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Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)

Primary Purpose

COPD, Acute Respiratory Failure

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Revefenacin Inhalation Solution [Yupelri]

Ipratropium Bromide

About this trial

This is an interventional treatment trial for COPD focused on measuring COPD, Acute Respiratory failure, Long acting muscarinic antagonist, nebulizer, mechanical ventilation

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Ronald Reagan Medical Center at UCLARecruiting
Santa Monica UCLA

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Revefenacin

Ipratropium

Arm Description

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.

Nebulized ipratropium will be delivered via nebulizer Q6 hours.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

PaCO2

Arterial partial pressure of CO2 measured at the drug trough

Respiratory therapist time at bedside

RT resource utilization as reflected in the total effective time spent at the bedside providing care

ICU Length of stay

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 spent ventilator-free from the day of enrollment in the study through the same-stay discharge from the hospital

Full Information

NCT ID

NCT04315558

First Posted

March 16, 2020

Last Updated

September 3, 2022

Sponsor

University of California, Los Angeles

Collaborators

Theravance Biopharma, Mylan Pharmaceuticals Inc

1. Study Identification

Unique Protocol Identification Number

NCT04315558

Brief Title

Revefenacin in Acute Respiratory Insufficiency in COPD

Acronym

RARICO

Official Title

Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 1, 2020 (Actual)

Primary Completion Date

June 1, 2023 (Anticipated)

Study Completion Date

June 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, Los Angeles

Collaborators

Theravance Biopharma, Mylan Pharmaceuticals Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COPD, Acute Respiratory Failure

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

pragmatic, randomized, controlled, double-blinded

Masking

ParticipantCare ProviderInvestigator

Masking Description

blinded medication delivery

Allocation

Randomized

Enrollment

21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Revefenacin

Arm Type

Experimental

Arm Description

Arm Title

Ipratropium

Arm Type

Active Comparator

Arm Description

Nebulized ipratropium will be delivered via nebulizer Q6 hours.

Intervention Type

Drug

Intervention Name(s)

Revefenacin Inhalation Solution [Yupelri]

Intervention Description

nebulized drug comparison

Intervention Type

Drug

Intervention Name(s)

Ipratropium Bromide

Intervention Description

nebulized drug comparison

Primary Outcome Measure Information:

Title

Reduction in total inspiratory resistance Rstat at the time of drug trough

Description

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

Time Frame

7 days

Secondary Outcome Measure Information:

Title

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

Description

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

Time Frame

7 days

Title

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

Description

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

Time Frame

7 days

Title

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

Description

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

Time Frame

7 days

Title

PaCO2

Description

Arterial partial pressure of CO2 measured at the drug trough

Time Frame

7 days

Title

Respiratory therapist time at bedside

Description

RT resource utilization as reflected in the total effective time spent at the bedside providing care

Time Frame

7 days

Title

ICU Length of stay

Description

Time spent in the ICU from the enrollment in the study through the same-stay discharge from the hospital

Time Frame

Hospital stay, expected to be less than 28 days

Title

Ventilator-free days to day 28

Description

Time spent ventilator-free from the day of enrollment in the study through the same-stay discharge from the hospital

Time Frame

Hospital stay, expected to be less than 28 days

Other Pre-specified Outcome Measures:

Title

Exploratory: Ventilator compliance analysis (ventilator dyssynchrony, pressure-volume curve analysis, expiratory flow curve analysis)

Description

Ventilator compliance analysis (ventilator dyssynchrony, pressure-volume curve analysis, expiratory flow curve analysis)

Time Frame

7 days

Title

Safety: Paradoxical bronchospasm, Hypersensitivity reaction, Severe urinary retention not explained by other reasons, Severe constipation not explained by other reasons

Description

Number of episodes of paradoxical bronchospasm, Hypersensitivity reaction, Severe urinary retention not explained by other reasons, Severe constipation not explained by other reasons

Time Frame

7 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Leslie Cortes

Phone

3102063669

LeCortez@mednet.ucla.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Maria (Carmela) Granone, MD

Phone

3108255316

MGranone@mednet.ucla.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Igor Z Barjaktarevic, MD, PhD

Organizational Affiliation

University of California, Los Angeles

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Donald Tashkin, MD

Organizational Affiliation

University of California, Los Angeles

Official's Role

Study Director

Facility Information:

Facility Name

Ronald Reagan Medical Center at UCLA

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marissa Dembek

Phone

310-825-2616

mdembek@mednet.ucla.edu

First Name & Middle Initial & Last Name & Degree

Nida Qadir, MD

Phone

3108258599

nqadir@mednet.ucla.edu

First Name & Middle Initial & Last Name & Degree

Nida Qadir, MD

Facility Name

Santa Monica UCLA

City

Santa Monica

State/Province

California

ZIP/Postal Code

90404

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marissa Dembek

Phone

310-825-2616

mdembek@mednet.ucla.edu

First Name & Middle Initial & Last Name & Degree

Joanne Bando, MD

Phone

3104490939

jbando@mednet.ucla.edu

First Name & Middle Initial & Last Name & Degree

Joanne Bando, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

31150963

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.

Results Reference

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PubMed Identifier

30974049

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.

Results Reference

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PubMed Identifier

31152911

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.

Results Reference

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PubMed Identifier

28987804

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.

Results Reference

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PubMed Identifier

7555146

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.

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PubMed Identifier

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Citation

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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.

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Citation

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Citation

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Citation

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Citation

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Revefenacin in Acute Respiratory Insufficiency in COPD

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