Y-ECCO Literature Review: Alice Moore
Alice Moore
Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial
Louis E, Resche-Rigon M, Laharie D, et al; GETAID and the SPARE-Biocycle research group
Lancet Gastroenterol Hepatol 2023;8:215–27.
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Introduction
Therapeutic strategies for Crohn’s Disease have evolved over the past decade, with mounting evidence that achieving deep remission (defined as clinical, biochemical and endoscopic remission) is associated with better long-term outcomes [1, 2]. Combination therapy with infliximab and azathioprine has been shown to be superior to either infliximab or azathioprine monotherapy in achieving clinical remission and endoscopic healing in azathioprine-naive patients, thus supporting the paradigm of early disease management and the use of treatment combinations to increase treatment success [3]. Concerns regarding the implications of long-term combination therapy, such as infections and lymphoproliferative disorders, have provided the rationale for a formal clinical trial of treatment de-escalation.
The aim of this trial was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy.
Methods
SPARE was a multicentre, open-label, randomised controlled trial performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn’s Disease in steroid-free clinical remission for more than 6 months, and on combination therapy of infliximab and immunosuppressant therapy for at least 8 months, were randomly assigned (1:1:1) to continue combination therapy (combination group) or discontinue infliximab (infliximab withdrawal group) or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab and presence of ulcers at baseline endoscopy.
The study duration was 104 weeks. In cases of relapse, treatment was optimised or resumed in all groups. Participants, those assessing outcomes and those analysing the data were not masked to group assignment.
The coprimary endpoints were the relapse rate (superiority analysis) and the mean time spent in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis.
Treatment failure was defined as not achieving remission after treatment escalation for relapse according to the protocol, or any major treatment side-effect leading to treatment cessation, or occurrence of an intra-abdominal abscess (size ≥3 cm) or a perianal abscess (size ≥2 cm), or occurrence of intestinal obstruction requiring surgical resection or endoscopic dilatation.
Key Findings
Between November 2, 2015 and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group and n=69 in the immunosuppressant withdrawal group). Four patients in the combination group withdrew consent immediately after randomisation and were not included in the analysis. Patient characteristics in the three groups were similar at baseline
Thirty-nine patients had a relapse [eight (12%) of 67 in the combination group, 25 (35%) of 71 in the infliximab withdrawal group and six (9%) of 69 in the immunosuppressant withdrawal group]. Two-year relapse rates were 14% (95% CI 4%–23%) in the combination group, 36% (24%–47%) in the infliximab withdrawal group and 10% (2%–18%) in the immunosuppressant withdrawal group [hazard ratio (HR) 3.45, 95% CI 1.56–7.69, p=0.003, for infliximab withdrawal vs combination and 4.76, 1.92–11.11, p=0.0004, for infliximab withdrawal vs immunosuppressant withdrawal].
Among 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 (one of two in the combination group, 22 of 23 in the infliximab withdrawal group and two of three in the immunosuppressant withdrawal group). Of the 11 patients who had a relapse and were not retreated, seven were classified as satisfying criteria for treatment failure and four were not retreated according to protocol.
The mean time spent in remission over 2 years was 698 days (95% CI 668–727) in the combination group, 684 days (651–717) in the infliximab withdrawal group and 706 days (682–730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was –14 days (95% CI –56 to 27) between the infliximab withdrawal group and the combination group and –22 days (–62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (–35 days).
Thirty-one serious adverse events were recorded, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group and one in the immunosuppressant withdrawal group) and Crohn’s Disease exacerbation (three in the combination group, four in the infliximab withdrawal group and one in the immunosuppressant withdrawal group). No death or malignancy was recorded.
Conclusion
The SPARE trial showed an increased risk of relapse over 2 years in patients with Crohn’s Disease in clinical remission on combination therapy when discontinuing infliximab as compared with patients continuing infliximab either as monotherapy or in combination with an immunosuppressant therapy. Conversely, discontinuing the immunosuppressant therapy did not affect the relapse rate. Retreatment with infliximab allowed rapid recapture and maintenance of remission in patients who relapsed, and treatment failure rates were similar across treatment groups. Despite this result, the non-inferiority hypothesis for the time spent in remission over 2 years after infliximab withdrawal was rejected.
Alongside infliximab withdrawal, other predictors of relapse were young age at onset and evidence of ongoing inflammation at baseline assessment.
The trial was limited by the absence of blinding, which may have impacted the assessment of the primary endpoint based on CDAI variations.
In conclusion, in patients with Crohn’s Disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should be considered only after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation.
References
- Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet 2017;390:2779–89.
- Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet 2015;386:1825–34.
- Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–95.
Alice Moore - Short Biography
Alice Moore is an IBD clinical fellow at Guy’ and St Thomas’ NHS Foundation Trust with an interest in capsule endoscopy for the assessment of IBD and biosimilar use in IBD.