Study to Evaluate ARINA-1 in the Prevention of Bronchiolitis Obliterans Progression in Participants With Bilateral Lung Transplant

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare ARINA-1 plus Standard of Care vs Standard of Care alone. The main question it aims to answer are: Evaluate the effectiveness of ARINA-1 in preventing bronchiolitis obliterans syndrome (BOS) progression in participants with a bilateral lung transplant To evaluate the effectiveness of ARINA-1 on improving quality of life decline and preventing or delaying the use of augmented immunosuppression in participants with pre-BOS relative to SOC. Participants will have clinic visits at screening, randomization (day 1) and weeks 4, 12, 18, and 24. After week 24, participants will have clinic visits at weeks 32, 40, and 48. Participants will also have a telehealth visit on day 2 and phone calls to assess adverse events (AEs), serious adverse events (SAEs), and review patient education will occur during weeks 5, 8, 36, and 44.

Official Title
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A Phase 3, Open-label, Randomized, Standard of Care-controlled, Parallel Study Arm Study to Demonstrate Efficacy and Safety of ARINA-1 in the Prevention of Bronchiolitis Obliterans Syndrome (BOS) Progression in Participants With a Bilateral Lung Transplant

Conditions
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Pre-Bronchiolitis Obliterans Syndrome

Intervention / Treatment
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* Drug: ARINA-1
* Other: Standard of care only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bilateral lung transplant >12 months from the time of Visit 1 / Randomization Age 18-75 years old at the time of consent Routinely followed at enrolling site Willing and able to comply with visit schedule and at-home requirements 10-24% decrease in FEV1 from the post-transplant baseline within the last 12 months. Capable of giving informed consent On a stable maintenance regimen of azithromycin for >4 weeks prior to the Screening Visit On a stable 3-agent immunosuppression regimen that includes a steroid, a calcineurin inhibitor (CNI), and cell cycle inhibitor (e.g., mycophenolate, azathioprine) >4 weeks prior to Screening If a woman of childbearing potential (WOCBP), must agree to use a reliable method of birth control for the entire duration of the study. Exclusion Criteria: Positive urine pregnancy test at screening and baseline visit Diagnosis of active congestive heart failure or symptomatic coronary artery disease > grade 3 based on the New York Heart Association Functional Classification (NYHA) criteria Restrictive allograft syndrome (RAS) defined by radiographic interstitial or alveolar opacities on chest X-ray or CT scan that are consistent with RAS Have advanced BOS, defined by >24% decrease in FEV1 in post-transplant baseline A diagnosis of probable antibody-mediated rejection (AMR) <12 months prior to the baseline visit Donor-specific antibodies (DSA) identified <6 months prior to the baseline visit. *The presence of DSA >6 months from the baseline visit is acceptable for enrollment into the study. Unresolved diffuse alveolar damage Receiving mechanical ventilation Chronic kidney disease stage IV or higher, including on dialysis Initiating a new maintenance therapy or changing immunosuppression maintenance therapy (e.g., changing tacrolimus to cyclosporine) <14 days prior to the baseline visit. Currently using an mTOR inhibitor or azathioprine Initiating or changing antibiotic (including azithromycin), antiviral, or antifungal therapy <14 days prior to the baseline visit. Use of alemtuzumab <6 months prior to the baseline visit Use of anti-thymocyte therapies (e.g., anti-thymocyte globulin) or photopheresis <90 days prior to the Screening Visit. Prior use of Trikafta (elexacaftor, ivacaftor, and tezacaftor is allowed as long as the participant has been on stable dose for >90 days prior to the Screening Visit. Initiating a multivitamin or other supplement (inhaled, oral, or IV) containing vitamin C, glutathione, or N-acetylcysteine <90 days prior to the baseline visit Significant unstable comorbidities, in the opinion of the site investigator Allery or previous adverse reaction to azithromycin A diagnosis of dynamic collapse / tracheobrochomalacia <90 days of the baseline visit. Subjects currently participating in, or who have participated in an interventional (drug or device) clinical study <30 days of the baseline visit. Have been diagnosed with ARAD within 6 weeks of the Screening Visit. Have used belatacept <6 months prior to Clinic Visit 1 Have had bronchial stents or cryotherapy within 12 months of the Screening Visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARINA-1 plus standard of care<br>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 | Drug: ARINA-1<br>* ARINA-1 (88 mg/mL ascorbic acid, ASC; 150 mg/mL reduced glutathione, GSH)<br>|
| Other: Standard of care only<br>Standard 3-therapy immunosuppression regimen and azithromycin | Other: Standard of care only<br>* Standard 3-therapy immunosuppression regimen and azithromycin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from baseline in FEV1 (%ΔFEV1) | Week 24 (mL) - Baseline (mL) = ΔFEV1 (mL) ΔFEV1 (mL) / Baseline (mL) x 100 = %ΔFEV1 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from baseline of Forced Expiratory Volume in one second (FEV1) | Week 48 (mL) - Baseline (mL) = ΔFEV1 (mL) ΔFEV1 (mL) / Baseline (mL) x 100 = %ΔFEV1 | 48 weeks | 
| Percentage change from baseline of Forced Vital Capacity (FVC) |  | 24 weeks | 
| Percentage change from baseline of FVC |  | 48 weeks | 
| Percentage change from baseline of FEF25-75% |  | 24 weeks | 
| Percentage change from baseline of FEF25-75% |  | 48 weeks | 
| Number of participants in each arm with augmented immunosuppression | number | 24 weeks | 
| Number of participants in each arm with augmented immunosuppression |  | 48 weeks | 
| Time to initiation of augmented immunosuppression | Length of time to when participant requires a change in their immunosuppression regimen | over the duration of the 48 week trial | 
| Change from baseline in Saint George's Respiratory Questionnaire total score | quality of life questionnaire, total score of 0 to 100, higher score = more limitations | 24 weeks | 
| Change from baseline in Saint George's Respiratory Questionnaire total score | quality of life questionnaire, total score of 0 to 100, higher score = more limitations | 48 weeks |