Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis

Abstract

Background: In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety.

Methods: During 4 baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment.

Results: Across the placebo-controlled studies, interruptions occurred in larger proportions of baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes.

Conclusions: Consistent with its pharmacologic properties, brief interruptions of baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA.

Trial registration: ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

Keywords: DMARDs (biologics); Drug interruption; JAK inhibitors; Rheumatoid arthritis.

Conflict of interest statement

Paul Emery reports consulting fees from Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz, Eli Lilly and Company; Yoshiya Tanaka reports grant/research support from Asahi-kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, and Ono and speaker/honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, Abbvie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, and Teijin; Tracy Cardillo, Douglas Schlichting, Terence Rooney, Scott Beattie, and Cameron Helt are full-time employees of and own stock in Eli Lilly and Company; Josef Smolen reports personal fees and other from Eli Lilly and Company, AbbVie, Janssen, MSD, Novartis Pharma, Pfizer, personal fees and other from Roche, personal fees from Amgen, AstraZeneca, Astro, Bristol-Meyers Squibb, Celgene, Celltrion, Chugai Pharmaceutical, Gilead, ILTOO, Medimmune, Samsung, Sanofi-Aventis, UCB.

Figures

Fig. 1

Duration of interruptions in the phase 3 studies RA-BEGIN (a), RA-BEAM (b), RA-BUILD (c), and RA-BEACON (d)a,b. aInterruptions are based on daily tablet baricitinib study drug, including in non-baricitinib groups, which represent interruptions of the matching placebo for baricitinib. bTemporary interruption is defined as a temporary withholding of study drug that is followed by resumption of study drug during the study. cPercentage of interruptions. MTX, methotrexate

Fig. 2

Percentage of 24-week responders among csDMARD/MTX-IR patients with/without interruption during the first 24 weeks. ACR20/50, 20%/50% improvement in American College of Rheumatology criteria; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DAS28-hsCRP, Disease Activity Score based on a 28-joint count and high-sensitivity C-reactive protein; IR, inadequate responder; MTX, methotrexate

Fig. 3

Time profile of daily diary scores among csDMARD/MTX-IR patients who were retreated following interruptionsa. Data presented are combined from RA-BEAM and RA-BUILD for duration of morning joint stiffness (a) morning joint stiffness severity (b), worst joint pain (c), and worst tiredness (d); electronic diary data were gathered daily from week 0 to 12. aExcludes interruptions without at least 3 diary entries during interruption. bAverage of values obtained within the first 3 days following randomization. cAverage of up to 3 most recent values obtained in the 7 days prior to interruption. dAverage of 3 most recent values in the last 7 days of the interruption. eAverage of last 3 available values obtained following interruption and prior to any subsequent interruption or week 12 study visit. N, number of interruptions with complete time profile; NRS, numeric rating scale