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Clinical Trial
. 2015 Apr 6;17(1):95.
doi: 10.1186/s13075-015-0612-7.

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

Joel M Kremer  1 , Alan J Kivitz  2 , Jesus A Simon-Campos  3 , Evgeny L Nasonov  4 , Hans-Peter Tony  5 , Soo-Kon Lee  6 , Bonnie Vlahos  7 , Constance Hammond  8 , Jack Bukowski  9 , Huihua Li  10 , Seth L Schulman  11 , Susan Raber  12 , Andrea Zuckerman  13 , John D Isaacs  14
Affiliations
Clinical Trial

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

Joel M Kremer et al. Arthritis Res Ther. .

Abstract

Introduction: Tofacitinib 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.

Methods: This 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.

Results: 148 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.

Conclusion: Increases 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 registration: Clinicaltrials.gov NCT01484561. Registered 30 November 2011.

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Figures

Figure 1
Figure 1
Consolidated standards of reporting trials (CONSORT) diagram.
Figure 2
Figure 2
Adjusted geometric mean fold-change from baseline (90% CI) in measured glomerular filtration rate (mGFR) (A), estimated GFR (eGFR) (B) and serum creatinine (SCr) (C) (full analysis set, analysis of covariance, observed case).
Figure 3
Figure 3
Box and whisker plot of change in measured glomerular filtration rate (mGFR) (full analysis set).
See this image and copyright information in PMC

References

    1. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381:451–460. doi: 10.1016/S0140-6736(12)61424-X. - DOI - PubMed
    1. Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495–507. doi: 10.1056/NEJMoa1109071. - DOI - PubMed
    1. Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib in combination with nonbiologic DMARDs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159:253–261. doi: 10.7326/0003-4819-159-4-201308200-00006. - DOI - PubMed
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