Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial

Abstract

IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA.MethodsThis was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft–Gault equation) and SCr; efficacy; and safety.Results148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study – ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies.ConclusionIncreases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance.Trial registrationClinicaltrials.gov NCT01484561. Registered 30 November 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0612-7) contains supplementary material, which is available to authorized users.

Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Key exclusion criteria included untreated infection with Mycobacterium tuberculosis or clinically significant infection, and history of malignancy except adequately treated squamous cell or basal cell skin cancer or cervical carcinoma in situ. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Studies were conducted in compliance with the Declaration of Helsinki, International Council for Harmonisation Guidelines for Good Clinical Practice and local country regulations. The study protocol was approved by the Institutional Review Board or Independent Ethics Committee at each centre.…”

“…Tofacitinib has demonstrated efficacy and manageable safety in patients with active RA in phase I-III trials and long-term extension (LTE) studies. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Results from these studies and adverse event (AE) profiles of other disease-modifying antirheumatic drugs (DMARDs) informed the selection of safety events of special interest: serious infection events (SIEs), opportunistic infections (OI; including tuberculosis (TB)), herpes zoster (HZ), malignancies, cardiovascular events and gastrointestinal (GI) perforations.…”

Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases

“…These infections were mainly upper respiratory tract infections, urinary tract infections, and viral gastroenteritis. However, serious cases of tuberculosis, fungal infection, Pneumocystis jirovecii pneumonia, and bacterial pneumonia were reported as well 66, 73, 81–84 . Given the broad range of cytokines that can be affected by tofacitinib, this outcome was not unexpected.…”

Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

“…Other laboratory abnormalities in jakinib-treated patients included sporadic elevations in serum creatinine 154 , but this usually returned to baseline upon drug discontination 42,43,154 . Acute renal failure was infrequent and associated with concurrent serious illness, primarily infection 155 ; chronic renal dysfunction has not been reported as an adverse effect of jakinibs 42,43,154 .…”

“…Acute renal failure was infrequent and associated with concurrent serious illness, primarily infection 155 ; chronic renal dysfunction has not been reported as an adverse effect of jakinibs 42,43,154 . Some jakinibs have also been reported to cause elevations in transaminases 127 .…”