DOP108Randomised controlled trial of withdrawal of thiopurines in patients with IBD switching from intravenous to subcutaneous infliximab: Results of the MINIMISE study

Abstract Background Combining thiopurines (TP) with intravenous (IV) infliximab (IFX) decreases the rate of immunogenicity. Subanalyses of registration studies show that subcutaneous (SC) IFX may be associated with a decreased chance of developing anti-drug antibodies (ADAb) compared to IV IFX. However, there are no randomised controlled trials (RCT) to inform the decision of whether to continue or discontinue TP when switching from IV to SC. Methods We conducted a multicentre, RCT of TP withdrawal in patients switching from IV to SC IFX. Patients with IBD in stable remission (HBI ≤4 or SCCAI ≤2) who had been receiving IV IFX for at least 22 weeks at stable doses of up to 5mg/kg q4w or 10mg/kg q8w along with a TP were randomised to continue or discontinue the TP. Patients had therapeutic IFX drug levels (DL) at screening and were stratified by HLA DQA1*05 status. Primary outcome was the proportion of patients who developed free antidrug antibodies (ADAb) at week 24 (ie detectable antibodies in the absence of detectable drug). Using a non-inferiority design to detect a 15% difference, 102 patients were required to meet the target of 88 evaluable patients at week 24. Results 102 patients (63=CD, 39=UC, 5=IBD-U) were randomised (Table 1). For the primary outcome, detection of free ADAb at 24W, 88 patients were evaluable (2 patients withdrew early, 8 patients attended outside 1 week window for week 24 assessment, 4 patients did not provide week 24 samples). TP withdrawal was non inferior to continuation (difference -2.4 (95% CI: -12.3 to 5.4) P = 0.46). 1/41 patients in the stop group developed free ADAb compared with 0/47 in the continue group; a sensitivity analysis including the samples from the early withdrawal patients and the patients who provided late samples at week 24, none of whom developed free ADAb, did not change the outcome. HLA DQA1*05 status did not affect IFX DL, nor free or total ADAb formation. Median IFX levels (ug/ml) at weeks 8, 16 and 24 were 15.5, 17.7 and 18.4 in the continue arm vs 17.0, 15.5 and 15.1 in the stop arm. The proportion of patients with total positive ADAb at the same time points was 21%, 22% and 20% (continue) and 12%, 15% and 18% (stop). There was no difference at week 24 in clinically active disease (HBI 4, SCCAI2), biomarker activity (FC 250 ug/g or CRP 5 mg/L) or combined clinical and biomarker activity (Figure 1). One patient reverted to IV IFX (stop group), one patient required admission for pneumonia and one patient developed a basal cell carcinoma (both continue group). Conclusion IBD patients in stable remission on combination therapy with IV IFX and TP can be safely switched to SC IFX without the need for continuation of the thiopurine to prevent ADAb Conflict of interest: Irving, Peter Miles: Grant: MSD, Pfizer, Takeda, Celltrion, Galapagos Personal Fees: AbbVie, Arena, BMS, Boomerang Medical, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Sapphire Medical, Sandoz, Shire, Takeda, Tillotts, Topivert, VH2, Vifor Pharma, Warner Chilcott Centritto, Andrea: No conflict of interest Choon, Xin Yi: No conflict of interest Yeo, Jie Han: No conflict of interest Blad, William: No conflict of interest Talbot, Alison: No conflict of interest Fitzgerald, Abbie-Lei: No conflict of interest Whitehead, Emma: No conflict of interest Elford, Alexander: No conflict of interest Colwill, Michael: I have received speaker fees or travel grants from Celltrion, Pfizer, Dr Falk, Takeda, Johnson & Johnson and Ferring. Baillie, Samantha: No conflict of interest Pramanik, Rashida: No conflict of interest Ayis, Salma: No conflict of interest Goubar, Aicha: No conflict of interest Arenas Hernandez, Monica: No conflict of interest Cordle, Jessica: No conflict of interest Lees, Charlie: Consultancy and lecture fees: Abbvie, Oshi Health, Gilead, Pfizer, Takeda, Janssen, Shire, Samsung Bioepis, Dr Falk, GSK, Galapagos, Trellus Health, Iterative Scopes, Fresnius Kabi Pollok, Richard: Galapagos consulting Sebastian, Shaji: Grant: Takeda, Tillots pharma, Biogen, Pfizer, Abbvie, Johnson & Johnson, Olympus -Odin Vision Personal Fees: Tillots, Johnson & Johnson, Olympus Odin Vision, AbbVie, Takeda, Merck, Pharmacosmos, Amgen, Eli Lilly, BMS, Odin Vision Non-financial Support: Tillots, Takeda, AbbVie, Celltrion, Johnson & Johnson, Eli Lilly, Alphasigma, Ferring Pharma Dart, Robin: Grant: Takeda Personal fees: N/A&#xBConsulting: Tillotts, UCB&#xBSpeaker fees: Takeda, UCB&#xBEducational sponsorship: Galapagos, Takeda Samaan, Mark: Advisory fees: Janssen, Takeda, Sandoz, Samsung Bioepis, Galapagos, AbbVie, Pfizer, STADA, Bristol-Myers Squibb, MSD, Sanofi, Tillotts, MSD Lecture fees: Bristol-Myers Squibb, Janssen, Takeda, MSD, Falk, AbbVie, Galapagos, Lilly, Advanz Harrow, Paul: No conflict of interest