Paul F. Pollack

Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial

Background: Adalimumab induced clinical remission after four weeks in patients with active Crohn’s disease in the CLASSIC I trial. Objective: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn’s disease in a follow-on randomised controlled trial (CLASSIC II). Methods: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn’s disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56. Results: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients. Conclusions: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn’s disease naive to anti-TNF treatment.

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 Induces and Maintains Mucosal Healing in Patients With Crohn's Disease: Data From the EXTEND Trial

BACKGROUND & AIMS We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohns disease (CD). METHODS A randomized, double-blind, placebo-controlled trial (extend the safety and efficacy of adalimumab through endoscopic healing [EXTEND]) evaluated adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD. The baseline degree of mucosal ulceration was documented by ileocolonoscopy. All patients received induction therapy (subcutaneous adalimumab 160/80 mg at weeks 0/2). At week 4, patients were randomly assigned to groups given 40 mg adalimumab or placebo every other week through week 52. Open-label adalimumab was given to patients with flares or no response, starting at week 8. Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52. RESULTS Twenty-seven percent of patients receiving adalimumab had mucosal healing at week 12 (the primary end point) versus 13% given placebo (P = .056). At week 52, rates of mucosal healing were 24% and 0, respectively (P < .001). Remission rates, based on the Crohns Disease Endoscopic Index of Severity, were 52% for adalimumab and 28% for placebo at week 12 (P = .006) and 28% and 3%, respectively, at week 52 (P < .001). Rates of clinical remission based on the Crohns Disease Activity Index were greater among patients given continuous adalimumab therapy versus placebo at weeks 12 (47% vs 28%; P = .021) and 52 (33% vs 9%; P = .001). Five serious (1 during induction and 4 during open-label therapy) and 3 opportunistic infections (1 in each group during double-blind therapy and 1 during open-label therapy) were reported (n = 135). CONCLUSIONS Following induction therapy with adalimumab, patients with moderately to severely active CD who continue to receive adalimumab are more likely to achieve mucosal healing than those given placebo.

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.

Adalimumab Induces Deep Remission in Patients With Crohn's Disease

BACKGROUND & AIMS Patients with moderate to severe ileocolonic Crohns disease (CD) who received adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission-a composite clinical and endoscopic end point. METHODS Rates of deep remission, defined as the absence of mucosal ulceration and CD Activity Index scores less than 150, were compared between patients given continuous adalimumab and those given only induction therapy followed by placebo. We assessed the relationships between deep remission and other outcomes among patients who received adalimumab. The outcomes of patients with deep remission were compared with those of patients with only the absence of mucosal ulceration or only clinical remission. RESULTS Rates of deep remission were 16% in patients given adalimumab vs 10% in those given placebo (P = .34) at week 12, and 19% vs 0% (P < .001) at week 52. Rates of deep remission were greatest among patients who received adalimumab and had CD for 2 years or less (33% at weeks 12 and 52). At week 52, patients who achieved deep remission at week 12 required significantly fewer adalimumab treatment adjustments, hospitalizations, and CD-related surgeries; had significantly less activity impairment; and had better quality of life and physical function compared with patients not achieving deep remission. Deep remission generally was associated with better outcomes than only an absence of mucosal ulceration; outcomes of patients with deep remission vs only clinical remission were similar. Deep remission was associated with estimated total cost savings of

Increased Risk of Malignancy With Adalimumab Combination Therapy, Compared With Monotherapy, for Crohn's Disease

10,360 (from weeks 12 through 52) compared with lack of deep remission. CONCLUSIONS In an exploratory study of patients with moderate to severe ileocolonic CD who received adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. These findings should be validated in large, prospective trials. ClinicalTrials.gov number: NCT00348283.

Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn’s disease

BACKGROUND & AIMS Few studies have assessed the risk of malignancy from anti-tumor necrosis factor monotherapy or combination therapy for Crohns disease (CD). We determined the relative risk of malignancy in patients with CD who received adalimumab monotherapy, compared with the general population. We also compared the risk of malignancy associated with combination adalimumab and immunomodulator therapy with that of adalimumab monotherapy. METHODS We performed a pooled analysis of data from 1594 patients with CD who participated in clinical trials of adalimumab (CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE studies; 3050 patient-years of exposure). We calculated rates of malignancy among patients; the expected rates of malignancy, based on the general population, were derived from the Surveillance, Epidemiology, and End Results registry and National Cancer Institute survey. RESULTS Compared with the general population, patients receiving adalimumab monotherapy did not have a greater than expected incidence of nonmelanoma skin cancer (NMSC) or other cancers, whereas those receiving combination therapy had a greater than expected incidence of malignancies other than NMSC (standardized incidence ratio, 3.04; 95% confidence interval [CI], 1.66-5.10) and of NMSC (standardized incidence ratio, 4.59; 95% CI, 2.51-7.70). Compared with patients receiving adalimumab monotherapy, those patients receiving combination therapy had an increased risk of malignancy other than NMSC (relative risk, 2.82; 95% CI, 1.07-7.44) and of NMSC (relative risk, 3.46; 95% CI, 1.08-11.06). CONCLUSIONS In patients with CD, the incidence of malignancy with adalimumab monotherapy was not greater than that of the general population. Co-administration of immunomodulator therapy and adalimumab was associated with an increased risk of NMSC and other cancers.

Subgroup analysis of the placebo-controlled CHARM trial: Increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease

Aliment Pharmacol Ther 31, 1296–1309

Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn's disease: results from CARE.

BACKGROUND AND AIMS We examined the impact of disease duration on clinical outcomes and safety in a post hoc analysis of a remission maintenance trial with adalimumab in patients with moderate to severe CD. METHODS Patients in the CHARM trial were divided into 3 disease duration categories: <2 (n=93), 2 to <5 (n=148), and ≥5 years (n=536). Clinical remission and response rates at weeks 26 and 56 were compared between adalimumab and placebo subgroups, and assessed through 3 years of adalimumab treatment in the ADHERE follow-on trial. Logistic regression assessed the effect of disease duration and other factors on remission and safety. RESULTS At week 56, clinical remission rates were significantly greater for adalimumab-treated versus placebo-treated patients in all 3 duration subgroups (19% versus 43% for <2 years; P=0.024; 13% versus 30% for 2 to <5 years; P=0.028; 8% versus 28% for ≥5 years, P<0.001). Logistic regression identified shorter duration as a significant predictor for higher remission rate in adalimumab-treated patients. Patients with disease duration <2 years maintained higher remission rates than patients with longer disease duration through 3 years of treatment. The incidence of serious adverse events in adalimumab-treated patients was lowest with disease duration <2 years. CONCLUSIONS Adalimumab was superior to placebo for maintaining clinical remission in patients with moderately to severely active CD after 1 year of treatment regardless of disease duration. Clinical remission rates through 3 years of treatment were highest in the shortest disease duration subgroup in adalimumab-treated patients, with a trend to fewer side effects.

Serum adalimumab concentration and clinical remission in patients with Crohn's disease.

Background: Data regarding the effectiveness of anti‐tumor necrosis factor (TNF) agents for resolution of extraintestinal manifestations (EIMs) are scarce. The CARE study evaluated clinical effectiveness, EIM resolution, and safety of adalimumab in a large pan‐European cohort of patients with moderate to severe Crohns disease (CD). Methods: In all, 945 patients with a Harvey–Bradshaw Index (HBI) ≥7 enrolled in this multicenter, open‐label phase IIIb trial. Patients received subcutaneous adalimumab, 160/80 mg at weeks 0/2, then 40 mg every other week. Dose adjustments were allowed for CD‐related concomitant medications (from week 8) and adalimumab (from week 12). Clinical endpoints were analyzed through week 20 for all patients, and after stratification by prior infliximab exposure and by reason for discontinuing infliximab (primary nonresponse [PNR] or other). Results: The remission rate (HBI <5) at week 20 was 52% (95% confidence interval, 49%–55%) overall, and was higher for infliximab‐naïve versus infliximab‐exposed patients (62% versus 42%, P < 0.001). Remission rates were similar for PNR (37%) and other reasons (43%; P = 0.278). Of 497 patients with baseline EIMs, 51% were free of EIM signs and symptoms at week 20. Serious infectious adverse events were reported in 5% of patients. Opportunistic infections and malignancies were rare (≤1%). There was one case of demyelinating disease, but no occurrences of lupus, tuberculosis, or death. Conclusions: In this large cohort of patients, adalimumab treatment resulted in rates of clinical remission and EIM resolution exceeding 50%, and substantial rates of effectiveness in patients who had PNR to infliximab. Adalimumab was well tolerated, with safety consistent with prior reports. (Inflamm Bowel Dis 2011)