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Improvements in health status with revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist for chronic obstructive pulmonary disease

Open AccessPublished:January 18, 2023DOI:https://doi.org/10.1016/j.rmed.2023.107123

      Highlights

      • COPD causes high symptom burden and poor QoL, particularly in women.
      • Revefenacin improved patient health status in 2 phase 3 COPD trials.
      • This post hoc analysis assessed PROs for revefenacin vs placebo overall and by sex.
      • Revefenacin improved several QoL measures vs placebo, particularly among women.

      Abstract

      Background

      Replicate 12-week phase 3 trials (0126 and 0127) of once-daily nebulized revefenacin 175 μg vs placebo demonstrated significant bronchodilation and improvements in health status in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). This post hoc analysis evaluated improvement in patient-reported outcomes (PROs), including the St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Clinical COPD Questionnaire (CCQ) in both women and men.

      Methods

      Participants were pooled from the two 12-week studies (411 [51%] women and 401 [49%] men). Changes in PROs were assessed overall and separately in men and women.

      Results

      Revefenacin improved SGRQ and CAT total scores from baseline in both studies; improvement in CCQ total score reached significance only in 0126. In pooled data, a greater proportion of patients achieved clinically meaningful response in SGRQ score (≥4-unit decrease from baseline) with revefenacin vs placebo (odds ratio, 1.5; 95% confidence interval, 1.1–2.1; P = 0.012). Clinically meaningful responses were also seen in CAT (≥2-unit decrease from baseline) and CCQ (≥0.4-unit decrease from baseline) scores with revefenacin vs placebo. When stratified by sex, improvements from baseline in SGRQ, CAT, and CCQ scores following revefenacin vs placebo reached statistical significance only in women.

      Conclusions

      Maintenance treatment with revefenacin improved health status in patients with moderate to very severe COPD; however, the effect was more pronounced for women than men.

      Clinicaltrials.gov

      NCT02459080; NCT02512510.

      Keywords

      Abbreviations

      COPD
      chronic obstructive pulmonary disease
      SGRQ
      St. George's Respiratory Questionnaire
      CAT
      COPD Assessment Test
      CCQ
      Clinical COPD Questionnaire
      PRO
      patient-reported outcome
      LABA
      long-acting beta-agonists
      OR
      odds ratio
      SD
      standard deviation
      BMI
      body mass index
      CI
      confidence interval
      FEV1
      forced expiratory volume in 1 s
      FVC
      forced vital capacity
      ICS
      inhaled corticosteroid
      mMRC
      modified Medical Research Council dyspnea scale
      LS
      least square
      SE
      standard error

      1. Introduction

      Chronic obstructive pulmonary disease (COPD) is characterized by high symptom burden, particularly among women, who often have more severe symptoms, earlier disease onset, and worse health-related quality of life (HRQoL) than men [
      • Celli B.
      • Vestbo J.
      • Jenkins C.R.
      • Jones P.W.
      • Ferguson G.T.
      • Calverley P.M.
      • Yates J.C.
      • Anderson J.A.
      • Willits L.R.
      • Wise R.A.
      Sex differences in mortality and clinical expressions of patients with chronic obstructive pulmonary disease. The TORCH experience.
      ,
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Jenkins C.R.
      • Chapman K.R.
      • Donohue J.F.
      • Roche N.
      • Tsiligianni I.
      • Han M.K.
      Improving the management of COPD in women.
      ,
      • Tsiligianni I.
      • Mezzi K.
      • Fucile S.
      • Kostikas K.
      • Shen S.
      • Banerji D.
      • Fogel R.
      Response to indacaterol/glycopyrronium (IND/GLY) by sex in patients with COPD: a pooled analysis from the IGNITE program.
      ]. Further, treatment options for COPD have shown mixed outcomes based on sex. Female patients treated with indacaterol/glycopyrronium achieved higher rates of minimal clinically important difference (MCID) in St. George's Respiratory Questionnaire (SGRQ) total scores vs males, whereas treatment with tiotropium showed no sex-based biases in patient-reported outcomes (PROs) [
      • Tashkin D.
      • Celli B.
      • Kesten S.
      • Lystig T.
      • Decramer M.
      Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial.
      ,
      • Tsiligianni I.
      • Mezzi K.
      • Fucile S.
      • Kostikas K.
      • Shen S.
      • Banerji D.
      • Fogel R.
      Response to indacaterol/glycopyrronium (IND/GLY) by sex in patients with COPD: a pooled analysis from the IGNITE program.
      ]. Revefenacin inhalation solution (Yupelri®) is a once-daily, nebulized, long-acting muscarinic antagonist approved in the US for the maintenance treatment of patients with COPD. Replicate 12-week pivotal phase 3 trials and a 52-week phase 3 trial showed that once-daily nebulized revefenacin was well tolerated and demonstrated statistically significant improvements in bronchodilation and health status in patients with moderate to very severe COPD at a dose of 175 μg vs placebo [
      • Ferguson G.T.
      • Feldman G.
      • Pudi K.K.
      • Barnes C.N.
      • Moran E.J.
      • Haumann B.
      • Pendyala S.
      • Crater G.
      Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: results from two replicate phase III clinical trials.
      ,
      • Donohue J.F.
      • Kerwin E.
      • Sethi S.
      • Haumann B.
      • Pendyala S.
      • Dean L.
      • Barnes C.N.
      • Moran E.J.
      • Crater G.
      Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease.
      ]. This analysis evaluated whether revefenacin vs placebo improved PROs in patients from the 12-week replicate studies. Subgroup analyses in women and men were conducted to evaluate improvements in PROs by sex.

      2. Materials and methods

      This was a post hoc subgroup analysis of two replicate, randomized, double-blind, 12-week phase 3 trials (Study 0126 [ClinicalTrials.gov: NCT02459080] and Study 0127 [ClinicalTrials.gov: NCT02512510]). The trials were performed in accordance with the principles stated in the Declaration of Helsinki. Study design and patient criteria were described previously [
      • Ferguson G.T.
      • Feldman G.
      • Pudi K.K.
      • Barnes C.N.
      • Moran E.J.
      • Haumann B.
      • Pendyala S.
      • Crater G.
      Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: results from two replicate phase III clinical trials.
      ].
      Participants received once-daily revefenacin 175 μg via a standard jet nebulizer (PARI LC Sprint® [Starnberg, Germany]) or placebo. PROs included SGRQ, COPD Assessment Test (CAT), and Clinical COPD Questionnaire (CCQ). Clinically meaningful improvements were defined as decreases of ≥4-units in SGRQ [
      • Jones P.W.
      St. George's respiratory questionnaire: MCID.
      ], ≥2-units in CAT [
      • Lee S.D.
      • Huang M.S.
      • Kang J.
      • Lin C.H.
      • Park M.J.
      • Oh Y.M.
      • Kwon N.
      • Jones P.W.
      • Sajkov D.
      The COPD assessment test (CAT) assists prediction of COPD exacerbations in high-risk patients.
      ], and ≥0.4-units in CCQ [
      • Kocks J.W.
      • Tuinenga M.G.
      • Uil S.M.
      • van den Berg J.W.
      • Ståhl E.
      • van der Molen T.
      Health status measurement in COPD: the minimal clinically important difference of the clinical COPD questionnaire.
      ] scores from baseline.
      Analyses were performed using the intent-to-treat analysis set. Day 85 least squares mean (LSM) changes from baseline in PROs and LSM treatment differences between revefenacin 175 μg and placebo were estimated using a mixed model for repeated measures (MMRM) including fixed-effect class terms for treatment group, smoking status, reversibility status, concomitant long-acting beta-agonist (LABA) use at baseline, sex, and age at baseline. Odds ratio (OR) estimates and differences between revefenacin 175 μg and placebo in least squares proportion of responders across PROs were compared using a repeated-measures logistic regression model with similar covariates as the MMRM (Appendix, Supplementary Methods).

      3. Results

      Patient demographics and baseline characteristics were described previously [
      • Ferguson G.T.
      • Feldman G.
      • Pudi K.K.
      • Barnes C.N.
      • Moran E.J.
      • Haumann B.
      • Pendyala S.
      • Crater G.
      Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: results from two replicate phase III clinical trials.
      ]. The post hoc subgroup analysis included 411 (51%) women and 401 (49%) men (Appendix, Table S1). For women vs men, the mean (standard deviation) age was 63 (9) vs 64 (9) years, baseline body mass index was 29.5 (7.5) vs 29.0 (6.3) kg/m2, 51% vs 45% were current smokers, and 36% vs 38% were concurrent LABA or inhaled corticosteroid + LABA users.
      Revefenacin improved SGRQ and CAT total scores from baseline in both studies and CCQ total score in Study 0126; improvement in CCQ did not reach statistical significance in Study 0127, where placebo response was larger than expected (Fig. 1A). In pooled data, statistically significantly greater percentages of patients achieved clinically meaningful improvements in SGRQ score with revefenacin vs placebo using 4-point (46.9% vs 36.2%; P = 0.012), 8-point (35.1% vs 22.5%; P = 0.001), and 12-point (26.0% vs 11.6%; P = 0.0001) thresholds (Fig. 1B). Increased rates of clinically meaningful CAT score responses were seen with revefenacin vs placebo in Study 0126 (50.4% vs 33.8%; P = 0.010), but the difference did not reach statistical significance in Study 0127 (48.4% vs 39.2%; Fig. 1B). In pooled data, the percentage of patients with clinically meaningful improvement in CCQ total score was statistically significantly greater with revefenacin vs placebo (43.3% vs 31.9%; P = 0.003; Fig. 1B).
      Fig. 1
      Fig. 1A) SGRQ, CAT, and CCQ total scores for Studies 0126 and 0127 and B) SGRQ, CAT, and CCQ responder analysis Responders were defined as follows: SGRQ, ≥4-point decrease; CAT, ≥2-point decrease; CCQ, ≥0.4-point decrease. aDenotes pooled study population (Studies 0126 and 0127). CAT, COPD Assessment Tool; CCQ, Clinical COPD Questionnaire; CI, confidence interval; COPD, chronic obstructive pulmonary disease; LS, least squares; OR, odds ratio; SE, standard error; SGRQ, St. George's Respiratory Questionnaire.
      In both men and women, revefenacin produced statistically significant improvements from baseline in CAT scores vs placebo; improvements with revefenacin vs placebo in SGRQ and CCQ scores reached statistical significance only in women (Appendix, Fig. S1). Percentages of patients with clinically meaningful improvements following treatment with revefenacin vs placebo were observed as follows: SGRQ score, 52.7% vs 36.2% of women (P = 0.014) and 40.8% vs 36.3% of men (not statistically significant); CAT score, 51.4% vs 33.3% of women (P = 0.006) and 46.9% vs 37.8% of men (not statistically significant); and CCQ score, 49.3% vs 31.9% of women (P = 0.002) and 37.1% vs 31.9% of men (not statistically significant; Appendix, Table S2).

      4. Discussion

      Replicate 3-month studies demonstrated overall HRQoL improvements in patients with moderate to very severe COPD treated with revefenacin, with greater changes from baseline in SGRQ, CAT, and CCQ scores following revefenacin vs placebo. There were greater than expected SGRQ and CAT responses with placebo and no statistically significant difference in CCQ score between revefenacin and placebo in Study 0127. Greater improvements and higher response rates were seen in women vs men following revefenacin vs placebo.
      Documented differences in COPD among men and women [
      • Jenkins C.R.
      • Chapman K.R.
      • Donohue J.F.
      • Roche N.
      • Tsiligianni I.
      • Han M.K.
      Improving the management of COPD in women.
      ,
      • Tsiligianni I.
      • Mezzi K.
      • Fucile S.
      • Kostikas K.
      • Shen S.
      • Banerji D.
      • Fogel R.
      Response to indacaterol/glycopyrronium (IND/GLY) by sex in patients with COPD: a pooled analysis from the IGNITE program.
      ,
      • Lopez Varela M.V.
      • Montes de Oca M.
      • Halbert R.J.
      • Muiño A.
      • Perez-Padilla R.
      • Tálamo C.
      • Jardim J.R.
      • Valdivia G.
      • Pertuzé J.
      • Moreno D.
      • Menezes A.M.
      Sex-related differences in COPD in five Latin American cities: the PLATINO study.
      ] include greater impairment in health status for women vs men for all SGRQ domains [
      • Ferrari R.
      • Tanni S.E.
      • Lucheta P.A.
      • Faganello M.M.
      • do Amaral R.A.
      • Godoy I.
      Gender differences in predictors of health status in patients with COPD.
      ] and higher rates of achieving MCID in SGRQ total score for women vs men following indacaterol/glycopyrronium [
      • Tsiligianni I.
      • Mezzi K.
      • Fucile S.
      • Kostikas K.
      • Shen S.
      • Banerji D.
      • Fogel R.
      Response to indacaterol/glycopyrronium (IND/GLY) by sex in patients with COPD: a pooled analysis from the IGNITE program.
      ]. Similarly, a differential response was observed in our study. However, baseline SGRQ, CAT, and CCQ scores were generally lower in the revefenacin vs placebo group among women, whereas baseline scores were better balanced among men. Further research is needed to ascertain the reasons underlying the different levels of improvement between women and men with revefenacin, although this could be related to sex-based differences in symptom burden often observed among patients with COPD.
      This post hoc analysis is limited by the 3-month treatment period, although a 52-week study showed that revefenacin resulted in longer-term improvements in PROs [
      • Donohue J.F.
      • Kerwin E.
      • Sethi S.
      • Haumann B.
      • Pendyala S.
      • Dean L.
      • Barnes C.N.
      • Moran E.J.
      • Crater G.
      Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease.
      ]. The study population had stable COPD and excluded patients with recent hospitalizations or respiratory infections, and the analysis presented was not prespecified.

      5. Conclusions

      Maintenance treatment with revefenacin can improve the health status of patients with moderate to very severe COPD; however, the effect may be more pronounced for women than for men.

      Funding

      This work was supported by Theravance Biopharma Ireland Limited (Dublin, Ireland). Medical writing support was funded by Mylan Inc., now merged with Upjohn to be Viatris (Canonsburg, PA, USA), and by Theravance Biopharma US, Inc. (South San Francisco, CA, USA).

      CRediT authorship contribution statement

      James F. Donohue: Investigation, Writing – original draft, Writing – review & editing. Gary T. Ferguson: Investigation, Writing – original draft, Writing – review & editing. Jill A. Ohar: Investigation, Writing – original draft, Writing – review & editing. David A. Lombardi: Investigation, Formal analysis, Writing – original draft, Writing – review & editing. Roslyn F. Schneider: Investigation, Writing – original draft, Writing – review & editing. Karmon Johnson: Investigation, Writing – original draft, Writing – review & editing.

      Declaration of competing interest

      JFD is a consultant and advisory committee member for Theravance Biopharma US, Inc.; Sunovion Pharmaceuticals; and Mylan, a Viatris company. GTF is a consultant and speaker for and received financial support from Theravance Biopharma US, Inc., and Mylan, a Viatris company. JAO has served on advisory boards for AstraZeneca, Boehringer Ingelheim, GSK, Mylan Inc., Reckitt Benckiser, Sunovion Pharmaceuticals, and Theravance Biopharma US, Inc. DAL was a contract employee of Theravance Biopharma US, Inc., at the time of this study. RFS is an employee of BioMarin Pharmaceuticals, Inc.; has received consulting fees from GSK, Merck, and BreathResearch; and has received salary from Pfizer and from Theravance Biopharma US, where she was employed when these analyses were done. KJ is an employee of Theravance Biopharma US, Inc.

      Acknowledgments

      Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Gautam Bijur, PhD, of Ashfield MedComms, an Ashfield Health Company, and editing support by Celia Nelson of Ashfield MedComms and Judith Philips, PhD, of AlphaBioCom LLC (King of Prussia, PA, USA), and funded by Mylan Inc., now merged with Upjohn to be Viatris (Canonsburg, PA, USA), and by Theravance Biopharma US, Inc. (South San Francisco, CA, USA).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article.

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