Long-term safety and tolerability of oral tofacitinib in patients with Crohn's disease: results from a phase 2, open-label, 48-week extension study

Abstract

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease.

Aims: This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease.

Methods: Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks' fixed, open-label treatment.

Results: Sixty-two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non-responder imputation). Study design prevented between-dose efficacy comparisons.

Conclusions: No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.

© 2019 John Wiley & Sons Ltd.

Figures

Figure 1

Open‐label extension study design. Patients were permitted to switch dose after week 8. If a patient discontinued early from the open‐label therapy, study procedures were to be completed as per end of treatment/early termination. b.d., twice daily; CDAI, Crohn's disease activity index

Figure 2

Patient disposition diagram. Safety analyses patient population. Includes enrolled patients who received ≥1 dose of study medication. N represents the total number of patients in each group; n represents the number of patients with events. †Dose assignment was determined based on last available haematocrit result prior to open‐label extension study entry. Baseline CDAI scores were recalculated using baseline haematocrit results received after treatment assignment was determined. Therefore, one patient in the tofacitinib 5 mg b.d. group and four patients in the 10 mg b.d. group had remission status that did not correspond to their initial dose assignment. b.d., twice daily; CDAI, Crohn's disease activity index

Figure 3

Proportion of patients in clinical remission at baseline and assigned tofacitinib 5 mg b.d., who had A, clinical remission at week 48, and B, sustained clinical remission at weeks 24 and 48, and also C, Kaplan‐Meier plot showing probability of relapse among those in clinical remission at baseline. Clinical remission was defined as CDAI 100 points from baseline, and an absolute CDAI score of >220 points. Patients who discontinued due to lack of efficacy were treated as a relapse event, with an event time at the time of drop out. All data represent full analysis set. N represents the total number of patients analysed, n represents the number of patients achieving clinical remission or sustained clinical remission. Clopper‐Pearson 95% confidence intervals are shown in panels A and B. The Kaplan‐Meier plot for relapse is shown to 365 days, as there were three patients or fewer at risk from days 365 through 458. b.d., twice daily; CDAI, Crohn's disease activity index; SE, standard error

Figure 4

A, Mean CDAI score through week 48, and mean changes from baseline at week 48 for B, CDAI, C, C‐reactive protein and D, faecal calprotectin, for tofacitinib 5 mg b.d. All data represent full analysis set (observed). N represents the total number of patients analysed at each time point, n represents the number of patients with data at week 48 or at baseline and week 48. b.d., twice daily; CDAI, Crohn's disease activity index; SD, standard deviation

Figure 5

Proportion of patients assigned tofacitinib 10 mg b.d. at baseline who had A, clinical remission at week 48 and B, sustained clinical remission at weeks 24 and 48. Clinical remission was defined as CDAI 

Figure 6

A, Mean CDAI score through week 48, and mean changes from baseline at week 48 for B, CDAI, C, C‐reactive protein and D, faecal calprotectin for tofacitinib 10 mg b.d. All data represent full analysis set (observed). N represents the total number of patients analysed at each time point, n represents the number of patients with data at week 48, or at baseline and week 48. b.d., twice daily; CDAI, Crohn's disease activity index; SD, standard deviation

Figure 7

Proportion of patients with IBDQ clinical remission (total score ≥170) patient‐reported outcome endpoint, by baseline and weeks 8, 24 and 48. N represents the total number of patients analysed at each time point, n represents the number of patients achieving IBDQ clinical remission. 95% Clopper‐Pearson exact confidence intervals are shown for proportions. BD, twice daily; IBDQ, Inflammatory Bowel Disease Questionnaire