title: Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01484561. Registered 30 November 2011.
authors.affiliation: Albany Medical College and The Center for Rheumatology, Albany, NY, USA. jkremer@joint-docs.com.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kremer
authors.affiliation: Altoona Center for Clinical Research, Duncansville, PA, USA. ajkivitz@yahoo.com.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Kivitz
authors.affiliation: Hospital CEM/BIOCEM, Merida, Mexico. jabrahamsimon@yahoo.com.mx.
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Simon-Campos
authors.affiliation: Nasonova State Institute of Rheumatology, Moscow, Russia. nasonov@irramn.ru.
authors.forename: Evgeny L
authors.initials: EL
authors.lastname: Nasonov
authors.affiliation: University Hospital Würzburg, Würzburg, Germany. Tony_H@ukw.de.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Tony
authors.affiliation: Yonsei University College of Medicine, Seoul, South Korea. SOOKONLEE@yuhs.ac.
authors.forename: Soo-Kon
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Pfizer Inc, Collegeville, PA, USA. bonnie.vlahos@pfizer.com.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Vlahos
authors.affiliation: Pfizer Inc, Collegeville, PA, USA. connie.hammond@pfizer.com.
authors.forename: Constance
authors.initials: C
authors.lastname: Hammond
authors.affiliation: Pfizer Inc, Collegeville, PA, USA. JACK.BUKOWSKI@PFIZER.COM.
authors.forename: Jack
authors.initials: J
authors.lastname: Bukowski
authors.affiliation: Pfizer Inc, Collegeville, PA, USA. Huihua.Li@pfizer.com.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: Pfizer Inc, Collegeville, PA, USA. seth.schulman@pfizer.com.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Schulman
authors.affiliation: Pfizer Inc, San Diego, CA, USA. susan.raber@pfizer.com.
authors.forename: Susan
authors.initials: S
authors.lastname: Raber
authors.affiliation: Pfizer Inc, Groton, CT, USA. andrea.zuckerman@pfizer.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zuckerman
authors.affiliation: National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle-upon-Tyne, UK. John.Isaacs@newcastle.ac.uk.
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003404:Creatinine / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D011758:Pyrroles / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D003404:Creatinine