ARINA-1 for Bronchiolitis Obliterans Syndrome

Recruiting at 24 trial locations

Overseen By Will Anderson

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Renovion, Inc.

Must be taking: Azithromycin, Immunosuppressants

Must not be taking: mTOR inhibitors, Azathioprine

Disqualifiers: Heart failure, Kidney disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 48 weeks

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well ARINA-1, an inhaled medicine, can slow or stop the progression of bronchiolitis obliterans syndrome (BOS), a serious lung condition, in individuals who have undergone a double lung transplant. It evaluates the effectiveness of ARINA-1 when used alongside usual treatments compared to usual treatments alone. Individuals who had a double lung transplant more than a year ago and have experienced a 10-24% drop in lung function since the transplant may be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires participants to be on a stable maintenance regimen of azithromycin and a stable 3-agent immunosuppression regimen for more than 4 weeks before the screening. If you are currently using an mTOR inhibitor, azathioprine, or have recently changed certain medications, you may need to adjust your current medications to participate.

Is there any evidence suggesting that ARINA-1 is likely to be safe for humans?

Research has shown that ARINA-1, an inhaled treatment via nebulizer, was well-tolerated in past studies. Patients with lung conditions who used ARINA-1 experienced symptom improvement without major side effects. Although detailed safety data from earlier studies is not provided, the treatment's progression to a Phase 3 trial suggests it has demonstrated promise in terms of safety. Phase 3 trials typically involve more participants, indicating the treatment has already shown a reasonable level of safety in smaller groups. Additionally, the FDA has granted ARINA-1 Fast Track designation, often reflecting confidence in its safety and effectiveness for serious conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for bronchiolitis obliterans syndrome, which typically involve a combination of immunosuppressive drugs and azithromycin, ARINA-1 is unique because it incorporates inhaled antioxidants—ascorbic acid (vitamin C) and reduced glutathione. This novel approach aims to directly target oxidative stress and inflammation in the lungs, potentially reducing damage more effectively. Researchers are excited about ARINA-1 because its direct delivery method via nebulization may enhance its effectiveness and offer a new way to manage this challenging condition.

What evidence suggests that ARINA-1 could be an effective treatment for bronchiolitis obliterans syndrome?

In this trial, participants will receive either ARINA-1 plus standard care or standard care alone. Research has shown that ARINA-1, when combined with standard care, can greatly improve symptoms for patients. In studies on patients with a similar lung condition, ARINA-1 significantly enhanced their quality of life, exceeding the levels needed for noticeable symptom relief. ARINA-1 helps control the immune system to prevent further lung damage. Early results suggest it may slow the progression of bronchiolitis obliterans syndrome (BOS) in lung transplant patients. This makes ARINA-1 a promising option for effectively managing BOS. ^{1 2 3 4 5}

Who Is on the Research Team?

Tim Whelan, MD

Principal Investigator

Medical University of South Carolina

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 who've had a bilateral lung transplant over a year ago and are experiencing a decline in lung function. They must be on stable medications, including azithromycin and immunosuppressants, willing to follow the study schedule, and women of childbearing age must use birth control. Exclusions include recent use of certain therapies or supplements, unresolved lung damage, severe heart or kidney disease, participation in other trials recently, and specific treatments within set timeframes.

Inclusion Criteria

I had a lung transplant more than a year ago.

I agree to use birth control during the study.

I am able to understand and agree to the study's procedures and risks.

Exclusion Criteria

I was diagnosed with ARAD less than 6 weeks ago.

I have severe heart failure or coronary artery disease.

I started taking supplements with vitamin C, glutathione, or N-acetylcysteine less than 90 days ago.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ARINA-1 plus Standard of Care or Standard of Care alone

48 weeks

Clinic visits at randomization (day 1), weeks 4, 12, 18, 24, 32, 40, and 48; telehealth visit on day 2; phone calls during weeks 5, 8, 36, and 44

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ARINA-1

Trial Overview The trial tests ARINA-1 combined with standard care against standard care alone to see if it can prevent worsening of bronchiolitis obliterans syndrome (BOS) after lung transplants. It also looks at whether ARINA-1 helps maintain quality of life by reducing the need for increased immunosuppression therapy.

How Is the Trial Designed?

Group I: Standard of care only Experimental Treatment 1 Intervention

Standard 3-therapy immunosuppression regimen and azithromycin

Group II: ARINA-1 plus standard of care Experimental Treatment 1 Intervention

ARINA-1 (88 mg/mL ascorbic acid, ASC; 150 mg/mL reduced glutathione, GSH); fixed dose, 4 mL solution inhaled twice daily via nebulization plus standard 3-therapy immunosuppression regimen and azithromycin

ARINA-1 is already approved in United States for the following indications:

Approved in United States as ARINA-1 for:

• Prevention of bronchiolitis obliterans syndrome (BOS) progression in bilateral lung transplant patients (Fast Track designation)

Who Is Running the Clinical Trial?

Renovion, Inc.

Lead Sponsor

Trials

3

Recruited

140+

Published Research Related to This Trial

Rhinovirus C15 (RV-C15) significantly reduces the effectiveness of bronchodilators like formoterol in relaxing airway muscles, which is crucial for asthma treatment, as shown in human lung models and airway smooth muscle cells.

The mechanism by which RV-C15 impairs bronchodilation appears to be independent of viral replication, indicating that soluble factors from infected airway epithelial cells may disrupt the function of β2-adrenergic receptors, warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rhinovirus C15 Attenuates Relaxation and cAMP Production in Human Airways and Smooth Muscle. Gebski, EB., Parikh, V., Lam, H., et al.[2023]

In a pilot study comparing bronchial epithelial cells from cystic fibrosis (CF) patients and healthy individuals, CF cells showed a reduced interferon (IFN) response when infected with major group rhinoviruses, suggesting a potential vulnerability in CF patients during these infections.

In contrast, infection with minor group rhinoviruses led to a significantly enhanced IFN response in CF cells compared to healthy cells, indicating that the immune response may vary depending on the type of rhinovirus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection. Schögler, A., Stokes, AB., Casaulta, C., et al.[2022]

Intrauterine growth retardation (IUGR) in infants is linked to increased expression of vannin-1, which activates the PI3K/Akt/NFκB signaling pathway, contributing to asthma development later in childhood.

The study found that the interaction between PGC1α and HNF4α promotes methylation of the Vnn1 gene, leading to elevated vannin-1 levels, which in turn causes inflammation and reactive oxygen species production in IUGR asthmatic mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methylated Vnn1 at promoter regions induces asthma occurrence via the PI3K/Akt/NFκB-mediated inflammation in IUGR mice. Xing, Y., Wei, H., Xiao, X., et al.[2023]

In children with asthma, the TLR7/8 agonist R848 was found to increase the expression of the IFN-λ receptor while decreasing the expression of the IFN-α receptor, indicating a shift in immune response that could be beneficial for antiviral defenses.

Rhinovirus infection and R848 treatment together suppressed the IFN-α receptor in T-cells, suggesting that targeting these pathways may offer new strategies for enhancing antiviral immunity in pediatric asthma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma. Krug, J., Kiefer, A., Koelle, J., et al.[2022]

RV568, a new anti-inflammatory drug, showed strong anti-inflammatory effects in cell and animal models related to COPD, often outperforming traditional corticosteroids.

In a 14-day trial with COPD patients, inhaled RV568 improved lung function and reduced harmful substances in sputum, while being well-tolerated with similar adverse events to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation. Charron, CE., Russell, P., Ito, K., et al.[2021]

In a study involving 934 patients with moderate-to-severe COPD, QVA149 was found to be non-inferior to the combination of tiotropium and formoterol in improving health-related quality of life, as measured by the St George's Respiratory Questionnaire-COPD.

QVA149 also demonstrated significant improvements in lung function, with greater increases in pre-dose FEV1 and forced vital capacity compared to the other treatment, while the safety profile was similar for both medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study. Buhl, R., Gessner, C., Schuermann, W., et al.[2022]

In a study involving 47 patients with chronic obstructive pulmonary disease (COPD), the combination of GSK233705 with salmeterol provided significantly greater bronchodilation compared to salmeterol or tiotropium alone, with increases in forced expiratory volume in 1 second (FEV1) of 215 mL and 203 mL, respectively.

The treatment was well tolerated, with similar rates of adverse events across all groups, indicating that GSK233705 is a safe addition to existing COPD therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of dual therapy with GSK233705 and salmeterol versus monotherapy with salmeterol, tiotropium, or placebo in a crossover pilot study in partially reversible COPD patients. Beier, J., van Noord, J., Deans, A., et al.[2021]

Navafenterol, a new dual-action medication for chronic obstructive pulmonary disease and asthma, was found to be well-tolerated in two phase I studies involving 24 healthy volunteers each, with no serious adverse events reported.

The studies showed a dose-dependent increase in heart rate but no significant safety concerns, indicating that navafenterol is a promising candidate for further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies. Balaguer, V., Albayaty, M., Jimenez, E., et al.[2022]

In asthmatic patients, rhinovirus infection leads to a delayed and deficient production of type I interferons in bronchoalveolar lavage (BAL) cells, which may correlate with more severe asthma symptoms.

Despite the deficiency in interferon production, the expression of key molecules involved in the interferon induction pathway remains intact in BAL cells, indicating that the defect is not due to a lack of these signaling components.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rhinovirus 16-induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients. Sykes, A., Edwards, MR., Macintyre, J., et al.[2021]

QVA149, a dual bronchodilator for COPD, showed a good safety profile over 52 weeks, with similar rates of adverse events compared to placebo and most events being mild to moderate.

The treatment provided rapid and sustained bronchodilation, significantly improving lung function in patients with moderate-to-severe COPD, with a lower discontinuation rate in the QVA149 group compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study. Dahl, R., Chapman, KR., Rudolf, M., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05654922

Study to Evaluate ARINA-1 in the Prevention of ... The goal of this Phase 3 clinical trial is to compare ARINA-1 (a nebulized immunomodulatory agent) plus Standard of Care vs Standard of Care alone.

2. renovion.com renovion.com/post/renovion-announces-positive-top-line-results-from-phase-2-climb-study-of-arina-1-rvn-301-in-patien

Renovion Announces Positive Top-Line Results from ... Elevate QOL in NCFBE patients with ARINA-1 treatment. Robust data show significant symptom improvement surpassing clinical thresholds.

3. trialx.com trialx.com/clinical-trials/listings/273387/study-to-evaluate-arina-1-in-the-prevention-of-bronchiolitis-obliterans-progression-in-participants-with-bilateral-lung-transplant/

Study to Evaluate ARINA-1 in the Prevention of ... Evaluate the effectiveness of ARINA-1 in preventing bronchiolitis obliterans syndrome (BOS) progression in participants with a bilateral lung ...

4. clinicaltrialsarena.com clinicaltrialsarena.com/news/renovion-enrols-patient-lung-transplant/

Renovion enrols first patient in ARINA-1 lung transplant trial Renovion has enrolled the first patient in a Phase III trial of ARINA-1 to prevent bronchiolitis obliterans syndrome.

5. renovion.com renovion.com/post/renovion-receives-fda-fast-track-designation-for-arina-1-for-the-prevention-of-bos-progression-in-lt

Renovion Receives FDA Fast Track Designation for ... The Fast Track designation accelerates the FDA regulatory path for ARINA-1 for the prevention of bronchiolitis obliterans syndrome (BOS) ...