Revefenacin in Acute Respiratory Insufficiency in COPD

Overview

RARICO is a pragmatic, randomized, controlled, double-blinded, multi-center trial evaluating the safety and feasibility of nebulized revefenacin in comparison to nebulized ipratropium in patients with COPD and acute respiratory failure requiring invasive mechanical ventilation.

Full Title of Study: “Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: April 2021

Detailed Description

Objective: To assess the efficacy of nebulized revefenacin in improving the lung mechanics of COPD patients with acute respiratory failure requiring invasive mechanical ventilation (MV), in comparison to a control group receiving the short-acting muscarinic antagonist ipratropium.

Hypothesis: Revefenacin is as efficacious as ipratropium in improving the lung mechanics of COPD patients with acute respiratory failure.

Study Design:

RARICO is a pragmatic, randomized, controlled, double-blinded, multi-center trial evaluating the safety and feasibility of nebulized revefenacin in comparison to nebulized ipratropium in patients with COPD and acute respiratory failure requiring invasive mechanical ventilation.

Interventions

  • Drug: Revefenacin Inhalation Solution [Yupelri]
    • nebulized drug comparison
  • Drug: Ipratropium Bromide
    • nebulized drug comparison

Arms, Groups and Cohorts

  • Experimental: Revefenacin
    • Revefenacin will be delivered once daily via nebulizer. In order to allow for full blinding and steady Q6 hours regimen in control arm, at hours 6, 12 and 18 after the Revefenacin dose, nebulized normal saline will be delivered.
  • Active Comparator: Ipratropium
    • Nebulized ipratropium will be delivered via nebulizer Q6 hours.

Clinical Trial Outcome Measures

Primary Measures

  • Reduction in total inspiratory resistance Rstat at the time of drug trough
    • Time Frame: 7 days
    • Reduction in total inspiratory resistance across the airways and ventilator circuit measured by the change in Static Resistance (Rstat) at the time of drug trough

Secondary Measures

  • Reduction in total inspiratory resistance Rdyn at the time of drug trough
    • Time Frame: 7 days
    • Reduction in total inspiratory resistance across the airways and ventilator circuit measured by the change in Dynamic Resistance (Rdyn) at the time of drug trough
  • Reduction in Resistive pressure (Pres) at the time of drug trough
    • Time Frame: 7 days
    • Reduction in total inspiratory resistance across the airways and ventilator circuit measured by the change in Resistive pressure (Pres) at the time of drug trough
  • Reduction in total inspiratory resistance Rstat at the time of drug peak
    • Time Frame: 7 days
    • Reduction in total inspiratory resistance across the airways and ventilator circuit measured by the change in Static Resistance (Rstat) at the time of drug peak
  • PaCO2
    • Time Frame: 7 days
    • Arterial partial pressure of CO2 measured at the drug trough
  • Respiratory therapist time at bedside
    • Time Frame: 7 days
    • RT resource utilization as reflected in the total effective time spent at the bedside providing care
  • ICU Length of stay
    • Time Frame: Hospital stay, expected to be less than 28 days
    • Time spent in the ICU from the enrollment in the study through the same-stay discharge from the hospital
  • Ventilator-free days to day 28
    • Time Frame: Hospital stay, expected to be less than 28 days
    • Time spent ventilator-free from the day of enrollment in the study through the same-stay discharge from the hospital

Participating in This Clinical Trial

Inclusion Criteria

  • Adults ≥ 40 years of age
  • Acute respiratory failure requiring invasive mechanical ventilation
  • Documented history of COPD based on spirometric evidence of FEV1/FVC<70%
  • Smoking history >10 years (current or prior)
  • Invasive mechanical ventilation for < 48 hours

Exclusion Criteria

  • Invasive mechanical ventilation for > 48 hours
  • Chronic invasive mechanical ventilation via tracheostomy. Patients with tracheostomy alone without chronic mechanical ventilation may be enrolled.
  • Expected duration of mechanical ventilation <24 hours
  • Hypersensitivity to muscarinic antagonists
  • Inability to tolerate albuterol
  • Lack of documented COPD history
  • For patients taking short- or long-acting muscarinic antagonists (SAMAs or LAMAs) at the time of screening, inability or unwillingness to undergo the SAMA or LAMA washout period (6 hours or 24 hours, respectively) prior to initiating study drug.
  • Presence of ARDS or acute congestive heart failure
  • Unwillingness or inability to remain on the study drug with for the duration of the study
  • Unwillingness or inability to have open-label muscarinic antagonists withheld for duration of the study
  • Unwillingness or inability to utilize the Puritan-Bennett 980 (PB980) ventilator
  • Pulmonary comorbidities such as pneumothorax or pneumomediastinum that, in the opinion of the investigator or clinical team, can pose a risk to subject safety or interfere with the subject's ability to complete the study procedures.
  • Documented restrictive lung disease or history of interstitial lung disease
  • Actual body weight exceeding 1 kg per centimeter of height
  • Pregnancy
  • AST or ALT > 3 times the upper limit of normal, or other clinically significant acute or chronic liver disease
  • Known history of glaucoma
  • Enrollment in other interventional clinical trial
  • Moribund patient not expected to survive >24 hours
  • Decision to withhold life-sustaining treatment, except in those patients committed to full support except cardiopulmonary resuscitation
  • Inability to obtain informed consent from patient or legally authorized representative (LAR)

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of California, Los Angeles
  • Collaborator
    • Theravance Biopharma
  • Provider of Information About this Clinical Study
    • Principal Investigator: Igor Barjaktarevic, MD, PhD, Principal Investigator – University of California, Los Angeles
  • Overall Official(s)
    • Igor Z Barjaktarevic, MD, PhD, Principal Investigator, University of California, Los Angeles
    • Donald Tashkin, MD, Study Director, University of California, Los Angeles
  • Overall Contact(s)
    • Leslie Cortes, 3102063669, LeCortez@mednet.ucla.edu

References

Donohue JF, Kerwin E, Sethi S, Haumann B, Pendyala S, Dean L, Barnes CN, Moran EJ, 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. Respir Med. 2019 Jul;153:38-43. doi: 10.1016/j.rmed.2019.05.010. Epub 2019 May 23.

Ferguson GT, Feldman G, Pudi KK, Barnes CN, Moran EJ, 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. Chronic Obstr Pulm Dis. 2019 Apr 9;6(2):154-165. doi: 10.15326/jcopdf.6.2.2018.0152. Epub 2019 Apr 9.

Donohue JF, Feldman G, Sethi S, Barnes CN, Pendyala S, Bourdet D, Crater G. Cardiovascular safety of revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy of chronic obstructive pulmonary disease: Evaluation in phase 3 clinical trials. Pulm Pharmacol Ther. 2019 Aug;57:101808. doi: 10.1016/j.pupt.2019.101808. Epub 2019 May 30.

Quinn D, Barnes CN, Yates W, Bourdet DL, Moran EJ, Potgieter P, Nicholls A, Haumann B, Singh D. Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies. Pulm Pharmacol Ther. 2018 Feb;48:71-79. doi: 10.1016/j.pupt.2017.10.003. Epub 2017 Oct 4.

Zieliński J. Effects of ipratropium bromide on pulmonary hemodynamics in COPD. Chest. 1995 Oct;108(4):1181-2.

Rezaie N, Shams-Hosseini NS, Kashanizadeh A, Karimi MA. Ipratropium bromide is more effective than Salmeterol – Fluticason combination on O2 saturation patients with COPD. J Res Med Sci. 2013 Aug;18(8):731.

Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular events associated with ipratropium bromide in COPD. Chest. 2010 Jan;137(1):13-9. doi: 10.1378/chest.08-2367. Epub 2009 Apr 10.

Khan SY, O'Driscoll BR. Is nebulized saline a placebo in COPD? BMC Pulm Med. 2004 Sep 30;4:9.

Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002 Nov 15;166(10):1338-44.

Breen D, Churches T, Hawker F, Torzillo PJ. Acute respiratory failure secondary to chronic obstructive pulmonary disease treated in the intensive care unit: a long term follow up study. Thorax. 2002 Jan;57(1):29-33.

Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8.

Maqsood MH, Rubab K, Maqsood MA. The Role of Revefenacin in Chronic Obstructive Pulmonary Disease. Cureus. 2019 Apr 10;11(4):e4428. doi: 10.7759/cureus.4428. Review.

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