Tofacitinib in Patients with Ulcerative Colitis: Inflammatory Bowel Disease Questionnaire Items in Phase 3 Randomized Controlled Induction Studies.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC. METHODS: Data were pooled from the randomized, 8­week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed. RESULTS: Significant improvements (nominal P < 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for "bowel movements been loose" at weeks 4 and 8, and "problem with rectal bleeding" at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients. CONCLUSIONS: Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

The Impact of Raising the Bar for Clinical Trials in Ulcerative Colitis.

In order to identify the practical implications for both health care practitioners and patients in understanding differences between the results of trials assessing therapies for ulcerative colitis [UC], we reviewed clinical trials of therapies for moderate to severe UC, with a focus on trial design. Over time, patient populations in UC trials have become more refractory, reflecting that patients are failing treatment with additional and different classes of drug, including conventional therapies, immunosuppressant drugs, and anti-tumour necrosis factor therapies. Outcomes used to measure efficacy have become increasingly stringent in order to meet the expectations of patients and physicians, and the requirements of regulatory bodies. Trial design has also evolved to integrate induction and maintenance therapy phases, so as to facilitate patient recruitment and to answer clinically important questions such as how efficacious therapies are in specific subpopulations of patients and during long-term use. As UC clinical trial design continues to evolve, and with limited head-to-head trials and real-world comparative effectiveness studies evaluating UC therapies, careful judgment is required to appreciate the differences and similarities in trial designs, and to understand how these variances may affect the observed efficacy and safety outcomes.

Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. AIMS: This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease. METHODS: Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks' fixed, open-label treatment. RESULTS: Sixty-two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non-responder imputation). Study design prevented between-dose efficacy comparisons. CONCLUSIONS: No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials.

OBJECTIVE: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD). DESIGN: We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. RESULTS: 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. CONCLUSIONS: Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. TRIAL REGISTRATION NUMBERS: NCT01393626 and NCT01393899.

Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts.

PURPOSE: To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (C(min,TN)) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients. METHODS: Dense sampling of sirolimus was performed over a single daily-dosing interval in 11 hepatic allograft recipients on day 28 and at 3 months after start of treatment. Serial trough concentration sampling was performed in 380 hepatic allograft recipients on days 1, 7, 14, 28, 42, 60, 90, 180, 270 and 360 after start of treatment. Occurrence of stomatitis, pneumonia, rejection, and death were collected for 360 days after start of treatment. Noncompartmental pharmacokinetic parameters were analyzed in the 11 densely sampled patients; C(min,TN) was determined in the 380 patients. RESULTS: Mean maximum concentration (C(max)), time to C(max) (t(max)), area under the curve for the given dose interval (AUC(tau)), and whole blood oral clearance at 3 months were 20.8 ± 7.6 ng/mL, 3 ± 1 h, 338 ± 144 ng·h/mL, and 10.0 ± 5.6 L/hr, respectively. In the 11 densely sampled patients, linear regression showed that C(min,TN) was highly predictive of AUC(tau) (r² = 0.77, P < 0.0001) at each analysis time point. Logistic regression showed a relationship between C(min,TN) in the 380 patients and pneumonia occurrence, but not between C(min,TN) and stomatitis, rejection, or death. CONCLUSIONS: In this study, the pharmacokinetic profile of sirolimus in hepatic allograft patients was consistent with that of renal transplantation recipients. With the exception of pneumonia, no correlation was observed between C(min,TN) and the occurrence of adverse events of interest.

Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial.

BACKGROUND: Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen. METHODS: This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275). Patients with history of posttransplant lymphoproliferative disease or known/suspected malignancy within 5 years before screening were excluded. As part of standard safety measurements, subjects were monitored for any malignancy occurrence; both skin and nonskin malignancies were reported, even if the patient discontinued from the therapy. Malignancy rates were analyzed based on exposure time to study drugs (i.e., number of events per 100 person-years of follow-up). RESULTS: At 2 years postconversion, the total number of malignancies per 100 person-years of exposure was significantly lower among SRL conversion patients compared with CNI continuation (2.1 vs. 6.0, P<0.001). Patients undergoing SRL-based, CNI-free therapy had significantly lower rates of the subset of nonmelanoma skin carcinomas through 2 years postconversion (1.2 vs. 4.3, P<0.001). This difference persisted after excluding patients with a history of malignancy before randomization. The rate of all other malignancies was not significantly different between treatment groups (P=0.058). CONCLUSION: In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.

The utility of ultrasound site selection for pediatric percutaneous liver biopsy.

BACKGROUND: The site for percutaneous liver biopsy is determined by physical examination and anatomic landmarks. The authors compared physical examination with ultrasound examination to determine liver location, size, and an optimal biopsy site. METHODS: A pediatric gastroenterology fellow or attending gastroenterologist initially selected a biopsy site by physical examination. An ultrasonographer performed a limited ultrasound examination to evaluate this site. RESULTS: Sixty biopsy sites from 58 patients were evaluated. Forty-six patients had no previous liver surgery. Two patients had had a Kasai procedure. Ten patients had had orthotopic liver transplantation. The mean age of the patients was 11.1 +/- 7.6 years. Ultrasonography detected the following potential complications of percutaneous biopsy at the site determined by physical examination: insufficient liver (7 of 15, 47.0%), diaphragm injury (4 of 15, 27.0%), bowel perforation (2 of 15, 13.0%), kidney laceration (1 of 15, 7.0%), and large blood vessel laceration (1 of 15, 7.0%). These ultrasound findings directed a change in biopsy site for 15 (25.0%) physical examination sites. Major biopsy complications were rare (1.7%). CONCLUSION: Ultrasound examination resulted in a location change to a more optimal site in 25.0% of the sites determined by physical examination. Ultrasound determination of the biopsy site should be considered before pediatric percutaneous liver biopsy.

Terminal ileum intubation in pediatric colonoscopy and diagnostic value of conventional small bowel contrast radiography in pediatric inflammatory bowel disease.

BACKGROUND: Small bowel contrast radiography is often suggested as the first diagnostic tool in evaluating pediatric inflammatory bowel disease. The purpose of this study was to determine the sensitivity and specificity of small bowel radiography compared with terminal ileal biopsies in diagnosing pediatric inflammatory bowel disease, and to determine the success rate and safety of terminal ileum intubation during pediatric colonoscopy. METHODS: We retrospectively reviewed the records of 164 subjects who had colonoscopies with terminal ileal biopsies between 1994 and 1996. Small bowel contrast radiography was performed in 84 subjects within two weeks of the colonoscopy. We also reviewed all the colonoscopy reports from the years 1994 to 1996 and 1999 to 2000 to determine the percentage of terminal ileal intubation. RESULTS: Eighty-four subjects with small bowel contrast radiography and terminal ileal biopsies were reviewed. Using small bowel radiography as a screening test for the diagnosis of terminal ileum inflammatory bowel disease resulted in a sensitivity of 45% (17/37) and a specificity of 96% (17/19). Between the years 1994 and 1996 the percentage of pediatric colonoscopies that resulted in terminal ileal intubation was 21.5%; between the years 1999 and 2000 the percentage increased to 65.6%. CONCLUSIONS: A normal small bowel radiography alone should not be used to rule out pediatric inflammatory bowel disease when the symptoms suggest it. Colonoscopy with terminal ileal intubation is feasible and safe; it should be attempted in all children with symptoms consistent with inflammatory bowel disease.