Subjects who had clinical benefit from the maintenance period received 300mg SC Q4W from W52 to W104. Among the W12 miri induction endoscopic improvers, IBDQ response rates at W52 were 75.6% (31/41) ...and 80.4% (37/46) and IBDQ remission rates were 65.9% (27/41) and 67.4% (31/46) in the IV-C and SC groups, respectively. At W104, the IBDQ response rates were 81.8% (27/33) and 78.0% (32/41) and IBDQ remission rates were 69.7% (23/33) and 56.1% (23/41) in the IV-C and SC groups, respectively. Week 52 and Week 104 IBDQ Outcomes in miri induction Week 12 Endoscopic Improvers Week 12 Endoscopic Improverse Week 52 Week 104 Week 52 Week 104 Miri IV-C N=41 Miri IV-C N=33 Miri SC N=46 Miri SC N=41 Total IBDQ scorea, mean (SD) 188.5 (26.6) 187.4 (21.8) 180.8 (25.4) 173.7 (32.1) IBDQ responseb, n (%) 31 (75.6) 27 (81.8) 37 (80.4) 32 (78.0) IBDQ remissionc, n (%) 27 (65.9) 23 (69.7) 31 (67.4) 23 (56.1) IBDQ score change from baseline a d mean 64.3 67.1 66.4 57.9 IBDQ Domain Scoresa, mean (SD) Bowel symptoms 58.6 (8.8) 58.8 (6.5) 57.3 (8.0) 54.3 (9.8) Systemic symptoms 27.7 (5.4) 26.8 (5.1) 25.8 (5.4) 24.7 (6.6) Emotional function 70.5 (11.1) 70.0 (9.9) 67.1 (11.0) 65.0 (13.1) Social function 31.8 (3.9) 31.8 (3.34) 30.6 (4.2) 29.7 (5.3) aMean and (SD) for scores and changes in scores do not utilize imputation and therefore are based on patients with observed data at the indicated timepoint (IV week 52 N=35; IV week 104 N=29; SC week 52 N=41; SC week 104 N=33). bIBDQ response: ≥16-point improvement in IBDQ score. cIBDQ remission: total IBDQ score ≥170. dChange from baseline. eEndoscopic improvement: ≥1 point improvement in SES-CD at Week 12.
Of the W12 endoscopic improvers, 74 finished W52 maintenance and entered the extension period (W52-W104) where 68 completed treatment through W104. CDAI and PRO remission were sustained through W104, ...with no differences observed in pts who received either IV-C and SC miri treatments during maintenance and continued into the extension period.Table 1. Abbreviations: CD = Crohn’s disease; SF = stool frequency; AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; PRO = patient-reported outcomes.
Introduction: We explored the potential relationship between early histologic and endoscopic responses on long term clinical outcomes after 2 years of mirikizumab (miri) treatment in a Phase 2 trial ...in patients with moderately-to-severely active Crohn’s disease (CD). Among patients receiving miri with active histological disease at baseline, we determined the relationship between histologic and/or endoscopic response or remission at W12 and W52 with clinical remission based on the Crohn’s Disease Activity Index (CDAI), patient-reported outcomes (PRO), and hospitalization rates at W104. AP= abdominal pain; CDAI= Crohn’s Disease Activity Index; GHAS= Global Histologic Disease Activity Score; PRO= patient-reported outcomes; N=number of patients in the histologic/endoscopic response group; n = number of patients in the specified category; RHI= Robarts Histologic Index; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF= stool frequency. aPatients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 12. bDefined as serious adverse event due to hospitalization.
Introduction: Mirikizumab (miri) treatment improved quality of life in patients with moderately-to-severely active Crohn’s disease (CD) through Week 52 (W52) as assessed by Medical Outcomes 36-Item ...Short Form Health Survey (SF-36) scores in the Phase 2 randomized, double-blind, parallel, placebo (PBO)-controlled study (SERENITY/NCT02891226). SF-36 Physical (PCS) and Mental (MCS) Component Summary, and 8 domain scores (physical functioning, role-physical, role-emotional, bodily pain, vitality, social functioning, mental and general health) were evaluated up to W104 and summarized by randomized treatment (i.e. pooled all IV and all SC) from W12-52 among endoscopic improvers at W12 who were rerandomized into maintenance and went onto the extension period. Conclusion: Treatment with miri is associated with a sustained improvement in quality of life as measured by SF-36 from W52 to W104 in patients with moderately-to-severely active CD.Table 1 Observed mean CFBL, (SD) Week 12 Endoscopic Improvers a Week 52 Week 104 Week 52 Week 104 Miri IV-C N=35 Miri IV-C N=29 Miri SC N=41 Miri SC N=38 PCS 10.47 (8.72) 11.68 (6.60) 10.70 (7.88) 9.96 (8.17) MCS 8.49 (11.30) 9.32 (12.35) 11.45 (11.42) 10.43 (11.59) Domain Scores Physical functioning 17.29 (18.48) 19.14 (17.17) 22.93 (22.30) 22.37 (22.83) Role-physical 30.89 (24.95) 32.33 (20.87) 32.01 (28.24) 26.64 (29.27) Role-emotional 13.10 (25.59) 16.95 (26.12) 22.36 (21.36) 19.96 (22.39) Bodily pain 27.20 (29.04) 35.28 (23.86) 34.61 (25.30) 31.00 (27.87) Vitality 28.04 (27.39) 26.72 (29.41) 30.79 (26.16) 29.11 (26.17) Social functioning 29.29 (29.85) 31.90 (24.91) 31.10 (24.71) 25.99 (30.26) Mental health 15.57 (20.39) 17.76 (23.59) 21.83 (23.63) 20.79 (22.74) General health 23.91 (20.38) 26.28 (21.70) 21.02 (18.31) 22.55 (18.38) aEndoscopic improvement: ≥1 point improvement in SES-CD at Week 12.
Recurrent event data frequently arise in longitudinal studies and observations on recurrent events could be terminated by a major failure event such as death. In many situations, there exist a large ...fraction of subjects without any recurrent events of interest. Among these subjects, some are unsusceptible to recurrent events, while others are susceptible but have no recurrent events being observed due to censoring. In this article, we propose a zero‐inflated generalized joint frailty model and a sieve maximum likelihood approach to analyze zero‐inflated recurrent events with a terminal event. The model provides a considerable flexibility in formulating the effects of covariates on both recurrent events and the terminal event by specifying various transformation functions. In addition, Bernstein polynomials are employed to approximate the unknown cumulative baseline hazard (intensity) function. The estimation procedure can be easily implemented and is computationally fast. Extensive simulation studies are conducted and demonstrate that our proposed method works well for practical situations. Finally, we apply the method to analyze myocardial infarction recurrences in the presence of death in a clinical trial with cardiovascular outcomes.
Inference for a two-stage enrichment design Lin, Zhantao; Flournoy, Nancy; Rosenberger, William F.
The Annals of statistics,
10/2021, Letnik:
49, Številka:
5
Journal Article
Recenzirano
Two-stage enrichment designs can be used to target the benefiting population in clinical trials based on patients' biomarkers. In the case of continuous biomarkers, we show that using a bivariate ...model that treats biomarkers as random variables more accurately identifies a treatment-benefiting enriched population than assuming biomarkers are fixed. Additionally, we show that under the bivariate model, the maximum likelihood estimators (MLEs) follow a randomly scaled mixture of normal distributions. Using random normings, we obtain asymptotically standard normal MLEs and construct hypothesis tests. Finally, in a simulation study, we demonstrate that our proposed design is more powerful than a single stage design when outcomes and biomarkers are correlated; the model-based estimators have smaller bias and mean square error (MSE) than weighted average estimators.
A two-stage adaptive optimal design is an attractive option for increasing the efficiency of clinical trials. In these designs, based on interim data, the locally optimal dose is chosen for further ...exploration, which induces dependencies between data from the two stages. When the maximum likelihood estimator (MLE) is used under nonlinear regression models with independent normal errors in a pilot study where the first stage sample size is fixed, and the second stage sample size is large, the Fisher information fails to normalize the estimator adequately asymptotically, because of dependencies. In this situation, three alternative random information measures are presented and are shown to provide better normalization of the MLE asymptotically. The performance of random information measures is investigated in simulation studies, and the results suggest that the observed information performs best when the sample size is small.
When there is a predictive biomarker, enrichment can focus the clinical trial on a benefiting subpopulation. We describe a two-stage enrichment design, in which the first stage is designed to ...efficiently estimate a threshold and the second stage is a "phase III-like" trial on the enriched population. The goal of this paper is to explore design issues: sample size in Stages 1 and 2, and re-estimation of the Stage 2 sample size following Stage 1. By treating these as separate trials, we can gain insight into how the predictive nature of the biomarker specifically impacts the sample size. We also show that failure to adequately estimate the threshold can have disastrous consequences in the second stage. While any bivariate model could be used, we assume a continuous outcome and continuous biomarker, described by a bivariate normal model. The correlation coefficient between the outcome and biomarker is the key to understanding the behavior of the design, both for predictive and prognostic biomarkers. Through a series of simulations we illustrate the impact of model misspecification, consequences of poor threshold estimation, and requisite sample sizes that depend on the predictive nature of the biomarker. Such insight should be helpful in understanding and designing enrichment trials.
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