Revefenacin in Acute Respiratory Insufficiency in COPD

NCT04315558 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: IRB#20-000129
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

COPD; Acute Respiratory Failure

Keywords

COPD; Acute Respiratory failure; Long acting muscarinic antagonist; nebulizer; mechanical ventilation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Reduction in total inspiratory resistance Rdyn at the time of drug trough

  7 days

• Reduction in Resistive pressure (Pres) at the time of drug trough

  7 days

• Reduction in total inspiratory resistance Rstat at the time of drug peak

  7 days

• PaCO2

  7 days

• Respiratory therapist time at bedside

  7 days

Other Outcomes (2)

• Exploratory: 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

  7 days

Study Arms (2)

Revefenacin

EXPERIMENTAL

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]

Ipratropium

ACTIVE COMPARATOR

Nebulized ipratropium will be delivered via nebulizer Q6 hours.

Drug: Ipratropium Bromide

Interventions

Revefenacin Inhalation Solution [Yupelri] DRUG

nebulized drug comparison

Revefenacin

Ipratropium Bromide DRUG

nebulized drug comparison

Ipratropium

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, Los Angeles: lead
• Theravance Biopharma: collaborator
• Mylan Pharmaceuticals Inc: collaborator

Study Sites (2)

Ronald Reagan Medical Center at UCLA

Los Angeles, California, 90095, United States

Location

Santa Monica UCLA

Santa Monica, California, 90404, United States

Location

Related Publications (12)

• 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.

  PMID: 31150963 BACKGROUND

• 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.

  PMID: 30974049 BACKGROUND

• 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.

  PMID: 31152911 BACKGROUND

• 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.

  PMID: 28987804 BACKGROUND

• 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.

  PMID: 7555146 BACKGROUND

• 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.

  PMID: 24379853 BACKGROUND

• 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.

  PMID: 19363211 BACKGROUND

• 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.

  PMID: 15458566 BACKGROUND

• 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.

  PMID: 12421743 BACKGROUND

• 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.

  PMID: 11809986 BACKGROUND

• 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.

  PMID: 10793162 BACKGROUND

• 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.

  PMID: 31245215 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

revefenacin; Ipratropium

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Atropine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Study Officials

• Igor Z Barjaktarevic, MD, PhD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

• Donald Tashkin, MD

  University of California, Los Angeles

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: blinded medication delivery
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: pragmatic, randomized, controlled, double-blinded

Study Record Dates

• First Submitted: March 16, 2020
• First Posted: March 19, 2020
• Study Start: November 1, 2020
• Primary Completion: January 1, 2025
• Study Completion: January 1, 2025
• Last Updated: August 13, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)