Robert Enns

Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.

Context Can adalimumab, an antitumor necrosis factor (anti-TNF) agent, induce remission in patients with Crohn disease who do not respond to or cannot tolerate another anti-TNF agent? Contribution This double-blind, placebo-controlled trial included 325 adults with Crohn disease who had symptoms despite treatment with infliximab or who could not tolerate infliximab because of adverse events. At 4 weeks, more patients randomly assigned to the adalimumab group achieved remission than did those in the placebo group (21% vs. 7%). Cautions The trial did not directly compare efficacy of different anti-TNF agents and did not assess maintenance of response or the long-term immunogenicity of adalimumab. The Editors Tumor necrosis factor (TNF) is an important proinflammatory cytokine in treating Crohn disease (1). Infliximab is a chimeric, anti-TNF monoclonal antibody effective in inducing and maintaining response and remission in patients with moderate to severe Crohn disease (2, 3). Some patients treated with infliximab experience a loss of efficacy over time or become intolerant of infliximab (47). Adalimumab, a human anti-TNF monoclonal antibody, is effective for inducing and maintaining remission in patients with Crohn disease who are naive to infliximab (810). Both adalimumab and certolizumab pegol (a pegylated humanized antibody fragment [Fab] to TNF) are effective for maintaining remission in a broad population of patients with Crohn disease who are naive to infliximab or who have responded to infliximab and then electively discontinued treatment despite continued response or because of lost response, intolerance, or both (10, 11). To our knowledge, no controlled trials have been conducted with these agents in a sample restricted to patients with lost response or intolerance to infliximab. We conducted a 4-week, placebo-controlled trial (GAIN [Gauging Adalimumab Efficacy in Infliximab Nonresponders]), in which adult patients with moderate to severe Crohn disease who had symptoms despite infliximab therapy or who could not take infliximab because of adverse events received adalimumab induction therapy. The Appendix shows the list of investigators for the GAIN trial group. Methods Design Overview This randomized, double-blind, placebo-controlled trial was conducted at 52 centers from November 2004 to December 2005 (last patient contact was on 26 June 2006). The protocol was approved by the institutional review board at each center. All patients provided written informed consent. Setting and Participants Fifty-two sites in the United States, Canada, Belgium, and France enrolled patients, with 1 to 29 patients at each site. We recruited patients from tertiary care centers, academic medical institutions, and independent research organizations. Eligible patients included men and women 18 to 75 years of age with Crohn disease for at least 4 months that was moderately to severely active at baseline, defined by a Crohns Disease Activity Index (CDAI) (12) score of 220 to 450 points (range, 0 to 600 points; greater scores indicate more severe disease activity). We required radiologic or endoscopic evidence to confirm the presence of Crohn disease. To be included, patients must have been intolerant of infliximab or must have previously responded to infliximab and then lost response. We excluded patients who had a primary nonresponse to infliximab as defined by the investigator, received infliximab or another TNF antagonist within the past 8 weeks, previously received adalimumab (Humira, Abbott Laboratories, Abbott Park, Illinois), or participated in an adalimumab clinical trial. Concurrent therapies, including stable dosages of 5-aminosalicylates, prednisone (40 mg/d), budesonide (9 mg/d), azathioprine, 6-mercaptopurine, methotrexate, and antibiotics, were permitted. We excluded patients who changed dosages or discontinued azathioprine, 6-mercaptopurine, or methotrexate treatment within 12 weeks of screening. Similarly, we excluded patients who changed dosages or discontinued 5-aminosalicylates, mesalamine, or sulfasalazine treatment within 4 weeks of screening. Prednisone (40 mg/d) and budesonide (9 mg/d) dosages must have been stable for 2 weeks or more before screening. Dosages of all these medications were required to remain stable during the study. We excluded patients with the short bowel syndrome, a symptomatic stricture, or bowel resection within the past 6 months; those who had undergone ostomy or ileoanal pouch; and those receiving total parenteral nutrition. We also excluded patients who had received antibiotic treatment for infections not related to Crohn disease within 3 weeks of the study and those with untreated tuberculosis or demyelinating disorders. We excluded female patients who were pregnant or were breast-feeding. We also excluded patients with a history of clinically significant drug or alcohol abuse in the past year; abnormal results on electrocardiography; or elevated concentrations of aspartate or alanine aminotransferase (>1.75 times the upper limit of the reference range), total bilirubin (51.3 mol/L [3 mg/dL]), or serum creatinine (>141.4 mol/L [>1.6 mg/dL]). Randomization and Intervention We randomly assigned eligible patients to receive subcutaneous injections of adalimumab, 160 mg at week 0 and 80 mg at week 2, or placebo at weeks 0 and 2 and followed patients through week 4. Patients, investigators, study site personnel, and Abbott Laboratories were unaware of treatment assignments. Randomization was completed through a central computer-generated scheme stratified by site, with block sizes of 4. Patient numbers were centrally assigned by an interactive voice-response system in consecutive order. The system provided access to blinded patient treatment information for medical emergencies only. Patients who successfully completed week 4 were eligible to enter an open-label extension study of the long-term safety of repeated administration of adalimumab. Outcomes and Measurements We classified patients as having a loss of response if they had a history of an initial response to infliximab, as defined by the investigator; had received at least 2 doses of infliximab of 5 mg/kg of body weight or more every 8 weeks; and had lacked improvement or had worsening in at least 1 of the following signs or symptoms related to Crohn disease at least 2 weeks after receiving the last dose of infliximab: stool frequency, daily abdominal pain, fever, recurring drainage from a previously nondraining fistula or development of a new draining fistula, rectal bleeding, or change in use of antidiarrheal medication. We classified patients as having intolerance of infliximab if they had a history of discontinuing infliximab treatment because of a clinically significant acute or delayed infusion reaction. We defined a clinically significant acute infusion reaction as an adverse reaction that occurred during or within 24 hours of an infliximab infusion, was considered to be related to the infusion by the physician, and manifested as at least 1 of the following symptoms: temperature greater than 100F; chills or rigors; itching; rash; flushing; urticaria or angioedema; breathing difficulties (dyspnea, chest paint or tightness, shortness of breath, wheezing, or stridor); and clinical hypotension (pallor, diaphoresis, faintness, or syncope), blood pressure less than 90/60 mm Hg, or orthostatic decrease in systolic blood pressure greater than 20 mm Hg. We defined a clinically significant delayed infusion reaction as an adverse reaction that occurred more than 24 hours and fewer than 15 days after an infliximab infusion; was considered to be related to the infusion by the physician; and was manifested through at least 1 of the following symptoms: myalgias, arthralgias, temperature greater than 100F, malaise, and rash. The primary efficacy end point was the proportion of patients with remission at week 4. Remission was defined as a CDAI score less than 150 points (12). Response was defined as a decrease from baseline in CDAI score of 70 points or more (70-point response) or of 100 points or more (100-point response) at week 4. Follow-up Procedures Patients were assessed 2 weeks before randomly assigned treatment began; on day 0; and at 1, 2, and 4 weeks. At each visit, the CDAI score was determined, adverse events and concomitant medications were recorded, and samples were collected for laboratory evaluations. The Inflammatory Bowel Disease Questionnaire (IBDQ) was administered to assess patient-reported outcomes at weeks 0 and 4 (total score range, 32 to 224; greater scores indicate better quality of life) (13). Safety evaluations included physical examinations. Laboratory evaluations included hematologic analysis; serum biochemical analysis; urinalysis; and determination of concentrations of C-reactive protein, adalimumab and antibodies to adalimumab, and infliximab and antibodies to infliximab. Adverse events were recorded through queries, observations by site personnel, and spontaneous patient reports. Investigators assessed and recorded any adverse event, including date of onset, description, severity, time course, duration, outcome, relationship of event to the study drug, alternate causes for events not considered to be probably related to the study drug, final diagnosis (if known), and any actions taken. Investigators rated the severity of each event (mild, moderate, or severe) and the relationship to study drug (probably related, possibly related, probably not related, or not related) on the basis of standard definitions. Serious adverse events were recorded through scheduled telephone contacts, study visits, and spontaneous patient reports from the time informed consent was signed until 70 days after withdrawal of study drug treatment. A data monitoring committee met every 4 to 6 months to discuss unblinded data and recommend either continuing or amending the study. A sponsor steering committee of senior executives w

Adalimumab for the treatment of fistulas in patients with Crohn’s disease

Objective: To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn’s disease (CD). Design: A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites. Patients: A subgroup of adults with moderate to severely active CD (CD activity index 220–450) for ⩾4 months who had draining fistulas at baseline. Interventions: All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension. Main Outcome Measures: Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression. Results: Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis). Conclusions: In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial. ClinicalTrials.gov Identifier: NCT00077779 and NCT00195715.

Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults - Update 2004

BACKGROUND Gastroesophageal reflux disease (GERD) is the most prevalent acid-related disorder in Canada and is associated with significant impairment of health-related quality of life. Since the last Canadian Consensus Conference in 1996, GERD management has evolved substantially. OBJECTIVE To develop up-to-date evidence-based recommendations relevant to the needs of Canadian health care providers for the management of the esophageal manifestations of GERD. CONSENSUS PROCESS A multidisciplinary group of 23 voting participants developed recommendation statements using a Delphi approach; after presentation of relevant data at the meeting, the quality of the evidence, strength of recommendation and level of consensus were graded by participants according to accepted principles. OUTCOMES GERD applies to individuals who reflux gastric contents into the esophagus causing symptoms sufficient to reduce quality of life, injury or both; endoscopy-negative reflux disease applies to individuals who have GERD and a normal endoscopy. Uninvestigated heartburn-dominant dyspepsia - characterised by heartburn or acid regurgitation - includes erosive esophagitis or endoscopy-negative reflux disease, and may be treated empirically as GERD without further investigation provided there are no alarm features. Lifestyle modifications are ineffective for frequent or severe GERD symptoms; over-the-counter antacids or histamine H2-receptor antagonists are effective for some patients with mild or infrequent GERD symptoms. Proton pump inhibitors are more effective for healing and symptom relief than histamine H2-receptor antagonists; their efficacy is proportional to their ability to reduce intragastric acidity. Response to initial therapy - a once-daily proton pump inhibitor unless symptoms are mild and infrequent (fewer than three times per week) - should be assessed at four to eight weeks. Maintenance medical therapy should be at the lowest dose and frequency necessary to maintain symptom relief; antireflux surgery is an alternative for a small proportion of selected patients. Routine testing for Helicobacter pylori infection is unnecessary before starting GERD therapy. GERD is associated with Barretts epithelium and esophageal adenocarcinoma but the risk of malignancy is very low. Endoscopic screening for Barretts epithelium may be considered in adults with GERD symptoms for more than 10 years; Barretts epithelium and low-grade dysplasia generally warrant surveillance; endoscopic or surgical management should be considered for confirmed high-grade dysplasia or malignancy. CONCLUSION Prospective studies are needed to investigate clinically relevant risk factors for the development of GERD and its complications; GERD progression, on and off therapy; optimal management strategies for typical GERD symptoms in primary care patients; and optimal management strategies for atypical GERD symptoms, Barretts epithelium and esophageal adenocarcinoma.

CDP571, a humanised monoclonal antibody to tumour necrosis factor α, for moderate to severe Crohn’s disease: a randomised, double blind, placebo controlled trial

Background: Targeting tumour necrosis factor α (TNF-α) has demonstrated efficacy in Crohn’s disease. Aim: To evaluate CDP571, a humanised antibody to TNF-α, for treating active Crohn’s disease. Patients: A total of 396 patients with moderate to severe Crohn’s disease. Methods: In a 28 week, randomised, double blind, placebo controlled trial, patients received intravenous CDP571 (10 mg/kg) or placebo every eight weeks to week 24. The primary outcome measure was clinical response (a decrease in the Crohn’s disease activity index (CDAI) to ⩾100 points or remission (CDAI score ⩽150 points)) at week 28. A secondary outcome measure was clinical response (using the same definition) at week 2. Results: Clinical response occurred at week 28 in 80/263 (30.4%) CDP571 patients and 31/132 (23.5%) placebo patients (p = 0.102). Clinical response at week 2 occurred in 90/263 (34.2%) CDP571 patients and 28/132 (21.2%) placebo patients (p = 0.011). Post hoc exploratory subgroup analysis of 159 patients with baseline C reactive protein (CRP) ⩾10 mg/l demonstrated significant differences between CDP571 and placebo in clinical response rates at weeks 2 (CDP571, 50/101 (49.5%); placebo, 9/58 (15.5%); p<0.001) and 28 (CDP571, 29/101 (28.7%); placebo, 7/58 (12.1%); p = 0.018). Adverse events occurred at similar frequencies in both treatment groups. Conclusions: CDP571 is modestly effective for short but not long term treatment of unselected patients with moderate to severe Crohn’s disease. The clinical relevance of this short term effect is unclear. Post hoc analysis suggests both short and long term efficacy of CDP571 in patients with elevated baseline CRP (⩾10 mg/l). CDP571 is well tolerated.

Commonly used preparations for colonoscopy: Efficacy, tolerability and safety - A Canadian Association of Gastroenterology position paper

INTRODUCTION The increased demand for colonoscopy, coupled with the introduction of new bowel cleansing preparations and recent caution advisories in Canada, has prompted a review of bowel preparations by the Canadian Association of Gastroenterology. METHODS The present review was conducted by the Clinical Affairs group of committees including the endoscopy, hepatobiliary/transplant, liaison, pediatrics, practice affairs and regional representation committees, along with the assistance of Canadian experts in the field. An effort was made to systematically assess randomized prospective trials evaluating commonly used bowel cleansing preparations in Canada. RESULTS Polyethylene glycol (PEG)-; sodium phosphate (NaP)-; magnesium citrate (Mg-citrate)-; and sodium picosulphate, citric acid and magnesium oxide (PSMC)-containing preparations were reviewed. Regimens of PEG 2 L with bisacodyl (10 mg to 20 mg) or Mg-citrate (296 mL) are as effective as standard PEG 4 L regimens, but are better tolerated. NaP preparations appear more effective and better tolerated than standard PEG solutions. PSMC has good efficacy and tolerability but head-to-head trials with NaP solutions remain few, and conclusions equivocal. Adequate hydration during preparation and up to the time of colonoscopy is critical in minimizing side effects and improving bowel cleansing in patients receiving NaP and PSMC preparations. All preparations may cause adverse events, including rare, serious outcomes. NaP should not be used in patients with cardiac or renal dysfunction (PEG solution is preferable in these patients), bowel obstruction or ascites, and caution should be exercised when used in patients with pre-existing electrolyte disturbances, those taking medications that may affect electrolyte levels and elderly or debilitated patients. Health Canadas recommended NaP dosing for most patients is two 45 mL doses 24 h apart. However, both safety and efficacy data on this dosing schedule are lacking. Many members of the Canadian Association of Gastroenterology expert panel administer both doses within 24 h, as studied in clinical trials, after careful one-on-one discussion of risks and benefits in carefully selected patients. Safety data on PSMC and combination preparations in North America are limited and clinicians are encouraged to keep abreast of developments in this area. CONCLUSIONS All four preparations reviewed provided effective bowel cleansing for colonoscopy in the majority of patients, with varying tolerability. Adequate hydration is essential in patients receiving the preparations.

Canadian Association of Gastroenterology position statement on screening individuals at average risk for developing colorectal cancer: 2010

The Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation published guidelines on colon cancer screening in 2004. Subsequent to the publication of these guidelines, many advances have occurred, thereby necessitating a review of the existing guidelines in the context of new technologies and clinical knowledge. The assembled guideline panel recognized three recent American sets of guidelines and identified seven issues that required comment from a Canadian perspective. These issues included, among others, the role of program-based screening, flexible sigmoidoscopy, computed tomography colonography, barium enema and quality improvement. The panel also provided context for the selection of the fecal immunochemical test as the fecal occult blood test of choice, and the relative role of colonoscopy as a primary screening tool. Recommendations were also provided for an upper age limit for colon cancer screening, whether upper endoscopy should be performed following a negative colonoscopy for a positive fecal occult blood test and when colon cancer screening should resume following negative colonoscopy.

The cost-effectiveness of screening for colorectal cancer

Background: Published decision analyses show that screening for colorectal cancer is cost-effective. However, because of the number of tests available, the optimal screening strategy in Canada is unknown. We estimated the incremental cost-effectiveness of 10 strategies for colorectal cancer screening, as well as no screening, incorporating quality of life, noncompliance and data on the costs and benefits of chemotherapy. Methods: We used a probabilistic Markov model to estimate the costs and quality-adjusted life expectancy of 50-year-old average-risk Canadians without screening and with screening by each test. We populated the model with data from the published literature. We calculated costs from the perspective of a third-party payer, with inflation to 2007 Canadian dollars. Results: Of the 10 strategies considered, we focused on three tests currently being used for population screening in some Canadian provinces: low-sensitivity guaiac fecal occult blood test, performed annually; fecal immunochemical test, performed annually; and colonoscopy, performed every 10 years. These strategies reduced the incidence of colorectal cancer by 44%, 65% and 81%, and mortality by 55%, 74% and 83%, respectively, compared with no screening. These strategies generated incremental cost-effectiveness ratios of

Treatment of Hospitalized Adult Patients With Severe Ulcerative Colitis: Toronto Consensus Statements

9159,

Canadian Association of Gastroenterology consensus guidelines on safety and quality indicators in endoscopy

611 and

Cost-effectiveness in Canada of intravenous proton pump inhibitors for all patients presenting with acute upper gastrointestinal bleeding

6133 per quality-adjusted life year, respectively. The findings were robust to probabilistic sensitivity analysis. Colonoscopy every 10 years yielded the greatest net health benefit. Interpretation: Screening for colorectal cancer is cost-effective over conventional levels of willingness to pay. Annual high-sensitivity fecal occult blood testing, such as a fecal immunochemical test, or colonoscopy every 10 years offer the best value for the money in Canada.