Revefenacin in Acute Respiratory Insufficiency in COPD

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.

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

Primary outcomes

• Respiratory Therapist Time Spent at the Bedside (Minutes Per Day) [7 days]: Respiratory therapist time spent delivering either Revefenacin or Ipratropium at the bedside (minutes per day)

Secondary outcomes

• Safety of Revefenacin: Paradoxical Bronchospasm, Hypersensitivity Reaction, Severe Urinary Retention Not Explained by Other Reasons, Severe Constipation Not Explained by Other Reasons [7 days]: Number of participants who experienced adverse events not explained by other reasons
• Reduction in Total Inspiratory Resistance Rdyn at the Time of Drug Trough [From the peak to trough within 24 hours]
• Ventilator Days to Day 28 [28 days post enrollment]: Time spent on ventilator from the day of enrollment in the study through Day 28

Other outcomes

• Survival to Day 28 [28 days]: alive at Day 28

Sex: All, ages: 40 Years to any

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)

Participant flow

Outcome results

• Respiratory Therapist Time Spent at the Bedside (Minutes Per Day) (Primary), Mean, minutes per day: Revefenacin Arm 7.2 +/- 1.0; Ipratropium Arm 26.8 +/- 5.3 (p 0.001)
• Safety of Revefenacin: Paradoxical Bronchospasm, Hypersensitivity Reaction, Severe Urinary Retention Not Explained by Other Reasons, Severe Constipation Not Explained by Other Reasons (Secondary), Number, events: Revefenacin 0; Ipratropium 0
• Reduction in Total Inspiratory Resistance Rdyn at the Time of Drug Trough (Secondary), Mean, cmH2O/L/s: Revefenacin -0.9 +/- 2.4; Ipratropium 2.6 +/- 3.3
• Ventilator Days to Day 28 (Secondary), Mean, day: Revefenacin 11.2 +/- 10.5; Ipratropium 12.2 +/- 9.8 (p 0.61)
• Survival to Day 28 (Other pre specified), Count of participants, Participants: Revefenacin 12; Ipratropium 5 (p 0.01)

Adverse events

Time frame: Hospital stay length, up to 60 days

Other adverse events by term

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• Study Protocol and Statistical Analysis Plan (PDF, 2020-05-06)
• Informed Consent Form (PDF, 2024-04-24)

• Igor Z Barjaktarevic, MD, PhD, Principal investigator, University of California, Los Angeles
• Donald Tashkin, MD, Study director, University of California, Los Angeles