Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn's Disease.

BACKGROUND: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). METHODS: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. RESULTS: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4-41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7-54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6-55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3-18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. CONCLUSION: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226.

Efficacy and Safety of Pancrelipase/Pancreatin in Patients With Exocrine Pancreatic Insufficiency and a Medical History of Diabetes Mellitus.

OBJECTIVES: The aim of this study was to perform exploratory analyses of the efficacy and safety of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency (EPI) with (n = 36) and without (n = 18) concurrent diabetes mellitus (DM). METHODS: This was a retrospective, post hoc, subgroup (±DM) analysis of a double-blind, randomized, placebo-controlled trial of pancrelipase in patients with EPI due to chronic pancreatitis or pancreatectomy (total or partial). After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units/meal, 36,000/snack) or placebo for 7 days. Outcomes included changes in coefficients of fat absorption (CFA) and nitrogen absorption (CNA) from baseline to the end of the double-blind period. RESULTS: Mean changes in nutrient absorption were greater with pancrelipase versus placebo in patients with DM (CFA, 36.0% vs 7.5%, P < 0.0001; CNA, 33.4% vs 3.7%, P = 0.0002) and without DM (CFA, 25.2% vs 12.3%, P = 0.0326; CNA, 39.1% vs 17.6%, P = 0.1187). Diabetes mellitus was not significantly associated with outcomes for CFA (P = 0.0802) and CNA (P = 0.2934). Incidences of adverse events, including hypoglycemia and hyperglycemia, were similar in the pancrelipase and placebo arms. CONCLUSIONS: Pancrelipase improved fat and protein absorption in patients with EPI due to chronic pancreatitis or pancreatectomy, with or without DM, and matched the safety profile previously reported.

Milk protein-based infant formula containing rice starch and low lactose reduces common regurgitation in healthy term infants: a randomized, blinded, and prospective trial.

OBJECTIVE: Spit-up (regurgitation) reduction with prethickened milk protein-based infant formulas containing rice starch has been clinically demonstrated in infants with heavy spit-ups but not in otherwise healthy normal infants with common spit-ups. The objective of this study was to evaluate growth, gastrointestinal tolerance, and efficacy to reduce common spit-up in normal, healthy term infants fed an investigational rice starch prethickened lactose-free milk protein-based infant formula. METHODS: This double-blind, randomized, parallel study evaluated the investigational rice starch prethickened lactose-free (low lactose < 100 mg/L) milk protein-based infant formula compared to a standard, commercially available, iso-nutrient, lactose-containing (100% of carbohydrate) milk-based infant formula (control) for growth and gastrointestinal tolerance in healthy term infants (n = 132/group) fed from 14 ± 3 days to 112 days of age. Data were classified and analyzed as evaluable (EV; subjects completing study per protocol) or intent-to-treat data (ITT; all subjects with available data). RESULTS: Growth as indicated by weight gain (primary variable) and formula intake were not significantly different (p > 0.05) between feeding groups (EV or ITT). Though both formulas were well tolerated, spit-up frequency was significantly lower (p < 0.05) in the rice versus control group by 53% at 28 days of age, 54% at 56 days, 48% at 84 days, and 32% at 112 days (EV). Importantly, infants in the rice group were 1.6 to 1.8 times more likely to report zero spit-up than infants in the control group. The rice group also had higher percentages of soft and yellow stools. CONCLUSIONS: The rice starch prethickened lactose-free milk protein-based formula (rice) supported normal growth and safe use as the sole source of feeding for normal infants over the first 4 months of life. The rice formula was efficacious in providing a clinically relevant reduction of spit-up frequency in otherwise healthy term infants.

Adalimumab induces deep remission in patients with Crohn's disease.

BACKGROUND & AIMS: Patients with moderate to severe ileocolonic Crohn's 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 $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.

Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn's disease.

BACKGROUND & AIMS: Few studies have assessed the risk of malignancy from anti-tumor necrosis factor monotherapy or combination therapy for Crohn's 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.

52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants.

BACKGROUND: The results of an open-label follow-up until week 52 of patients with moderately to severely active ulcerative colitis who participated in a double-blind placebo-controlled adalimumab induction trial (ULTRA 1, NCT00385736) are reported. METHODS: The study included adult anti-tumor necrosis factor-naive patients who completed double-blind adalimumab induction under an amended protocol (intent-to-treat [ITT]-A3 population) or any version of the protocol (ITT-E). Patients randomized to placebo received adalimumab beginning at week 8; patients randomized to adalimumab continued every other week dosing. Weekly dosing was allowed beginning at week 14 (original protocol) or week 12 (amended protocol). Clinical remission (Mayo score ≤2, no subscore >1), clinical response (decrease in Mayo score ≥3 points and ≥30% from baseline, plus decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1), mucosal healing (endoscopy subscore ≤1), escalation to weekly dosing, and reduction in corticosteroid use were assessed at week 52 in the pooled ITT-A3 and pooled ITT-E populations, using modified nonresponder imputation. RESULTS: Rates of clinical remission, clinical response, and mucosal healing at week 52 for the ITT-A3 population (N = 390) were 29.5%, 53.6%, and 46.7%, respectively; 38.8% of week 8 responders achieved clinical remission at week 52. Of patients using baseline corticosteroids (N = 234), 56.0% were corticosteroid-free at week 52 (26.1% in clinical remission). Results of the ITT-E population were similar. No new safety issues were identified. CONCLUSIONS: In this open-label study, adalimumab was effective for maintaining clinical remission in anti-tumor necrosis factor-naive patients with moderately to severely active ulcerative colitis who did not adequately respond to conventional therapy.

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

BACKGROUND: Drug concentration monitoring may be useful to guide therapeutic adjustments for anti-tumor necrosis factor agents in Crohn's disease. The relationship between serum adalimumab concentrations and clinical outcomes was assessed using data from CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease (CLASSIC) I/II. METHODS: Serum adalimumab concentrations at week 4 of CLASSIC I and weeks 4, 24, and 56 of CLASSIC II were compared by clinical remission status (yes/no). Logistic regression and Classification and Regression Tree analyses explored factors associated with remission at weeks 4, 24, and 56. Threshold analyses and receiver operating characteristic curves evaluated the relationship between serum concentrations and clinical remission/response. RESULTS: Serum adalimumab concentrations for 275 patients were available. Median adalimumab concentrations were significantly higher in patients who achieved clinical remission than those who did not at week 4 of CLASSIC I (8.10 versus 5.05 µg/mL, P < 0.05). At all time points, adalimumab concentrations demonstrated considerable variability and overlap between patients with and without remission. With Classification and Regression Tree analyses, baseline Crohn's Disease Activity Index, baseline C-reactive protein, and adalimumab concentrations were associated with early remission at week 4 of CLASSIC I and week 4 of CLASSIC II, but not at weeks 24 and 56. Receiver operating characteristic curves demonstrated low utility of cutoff thresholds to discriminate by clinical response/remission status. CONCLUSIONS: A positive association between serum adalimumab concentration and remission was identified at several time points. A threshold concentration reliably associated with remission was not identified. Further prospective evaluations are needed before recommendations for adalimumab concentration monitoring can be made.

Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: results from the CARE trial.

BACKGROUND AND AIMS: Crohn's disease negatively affects patients' quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial (N=945). The population comprised both infliximab-naïve and -exposed patients, including infliximab primary non-responders. METHODS: Patients received adalimumab induction therapy (160 mg/80 mg at Weeks 0/2), followed by adalimumab 40 mg every other week for up to 20 weeks (patients with flares/non-response could receive 40 mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20. RESULTS: Mean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naïve and 47% of infliximab primary non-responders achieved clinically important improvements (≥9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement ≥7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naïve and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were €3070 per infliximab-naïve patient and €2059 per infliximab-exposed patient. CONCLUSIONS: Adalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohn's disease. Patients who failed prior infliximab therapy and patients naïve to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naïve patients (NCT00409617).

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 Crohn's 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 Crohn's 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 Crohn's 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.

Effect of adalimumab on clinical laboratory parameters in patients with Crohn's disease: results from the CHARM trial.

BACKGROUND: Nutritional deficiencies and anemia are common in Crohn's disease (CD). METHODS: We evaluated the effect of adalimumab on changes in laboratory values using data from CHARM, in which patients were randomized to adalimumab 40 mg every other week (eow), adalimumab 40 mg weekly, or placebo for 56 weeks. Mean changes in laboratory values from baseline to Weeks 26 and 56 were compared between adalimumab and placebo using analysis of covariance models. Percentages of patients with suboptimal laboratory values at Weeks 26 and 56 were compared between treatment groups using Cochran-Mantel-Haenszel (CMH) tests. Pearson correlation coefficients for associations between changes in Crohn's Disease Activity Index (CDAI) score and changes in laboratory values were estimated at Weeks 4, 26, and 56. RESULTS: The intention-to-treat analysis included 778 patients randomized to adalimumab eow (N = 260), adalimumab weekly (N = 257), or placebo (N = 261). Baseline abnormalities in laboratory values were common across treatment groups. CMH tests revealed significantly lesser rates of suboptimal laboratory values with adalimumab vs. placebo at Week 26, including hypoalbuminemia, calcium deficiency, low hemoglobin, low hematocrit, low red blood cell count, elevated platelet count, and elevated C-reactive protein concentration (all P < 0.05). These improvements persisted at Week 56. Improvements in CDAI from baseline to Weeks 4, 26, and 56 were significantly correlated with changes from baseline for albumin, hemoglobin, and C-reactive protein (all P < 0.001). CONCLUSIONS: Adalimumab therapy for moderately to severely active CD was associated with significant improvements in nutritional, hematologic, and inflammatory markers.

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

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 Crohn's 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.

Dosage adjustment during long-term adalimumab treatment for Crohn's disease: clinical efficacy and pharmacoeconomics.

BACKGROUND: Data from CHARM, a 56-week, randomized controlled trial of adalimumab for patients with moderately to severely active Crohn's disease (CD), were used to evaluate outcomes of adalimumab dosage adjustment. METHODS: Patients randomized to blinded adalimumab 40 mg every other week (EOW) in CHARM were the focus of the analysis. At ≥12 weeks, patients with flares or lack of response versus baseline (including patients who responded and then lost response) could move sequentially to open-label (OL) adalimumab EOW and then to OL adalimumab weekly. RESULTS: Of 260 patients randomized to adalimumab EOW, 140 (54%) continued blinded EOW therapy and 120 (46%) moved to OL therapy. Of patients on OL therapy, 49 (19%) continued EOW therapy and 71 (27%) moved to weekly therapy; 36 (14%) completed the trial on weekly therapy. Of 71 patients on weekly therapy, 37% achieved clinical remission (Crohn's Disease Activity Index [CDAI] <150), 58% achieved CR-100 (CDAI decreased ≥100 points), and 63% achieved CR-70 (CDAI decreased ≥70 points). Of the 49 patients who remained on OL EOW therapy, 39% achieved clinical remission, 59% achieved CR-100, and 63% achieved CR-70. In a logistic regression, greater baseline CDAI predicted changing to weekly therapy. A model of dosage-adjustment cost indicated a modest per-patient drug-acquisition cost increase ($574 over yearly EOW dosing cost [$22,518]). CONCLUSIONS: Of patients randomized to blinded EOW therapy, 19% moved to OL EOW therapy and 27% moved to OL weekly therapy for flares or lack of response versus baseline. Weekly therapy was associated with clear clinical benefits and a small cost increase.

Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn's disease: results from the CHARM trial.

OBJECTIVES: To compare outcomes of induction dosing followed by continuous adalimumab treatment with those of induction dosing with reinitiation of adalimumab (in the event of clinical deterioration) for patients with moderate-to-severe Crohn's disease (CD) who participated in the Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). METHODS: In the CHARM trial, all patients received open-label induction therapy with adalimumab 80 mg and 40 mg at weeks 0 and 2, respectively. In total, 778 patients were randomized at week 4 to one of three groups: (1) placebo after initial induction doses (followed by reinitiation of adalimumab therapy); (2) continuous maintenance treatment with adalimumab 40 mg every other week (e.o.w.); and (3) continuous maintenance treatment with adalimumab 40 mg every week. At/after week 12, patients receiving placebo with flare or non-response could reinitiate open-label adalimumab 40 mg e.o.w., and patients receiving continuous blinded adalimumab therapy could switch to open-label 40 mg e.o.w. Patients in all groups could switch to weekly therapy with continued flare/non-response. In the previously published primary analysis, results for only those patients who had responded at week 4 (decrease in Crohn's Disease Activity Index (CDAI) of > or = 70 points, referred to as "randomized responders") and remained on blinded therapy were analyzed. In this analysis, data from all randomized patients were analyzed based on original randomized treatment using an intention-to-treat analysis, regardless of whether they subsequently switched to open-label therapy. Disease activity, clinical remission, number of flares, Inflammatory Bowel Disease Questionnaire (IBDQ) score, number of CD-related surgeries, and hospitalization incidence were compared between the continuous and induction only/reinitiation adalimumab groups. RESULTS: Results for all outcome measures were superior for both continuous groups compared with the induction only/reinitiation group. On the basis of median CDAI and IBDQ results, patients in both continuous treatment groups achieved statistically significantly greater improvements vs. the induction only/reinitiation group (P < 0.05). At week 56, a significantly greater percentage of patients who had received continuous adalimumab (51% for e.o.w. and 49% for weekly) were in clinical remission vs. the induction only/reinitiation group (38%, P < 0.05). Continuous adalimumab therapy was also associated with fewer flares and fewer CD-related surgeries (P < 0.05). Patients in both continuous adalimumab groups had significantly lower risks of CD-related and all-cause hospitalizations than did patients in the induction only/reinitiation group (P < 0.05). CONCLUSIONS: For patients with active CD, continuous treatment with adalimumab was more effective than a strategy of induction dosing followed by reinitiation of adalimumab with clinical deterioration for maintenance of clinical remission, improved quality-of life outcomes, reduced flares, and a decrease in number of surgeries and risk of hospitalization.

Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn's disease: patient-reported outcomes of the CHARM trial.

OBJECTIVES: We evaluated the effects of adalimumab maintenance therapy on health-related quality of life (HRQOL) in patients with moderate to severe Crohn's disease. METHODS: In a Phase III, randomized, double-blind clinical trial (CHARM) of moderate to severe Crohn's disease patients, HRQOL outcomes were compared between the adalimumab maintenance treatment groups (every other week and weekly injection) and the adalimumab induction-only group. The Zung Self-Rating Depression Scale, functional assessment of chronic illness therapy (FACIT)-Fatigue, visual analog pain scales, Inflammatory Bowel Disease questionnaire (IBDQ), and Medical Outcomes Study 36-item Short Form Health Survey (SF-36) were analyzed for 499 randomized responders (a decrease of > or =70 points from baseline in the Crohn's Disease Activity Index [CDAI]) at baseline and weeks 4, 12, 26, and 56. RESULTS: CHARM patients' HRQOL was substantially impaired at baseline. Following a 4-week adalimumab induction therapy, patients experienced statistically significant improvements in all HRQOL measures (P < 0.0001). Compared with patients who were assigned to placebo after induction therapy, patients who continued adalimumab at 40 mg every other week maintenance therapy reported less depression (P < 0.01), fewer fatigue symptoms (P < 0.001), greater improvements in the IBDQ (P < 0.05), greater SF-36 physical component summary scores (P < 0.05), and less abdominal pain (P < 0.05) from weeks 12 to 56. They also had greater SF-36 mental component summary scores at week 56 (P < 0.05). Patients who continued adalimumab at 40-mg weekly maintenance therapy reported less depression and fewer fatigue symptoms at week 56, greater improvement in IBDQ, and less abdominal pain from weeks 12 to 56 (all P < 0.05 vs. placebo). CONCLUSIONS: Adalimumab maintenance therapy provided sustained improvements in HRQOL for patients with moderate to severe Crohn's disease through week 56.

Loss of treatment response to infliximab maintenance therapy in Crohn's disease: a payor perspective.

OBJECTIVES: To assess the incidence and economic implications of loss of treatment response among patients with Crohn's disease (CD) treated with infliximab maintenance therapy. METHODS: This was a retrospective observational study of infliximab response and costs among patients with CD using a large health-care claims database. Patients with CD receiving infliximab maintenance therapy with an initial response were selected from the Integrated Healthcare Information Services claims database (1999-2005). Patients' claim histories were used to identify patterns of response to infliximab treatment. Incidence of loss of response was estimated using Kaplan-Meier method. Annual total health-care and CD-related costs were estimated and adjusted for inflation to 2005 US dollars. Generalized linear model was used to assess the impact of loss of response on treatment costs. RESULTS: The study sample included 262 patients with CD with an initial response to infliximab therapy. Within 24 months of therapy initiation, 77% of patients lost treatment response. Upward dose adjustment, a new drug therapy for CD, and CD-related emergency room or inpatient visits were the three most common indicators of loss of response. Both annual total and CD-related health-care costs for patients who lost treatment response during the first year were found to be approximately one-third higher than for those who did not lose response. CONCLUSIONS: The majority of patients who had initial responses to infliximab maintenance treatment subsequently lost response within 2 years. Loss of response was associated with a significant increase in total health-care and CD-related costs.

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

BACKGROUND: Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent. OBJECTIVE: To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events. DESIGN: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005). SETTING: 52 sites in the United States, Canada, and Europe. PATIENTS: 325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points). INTERVENTION: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points. MEASUREMENTS: The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured. RESULTS: A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection. LIMITATIONS: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab. CONCLUSION: Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy. For more information on adalimumab in Crohn disease, click here. ClinicalTrials.gov registration number: NCT00105300.

Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.

BACKGROUND & AIMS: This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD). METHODS: Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56. RESULTS: The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively). CONCLUSIONS: Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug.

Safety and efficacy of a premixed, rice-based oral rehydration solution.

UNLABELLED: The authors compared the safety and efficacy of a ready-to-use, premixed, rice-based oral rehydration solution (R-ORS) with a glucose-based oral rehydration solution (G-ORS), each containing 75 mmol/L sodium, in Mexican children with acute diarrhea for less than 5 days. METHODS: One hundred eighty-nine boys 3 to 24 months old admitted to the hospital with acute diarrhea and signs of dehydration were randomly assigned to receive either G-ORS or R-ORS. Intake and output were measured every 3 hours. RESULTS: In the group treated with R-ORS, significantly fewer patients required supplemental intravenous fluids during the rehydration phase compared to the G-ORS group (1% v 8.7%; P < 0.01). Mean stool output, percent weight gain, ORS intake, urine output, and number of patients who vomited during rehydration were similar in the two groups. The mean total stool output after the first 24 hours of maintenance phase was significantly lower in the R-ORS group than in the G-ORS group. CONCLUSIONS: The authors found rice-based ORS to be safe, and its use reduced the rate of intravenous fluid therapy in comparison with the use of a glucose-based ORS.

Evaluation of the safety of palivizumab in the second season of exposure in young children at risk for severe respiratory syncytial virus infection.

BACKGROUND: Palivizumab reduces respiratory syncytial virus (RSV) hospitalisations in high-risk infants. Those with severe bronchopulmonary dysplasia may require two seasons of prophylaxis. There is concern that this humanised antibody might cause an adverse immune response in a second season of use. OBJECTIVE: To evaluate and compare the occurrence of anti-palivizumab antibodies and clinical adverse events in subjects receiving monthly palivizumab injections for a first and second season, and to assess frequency and severity of RSV disease in the two groups. DESIGN AND PATIENTS: Subjects aged or=1 : 80). Serum palivizumab concentrations were similar for the two groups. Nine (12.7%) first season and 8 (12.7%) second season subjects experienced one or more serious adverse events; most were respiratory and all were considered to be not or probably not related to palivizumab. No deaths occurred during the study. CONCLUSIONS: Monthly palivizumab injections were not associated with adverse immune responses or adverse events in young children receiving palivizumab for one or two seasons. Children receiving palivizumab for a second season did not experience more severe adverse events than those receiving it for the first time.