Lakshmi Padgett

Block designs : analysis, combinatorics, and applications

# Linear Estimation and Tests for Linear Hypotheses # General Analysis of Block Designs # Randomized Block Designs # Balanced Incomplete Block Designs -- Analysis and Combinatorics # Balanced Incomplete Block Designs -- Applications # t-Designs # Linked Block Designs: Partially Balanced Incomplete Block Designs # Lattice Designs: Miscellaneous Designs

Randomised clinical trial: a placebo‐controlled study of intravenous golimumab induction therapy for ulcerative colitis

Tumour necrosis factor alpha (TNFα)‐antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα‐antagonist‐naïve patients with moderate‐to‐severe active UC despite conventional treatment.

Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase 3 study.

Background:To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). Methods:This phase 3, randomized, open-label multicenter study enrolled 60 children (6–17 yr) with moderate-to-severely active UC (Mayo score, 6–12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every 8 weeks (q8w) through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Results:Infliximab pharmacokinetics were not influenced by age (6–11 yr versus 12–17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 &mgr;g/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 &mgr;g/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 &mgr;g/mL) versus q12w (0.8 &mgr;g/mL) and with infliximab 10 mg/kg (2.9 &mgr;g/mL) versus 5 mg/kg (1.1 &mgr;g/mL) among patients who are regimen adjusted. Conclusions:Infliximab pharmacokinetics/exposure–response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.

Maintenance of Efficacy and Continuing Safety of Golimumab for Active Ulcerative Colitis: PURSUIT-SC Maintenance Study Extension Through 1 Year

Objectives:The safety and efficacy of subcutaneous golimumab through 2 years of maintenance therapy was evaluated in patients with moderate-to-severe ulcerative colitis (UC).Methods:Patients completing treatment through week 52 (placebo, golimumab 50, 100, every-4-weeks (q4w)) and evaluations at week 54 were eligible for this long-term extension (LTE) trial. Patients receiving placebo or golimumab 50 mg with worsening disease during the LTE could receive golimumab 100 mg. Efficacy assessments included the Mayo physician’s global assessment (PGA) subscore, inflammatory bowel disease questionnaire (IBDQ), and corticosteroid use. Patients who were randomized to golimumab at PURSUIT-Maintenance baseline and continued receiving golimumab during the LTE were analyzed for efficacy (using intention-to-treat and “as observed” analyses; N=195) and safety (N=200). Patients treated with golimumab at any time from induction baseline through week 104 (N=1240) constituted the overall safety population.Results:Baseline demographics and disease characteristics of patients entering the LTE receiving golimumab were similar to those of all patients randomized to golimumab maintenance at baseline. At week 104, 80.5% (157/195) of patients had a PGA=0/1 (range weeks 56–104: 80.5–91.8%) and 56.4% (110/195) had a PGA=0 (weeks 56–104: range: 53.8–58.5%). Through week 104, 86% of patients maintained inactive or mild disease activity. Among 174 corticosteroid-free patients at week 54, 88.5% remained corticosteroid-free at week 104. At week 104, 62.2% (120/193) had an IBDQ score ≥170. Tuberculosis, opportunistic infection, and malignancy rates were low, and the overall safety profile was similar to that reported through week 54. Two non-melanoma skin cancers, one metastatic colon cancer, and two deaths (biventricular heart dysfunction, sepsis) occurred between weeks 54 and 104.Conclusion:Subcutaneous golimumab q4w through 2 years maintained clinical benefit and reduced corticosteroid use among patients who did well in the maintenance study. No new safety signals were observed.

Subcutaneous Golimumab in Pediatric Ulcerative Colitis: Pharmacokinetics and Clinical Benefit

Background: Current treatments for pediatric ulcerative colitis (UC) are limited. We evaluated the pharmacokinetics and clinical benefits of subcutaneous golimumab, an anti-tumor necrosis factor agent, in moderately-to-severely active pediatric patients with UC refractory to conventional therapy. Methods: We report a multicenter, open-label study of golimumab with a pharmacokinetics phase (week 0–14). Patients had moderately-to-severely active UC and were naive to anti-tumor necrosis factor treatment. At weeks 0 and 2, patients received golimumab induction dosed by weight (<45 kg [90/45 mg/m2]; ≥45 kg [200/100 mg]). Week 6 clinical responders continued golimumab q4w. Serum golimumab concentrations, clinical outcomes (Mayo score, PUCAI score), and adverse events are reported. Results: Thirty-five patients (71.4% pancolitis) aged 6 to 17 years had baseline median (interquartile range), age, weight, and disease duration of 15.0 (11.0–16.0) years, 50.6 (35.2–59.0) kg, and 1.2 (0.6–3.1) years, respectively. Baseline Mayo and PUCAI scores were 8.0 (6.0–9.0) and 45 (35.0–65.0), respectively. Median (interquartile range) serum golimumab concentrations were comparable to a historical reference adult UC population at weeks 2 (5.72 [3.80–9.17] &mgr;g/mL), 4 (7.61 [3.22–9.51] &mgr;g/mL), and 6 (2.64 [0.92–3.83] &mgr;g/mL). Serum golimumab concentrations were generally lower in the <45 kg than ≥45 kg weight subgroup. At week 6, 60%, 34%, and 54%, of patients achieved Mayo clinical response, PUCAI clinical remission, and mucosal healing (Mayo subscore 0/1). No clinically important safety concerns were reported. Conclusions: This open-label study demonstrates that pediatric and adult golimumab pharmacokinetics are similar. Clinical benefit and safety shows promise in biologically naive pediatric patients with UC.