Objectives:
The subjectivity of the Physician Global Assessment (PGA) is a limitation of the Mayo score in assessing severity of ulcerative colitis (UC). We compared treatment efficacy using endpoint ...definitions based on modified Mayo (mMayo) score, versus those based on Mayo score, using data from the tofacitinib OCTAVE program.
Design:
This post hoc analysis included data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain).
Methods:
Remission and clinical response with nonresponder imputation (NRI) were assessed using mMayo (without PGA) and Mayo scores, and further stratified by prior tumor necrosis factor inhibitor (TNFi) failure status.
Results:
At week 8 of OCTAVE Induction 1 and 2, remission rates with placebo and tofacitinib 10 mg twice daily (BID), respectively, were 7.7% and 24.8% (mMayo) and 6.0% and 17.6% (Mayo). At week 52 of OCTAVE Sustain, remission rates with placebo, tofacitinib 5 and 10 mg BID, respectively, were 12.1%, 35.9%, and 42.1% (mMayo) and 11.1%, 34.3%, and 40.6% (Mayo). A statistically significant (p < 0.05) treatment effect of tofacitinib versus placebo was observed for remission and clinical response at all time points, regardless of scoring definition or prior TNFi failure status.
Conclusions:
A significant effect of tofacitinib versus placebo was demonstrated across efficacy endpoints using mMayo score, consistent with previously reported data using Mayo score. Treatment effect sizes were generally similar regardless of scoring definition. This observation may help contextualize tofacitinib therapy outcomes with those of new UC therapies and support the use of Mayo score-based endpoints in UC clinical trials.
Trail registration:
ClinicalTrials.gov identifiers: NCT01465763; NCT01458951; NCT01458574.
Summary
Background
Identifying predictors of therapeutic response is the cornerstone of personalised medicine.
Aim
To identify predictors of long‐term healing of severe inflammatory lesions based on ...magnetic resonance enterography (MRE) findings in patients with Crohn’s disease (CD) treated with tumour necrosis factor alpha (TNF‐α) inhibitors.
Methods
This prospective longitudinal single‐centre study included patients with clinically active CD requiring treatment with TNF‐α inhibitors with at least one intestinal segment with a severe inflammatory lesion detected by MRE (segmental MaRIA ≥11). MRE data were obtained at baseline, and at weeks 14 and 46. The primary endpoint was healing of severe inflammatory lesions (MaRIA <11) in each segment. The secondary endpoint was healing of all severe inflammatory lesions on a per‐patient analysis.
Results
We included 58 patients with 86 intestinal segments with severe inflammatory lesions. At week 46, healing of severe lesions was found in 51/86 (59.3%) segments, and complete healing of inflammatory lesions in all segments was found in 28/58 (48.6%) patients. Multivariable analysis found baseline‐negative predictors of long‐term healing of severe inflammation were ileal (as opposed to colonic) location (OR 0.00, 0.00‐0.56 P = 0.002) and presence of creeping fat on MRE (OR 0.00 0.00‐0.57; P = 0.001). Persistence of segmental MaRIA score >10.6 at week 14 was a negative predictor of healing at week 46 (OR 0.3 0.04‐‐0.38; P < 0.001).
Conclusion
In patients with CD, the absence of creeping fat detected at baseline MRE and location of severe inflammatory lesions are clinically relevant predictors of long‐term healing of severe inflammation under treatment with TNF‐α inhibitors.
Abstract
Background
Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We report health-related quality of life (HRQoL) outcomes in patients with ...ulcerative colitis in the phase 3 open-label, long-term extension study, OCTAVE Open.
Methods
The Inflammatory Bowel Disease Questionnaire (IBDQ), EuroQoL-5 Dimensions Health Questionnaire, and 36-Item Short Form Survey scores were analyzed up to month (M) 72 in 4 subpopulations: patients in remission at baseline (maintenance remitters) assigned tofacitinib 5 mg twice daily and patients not in remission at baseline (maintenance nonremitters, maintenance treatment failures, and induction nonresponders IndNRs) assigned tofacitinib 10 mg twice daily in OCTAVE Open. Data were analyzed overall and stratified by corticosteroid use at baseline, prior tumor necrosis factor inhibitor failure, and prior immunosuppressant failure.
Results
Among maintenance remitters and nonremitters, HRQoL outcomes were maintained up to M72: 80.0% and 100.0% of patients had an IBDQ total score ≥170, respectively. At baseline, 7.4% of maintenance treatment failures had an IBDQ total score ≥170, and this increased to 54.3% and 75.0% at M2 and M72, respectively. Corresponding values for IndNRs were 22.6%, 51.0%, and 86.0%. HRQoL outcomes were independent of treatment history. Among patients not in remission at baseline, improvement in EuroQoL-5 Dimensions Health Questionnaire and 36-Item Short Form Survey scores was maintained or achieved by M2, and steady to M72 or M33, with maintenance treatment failures and IndNR subpopulations undergoing the biggest improvements from baseline.
Conclusions
A continued favorable impact on HRQoL was revealed with long-term tofacitinib treatment in OCTAVE Open, regardless of baseline remission status or treatment history. (ClinicalTrials.gov; number: NCT01470612).
Lay Summary
Health-related quality of life was assessed in patients with ulcerative colitis in an open-label, long-term extension study, OCTAVE Open. Patients had sustained beneficial effects on health-related quality of life with long-term tofacitinib treatment, regardless of treatment history/remission status at OCTAVE Open baseline.
Abstract
Background and Aims
Tofacitinib is an oral small molecule Janus kinase JAK inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety exposure: ...≤7.8 years from the global clinical programme.
Methods
Patients receiving tofacitinib 5 or 10 mg twice daily BID from completed phase P2/3 placebo-controlled studies, an open-label, long-term extension study final data cut-off: August 24, 2020, and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 2020 Cohort) were included. Proportions with adverse events AEs and serious AEs, and incidence rates IRs; unique patients with events/100 patient-years for deaths and AEs of special interest AESI were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events MACE and gastrointestinal perforations were adjudicated.
Results
In total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 83% received a predominant dose of 10 mg BID; 412/1157 35.6% received tofacitinib for >4 years; 992/1157 85.7% had AEs, 244/1157 21.1% had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs 95% confidence intervals for all tofacitinib doses were: deaths, 0.23 0.09–0.46; serious infections, 1.69 1.26–2.21; herpes zoster non-serious and serious, 3.30 2.67–4.04; opportunistic infections, 1.03 0.70–1.46; malignancies (excluding non-melanoma skin cancer NMSC), 0.84 0.55–1.24; NMSC, 0.73 0.45–1.10; MACE, 0.29 0.13–0.55; deep vein thrombosis, 0.03 0.00–0.18; pulmonary embolism, 0.19 0.07–0.42; gastrointestinal perforations, 0.10 0.02–0.28.
Conclusions
AESI IRs were stable to 7.8 years and generally <2.0 in the Overall plus P3b/4 2020 Cohort, with the exception of herpes zoster a known risk of tofacitinib treatment. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304
JCC Topic/keyword selection: 3. Clinical trials
An infographic plain language summary of this paper is available at: 10.25454/pfizer.figshare.20585331
Graphical Abstract
Graphical Abstract
