Clinical trial NCT04315558: Revefenacin in Acute Respiratory Insufficiency in COPD
Official title: Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: COPD
Acute Respiratory Failure
Keywords: COPD
Acute Respiratory failure
Long acting muscarinic antagonist
nebulizer
mechanical ventilation
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: Theravance Biopharma
name: Mylan Pharmaceuticals Inc
First posted: 2020-03-19
Enrollment: 21
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: pragmatic, randomized, controlled, double-blinded
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Reduction in total inspiratory resistance Rstat at the time of drug trough
timeFrame: 7 days
Secondary outcomes:
measure: Reduction in total inspiratory resistance Rdyn at the time of drug trough
timeFrame: 7 days
measure: Reduction in Resistive pressure (Pres) at the time of drug trough
timeFrame: 7 days
measure: Reduction in total inspiratory resistance Rstat at the time of drug peak
timeFrame: 7 days
measure: PaCO2
timeFrame: 7 days
measure: Respiratory therapist time at bedside
timeFrame: 7 days
measure: ICU Length of stay
timeFrame: Hospital stay, expected to be less than 28 days
measure: Ventilator-free days to day 28
timeFrame: Hospital stay, expected to be less than 28 days
Other outcomes:
measure: Exploratory: Ventilator compliance analysis (ventilator dyssynchrony, pressure-volume curve analysis, expiratory flow curve analysis)
timeFrame: 7 days
measure: Safety: Paradoxical bronchospasm, Hypersensitivity reaction, Severe urinary retention not explained by other reasons, Severe constipation not explained by other reasons
timeFrame: 7 days
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan Medical Center at UCLA
state: California
city: Santa Monica
country: United States
facility: Santa Monica UCLA
state: California
Study officials:
affiliation: University of California, Los Angeles
name: Igor Z Barjaktarevic, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Donald Tashkin, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.