[en] BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Panés, Julián; Hospital Clinic de Barcelona, August Pi i Sunyer Biomedical Research Institute,
Colombel, Jean-Frederic; Icahn School of Medicine at Mt Sinai, New York, New York.
D'Haens, Geert R; Amsterdam Gastroenterology Endocrinology Metabolism and Gastroenterology and
Schreiber, Stefan; Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel
Panaccione, Remo; Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Peyrin-Biroulet, Laurent; Department of Gastroenterology, Centre Hospitalier Régional Universitaire de
Loftus, Edward V Jr; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
Danese, Silvio; Gastroenterology and Endoscopy, Istituto di Ricovero e Cura a Carattere
Tanida, Satoshi; Department of Gastroenterology and Metabolism, Nagoya City University Graduate
Okuyama, Yusuke; Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto,
Louis, Edouard ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive ; Department of Gastroenterology, University Hospital Centre Hospitalier
Armuzzi, Alessandro; Inflammatory Bowel Diseases Unit, Fondazione Policlinico Universitario A. Gemelli
Ferrante, Marc; Department of Gastroenterology and Hepatology, University Hospitals Leuven,
Vogelsang, Harald; Medical University of Vienna, Vienna, Austria.
Hibi, Toshifumi; Center for Advanced Inflammatory Bowel Disease Research and Treatment, Kitasato
Watanabe, Mamoru; Advanced Research Institute and Department of Gastroenterology and Hepatology,
Lefebvre, Jessica; AbbVie Inc, North Chicago, Illinois.
Finney-Hayward, Tricia; AbbVie Ltd, Maidenhead, Berkshire, England, United Kingdom.
Sanchez Gonzalez, Yuri; AbbVie Inc, North Chicago, Illinois.
Doan, Thao T; AbbVie Inc, North Chicago, Illinois.
Mostafa, Nael M; AbbVie Inc, North Chicago, Illinois.
Ikeda, Kimitoshi; AbbVie GK, Minato-ku, Tokyo, Japan.
Xie, Wangang; AbbVie Inc, North Chicago, Illinois.
Huang, Bidan; AbbVie Inc, North Chicago, Illinois.
Petersson, Joel; AbbVie Inc, North Chicago, Illinois.
Kalabic, Jasmina; AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany.
Robinson, Anne M; AbbVie Inc, North Chicago, Illinois.
Sandborn, William J; Gastroenterology Department, University of California San Diego, La Jolla,
Kobayashi, T., Siegmund, B., Le Berre, C., et al. Ulcerative colitis. Nat Rev Dis Primers, 6, 2020, 74.
Rubin, D.T., Ananthakrishnan, A.N., Siegel, C.A., et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol 114 (2019), 384–413.
Turner, D., Ricciuto, A., Lewis, A., et al. STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 160 (2021), 1570–1583.
Humira (adalimumab). Highlights of prescribing information. AbbVie Inc. Available at: https://www.rxabbvie.com/pdf/humira.pdf. Accessed March 22, 2021.
Humira (INN-adalimumab). Annex I: summary of product characteristics. AbbVie Biotechnology GmbH. Available at: https://www.ema.europa.eu/en/documents/product-information/humira-epar-product-information_en.pdf. Accessed January 8, 2021.
Report on the Deliberation Results. Humira (INN-adalimumab). AbbVie GK. September 14, 2016. Available at: https://www.pmda.go.jp/files/000224547.pdf Accessed January 14, 2021.
Sandborn, W.J., van Assche, G., Reinisch, W., et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 142 (2012), 257–265.e1–e3.
Mostafa, N.M., Eckert, D., Pradhan, R.S., et al. Exposure-efficacy relationship (ER) for adalimumab during induction phase of treatment of adult patients with moderate to severe ulcerative colitis. United Eur Gastroenterol J 1:Suppl 1 (2013), A221–A222.
Gemayel, N.C., Rizzello, E., Atanasov, P., et al. Dose escalation and switching of biologics in ulcerative colitis: a systematic literature review in real-world evidence. Curr Med Res Opin 35 (2019), 1911–1923.
Taxonera, C., Iglesias, E., Munoz, F., et al. Adalimumab maintenance treatment in ulcerative colitis: outcomes by prior anti-TNF use and efficacy of dose escalation. Dig Dis Sci 62 (2017), 481–490.
Van de Vondel, S., Baert, F., Reenaers, C., et al. Incidence and predictors of success of adalimumab dose escalation and de-escalation in ulcerative colitis: a real-world Belgian cohort study. Inflamm Bowel Dis 24 (2018), 1099–1105.
Cheifetz, A., Overview of therapeutic drug monitoring of biologic agents in patients with inflammatory bowel disease. Gastroenterol Hepatol (N Y) 13 (2017), 556–559.
Feuerstein, J.D., Nguyen, G.C., Kupfer, S.S., et al. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology 153 (2017), 827–834.
Su, H.Y., Ward, M.G., Sparrow, M.P., Therapeutic drug monitoring in inflammatory bowel disease: too little too early?-comments on the American Gastroenterology Association Guideline. Transl Gastroenterol Hepatol, 2, 2017, 113.
Rutgeerts, P., Sandborn, W.J., Feagan, B.G., et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353 (2005), 2462–2476.
Irvine, E.J., Feagan, B., Rochon, J., et al. Canadian Crohn's Relapse Prevention Trial Study Group. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Gastroenterology 106 (1994), 287–296.
Reilly, M.C., Zbrozek, A.S., Dukes, E.M., The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 4 (1993), 353–365.
Ware, J.E. Jr., SF-36 Health Survey update. Spine (Phila Pa 1976) 25 (2000), 3130–3139.
Maruish, M.E., (eds.) User's Manual for the SF-36v2 Health Survey, 3rd ed., 2011, QualityMetric Inc.
Geboes, K., Riddell, R., Ost, A., et al. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 47 (2000), 404–409.
Mosli, M.H., Feagan, B.G., Zou, G., et al. Development and validation of a histological index for UC. Gut 66 (2017), 50–58.
Common Terminology Criteria for Adverse Events. National Institutes of Health, National Cancer Institute, Division of Cancer Treatment & Diagnosis. Updated September 21, 2020. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed March 15, 2022.
Gastonguay MR. The use of exposure-response with therapeutic proteins in pediatric drug development. Presented at: Accelerating Drug Development for Polyarticular Juvenile Idiopathic Arthritis (pJIA), Silver Spring, MD; October 2, 2019.
Reinisch, W., Sandborn, W.J., Hommes, D.W., et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 60 (2011), 780–787.
Berends, S.E., Strik, A.S., Lowenberg, M., et al. Clinical pharmacokinetic and pharmacodynamic considerations in the treatment of ulcerative colitis. Clin Pharmacokinet 58 (2019), 15–37.
Sanchez-Hernandez, J.G., Perez-Blanco, J.S., Rebollo, N., et al. Biomarkers of disease activity and other factors as predictors of adalimumab pharmacokinetics in inflammatory bowel disease. Eur J Pharm Sci, 150, 2020, 105369.
Sharma, S., Eckert, D., Hyams, J.S., et al. Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn's disease: results from a randomized, multicenter, phase-3 study. Inflamm Bowel Dis 21 (2015), 783–792.
Awni, W., Eckert, D., Sharma, S., et al. P412 Pharmacokinetics of adalimumab in adult patients with moderately to severely active ulcerative colitis. J Crohns Colitis, 7, 2013, S175.
Reinisch, W., Sandborn, W.J., Panaccione, R., et al. 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants. Inflamm Bowel Dis 19 (2013), 1700–1709.
Sandborn, W.J., Colombel, J.F., D'Haens, G., et al. One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther 37 (2013), 204–213.
