Abstract
Background & Aims: Dose-optimization strategies for biologic therapies in Crohn's disease (CD) are not well established. The SERENE CD (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Crohn's Disease) trial evaluated higher vs standard adalimumab induction dosing and clinically adjusted (CA) vs therapeutic drug monitoring (TDM) maintenance strategies in patients with moderately to severely active CD. Methods: In this phase 3, randomized, double-blind, multicenter trial, eligible adults (Crohn's Disease Activity Index score of 220–450, endoscopic evidence of mucosal inflammation, and previous failure of standard therapies) were randomized to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3; n = 308) or standard induction regimen (adalimumab 160 mg at week 0 and 80 mg at week 2; n = 206) followed by 40 mg every other week from week 4 onward. Co-primary end points included clinical remission at week 4 and endoscopic response at week 12. At week 12, patients were re-randomized to maintenance therapy optimized by Crohn's Disease Activity Index and C-reactive protein (CA; n = 92) or serum adalimumab concentrations and/or clinical criteria (TDM; n = 92); exploratory end points were evaluated at week 56. Results: Similar proportions of patients receiving higher induction regimen and standard induction regimen achieved clinical remission at week 4 (44% in both; P = .939) and endoscopic response at week 12 (43% vs 39%, respectively, P = .462). Week 56 efficacy was similar between CA and TDM. Safety profiles were comparable between dosing regimens. Conclusions: Higher induction regimen was not superior to standard induction regimen, and CA and TDM maintenance strategies were similarly efficacious. Adalimumab therapy was well tolerated, and no new safety concerns were identified. (ClinicalTrials.gov, Number: NCT02065570).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1876-1890 |
| Number of pages | 15 |
| Journal | Gastroenterology |
| Volume | 162 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jun 2022 |
Funding
Funding AbbVie funded the research for this study and provided writing support for this manuscript. AbbVie Inc participated in the study design; study research; collection, analysis, and interpretation of data; and writing, reviewing, and approving of this manuscript. All authors had access to the data, and participated in the development, review, and approval, and in the decision to submit this manuscript for publication. Medical writing assistance was funded by AbbVie. AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study. AbbVie would also like to acknowledge Jasmina Kalabic, senior medical director at AbbVie, for her medical expertise and support throughout the study; James W. Butler, a former AbbVie employee, for support of data analysis; Donyalle Richardson, study management associate III at AbbVie, and Cordula Ubrig, study project manager I at AbbVie, for operational leadership and oversight; Yuri Sanchez Gonzales, director of health economics and outcomes research at AbbVie, for support of patient-reported outcomes analysis; and Bidan Huang, senior director, and statistics TA head, specialty data and statistical science at AbbVie, for her central role in the statistical analysis and design of the study. AbbVie funded the research for this study and provided writing support for this article. Medical writing assistance, funded by AbbVie, was provided by Lisa M. Pitchford, PhD, of JB Ashtin. Geert R. D'Haens, MD, PhD (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). William J. Sandborn, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Edward V. Loftus, Jr, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Stephen B. Hanauer, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Stefan Schreiber, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Laurent Peyrin-Biroulet, MD, PhD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Remo Panaccione, MD (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Julián Panés, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Filip Baert, MD, PhD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Jean-Frederic Colombel, MD (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Marc Ferrante, MD, PhD (Data curation: Equal; Writing – original draft: Equal; writing – review & editing: Equal). Edouard Louis, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Alessandro Armuzzi, MD, PhD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Qian Zhou, PhD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Venkata S. Goteti, PhD (Data curation: Equal; Formal analysis: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Nael M. Mostafa, PhD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Thao T. Doan, MD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Joel Petersson, MD (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Tricia Finney-Hayward, PhD (Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Alexandra P. Song, MD, MPH (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Anne M. Robinson, PharmD (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Silvio Danese, MD, PhD (Conceptualization: Equal; Data curation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Conflicts of interest The authors disclose the following: Geert R. D‘Haens has served as advisor for AbbVie, Ablynx, Active Biotech AB, Agomab Therapeutics, Alimentiv, Allergan, Alphabiomics, Amgen, AM Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Dr Falk Pharma, DSM Pharma, Echo Pharmaceuticals, Engene, Exeliom Biosciences, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Gossamerbio, Immunic, Johnson and Johnson, Kintai Therapeutics, Lilly, Lument, Medtronic, Mitsubishi Pharma, Merck Sharp and Dome, Mundipharma, Novo Nordisk, Otsuka, Pfizer, ProciseDx, Prodigest, Prometheus Laboratories/Nestle, Progenity, Protagonist, RedHill, Salix, Samsung Bioepis, Sandoz, Seres/Nestec/Nestle, Setpoint, Takeda, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor. He has received speaker fees from AbbVie, Biogen, Ferring, Galapagos/Gilead, Johnson and Johnson, Merck Sharp and Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor. William J. Sandborn has received research grants from AbbVie, Abivax, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Allakos, Amgen, Arena, AstraZeneca, Atlantic Pharmaceuticals, Beigene, Boehringer Ingelheim, Bristol-Meyers Squibb, Celltrion, Clostrabio, Forbion, Galapagos, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Iota Biosciences, Janssen, Lilly, Morphic Therapeutics, Novartis, Oppilan Pharma (now Venytx Biosciences), Pfizer, Pharm Olam, Polpharm, Progenity, Prometheus Biosciences, Protagonists Therapeutics, PTM Therapeutics, Seres Therapeutics, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Gastrosciences, Xencor, and Zealand Pharmaceuticals; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (now Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Gastrosciences; and employee at Shoreline Biosciences. Spouse: Iveric Bio - consultant, stock options; Progenity - stock; Oppilan Pharma (now Ventyx Biosciences) - stock; Prometheus Biosciences - employee, stock, stock options; Prometheus Laboratories – stock, stock options, consultant; Ventyx Biosciences – stock, stock options; Vimalan Biosciences – stock, stock options. Edward V Loftus, Jr, has been a consultant for AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, Genentech, Gilead, Iterative Scopes, Janssen, Lilly, Ono Pharma, Pfizer, Sun Pharma, Takeda, and UCB. He has received research grants from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Gilead, Janssen, MedImmune, Pfizer, Receptos (Celgene), Robarts Clinical Trials, Takeda, Theravance, and UCB. Stephen B. Hanauer has been a consultant and/or speaker for AbbVie, Actavis, Allergan, Amgen, Arena Pharmaceuticals, Astra-Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Genentech, Gilead, GlaxoSmithKline, Gossamer, Janssen, Lilly, Merck, Nestlé, Novartis, Pfizer, Prometheus Biosciences, Protagonist, Salix, Samsung Bioepis, Sanofi, Seres Therapeutics, Shire, Takeda, and Therakos. He has received research grants from AbbVie, Allergan, Amgen, Celgene, Genentech, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, Prometheus Biosciences, Receptos (Celgene), and Sanofi. Stefan Schreiber has been a consultant for AbbVie, Amgen, Arena, Bristol-Myers Squibb, Boehringer Ingleheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GlaxoSmithKline, Gilead, IMAB-Biopharma, Janssen, Lilly, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, and Theravance. Laurent Peyrin-Biroulet has received personal fees from AbbVie, Allergan, Alma Bio Therapeutics, Amgen, Arena, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring, Genentech, Gilead, Hikma, InDex Pharmaceuticals, Janssen, Merck, Nestlé, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna Biological, Takeda, and Tillotts Pharma; and grants from AbbVie, Merck, and Takeda. He also holds Clementia Pharmaceuticals stock options. Remo Panaccione has received consulting fees from AbbVie, Abbott, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance, and UCB. He has received speaker fees from AbbVie, Arena, Celgene, Ferring, Gilead Sciences, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda. He has received research/educational support from AbbVie, Ferring, Janssen, Pfizer, and Takeda; and has served on an advisory board for AbbVie, Amgen, Arena, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Theravance. Julian Panés has received research grants from AbbVie and Pfizer; speaker's fees from AbbVie, Ferring, Janssen, Pfizer, and Takeda; and has been a consultant for AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GlaxoSmithKline, Janssen, Origo, Pandion, Pfizer, Progenity, Robarts Clinical Trials, Roche, Takeda, Theravance, and Wassermann. Filip Baert has been a consultant and/or speaker from AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Janssen, Merck, Mundipharma, Pfizer, Sandoz, Takeda, and Vifor Pharma. He has received research grants from AbbVie, Amgen, Chiesi, Janssen, Ipsen, and Merck. Jean-Frederic Colombel reports receiving research grants from AbbVie, Janssen, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Ferring, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ferring, Galmed Research, Genentech, GlaxoSmithKline, Janssen, Kaleido Biosciences, Lilly, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, and Vifor. He holds stock options in Intestinal Biotech Development. Marc Ferrante has been a consultant for AbbVie, Boehringer Ingelheim, Celltrion, Janssen, Lilly, Medtronic, Merck, Pfizer, Sandoz, Takeda, and Thermo Fisher. He has received research grants from AbbVie, Amgen, Biogen, Janssen, Pfizer, and Takeda; and speaker's fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen, Lamepro BV, Merck, Mylan, Pfizer, Sandoz, Takeda, and Truvion Healthcare. Edouard Louis has received research grants from Janssen, Pfizer, and Takeda; educational grants from AbbVie, Janssen, and Takeda; speaker fees from AbbVie, Celegene, Dr Falk Pharma, Ferring, Janssen, Merck, Pfizer, and Takeda; and has participated on advisory boards for AbbVie, Arena, Celgene, Ferring, Gilead-Galapagos, Janssen, Lilly, Merck, Pfizer, and Takeda; and has been a consultant for AbbVie. Alessandro Armuzzi has been a consultant or advisory board member for AbbVie, Allergan, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Gilead, Janssen, Lilly, Merck, Mylan, Pfizer, Roche, Samsung Bioepis, Sandoz, Sofar SpA, and Takeda. He has received speaker's fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Ferring, Galapagos, Gilead, Janssen, Medtronic, Merck, Mitsubishi Tanabe Pharma, Novartis, Nikkiso, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda and TiGenix; and research grants from Merck, Pfizer, and Takeda. Qian Zhou, Venkata S. Goteti, Nael M. Mostafa, Thao T. Doan, Joel Petersson, Tricia Finney-Hayward, Alexandra P. Song, and Anne M. Robinson are full-time employees of AbbVie, and may own AbbVie stock or options. Silvio Danese has received research grants from AbbVie, Amgen, Genentech, Gilead, Janssen, Pfizer, Receptos (Celgene), Robarts Clinical Trials, Seres Therapeutics, Takeda, and UCB. He has been a consultant for AbbVie, Allergan, Amgen, Bristol-Myers Squibb, Celgene, Celltrion, Janssen, Lilly, Pfizer, Takeda, and UCB. Funding AbbVie funded the research for this study and provided writing support for this manuscript. AbbVie Inc participated in the study design; study research; collection, analysis, and interpretation of data; and writing, reviewing, and approving of this manuscript. All authors had access to the data, and participated in the development, review, and approval, and in the decision to submit this manuscript for publication. Medical writing assistance was funded by AbbVie.
Keywords
- Biologic Agent
- Inflammatory Bowel Disease
- Monoclonal Antibody
- TNF Inhibitor
ASJC Scopus subject areas
- Hepatology
- Gastroenterology