Revefenacin for COPD-Related Respiratory Insufficiency

(RARICO Trial)

No longer recruiting at 1 trial location

Overseen By Leslie Cortes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Los Angeles

Must not be taking: Muscarinic antagonists

Disqualifiers: ARDS, Congestive heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 7 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates the safety and feasibility of using nebulized revefenacin, a medication inhaled through a nebulizer, to assist people with COPD who experience severe breathing problems and require mechanical ventilation. The study compares revefenacin with another nebulized treatment, ipratropium bromide, to determine which is more effective for these patients. Individuals with a long history of COPD, over 10 years of smoking, and current use of a ventilator may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

If you are taking short- or long-acting muscarinic antagonists, you will need to stop them for a washout period (time without taking certain medications) of 6 hours for short-acting and 24 hours for long-acting before starting the study drug. Other medications are not specified, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that revefenacin is generally safe for people with COPD and is well-tolerated when used daily. In trials, most participants did not experience serious side effects. Some reported mild issues like a cough or headache, but these were uncommon. The FDA has already approved revefenacin for COPD, indicating thorough safety testing.

Ipratropium has long been used to help with breathing problems in COPD. It is usually well-tolerated, though some individuals might experience a dry mouth or dizziness. These side effects are typically mild and manageable.

Overall, past research and approvals have demonstrated that both treatments are safe for people with COPD. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for COPD?

Unlike the standard treatments for COPD, such as inhaled bronchodilators like albuterol and ipratropium bromide, Revefenacin offers a unique approach. It is a long-acting muscarinic antagonist (LAMA) that is delivered once daily via nebulizer, which can be more convenient for patients who struggle with handheld inhalers. Researchers are excited about Revefenacin because its once-daily dosing could improve adherence and provide consistent symptom control throughout the day. Additionally, its targeted action might reduce the risk of systemic side effects commonly associated with other COPD medications.

What evidence suggests that this trial's treatments could be effective for COPD-related respiratory insufficiency?

Studies have shown that revefenacin, which participants in this trial may receive, improves lung function in people with COPD. Research indicates it can increase lung capacity by at least 100 mL, with effects lasting over four hours. Importantly, revefenacin provides consistent symptom control with just one daily dose, enhancing breathing throughout the day. These findings suggest it may help manage breathing problems in people with COPD. Another treatment option in this trial is ipratropium, delivered via nebulizer every six hours. ^{4 6 7 8 9}

Who Is on the Research Team?

Igor Barjaktarevic, MD

Principal Investigator

University of California, Los Angeles

Donald Tashkin, MD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

Adults over 40 with a history of smoking for more than 10 years and diagnosed COPD, currently needing mechanical ventilation due to acute respiratory failure. They must have been on the ventilator for less than 96 hours and have confirmed COPD by specific lung function tests.

Inclusion Criteria

I have been on a breathing machine for less than 96 hours.

You have a history of COPD shown by a specific breathing test.

I am on a breathing machine due to severe breathing problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive nebulized revefenacin or ipratropium while on invasive mechanical ventilation

7 days

Daily monitoring in ICU

Follow-up

Participants are monitored for safety and effectiveness after treatment

Hospital stay, expected to be less than 28 days

What Are the Treatments Tested in This Trial?

Interventions

• Ipratropium Bromide
• Revefenacin Inhalation Solution [Yupelri]

Trial Overview The trial is testing revefenacin inhalation solution against ipratropium bromide in patients with COPD who are receiving invasive mechanical ventilation. The goal is to see which treatment is safer and works better under these conditions.

How Is the Trial Designed?

Group I: Revefenacin Experimental Treatment 1 Intervention

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.

Group II: Ipratropium Active Control 1 Intervention

Nebulized ipratropium will be delivered via nebulizer Q6 hours.

Ipratropium Bromide is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Atrovent for:

• Chronic obstructive pulmonary disease (COPD)
• Bronchospasm

Approved in United States as Atrovent for:

• Chronic obstructive pulmonary disease (COPD)
• Bronchospasm

Approved in Canada as Combivent for:

• Chronic obstructive pulmonary disease (COPD)
• Bronchospasm

Approved in Japan as Ipravent for:

• Chronic obstructive pulmonary disease (COPD)
• Bronchospasm

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Theravance Biopharma

Industry Sponsor

Trials

74

Recruited

8,600+

Rick E. Winningham

Theravance Biopharma

Chief Executive Officer since 2014

Bachelor's degree in Economics from Southern Methodist University

Laurie Smaldone Alsup

Theravance Biopharma

Chief Medical Officer since 2018

MD from McGill University

Mylan Pharmaceuticals Inc

Industry Sponsor

Trials

166

Recruited

13,000+

Dr. Patrizia Cavazzoni

Mylan Pharmaceuticals Inc

Chief Medical Officer

MD from Harvard Medical School

Heather Bresch

Mylan Pharmaceuticals Inc

Chief Executive Officer since 2012

BA from West Virginia University

Published Research Related to This Trial

In a study involving 780 patients with COPD, both doses of inhaled formoterol (12 or 24 microg) were found to be significantly more effective than ipratropium bromide in improving lung function, as measured by forced expiratory volume in 1 second (FEV1) over 12 weeks.

Formoterol also led to significant improvements in patient symptoms and quality of life compared to placebo, while ipratropium did not show meaningful clinical benefits despite improving airflow obstruction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Dahl, R., Greefhorst, LA., Nowak, D., et al.[2022]

In a study of 20 patients with mild to moderate persistent asthma, nebulized Ipraterol demonstrated a rapid bronchodilation effect similar to Berodual, significantly increasing FEV1 within 5 minutes and maintaining this effect for up to 6 hours.

Ipraterol provided comparable improvements in pulmonary function to Berodual without significant systemic absorption leading to hypokalemia, indicating it is a safe and effective alternative for asthma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bronchodilator effect of Ipraterol on methacholine-induced bronchoconstriction in asthmatic patients. Maneechotesuwan, K., Suthamsmai, T., Ratanasaenglert, K., et al.[2013]

Revefenacin (YUPELRI™) is the first and only once-daily nebulized bronchodilator approved in the USA for treating chronic obstructive pulmonary disease (COPD), highlighting its unique position in COPD management.

The approval by the US Food and Drug Administration in November 2018 was based on positive results from three phase III trials, demonstrating its efficacy for maintenance treatment in COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Revefenacin: First Global Approval. Heo, YA.[2023]

The ipratropium bromide/albuterol Respimat inhaler (CVT-R) demonstrated significantly higher patient satisfaction compared to both the metered-dose inhaler (CVT-MDI) and the dual monotherapy inhalers (I + A) over a 48-week study involving 470 COPD patients.

While the time to first COPD exacerbation was slightly longer for CVT-R, it did not reach statistical significance, and the rates of adverse events were similar across all treatment groups, indicating that CVT-R is a safe and effective alternative with potential clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COPD patient satisfaction with ipratropium bromide/albuterol delivered via Respimat: a randomized, controlled study. Ferguson, GT., Ghafouri, M., Dai, L., et al.[2021]

In a 1-year study involving 456 patients with moderate-to-severe COPD, the new ipratropium bromide metered-dose inhaler (IB HFA) demonstrated similar efficacy and safety compared to the traditional chlorofluorocarbon (IB CFC) inhaler, with no significant differences in adverse events.

Both inhalers achieved therapeutic bronchodilatory responses in a high percentage of patients (76-81% for IB HFA and 72-84% for IB CFC), indicating that IB HFA is a viable alternative for long-term COPD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-Year Evaluation of the Safety and Efficacy of Ipratropium Bromide HFA and CFC Inhalation Aerosols in Patients with Chronic Obstructive Pulmonary Disease. Brazinsky, SA., Lapidus, RJ., Weiss, LA., et al.[2023]

In a study of 110 patients with COPD and respiratory failure, the combination of ipratropium bromide and non-invasive ventilation significantly improved blood gas indexes and pulmonary function compared to non-invasive ventilation alone.

Patients receiving the combination treatment also experienced better overall efficacy, improved quality of life, and fewer adverse reactions, highlighting the safety and effectiveness of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipratropium bromide and noninvasive ventilation treatment for COPD. Lin, S., Li, X., Xie, B., et al.[2022]

In a post hoc analysis of two 12-week phase 3 trials involving 812 patients with moderate to very severe COPD, once-daily nebulized revefenacin significantly improved patient-reported outcomes, including the St. George's Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT), compared to placebo.

The improvements in health status were more pronounced in women, with a greater proportion achieving clinically meaningful responses in SGRQ scores, indicating that revefenacin is an effective maintenance treatment for COPD, particularly in female patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvements in health status with revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist for chronic obstructive pulmonary disease. Donohue, JF., Ferguson, GT., Ohar, JA., et al.[2023]

In a 12-week study involving 1209 patients with moderate to severe COPD, the ipratropium bromide/albuterol Respimat inhaler showed comparable efficacy to the CFC-metered dose inhaler (MDI) for improving lung function, measured by forced expiratory volume in 1 second (FEV1).

The Respimat inhaler demonstrated superior efficacy compared to the mono-component ipratropium Respimat inhaler, while all treatments were well tolerated, indicating that the combination inhaler is both effective and safe for COPD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipratropium bromide/albuterol delivered via Respimat inhaler versus MDI. Zuwallack, R., De Salvo, MC., Kaelin, T., et al.[2015]

The combination therapy of albuterol and ipratropium bromide improves airflow in COPD patients more effectively than either medication alone, simplifying treatment and enhancing patient compliance.

However, newer and more potent medications have emerged that offer greater benefits than the albuterol-ipratropium combination, indicating a shift in preferred treatment options for stable COPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled albuterol/salbutamol and ipratropium bromide and their combination in the treatment of chronic obstructive pulmonary disease. Gordon, J., Panos, RJ.[2015]

Citations

1. yupelrihcp.com yupelrihcp.com/efficacy-and-safety/efficacy-data

Efficacy Data | YUPELRI® (revefenacin) inhalation solution Delivers a full 24 hours of lung function improvement in a single nebulized daily dose · Delivers consistent control † over 12 weeks for better breathing and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7052452/

Efficacy and safety of revefenacin for nebulization in ... Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse ...

3. aafp.org aafp.org/pubs/afp/issues/2020/0115/p121.html

Revefenacin (Yupelri) for the Treatment of Chronic ... Revefenacin improved FEV1 by at least 100 mL from baseline with effects lasting four hours or more; participants' mean number of albuterol puffs ...

4. investor.theravance.com investor.theravance.com/news-releases/news-release-details/theravance-announces-publication-yupelrir-revefenacin-area-under

News Release Details YUPELRI provides consistent and durable improvements in lung function, as compared with placebo, over a full 24-hours.

5. journal.copdfoundation.org journal.copdfoundation.org/jcopdf/id/1230/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

Phase III Trials of Revefenacin in COPD Patients Revefenacin is a novel, once-daily, lung-selective LAMA in late-stage clinical development for the treatment of patients with COPD.

6. yupelrihcp.com yupelrihcp.com/efficacy-and-safety

Efficacy & Safety - YUPELRI® (revefenacin) inhalation solution Indication. YUPELRI inhalation solution is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

7. yupelrihcp.com yupelrihcp.com/efficacy-and-safety/safety-profile

Safety Profile | YUPELRI® (revefenacin) inhalation solution YUPELRI inhalation solution is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/210598s000lbl.pdf

HIGHLIGHTS OF PRESCRIBING INFORMATION The revefenacin safety database included 2,285 subjects with COPD in two 12-week efficacy ... • YUPELRI is a prescription medicine used to treat chronic ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1094553918303067

Cardiovascular safety of revefenacin, a once-daily, lung ... Phase 3 clinical trials in patients with COPD have shown that revefenacin has an overall favorable safety and tolerability profile with limited systemic side ...