Esophagus to Small Intestine
Lancet Gastroenterol Hepatol. 2022;7(4):294–306
Treat to target versus standard of care for patients with Crohn’s disease treated with ustekinumab (STARDUST): An open-label, multicenter, randomized phase 3b trial
Background: A treat-to-target (T2T) strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimized management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a T2T 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, multicenter, randomized 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 1 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 points from baseline were randomly assigned (1:1) to receive standard-of-care (SOC) or T2T maintenance treatment through week 48. Randomization 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 1 dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to 1 of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (i.e., on an intention-to-treat basis). Patients assigned to the T2T 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 SOC arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labeling. The primary efficacy end point was endoscopic response at week 48 (SES-CD score ≥ 50% decrease from baseline), analyzed by non-responder imputation.
Findings: 498 patients received standard induction treatment, of whom 440 were randomly assigned to the T2T group (n = 219) or the SOC group (n = 221). At week 48, there was no significant difference in endoscopic response (83 of 219 patients [38%] vs. 66 of 221 patients [30%]; 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 2 groups; clinical response was significantly lower in the T2T group than in the SOC 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 of 219 patients [13%] in the T2T group vs. 29 of 221 patients [13%] in the SOC 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 patients might benefit from a treat-to-target strategy with ustekinumab.