Treat to target versus standard of care for patients with Crohn's disease treated with ustekinumab (STARDUST): an open-label, multicentre, randomised phase 3b trial

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Silvio Danese, Vita-Salute San Raffaele University
  • ,
  • Severine Vermeire, KU Leuven
  • ,
  • Geert D'Haens, University of Amsterdam
  • ,
  • Julian Panés, CIBER - Center for Biomedical Research Network
  • ,
  • Axel Dignass, Markus-Krankenhaus Frankfurt
  • ,
  • Fernando Magro, University of Porto
  • ,
  • Maciej Nazar, Polska Sp. z o.o
  • ,
  • Manuela Le Bars, Medical Affairs
  • ,
  • Marjolein Lahaye, Janssen-Cilag
  • ,
  • Lioudmila Ni, Medical Affairs
  • ,
  • Ivana Bravata, Janssen-Cilag SpA
  • ,
  • Frederic Lavie, Medical Affairs
  • ,
  • Marco Daperno, Ospedale Mauriziano Umberto I
  • ,
  • Milan Lukáš, Clinical and Research Center for Inflammatory Bowel Diseases
  • ,
  • Alessandro Armuzzi, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • ,
  • Mark Löwenberg, University of Amsterdam
  • ,
  • Daniel R. Gaya, Glasgow Royal Infirmary
  • ,
  • Laurent Peyrin-Biroulet, CHU de Nancy, Universite de Lorraine
  • ,
  • STARDUST study group

Background: A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab. Methods: This open-label, multicentre, randomised phase 3b trial included adults with active, moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220–450 and Simple Endoscopic Score in Crohn's Disease [SES-CD] ≥3) for whom conventional therapy or one biologic therapy, or both, had failed. Patients received intravenous ustekinumab approximating 6 mg/kg at baseline and subcutaneous ustekinumab 90 mg at week 8. At week 16, patients with a CDAI improvement of 70 or more points from baseline were randomly assigned (1:1) to receive standard-of-care or treat-to-target maintenance treatment through week 48. Randomisation was balanced by using randomly permuted blocks and was stratified by biologic history status and baseline SES-CD score. All patients who signed informed consent, who were not screening failures, and who received at least one dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to one of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (ie, on an intention-to-treat basis). Patients assigned to the treat-to-target arm received ustekinumab every 12 weeks or every 8 weeks based on SES-CD improvement from baseline and could escalate to every 4 weeks through week 48 if prespecified targets were missed. Patients assigned to the standard-of-care arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labelling. The primary efficacy endpoint was endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline), analysed by non-responder imputation. This trial is registered at ClinicalTrials.gov, NCT03107793, and is active but not recruiting. Findings: 498 patients received standard induction treatment, of whom 440 were randomly assigned to the treat-to-target group (n=219) or the standard-of-care group (n=221). At week 48, there was no significant difference in endoscopic response (83 [38%] of 219 patients vs 66 [30%] of 221 patients; p=0·087), endoscopic remission (25 [11%] vs 32 [15%]; p=0·334), mucosal healing (31 [14%] vs 37 [17%]; p=0·449), and clinical remission (135 [62%] vs 154 [70%]; p=0·072) between the two groups; clinical response was significantly lower in the treat-to-target group than in the standard-of-care group (149 [68%] vs 172 [78%]; p=0·020). Other endoscopic, clinical, and biomarker outcomes were generally not significantly different between groups. The most commonly reported treatment-emergent adverse events were nasopharyngitis (29 [13%] of 219 patients in the treat-to-target group vs 29 [13%] of 221 patients in the standard-of-care group), abdominal pain (23 [11%] vs 19 [9%]), arthralgia (24 [11%] vs 19 [9%]), and headache (24 [11%] vs 21 [10%]). Interpretation: Timely escalation of ustekinumab therapy for patients with Crohn's disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. Future studies need to confirm if some subgroups of patient might benefit from a treat-to-target strategy with ustekinumab. Funding: Janssen-Cilag.

OriginalsprogEngelsk
TidsskriftThe Lancet Gastroenterology and Hepatology
Vol/bind7
Nummer4
Sider (fra-til)294-306
Antal sider13
ISSN2468-1253
DOI
StatusUdgivet - apr. 2022

Bibliografisk note

Funding Information:
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc, and Vifor; and reports payment for expert testimony from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. SV reports grants or contracts from AbbVie, Johnson & Johnson, Pfizer, Galapagos, and Takeda; consulting fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, Imidomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, and Zealand Pharma; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or education events from AbbVie, Alimentiv, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Janssen, Johnson & Johnson, Pfizer, Takeda, and Tillots Pharma AG. GD'H reports consulting fees from AbbVie, Alimentiv, Arena, AstraZenea, Bristol Myer Squibb, Boehringer Ingelheim, Eli Lilly, Exeliom, Gossamer Bio, Johnson & Johnson, Pfizer, Prometheus, and Protagonist; and payment of honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Myer Squibb, Johnson & Johnson, and Pfizer. JP reports research grants from AbbVie and Pfizer; consulting fees from AbbVie, Arena, Athos, Boehringer Ingelheim, Celgene, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Nestle, Origo, Pandion, Pfizer, Progenity, Protagonist, Takeda, Theravance, and Wassermann; reports payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Janssen, Pfizer, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for Alimentiv; and has owner stock options in Oppilan. AD reports consultancy fees from AbbVie, Amgen, BMS/Celgene, Boehringer-Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, Janssen, MSD, Lilly, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts, and Vifor; payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AbbVie, Falk Foundation, Ferring, Immunowissen.tv, Janssen, Lilly, Med Update GmbH, MSD, Pfizer, Pharmacosmos, Streamed Up, Takeda, Thieme-Verlag, Tillotts, and Vifor. FM has served as a speaker and received honoraria from Merck Sharp & Dohme, AbbVie, Vifor, Falk, Laboratórios Vitória, Ferring, Hospira, and Biogen. MN is an employee of Janssen-Cilag, Polska Sp. z o.o and has stocks or stock options in Johnson & Johnson. MLB is an employee of Janssen-Cilag, France and has stocks or stock options in Janssen. FL is an employees of Janssen-Cilag, France and has restricted share units from Johnson & Johnson. MLa is an employee of Janssen-Cilag, B.V. and has restricted stocks in Janssen. LN is an employee of Janssen-Cilag, Russia. IB is an employee of Janssen-Cilag, Italy. MD reports consulting fees from Bioclinica; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Janssen, Pfizer, Roche, and Takeda; and support for attending meetings and/or travel from AbbVie, Chiesi, Janssen, Mundifarma, SOFAR, Roche, and Takeda. MLu reports no competing interests. AA reports consultancy fees from AbbVie, Allergan, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sandoz, and Takeda; payment or honoraria for lecture, presentations, speakers bureaus, manuscript writing, or education events from AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, and Tigenix; research grants from MSD, Takeda, and Pfizer; and support for attending meetings and/or travel from AbbVie, Janssen, Pfizer, and Takeda. MLö has received a research grant from Galapagos and consulting fees from Alimentiv, Bristol Myers Squibb, Galapagos, Gilead, Takeda, and Tillotts. DRG reports consulting fees from Galapagos and Pfizer; payment or honoraria for lectures from AbbVie and Pfizer; and support for attending meetings and travel from AbbVie, Ferring, Janssen, and Tillots. LP-B reports grants or contracts from AbbVie, Fresenius Kabi, MSD, and Takeda; consulting fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, Theravance, and Pandion Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Galapagos, Janssen, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Arena, Gilead, Hikma, Amgen, and Vifor; support for attending meeting and/or travel from AbbVie, Galapagos, Janssen, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Arena, Gilead, Hikma, Amgen, and Vifor; participation on a Data Safety Monitoring Board or Advisory Board for Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, Theravance, and Pandion Therapeutics; and stock or stock options in CTMA.

Funding Information:
Janssen-Cilag Limited and the authors thank the patients who participated in STARDUST, and all study investigators and their research teams for their contributions. Janssen-Cilag funded the study and participated in the study design, interpretation of data, review, and approval of the publication. Under the direction of the authors and in accordance with Good Publication Practices, James P Barrett (Janssen Scientific Affairs, Horsham, PA, USA) provided writing and editorial assistance. The authors thank Sheldon Sloan (former Janssen employee) and Raivo Kittus (Janssen employee) for their contribution to the STARDUST study design, data acquisition, and data interpretation.

Publisher Copyright:
© 2022 Elsevier Ltd

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