Efficacy and Safety of Tofacitinib Dose De-escalation and Dose Escalation for Patients With Ulcerative Colitis

Results From OCTAVE Open

Bruce E. Sands; Alessandro Armuzzi; John K. Marshall; James O. Lindsay; William J. Sandborn; Silvio Danese; Julián Panés; Brian Bressler; Jean-Frédéric Colombel; Nervin Lawendy; Eric Maller; Haiying Zhang; Gary Chan; Leonardo Salese; Konstantinos Tsilkos; Amy Marren; Chinyu Su


Aliment Pharmacol Ther. 2020;51(2):271-280. 

In This Article

Abstract and Introduction


Background: For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC.

Aim: To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC.

Methods: We evaluated data (November 2017 data cut-off) from OCTAVE Open, an ongoing, open-label, long-term extension study. The dose de-escalation group comprised 66 tofacitinib induction responders in remission following 52 weeks' tofacitinib 10 mg b.d. maintenance therapy, subsequently de-escalated to 5 mg b.d. in OCTAVE Open. The dose escalation group comprised 57 tofacitinib induction responders who experienced treatment failure while receiving 5 mg b.d. maintenance therapy, subsequently escalated to 10 mg b.d. in OCTAVE Open.

Results: After tofacitinib de-escalation, 92.4% (61/66) and 84.1% (53/63) of patients maintained clinical response and 80.3% (53/66) and 74.6% (47/63) maintained remission, at months 2 and 12, respectively. After dose escalation, 57.9% (33/57) and 64.9% (37/57) of patients recaptured clinical response and 35.1% (20/57) and 49.1% (28/57) were in remission, at months 2 and 12, respectively. The incidence rate of herpes zoster with dose escalation (7.6 patients with events/100 patient-years) was numerically higher than in the overall tofacitinib UC programme.

Conclusions: Following tofacitinib de-escalation in patients already in remission on 10 mg b.d., most maintained remission, although 25.4% lost remission, at month 12. For induction responders who dose-escalated following treatment failure on 5 mg b.d. maintenance therapy, 49.1% achieved remission by month 12. (ClinicalTrials.gov number: NCT01470612).


For patients with ulcerative colitis (UC), the goals of treatment are to induce and maintain disease remission, to improve patients' quality of life, and to prevent both disease- and medication-related complications.[1,2] It is not uncommon for therapy to be de-escalated: (a) to reduce the risk of dose-dependent side effects associated with long-term immunosuppression; (b) for the management of intercurrent illnesses (such as bacterial or certain viral infections), for which concomitant, full-dose immunosuppressant therapies might impede or delay recovery; (c) to reduce the burden of therapy for patients in sustained remission; and (d) to decrease the cost of treatment.[3,4] However, for patients who experience a disease flare or lose response, the ability to recapture the initial response by escalating the dose is an important consideration.

Tofacitinib is an oral, small molecule Janus kinase (JAK) inhibitor for the treatment of UC. Three global, phase 3, randomised, double-blind, placebo-controlled trials (OCTAVE Induction 1 and 2, NCT01465763 and NCT01458951; and OCTAVE Sustain, NCT01458574) reported the efficacy and safety of tofacitinib as induction and maintenance therapy for patients with moderately to severely active UC.[5] OCTAVE Open (NCT01470612) is an ongoing, open-label, long-term extension study that enrolled patients who completed or lost response to treatment in OCTAVE Sustain, and also included non-responders from OCTAVE Induction 1 and 2.[6]

The safety profile of tofacitinib in the UC clinical programme appeared similar to that reported in patients with rheumatoid arthritis and—with the exception of higher rates of herpes zoster infection—similar to biologic therapies for the treatment of UC.[7] Dose-related increases in the rate of herpes zoster infections observed during OCTAVE Sustain[5,7,8] and an increased incidence of venous thromboembolic events manifested as pulmonary embolism events observed in patients treated with tofacitinib 10 mg twice daily (b.d.) compared to tofacitinib 5 mg b.d. or tumour necrosis factor inhibitors in one large ongoing randomised post-authorisation safety surveillance study in patients with rheumatoid arthritis who were 50 years or older with at least one cardiovascular risk factor, provide a rationale for treating patients with the lowest effective dose for maintenance therapy. For patients who lose response to tofacitinib 5 mg b.d. as maintenance therapy, escalating the dose to 10 mg b.d. may be a suitable treatment strategy. However, tofacitinib 10 mg b.d. should be used with caution in patients for whom 10 mg b.d. is the recommended dose and in whom venous thromboembolic risk factors are identified.

We analysed the efficacy and safety of two adjustments of tofacitinib maintenance dosing for patients in OCTAVE Open: (a) dose de-escalation to tofacitinib 5 mg b.d. for patients in remission following 52 weeks of maintenance therapy with tofacitinib 10 mg b.d.; and (b) dose escalation to tofacitinib 10 mg b.d. for patients who lost response while receiving tofacitinib 5 mg b.d. as maintenance therapy (Figure 1).

Figure 1.

(A) Overview of the phase 3 OCTAVE programme, and treatment sequences for patients in (B) the tofacitinib maintenance remitter dose de-escalation subpopulation and (C) the tofacitinib maintenance failure dose escalation subpopulation. OCTAVE Open is ongoing; data as of November 2017 data cut-off. b.d., twice daily; N, number of patients included in each treatment group or subpopulation