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Ustekinumab (Stelara) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Apr.
The CDR review included four multinational, multi-centre, double-blind randomized controlled trials.7–10 The UNITI-1 and UNITI-2 studies investigated the efficacy and safety of IV ustekinumab versus placebo for inducing clinical response in patients with moderate to severely active Crohn’s disease after six weeks. Patients enrolled in UNITI-1 also had to have had an inadequate response with, intolerance to, or a contraindication to TNF antagonists, whereas the UNITI-2 population comprised patients who had had an inadequate response with, intolerance to, or a contraindication to conventional therapies (i.e., corticosteroids, AZA, 6-MP, and/or MTX). Patients who completed the UNITI studies and were still classified as responders by week 8 of could enroll in the maintenance-treatment study, IM-UNITI. IM-UNITI investigated clinical remission over 44 weeks for two regimens of SC ustekinumab versus placebo. Patients completing IM-UNITI could continue into the long-term extension study.55 Last, a phase II dose-ranging study, CERTIFI, was included but was considered only as supportive owing to a number of important limitations (e.g., the adaptive randomization methodology). Evaluation of clinical remission and clinical response in the UNITI studies and IM-UNITI were based on changes in CDAI scores. Mucosal healing and reduction in the need for Crohn’s disease–related surgery were outcomes of interest in the CDR review protocol; however, none of the studies were appropriately designed to evaluate these end points. The manufacturer conducted an endoscopy substudy26 to evaluate mucosal healing; however, the substudy was limited methodologically and by the small sample size, particularly for the maintenance of effect (N = 70), to be able to draw any conclusions from this evidence. It was considered an exploratory analysis for the purposes of this review.
According to the clinical expert consulted by CDR, despite potential imbalances between treatment groups and study baseline characteristics, the trial populations were generally reflective of patients with moderate-to-severe Crohn’s disease who are treated in Canadian clinical practice. One notable potential imbalance was in the concomitant use of oral corticosteroids at baseline in UNITI-2; 44% of ustekinumab-treated patients and 36% of placebo patients were receiving these drugs (Table 11). ▬ The extent of corticosteroid exposure during UNITI-2 was not reported; however, the study protocol required that patients maintain their dose at a stable level throughout. Similar potential imbalance in corticosteroid use was noted for the maintenance study as well. These potential imbalances in concomitant oral corticosteroids may have led to an overestimation of the response and remission outcomes for ustekinumab versus placebo in UNITI-2 and IM-UNITI.
The definition of inadequate response to TNF antagonists may have led to misclassification of previous TNF treatment failure in some patients, based in part on the dosages of infliximab and adalimumab used to define this population. The number of patients who had received the approved dosages of infliximab and adalimumab, and therefore the number who had an adequate trial of TNF antagonist, was not specified. As well, the criteria included a TNF antagonist, certolizumab, that is not approved in Canada for the treatment of Crohn’s disease.
There were no head-to-head comparisons of ustekinumab versus infliximab, adalimumab, or vedolizumab, which are the other biologics approved for the treatment of Crohn’s disease in Canada. Therefore, the CDR review considered the results of three indirect comparisons that have been conducted to evaluate the comparative efficacy and safety of ustekinumab versus these drugs (Appendix 7).12–15
The 44-week maintenance-treatment study, IM-UNITI, included patients from the UNITI induction studies who had a clinical response using a dose that is not Health Canada–approved, ustekinumab 130 mg IV.
Both UNITI induction studies demonstrated that ustekinumab 6 mg/kg IV is statistically significantly superior to placebo for inducing clinical response in adult patients with moderately to severely active Crohn’s disease after six weeks. Likely of greater importance to patients, ustekinumab was also statistically significantly superior to placebo in inducing clinical remission by week 8. It demonstrated efficacy in two subpopulations: those with an inadequate response or intolerance to conventional therapies (corticosteroids or immunomodulators; UNITI-2 population) and in those with an inadequate response or intolerance to TNF antagonists (UNITI-1 population). The manufacturer did not report between-group percentage differences for the remission and response outcomes. Based on crude calculations, the ustekinumab versus placebo percentage difference for clinical response was approximately 27% in UNITI-2 and 12% in UNITI-1, and the estimates for clinical remission were approximately 21% in UNITI-2 and 14% in UNITI-1. Perhaps not surprisingly, the treatment effect differences in UNITI-1 are lower, given that study’s population likely had more advanced Crohn’s disease (i.e., had experienced a treatment failure with at least one TNF antagonist) as compared with UNITI-2 (i.e., had experienced treatment failure with conventional therapy only). The results from the induction phase of the CERTIFI study, with the same population enrolled as UNITI-1, were generally supportive of those of the UNITI studies.
The clinical expert consulted by CDR stated that these results are likely to be clinically meaningful, especially for remission among patients who had a treatment failure with TNF antagonists. According to the clinical expert, achieving response and remission after a patient experiences a failure with the initial biologic therapy is often difficult. And, because of its alternative mechanism of action, ustekinumab, like vedolizumab, may offer a biologically plausible alternative to trying another TNF antagonist among patients who experience treatment failure with the initial TNF antagonist. However, there is no trial-based comparative evidence for this and it remains hypothetical (see discussion of the manufacturer-provided network meta-analysis [NMA] in Appendix 7).
Both ustekinumab maintenance regimens were found to be statistically significantly superior in achieving clinical remission, as well as clinical response, after 44 weeks compared with placebo. However, the results are difficult to interpret. First, in accordance with the study protocol, these patients underwent a pre-specified corticosteroid-tapering regimen. Yet, the extent of exposure to oral corticosteroids in the treatment groups and its impact on the outcomes at week 44 were not clear from the manufacturer-provided clinical study reports. ▬ Outcomes were not assessed for induction dose subgroups, because they were out of scope for this review. However, induction dose (ustekinumab 130 mg or 6 mg/kg) was a pre-specified subgroup in IM-UNITI (results for clinical remission at week 44 are presented in Appendix 4 for these subgroups). It does not appear that including this subpopulation in IM-UNITI had an important effect on clinical remission at week 44, based on similar estimates of effect for ustekinumab versus placebo in the 130 mg induction-dose subgroup and the 6 mg/kg induction-dose subgroup. Nonetheless, including this subpopulation reduces the generalizability of the maintenance study results, because not all patients were treated with the Health Canada–approved induction regimen.
An important consideration for patients and clinicians is whether the treatment can keep patients in remission over time. Approximately 78 patients per treatment group were in clinical remission at the start of IM-UNITI. Of these, 56% to 67% of ustekinumab-treated patients and 46% of placebo-treated patients were in remission at week 44; however, the difference between groups was only statistically significant for ustekinumab every eight weeks versus placebo. This outcome is difficult to interpret because it is based on a subset of patients, given that patients were not required to be in remission at the start of maintenance treatment. No pre-specified definition of durable clinical remission was provided in the study protocol; hence, it is not clear whether the study met a minimum threshold to conclude that these patients remained in remission in a clinically meaningful way.
Long-term treatment with corticosteroids is associated with an increased risk of serious AEs and is an important concern, as reported by patients. At the beginning of IM-UNITI, approximately one-half of the patients were receiving concomitant treatment with corticosteroids. A statistically significantly greater proportion of ustekinumab-treated patients (43% to 47%) achieved corticosteroid-free clinical remission at 44 weeks compared with the placebo group (30%). The clinical expert consulted by CDR considered the effect of ustekinumab to be clinically relevant for patients with Crohn’s disease who are dependent on corticosteroids. Of note, corticosteroid-dependent patients with Crohn’s disease are included in the Health Canada indication for ustekinumab.
In their input to CDR for this review, the patient groups noted that they hope for additional non-surgical options to treat Crohn’s disease. They noted that surgery is associated with risks and should be considered the option of last resort. The clinical expert consulted by CDR also noted the importance of having additional non-surgical treatment options for patients with refractory Crohn’s disease. None of the included studies was adequately designed to investigate the efficacy of ustekinumab for reducing the need for surgical intervention in patients with Crohn’s disease, ▬.
Crohn’s disease has a profound negative impact on the quality of life of those living with the condition, according to the patient groups who provided input for this review. The UNITI studies and IM-UNITI used the SF-36 and IBDQ to assess the effects of ustekinumab on quality of life. Statistical analyses were conducted, but only for a subpopulation of patients for the SF-36. Analyses did not appear to be based on an intention-to-treat principle, and they were not adjusted for multiple comparisons. As well, adjusted least squares differences between groups were not reported for these outcomes. Therefore, the results for these patient-important outcomes need to be interpreted with these issues in mind. Ustekinumab was generally associated with greater improvement in these end points than placebo. ▬35 ▬ It did not appear that the median difference in the IBDQ between ustekinumab and placebo groups in IM-UNITI (approximately 12 points for both groups) exceeded the published MCID for the IBDQ (i.e., an improvement of 16 points);34 ▬. Of note, the European product monograph for ustekinumab states that improvements in IBDQ and SF-36 (MCS in both UNITI-1 and UNITI-2; PCS in UNITI-2), compared with placebo, were clinically meaningful.56 The basis for this conclusion is not specified.
Patient groups also identified missed work days as a key issue related to Crohn’s disease. The UNITI studies and IM-UNITI pre-specified several analyses to evaluate the effects of ustekinumab on missed work time and productivity. ▬ (Appendix 5), ▬.
In total, the UNITI studies plus IM-UNITI consist of one year of treatment experience with ustekinumab for Crohn’s disease. Patients who completed IM-UNITI could continue in the ongoing extension study, which is planned to follow patients from week 44 of IM-UNITI to week 272; interim data up to week 92 were provided by the manufacturer and are summarized in Appendix 6. ▬
The Canadian product monographs for both infliximab and adalimumab provide details about dose-escalation scenarios for patients who fail to respond or who lose response to those products.18–20 In contrast, the controlled phases of the pivotal studies for vedolizumab did not evaluate dosage escalation, and the current Canadian product monograph does not provide guidance regarding potential dosage-escalation scenarios. Dose escalation was investigated in the IM-UNITI study, in which patients who had a loss of clinical response at any scheduled visit between week 8 and week 32 were eligible for dosage adjustment (Section 3.2.3.1). A total of 57 patients treated with ustekinumab lost response and required dosage adjustment. Twenty-nine patients (22%) in the ustekinumab every 12 weeks group had a dosage adjustment to the every eight weeks regimen and, when assessed 16 weeks after their dosage was adjusted, 41.4% were reported to be in remission and 55% regained response. Twenty-eight patients (21%) in the ustekinumab every eight weeks group met the criteria for dosage adjustment due to loss of response but continued to receive ustekinumab 90 mg every eight weeks per protocol. When assessed 16 weeks afterwards, in all, 32.1% were reported to be in remission and 46% regained response. The product monograph for ustekinumab indicates that patients receiving the every 12 weeks regimen may have their dosage adjusted to every eight weeks if treatment goals are not being met. However, given the small number of patients evaluated and the absence of controlled studies examining dose escalation with ustekinumab, there is uncertainty regarding the overall clinical benefit and the comparative effectiveness of different dosage-escalation scenarios.
In the absence of head-to-head trials comparing the efficacy of ustekinumab with TNF antagonists or vedolizumab, CDR examined the results of two NMAs (Appendix 7).12,13 The manufacturer submitted an NMA of ustekinumab versus infliximab, adalimumab, and vedolizumab.12 The results of the manufacturer’s NMA suggested that there are no statistically significant differences in clinical response (CDAI-70), enhanced clinical response (CDAI-100), or clinical remission (CDAI < 150) between ustekinumab 6 mg/kg and adalimumab 80/40 mg, adalimumab 160/80 mg, or vedolizumab 300 mg in the induction phase in either the subpopulation that had experienced a failure of conventional therapy or of TNF antagonist therapy. Statistically significant differences in clinical response (CDAI-70) and clinical remission (CDAI < 150) in favour of infliximab 5 mg/kg compared with ustekinumab 6 mg/kg were reported in the subpopulation that had experienced a failure of conventional therapy. However, a number of variables were markedly different between the infliximab trials (namely ACCENT-1) and trials for other drugs, and these increase uncertainty concerning the indirect comparison for induction outcomes. Although the manufacturer conducted an NMA comparing maintenance therapies using treatment-sequence methodology, there is a very high degree of uncertainty as to the validity of the analysis methods, and as to trial-level clinical, design, and methodological heterogeneity. No firm conclusions on the comparative effectiveness of ustekinumab for maintenance treatment can be made from the manufacturer’s NMA. Similar to the manufacturer’s indirect comparison that was submitted to CDR, there is substantial clinical and methodological heterogeneity across the various studies included in the published NMA by Singh et al.,13 as well as important limitations of the indirect comparison methods used.
Overall, there appear to be no statistically significant differences between ustekinumab, vedolizumab, and adalimumab for induction treatment, although the limitations related to the heterogeneity within the network means a conclusion of similar effects cannot be made conclusively. However, there is considerable uncertainty as to the validity of the treatment-sequence analysis, and no conclusion can be drawn regarding its results.
The proportions of patients who experienced at least one adverse event or serious adverse event were similar between the ustekinumab and placebo groups across all of the included studies. Nasopharyngitis and upper respiratory tract infections appeared to be more frequent with ustekinumab treatment than with placebo. As may be expected, patients treated with ustekinumab tended to report more administration-related reactions than those on placebo; however, there were no reports of anaphylaxis in any of the studies. Higher proportions of patients receiving placebo than receiving ustekinumab discontinued due to an adverse event, primarily because of gastrointestinal-related events, including worsening Crohn’s disease. The interim report on the long-term extension study of IM-UNITI did not provide adverse event data.
The manufacturer provided a pooled analysis to Health Canada, which was also submitted to CDR,26 consisting of one year of follow-up across all pooled indications for ustekinumab, with a total of 5,884 patients treated with ustekinumab (1,749 patients in the combined Crohn’s disease studies, 3,117 in the combined psoriasis studies, and 1,018 in the combined psoriatic arthritis studies). Overall, the frequencies of AEs, SAEs, infections, serious infections, and WDAEs were similar between placebo-treated patients and ustekinumab-treated patients from the Crohn’s disease studies compared with the adverse event profile in the approved indications of psoriasis and psoriatic arthritis. However, event proportions in the combined Crohn’s disease studies were generally higher than those observed across the psoriatic indications and pooled indications, both among placebo- and ustekinumab-treated patients. The manufacturer suggested that this was a result of the underlying disease rather than ustekinumab treatment. There may be some validity to this, given that the most common event for SAEs and WDAEs in the studies included in this review were gastrointestinal disorders, including Crohn’s disease–related events.
The CDR review summarized an NMA conducted by Mocko et al.,14,15 which reported no statistically significant differences in the incidence of AEs, serious AEs, discontinuations due to AEs, or some of the more prominent AEs (e.g., infections, injection-site reactions, nausea, headache, arthralgia, etc.) among adalimumab, ustekinumab, or vedolizumab during induction therapy and adalimumab, infliximab, and vedolizumab during maintenance therapy in patients with Crohn’s disease (Appendix 7). However, several major limitations associated with the conduct of this NMA introduce a very high degree of uncertainty regarding the results. Hence, caution is required when interpreting the authors’ observations that there are no differences in safety among these drugs during the induction and maintenance phases of therapy for patients with CD.
Patient groups expressed an understanding of the potential risks associated with biologic treatments and noted that those living with Crohn’s disease are often willing to accept these risks rather than undergo surgery, which they consider a last resort.
Based on current standards of practice with existing therapies, the clinical expert consulted by CDR indicated that there are several areas of unmet need where ustekinumab may play a role:
The clinical expert suggested that, before starting ustekinumab therapy, it is advisable to conduct the following:
This information is based on information provided in draft form by the clinical expert consulted by CDR reviewers for the purpose of this review.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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