and hours worked per week of patients in clinical remission and patients not in clinical remission were compared. RESULTS: Ulcerative colitis patients in clinical response or remission had significantly improved IBDQ and SF-36 scores at week 30 compared with those of nonresponders (P<0.001). Among those not employed at baseline, including those receiving disability compensation, greater percentages of patients in remission at week 30 were employed (20.6%) and not receiving disability compensation (58.8%) than were those not in remission (8.3% and 20.0%, respectively; P<0.05 for both comparisons). At week 30, improvements from baseline in productivity and both actual and fully productive hours worked per week were greater for patients in remission compared with those not in remission (P<0.05 for all three comparisons). CONCLUSIONS: These results confirm the validity of response and remission as defined using the Mayo score.

The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients.

OBJECTIVES: The impact of infliximab induction and maintenance therapy on health-related quality of life (HRQL) was evaluated in patients with ulcerative colitis (UC). METHODS: In two placebo-controlled, double-blind studies (the Active Ulcerative Colitis Trials 1 and 2 [ACT 1 and 2]), 728 patients were randomized to placebo or infliximab 5 mg/kg or 10 mg/kg. Infusions were administered at weeks 0, 2, 6, and every 8 wk thereafter, up to week 22 (ACT 2) or 46 (ACT 1). Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS, respectively) scores were analyzed. RESULTS: Baseline scores for the pooled patient population indicated substantial impairment in HRQL. Improvement at week 8 in the total IBDQ score was significantly greater in the infliximab 5-mg/kg (40, P < 0.001) and 10-mg/kg (36, P < 0.001) groups compared with the placebo group (28). Improvement at week 8 was also significantly greater in the infliximab 5- and 10-mg/kg groups for the PCS (6.8 and 5.9, respectively) and MCS (5.9 and 6.4, respectively) compared with placebo (PCS = 3.7, MCS = 3.0, P < 0.01 for all comparisons). Continued benefit was seen at weeks 30 and 54 with infliximab maintenance therapy (P < 0.001 for all comparisons). Improvement in total IBDQ score correlated significantly (P < 0.001) with improvement in both PCS and MCS scores, and Mayo score. CONCLUSIONS: Infliximab therapy substantially improved HRQL in patients with UC. This benefit was sustained through 1 yr with maintenance infliximab therapy.

Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children.

BACKGROUND AND AIMS: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease. METHODS: Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score > or =15 points; total score < or =30) and clinical remission (PCDAI score < or =10 points) were evaluated at weeks 10, 30, and 54. RESULTS: At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). CONCLUSIONS: Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing.

Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study.

Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a subset of 344 patients from the large and well-defined cohort of 573 patients with Crohn's disease from the ACCENT I study. No association could be observed between FCGR3A-158 gene polymorphism and the clinical response to infliximab, which was primarily defined as a decrease of >or=70 points in the Crohn's disease activity index or clinical remission (Crohn's disease activity index <150). We did, however, confirm a trend towards a greater decrease in C-reactive protein after infliximab in V/V homozygotes as compared with V/F heterozygotes and F/F homozygotes (-79.4, -76.5, and -64.3%, respectively, at week 6; P=0.085; one-tailed P=0.043). This finding has no immediate clinical impact but may enhance the understanding of the complex mechanisms of action of anti-tumor necrosis factor agents in Crohn's disease.

Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease.

OBJECTIVE: Theoretical concern exists that rapid luminal healing in Crohn's disease (CD) with therapies like infliximab increases the risk of intestinal stenosis, stricture, or obstruction (SSOs). METHODS: Data were analyzed from the ongoing observational TREAT (the Crohn's Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study. Investigators reported SSOs as adverse events or serious adverse events. RESULTS: In TREAT, SSOs occurred at a significantly higher rate in patients treated with infliximab compared with patients who received other treatments only (1.95 events/100 patient-years vs 0.99 events/100 patient-years; p < 0.001). Using multivariable analyses, however, infliximab therapy was not associated with SSO development. CD severity at the time of event onset (hazard ratio (HR) = 2.35, 95% confidence internal (CI) 1.35-4.09); CD duration (HR = 1.02, 95% CI 1.00-1.04); ileal disease (HR = 1.56, 95% CI 1.04-2.36); and new corticosteroid use (HR = 2.85, 95% CI 1.23-6.57) were associated with SSOs. In ACCENT I, no increase in SSOs was reported in patients who received infliximab maintenance therapy compared with those who received episodic therapy, despite higher median cumulative infliximab exposure. Additionally, there was no increase in SSO development with rapid mucosal healing (healing at week 10). CONCLUSIONS: Although unadjusted analyses suggested that patients who received infliximab were twice as likely to develop SSOs, multivariable analysis adjusting for other factors demonstrated that only disease duration, disease severity, ileal disease, and new corticosteroid use were significantly associated with SSO development.