Nalbuphine ER for Chronic Cough

(RIVER Trial)

No longer recruiting at 15 trial locations

Overseen By Connie Crum, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Trevi Therapeutics

Must not be taking: Opiates, Benzodiazepines, MAOIs, others

Disqualifiers: Sleep apnea, COPD, Asthma, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests Nalbuphine ER (an extended-release medication) to determine if it can reduce the number of daily coughs in people with chronic cough unresponsive to other treatments. Participants will either begin with Nalbuphine ER and then switch to a placebo (a pill with no medicine) or do the reverse. The study aims to assess the medication's effectiveness and safety. Suitable candidates have experienced a stubborn chronic cough for at least a year and do not have major lung issues like COPD or uncontrolled asthma. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to early findings.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot use opiates, benzodiazepines, MAOIs, pregabalin, gabapentin, thalidomide, ACE inhibitors, or medications with a known risk of Torsade de Pointes within specified timeframes before the trial starts.

Is there any evidence suggesting that Nalbuphine ER is likely to be safe for humans?

Research has shown that Nalbuphine ER has been tested for safety in people with chronic cough. In a recent study involving patients with idiopathic pulmonary fibrosis, Nalbuphine ER reduced cough frequency. The treatment was well-tolerated, causing no significant side effects, and appears safe. Although larger studies are needed, early safety results are encouraging. As this trial is in a mid-stage, some evidence of safety exists, but further research will provide clearer details. For those considering joining a trial for Nalbuphine ER, this information offers insight into its current safety profile. ^{1 2 3 4 5}

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

Nalbuphine ER is unique because it targets chronic cough differently from standard treatments like gabapentin or codeine-based medications. Most current options work by suppressing the cough reflex in the brain, but Nalbuphine ER acts as an opioid receptor modulator, potentially offering relief with fewer side effects commonly associated with traditional opioids. Researchers are excited about its extended-release formula, which could provide longer-lasting relief and improve patient adherence compared to medications that require frequent dosing.

What evidence suggests that Nalbuphine ER might be an effective treatment for chronic cough?

In this trial, participants will receive either Nalbuphine ER or a placebo during different treatment periods. Studies have shown that Nalbuphine ER can significantly reduce cough frequency. In a trial involving individuals with idiopathic pulmonary fibrosis, participants experienced a noticeable drop in coughing episodes. The RIVER trial also found that Nalbuphine ER effectively reduced cough frequency in individuals with refractory chronic cough, a persistent cough unresponsive to standard treatments. These findings suggest Nalbuphine ER might be a promising option for managing chronic cough. Overall, research indicates Nalbuphine ER's potential as an effective treatment for reducing cough symptoms. ^{1 2 5 6 7}

Who Is on the Research Team?

Chief Development Officer

Principal Investigator

Trevi Therapeutics

Are You a Good Fit for This Trial?

This trial is for people who have had a persistent cough that doesn't respond to treatment (refractory chronic cough) for at least one year. They should not have any significant chest abnormalities on recent imaging tests.

Inclusion Criteria

My recent chest scans show no major issues related to kidney cancer.

I have had a chronic cough for over a year that doesn’t respond to treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Period 1

Participants receive NAL ER at escalating doses or placebo

4 weeks

Weekly visits (in-person)

Treatment Period 2

Participants receive placebo or NAL ER at escalating doses

4 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nalbuphine ER
• Placebo

Trial Overview The study is testing Nalbuphine ER, a medication, against a placebo in two 21-day periods with a break in between. Participants will receive either the medication or placebo first and then switch to the other after the break.

How Is the Trial Designed?

Group I: First Placebo then NAL ER Experimental Treatment 2 Interventions

Participants will receive placebo matched to NAL ER in Treatment Period 1, followed by NAL ER at escalating doses (27 mg QD to BID, 54 mg BID, and 108 mg BID) in Treatment Period 2.

Group II: First NAL ER, then Placebo Experimental Treatment 2 Interventions

Participants will receive NAL ER at escalating doses (27 mg QD to BID, 54 mg BID, and 108 mg BID) in Treatment Period 1, followed by placebo matched to NAL ER in Treatment Period 2.

Nalbuphine ER is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Nubain for:

• Moderate to severe pain
• Preoperative and postoperative analgesia
• Obstetrical analgesia during labor and delivery

Approved in European Union as Nalbuphine for:

• Moderate to severe pain
• Preoperative and postoperative analgesia
• Obstetrical analgesia during labor and delivery

Approved in Canada as Nalbuphine for:

• Moderate to severe pain
• Preoperative and postoperative analgesia
• Obstetrical analgesia during labor and delivery

Who Is Running the Clinical Trial?

Trevi Therapeutics

Lead Sponsor

Trials

11

Recruited

1,400+

Citations

1. ir.trevitherapeutics.com ir.trevitherapeutics.com/2025-06-02-Trevi-Therapeutics-Announces-Positive-Topline-Results-from-the-Phase-2b-CORAL-Trial-of-Haduvio-in-Patients-with-Idiopathic-Pulmonary-Fibrosis-Chronic-Cough

Trevi Therapeutics Announces Positive Topline Results ... The primary endpoint in the CORAL trial was achieved, demonstrating statistically significant reductions in 24-hour cough frequency across all dose groups at ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04030026

NCT04030026 | A Study of Nalbuphine (Extended Release ... To evaluate the safety and tolerability of nalbuphine ER tablets in the study population and to evaluate the effect of NAL ER tablets on the mean daytime ...

3. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2300083

Nalbuphine Tablets for Cough in Patients with Idiopathic ... In this short-term crossover trial, NAL ER reduced cough in individuals with IPF. Larger and longer trials are needed to assess the impact on cough versus drug ...

4. ir.trevitherapeutics.com ir.trevitherapeutics.com/2025-09-18-Trevi-Therapeutics-Announces-Two-Posters-from-the-Phase-2a-RIVER-Trial-Data-Will-be-Featured-at-the-European-Respiratory-Society-ERS-Congress-2025

Sep 18, 2025 Late Breaking Abstract - Efficacy and safety of nalbuphine extended-release in refractory chronic cough: results from the phase 2a RIVER trial

5. filecache.investorroom.com filecache.investorroom.com/mr5ir_trevi_ir/181/031025%20-%20RIVER%20TLD%20Presentation%20%28FINAL%29.pdf

Refractory Chronic Cough Improvement Via NAL ER (RIVER ... Primary efficacy analysis conducted on log-transformed cough frequency data. NAL ER = Nalbuphine extended-release tablets. NAL ER is an ...

6. trevitherapeutics.com trevitherapeutics.com/publications/

Posters & Publications Nalbuphine extended release treatment achieved rapid and sustained reduction in reported cough frequency in patients with idiopathic pulmonary fibrosis.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05964335

Cough Reduction in IPF With Nalbuphine ER The main purpose of the study is to evaluate the effect of NAL ER on 24-hour cough frequency using objective digital cough monitoring and to assess safety and ...