Hanauer, Stephen B.

Background/Objectives: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). Methods: In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs’ treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. Results: A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. Conclusions: PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.

ABSTRACTBackgroundPatients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high‐risk orphan population.AimTo provide guidance for clinical trial design methodology in these patients.MethodsWe created a multi‐centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate–severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches.ResultsThe Truelove‐Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient‐reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS‐2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post‐discharge follow‐up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population.ConclusionWe provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified.

Abstract Background The LIBERTY-CD study demonstrated a broad level of benefit for subcutaneous (SC) infliximab (IFX) maintenance therapy compared with placebo in patients (pts) with moderate-to-severe active Crohn’s disease (CD) who responded to intravenous IFX induction. Characterising subgroups of pts with different levels of response could help to better position SC IFX therapy. Methods This was a post hoc analysis of 231 pts from the CT-P13 SC arm of the randomised, parallel-group, placebo-controlled LIBERTY-CD study (NCT03945019). Unsupervised group-based trajectory modelling (GBTM) was conducted to deconvolute cohort-level data into response trajectories. Longitudinal patient reported outcomes (PRO-2: abdominal pain and stool frequency) were used to investigate whether pts who received SC IFX maintenance therapy cluster into response trajectories. Efficacy endpoints (clinical remission, endoscopic response and remission, corticosteroid-free remission and comprehensive disease control [CDC] rate) were analysed and compared between different trajectories. Trough levels of IFX (TLI) were evaluated by trajectory throughout the treatment period. Baseline characteristics were analysed in a descriptive manner to explore predictors for super-response. Results Four distinct trajectories were clearly separated and stabilised around Week (W) 10–14 (Figure): rapid and sustained improvement (super-responders, n=61), rapid, but slightly less drastic than super-responders, then sustained improvement (fast responders, n=56), gradual then sustained improvement (slow responders, n=63) and partial improvement during the maintenance phase (limited responders, n=51). Super-responders had the highest rates of W54 clinical remission (73.8%; p=0.002), endoscopic response (63.9%; p=0.009), corticosteroid-free remission (63.6%; p=0.007), endoscopic remission (42.6%; p=0.094) and CDC (37.7%; p=0.013) among trajectories (Table). Super-responders also maintained the highest TLI from W10 throughout the maintenance period. Super-responders showed a trend towards lower baseline body weight, body mass index and oral corticosteroid use, but higher Crohn’s Disease Activity Index score and prior biologic/Janus kinase inhibitor use compared to other trajectories. Conclusion Distinct subpopulations with different levels of responses were detected by GBTM using data from a large group of pts with moderate-to-severe active CD who were treated with SC IFX for 1 year. Super-responders with rapid and sustained improvements during SC IFX therapy had a higher likelihood of achieving desirable long-term outcomes, with substantial individual benefit (CDC). Baseline characteristics and TLI were associated with super-response.

Abstract Background The disease severity index (DSI) for inflammatory bowel disease (IBD) combines measures of disease phenotype, inflammatory activity, and patient-reported outcomes. We aimed to validate the DSI and assess its utility in predicting a complicated IBD course. Methods A multicenter cohort of adults with IBD was recruited. Intraclass correlation coefficients (ICCs) and weighted Kappa assessed inter-rater reliability. Cronbach’s alpha measured internal consistency of DSI items. Spearman’s rank correlations compared the DSI with endoscopic indices, symptom indices, quality of life, and disability. A subgroup was followed for 24 months to assess for a complicated IBD course. Area under the receiver operating characteristics curve (AUROC) and multivariable logistic regression assessed the utility of the DSI in predicting disease progression. Results Three hundred and sixty-nine participants were included (Crohn’s disease [CD], n = 230; female, n = 194; mean age, 46 years [SD, 15]; median disease duration, 11 years [interquartile range, 5-21]), of which 171 (CD, n = 99; ulcerative colitis [UC], n = 72) were followed prospectively. The DSI showed inter-rater reliability for CD (ICC 0.93, n = 65) and UC (ICC 0.97, n = 33). The DSI items demonstrated inter-rater agreement (Kappa &gt; 0.4) and internal consistency (CD, α &gt; 0.59; UC, α &gt; 0.75). The DSI was significantly associated with endoscopic activity (CDn=141, r = 0.65, P &lt; .001; UCn=105, r = 0.80, P &lt; .001), symptoms (CDn=159, r = 0.69, P &lt; .001; UCn=132, r = 0.58, P &lt; .001), quality of life (CDn=198, r = −0.59, P &lt; .001; UCn=128, r = −0.68, P &lt; .001), and disability (CDn=83, r = −0.67, P &lt; .001; UCn=52, r = −0.74, P &lt; .001). A DSI of 23 best predicted a complicated IBD course (AUROC = 0.82, P &lt; .001) and was associated with this end point on multivariable analyses (aOR, 9.20; 95% confidence interval, 3.32-25.49). Conclusions The DSI reliably encapsulates factors contributing to disease severity and accurately prognosticates the longitudinal IBD course.

INTRODUCTION: Limited guidance exists for the postdischarge care of patients with ulcerative colitis hospitalized for moderate-severe flares. METHODS: RAND methodology was used to establish appropriateness of inpatient and postdischarge steroid dosing, discharge criteria, follow-up, and postdischarge biologic or small molecule initiation. A literature review informed on the panel's voting, which occurred anonymously during 2 rounds before and after a moderated virtual session. RESULTS: Methylprednisolone 40–60 mg intravenous every 24 hours or hydrocortisone 100 mg intravenous 3 times daily is appropriate for inpatient management, with methylprednisolone 40 mg being appropriate if intolerant of higher doses. It is appropriate to discharge patients once rectal bleeding has resolved (Mayo subscore 0–1) and/or stool frequency has returned to baseline frequency and form (Mayo subscore 0–1). It is appropriate to discharge patients on 40 mg of prednisone after observing patients for 24 hours in hospital to ensure stability before discharge. For patients being discharged on steroids without in-hospital biologic or small molecule therapy initiation, it is appropriate to start antitumor necrosis factor (TNF) therapy after discharge for anti-TNF-naive patients. For anti-TNF-exposed patients, it is appropriate to start vedolizumab or ustekinumab for all patients and tofacitinib for those with a low risk of adverse events. It is appropriate to follow up patients clinically within 2 weeks and with lower endoscopy within 4–6 months after discharge. DISCUSSION: We provide recommendations on the inpatient and postdischarge management of patients with ulcerative colitis hospitalized for moderate-severe flares.

Abstract Background Entry criteria and outcome measures of Crohn’s disease (CD) clinical trials have evolved. Patients are now required to have active inflammation on screening endoscopy, with some studies requiring moderate-severe SES-CD scores. Recent trials have endoscopic response as a co-primary endpoint and endoscopic remission (ER) and deep remission (DR) as major secondary endpoints. Pivotal CD maintenance studies typically examine only responders to induction. The SEAVUE study required ≥1 ulceration of any size (SES-CD≥3) at baseline and had a treat-through design. To examine the results in the context of these trial design characteristics, we evaluated endoscopic outcomes at wk52 in the subgroup of pts with moderate-severe baseline SES-CD scores in SEAVUE, as well as those who were in clinical response after induction. Methods Biologic-naïve pts failing or intolerant to conventional therapy with CDAI≥220/≤450 and SES-CD≥3 were eligible. Pts were randomized, 1:1 to UST (~6mg/kg IV at wk0 then, 90mg SC q8w) or ADA (SC, 160mg at wk0, 80mg at wk2, then, 40mg q2w). Endoscopic outcomes were evaluated in all pts and the subgroup with moderate-severe endoscopic disease (baseline SES-CD≥6 for ileocolonic or colonic disease or SES-CD≥4 for isolated ileal disease). Endoscopic response was a ≥50% reduction from baseline in SES-CD, SES-CD≤3, or SES-CD=0 for pts with baseline SES-CD=3. ER was SES-CD≤3 or, 0 in pts with baseline SES-CD=3. DR was CDAI&lt;150 and ER. Results Endoscopic outcomes for the subgroup with moderate-severe endoscopic disease were similar to those of the full cohort of pts. In UST-treated pts, endoscopic response was achieved at wk52 in, 41.9% in the full cohort and, 43.1% in the moderate-severe subgroup (Table, 1). In ADA-treated pts, endoscopic responses were, 36.9% and, 35.4%, respectively. For pts who were in clinical response after induction (Table, 1), endoscopic response rates were, 48.2% in the full cohort and, 49.5% in the moderate-severe subgroup for UST and, 44.8% and, 43.1%, respectively, for ADA. ER and DR rates were generally similar between the full cohort and the moderate-severe subgroup (Table, 2; eg, ERs were UST, 28.5% and ADA, 30.7% in full cohort; UST, 27.1% and, 27.8% ADA in subgroup). ER and DR rates were, 3%-7% higher in induction responders compared with the full cohort. Of note, even among wk16 nonresponders, some pts attained endoscopic outcomes at wk52 (eg, endoscopic responses in wk16 nonresponders were UST, 21.4% and ADA 13.3%). Conclusion In SEAVUE, both the UST and ADA treatment groups achieved high endoscopic response, ER, and DR rates at wk52. Results in pts with moderate-severe endoscopic disease were similar to those of the full cohort, but clinical responders after induction had higher rates than the full cohort.

Abstract Background We studied the efficacy and safety of ustekinumab (UST) vs adalimumab (ADA) through 1 year in biologic-naïve patients (pts) with moderate-to-severe Crohn’s disease. Methods SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in adults with CD Activity Index (CDAI) scores ≥220/≤450. Biologic-naïve pts failing/intolerant to conventional therapy with any size ulcer on baseline (BL) ileocolonoscopy were eligible. Pts were randomized 1:1 to UST (⁓6mg/kg IV at BL then 90mg SC every 8 weeks [Ws]) or ADA (160/80mg SC at BL/W2, then 40mg SC every 2 Ws) per US-approved regimens (no dose modifications). Primary endpoint was clinical remission at W52 (CDAI &lt;150). Major secondary endpoints were corticosteroid-free remission, clinical response (≥100-point CDAI decrease from BL), remission in pt-reported CDAI components (PRO-2 symptom remission: abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3), and endoscopic remission (SES-CD score ≤3/0 for pts with BL score=3) at W52 and clinical remission at W16. Results 386 pts were randomized to UST or ADA. BL demographics and disease characteristics were balanced between groups and indicative of pts with early, moderate-to-severe CD (median CD duration, 2.58 years; CDAI, 289.5; SES-CD, 8.0). At W52, 65% of UST-treated and 61% of ADA-treated pts achieved clinical remission (Δ=4.0%; 95% CI, -5.5%, 13.5%; p=0.417). Major secondary endpoints, including endoscopic remission, were similar between groups (Table 1), as were remission rates at assessment points through W52. Some other secondary endpoints showed numerical (not statistical) differences between UST and ADA (Table 1). Key safety events are summarized in Table 2. Among UST-treated and ADA-treated pts, 34.0% and 40.5% had infections, 2.6% and 7.2% had serious adverse events (AEs) of worsening CD, and 6.3% and 11.3% had AEs that led to discontinuation (DC) of study drug, respectively. One ADA-treated pt had active pulmonary TB. Injection-site reactions associated with active treatment occurred in 1.0% of UST-treated and 10.3% of ADA-treated pts. Overall, 15.2% of UST-treated and 23.6% of ADA-treated pts DC before W52. Reasons for DC were primarily lack of efficacy (UST, 2.1% vs ADA, 5.1%), AEs (UST, 5.7% vs ADA, 10.7%), and withdrawal of consent (UST, 5.8% vs ADA, 5.1%). Time to treatment DC was longer with UST vs ADA (post hoc analysis). Conclusion Both UST and ADA were highly effective in this population of biologic-naïve pts. Rates of clinical remission at W52 were not statistically significantly different between treatment groups. DC rates were numerically lower for UST. Safety results were consistent with prior experience for both treatments.