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N Engl J Med. 2019 Sep 26;381(13):1201-1214. doi: 10.1056/NEJMoa1900750.

Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

Collaborators (284)

Brown S, Connor S, De Cruz P, Ding NJ, Florin T, Hendy P, Leong R, Moore G, Pavli P, Sparrow M, Gassner S, Vogelsang H, Baert F, Colard A, De Vos M, D'heygere F, Ferrante M, Louis E, Staessen D, Berova T, Churchev J, Draganova R, Gancheva D, Ivanova N, Marinova I, Markov M, Nikolov R, Tsonev N, Vassileva G, Afif W, Berstein C, Bressler B, Jairath V, Lachance JR, Singh R, Tilbe K, Komarek V, Kozeluhova J, Lukas M, Volfova M, Dahlerup J, Altwegg R, Beorchia S, Bouguen G, Cadiot G, Dupas JL, Desreumaux P, Flourie B, Grimaud JC, Guillaud O, Moreau J, Roblin X, Zerbib F, Baumgart D, Beckebaum S, Bokemeyer B, Ebert M, Hasselblatt P, Lügering A, Maaser C, Schiefke I, Schreiber S, Seidler U, Altorjay I, Kiss GG, Literati-Nagy B, Patai A, Pecsi G, Salamon A, Schnabel R, Székely A, Tulassay Z, Varga M, Fich A, Fishman S, Konikoff F, Lichtenstein L, Rainis T, Sbeit W, Schwartz D, Annese V, Biancone L, Bossa F, Costintino R, Danese S, Fries W, Gasbarrini A, Guidi L, Kohn A, Maconi G, Rocca R, Rogai F, Villa E, Zoli G, Akiho H, Aoyama N, Arisawa T, Hidaka H, Hisamatsu T, Horiki N, Inaba T, Inoue S, Ishida T, Ishida H, Ishiguro Y, Ishihara S, Iwabuchi M, Kato J, Katsushima S, Kobayashi T, Kojima Y, Kurihara H, Masuo T, Matsui T, Matsumoto T, Matsuoka K, Mitsuyama K, Motoya S, Nakagawa T, Nakai K, Nakamura S, Niihara T, Ohnishi Y, Ohta A, Osada T, Ryuichi I, Sakai Y, Sakata Y, Sameshima Y, Sano K, Shibatoge M, Shibuya T, Suzuki Y, Takeshima F, Tanaka S, Taruishi M, Tokito S, Ueo T, Watanabe K, Yamagami H, Cheon JH, Cho KB, Kim ES, Kim ES, Kim HJ, Kim Y, Lee KM, Yang SK, D'Haens G, Pierik M, Gearry R, Inns S, Rowbotham D, Schultz M, Bochenek A, Gawdis-Wojnarska B, Kleczkowski D, Leszczyszyn J, Malecka-Panas E, Mamos A, Petryka R, Regula J, Rozciecha J, Stefanuik P, Wozniak-Stolarska B, Cimpoeru N, Craciun E, Ovidiu CF, Goldis E, Ionita-Radu F, Lazar D, Suciu I, Abdulkhakov R, Alikhanov B, Apartsin K, Bakulin I, Belousova E, Gofman A, Grinevich V, Kulyapin A, Nizov A, Osipenko M, Simanenkov V, Tkachev A, Uspenskiy Y, Valuyskikh E, Jovanovic I, Nagorni A, Svorcan P, Zdravkovic N, Bunganic I, Abrahamovych O, Bilianskyi L, Datsenko O, Golovchenko O, Kharchenko N, Klymenko V, Levchenko O, Lozynskyy Y, Murenets N, Oliinyk O, Prystupa L, Pyrogovskyi V, Reznikova V, Rishko I, Stanislavchuk M, Vizir V, Yatsyshyn R, Arasaradnam R, Bloom S, Cummings F, Iqbal T, Irving P, Kaser A, Shonde A, Subramanian S, Aberra F, Aguilar H, Araya V, Bakken A, Beaulieu D, Cappa JA, Chiorean M, Cohen N, Dryden G, DuVall G, Ehrlich A, Eisner M, Ertan A, Fogel R, Friedenberg K, Gatof D, Glover S, Grosman I, Gunaratnam N, Gupta N, Haynes P, Hemaidan A, Higgins P, Hou J, Hudesman D, Iskandar H, Jazrawi S, Jones M, Karnam U, Khurana S, Killpack M, Kreines M, Lawlor G, Lee S, Loftus E, Lukin DJ, Marcet J, Mattar M, Melmed G, Minor T, Mirkin K, Mutlu E, Nichols M, Nudell J, Rai R, Ramos C, Randall C, Rausher D, Ritter T, Singh Saini S, Salzberg B, Saubermann L, Scherl E, Sedghi S, Sellin J, Shafran I, Sorrentino D, Suiter D, Swaminath A, Tiongco F, Vrabie R, Walp K, Warner N, Winstead N, Wolf DC, Woods J, Yen E, Younes Z.

Author information

1
From the Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Division of Gastroenterology, University of California, San Diego, La Jolla (W.J.S.), and the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles (S.T.) - both in California; the Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada (R.P.); Janssen Research and Development, Spring House, PA (C.D.O., H.Z., J.J., O.J.A., K.L., P.S., C.M.); the Gastroenterology Department and INSERM 1256, Nutrition, Genetics, and Environmental Risk Exposure, Nancy University Hospital, Université de Lorraine, Nancy, France (L.P.-B.); the Division of Gastroenterology and Hepatology, University Hospitals Leuven and Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium (G.V.A.); the IBD Center, Department of Gastroenterology, Humanitas Research Hospital and Humanitas University, Milan (S.D.); the Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami (M.T.A.); and the Division of Gastroenterology, Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo (T.H.).

Abstract

BACKGROUND:

The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.

METHODS:

We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components).

RESULTS:

The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.

CONCLUSIONS:

Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

PMID:
31553833
DOI:
10.1056/NEJMoa1900750
[Indexed for MEDLINE]

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