Study design and data source
inflammation, ICH, UC
PATHOLOGY, INFLAMMATION, DISEASE, REMISSION
The upadacitinib phase 3 program consists of 2 identical induction studies (U-ACHIEVE induction and U-ACCOMPLISH) and 1 maintenance study (U-ACHIEVE maintenance). In the induction studies, patients were randomized to receive upadacitinib 45 mg or placebo for 8 weeks. At Week 8, patients who did not achieve a clinical response were eligible to receive an additional 8 weeks of treatment with upadacitinib 45 mg. Patients who achieved a clinical response following upadacitinib 45 mg for 8 or 16 weeks were eligible to enroll in the U-ACHIEVE maintenance study and were randomized 1:1:1 to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo. Randomization was stratified by bio-IR status (bio-IR vs non-bio-IR), corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or > 7) at Baseline. Within bio-IR, the randomization was further stratified by number of prior biologic treatments (≤ 1 or > 1). Within non-bio-IR, the randomization was further stratified by previous biologic use (yes or no). We performed post hoc analyses of data from the Phase 3 U-ACHIEVE upadacitinib maintenance trial to evaluate the relationship between the HEMR/HEMI endpoints and achievement of long-term clinical and patient-reported outcomes at Week 52. Histologic, clinical, and patient-reported outcomes data from the Phase 3 U-ACHIEVE [NCT02819635] upadacitinib maintenance trial were evaluated in this analysis. The objective of the U-ACHIEVE maintenance trial was to evaluate the efficacy and safety of upadacitinib compared with placebo in achieving clinical remission in patients with moderately to severely active UC who had a clinical response per adapted Mayo score following induction with upadacitinib 45 mg once daily (QD). In the maintenance trial, patients were randomized 1:1:1 to upadacitinib 15 mg QD, upadacitinib 30 mg QD, or placebo QD. Details of the U-ACHIEVE induction and maintenance trials are reported elsewhere [A full colonoscopy was performed for all patients at screening. At Weeks 8 and 52, endoscopies were either a colonoscopy or a flexible sigmoidoscopy, depending on the extent of disease at screening, and were performed up to the segment where a clear demarcation of inflammation was observed. In patients who required 16 weeks of upadacitinib induction therapy, an additional colonoscopy or a flexible sigmoidoscopy was performed at Week 16. During all endoscopies, biopsies for histologic evaluation were taken from the rectosigmoid colon (approximately 15–30 cm from the anal verge) and from the area of most inflammation. For follow-up endoscopies, in the absence of any visible lesions or areas of general inflammation characteristic of UC, biopsies were to be collected from normal mucosa in the same segments as noted above. Tissue samples were processed, mounted to slides, and digitized using a whole slides scanner. For each image, a central reader performed the reading and provided a histologic score. Both histologic and endoscopic scoring were performed by the central readers, who were properly trained regarding lesion definition and identification, proficient in scoring and blinded to other clinical or study data. The pathologists who participated as blinded central readers have extensive experience as pathologists (14, 17, 20, and 28 years) and specifically in the field of gastrointestinal pathology (8, 9, 12, and 16 years, respectively).The Geboes histologic score is an index commonly used to measure histologic disease activity in UC, which has undergone content and construct validation and reliability testing [The U-ACHIEVE maintenance trial was conducted in accordance with the protocol, International Conference on Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. All participants provided written informed consent before any study-related procedures were performed. All authors had access to the study data and reviewed and approved the final manuscript.