Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)

Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)

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.

Study Overview

• Status: Completed
• Conditions: COPD; Acute Respiratory Failure
• Intervention / Treatment: Drug: Revefenacin Inhalation Solution [Yupelri]; Drug: Ipratropium Bromide

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan Medical Center at UCLA
    • Santa Monica, California, United States, 90404
      • Santa Monica UCLA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 < 96 hours

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Revefenacin Inhalation Solution [Yupelri]; nebulized drug comparison
Active Comparator: Ipratropium; Nebulized ipratropium will be delivered via nebulizer Q6 hours.	Drug: Ipratropium Bromide; nebulized drug comparison

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in total inspiratory resistance Rstat at the time of drug trough	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	7 days

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Ventilator compliance analysis (ventilator dyssynchrony, pressure-volume curve analysis, expiratory flow curve analysis)	Ventilator compliance analysis (ventilator dyssynchrony, pressure-volume curve analysis, expiratory flow curve analysis)	7 days
Safety: Paradoxical bronchospasm, Hypersensitivity reaction, Severe urinary retention not explained by other reasons, Severe constipation not explained by other reasons	Number of episodes of paradoxical bronchospasm, Hypersensitivity reaction, Severe urinary retention not explained by other reasons, Severe constipation not explained by other reasons	7 days

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: Mylan Pharmaceuticals Inc; Theravance Biopharma
• Investigators: Principal Investigator: Igor Z Barjaktarevic, MD, PhD, University of California, Los Angeles; Study Director: Donald Tashkin, MD, University of California, Los Angeles

Publications and helpful links

General Publications

• 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. doi: 10.1164/rccm.2107138.
• 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.
• Zielinski J. Effects of ipratropium bromide on pulmonary hemodynamics in COPD. Chest. 1995 Oct;108(4):1181-2. doi: 10.1378/chest.108.4.1181-b. No abstract available.
• 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. No abstract available.
• 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. doi: 10.1186/1471-2466-4-9.
• 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. doi: 10.1136/thorax.57.1.29.
• 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.
• 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. doi: 10.1056/NEJM200005043421801.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Actual): January 1, 2025
• Study Completion (Actual): January 1, 2025

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: March 17, 2020
• First Posted (Actual): March 19, 2020

Study Record Updates

• Last Update Posted (Actual): August 13, 2025
• Last Update Submitted That Met QC Criteria: August 7, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: mechanical ventilation; COPD; nebulizer; Long acting muscarinic antagonist; Acute Respiratory failure
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Anticonvulsants; Cholinergic Antagonists; Cholinergic Agents; Bromides; Ipratropium
• Other Study ID Numbers: IRB#20-000129

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No