INSPO-BOS: Inhaled Sirolimus in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome.

Sponsor

Steven Hays, MD (Other)

Overall Status

Recruiting

CT.gov ID

NCT06018766

Collaborator

AI Therapeutics, Inc. (Industry)

Enrollment

Location

Arms

27.5

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this clinical trial is to learn about the safety and effectiveness of inhaled sirolimus in patients who have developed bronchiolitis obliterans syndrome (BOS), a form of chronic rejection, after lung transplantation.

The main questions it aims to answer are:

Is inhaled sirolimus safe in these patients?
Is inhaled sirolimus effective in slowing BOS progression?

Participants will:

Be randomly assigned to inhale either sirolimus or placebo (a look-alike substance that contains no active drug) daily for 48 weeks
Attend 10 study visits (mixture of in-person and telehealth) over the 48 week period
Undergo pulmonary function testing, bronchoscopy, lab testing, and physical examination
Submit weekly home spirometry monitoring

Researchers will compare participants assigned to inhaled sirolimus versus placebo to see if sirolimus is safely tolerated and to assess the effectiveness of inhaled sirolimus on slowing BOS progression.

Condition or Disease	Intervention/Treatment	Phase
Bronchiolitis Obliterans Syndrome Due to and After Lung Transplantation (Disorder) Chronic Lung Allograft Dysfunction	Drug: Sirolimus Drug: Placebo	Phase 2

Detailed Description

Chronic rejection, commonly denoted as bronchiolitis obliterans (BO), obliterative bronchiolitis (OB), or bronchiolitis obliterans syndrome (BOS), is the leading cause of death beyond the first year after lung transplantation. Whereas the development of BOS is rare within the first year after lung transplantation, annual increments of approximately 10% are recorded in subsequent years, resulting in a cumulative incidence range of 40-50% within the first five years and 70-80% within 10 years of transplantation.

No current effective treatment for BOS exists. BOS represents the leading cause of morbidity and mortality after lung transplantation, limiting 5-year survival to well below other solid organ transplants. BOS is characterized by an inexorable lung function decline despite currently available immunomodulatory treatments. Sirolimus has been shown to block T-cell proliferative effects induced by cytokines, alloantigens, and mitogens in a dose-dependent manner(4, 5). Oral sirolimus has been shown in small studies to have a beneficial impact on rapidly progressive BOS; however, administration in this patient population has been challenged by a high degree of intolerance with the side effects. The development of inhaled sirolimus for lung transplant related BOS, conceptually a T-cell driven process against transplanted alloantigen, is based on the principal hypothesis that administration of a sirolimus dose to the rejecting lung allograft(s) by inhalation will result in improved efficacy by depositing higher drug concentrations directly within the allograft by inhalation than would be achieved by oral administration due to systemic toxicities associated with systemic sirolimus. Because of known reduced systemic bioavailability of inhaled sirolimus compared to oral sirolimus dosing, amelioration of the substantial adverse event profile compared to systemic drug is expected. Inhaled sirolimus is also expected to reduce serious complication risks by obviating requirements for maintenance and augmented immune drugs used to treat BOS.

The primary objective is to assess the clinical efficacy of inhaled sirolimus in lung transplant recipients with bronchiolitis obliterans syndrome as measured by progression free survival and change in forced expiratory volume in one second (FEV1) over a 48-week period. Another primary objective is to assess the safety and tolerability of inhaled sirolimus in lung transplant recipients with bronchiolitis obliterans syndrome.

Secondary objectives are:

To determine the impact of inhaled sirolimus on genetic markers of bronchiolitis obliterans syndrome and activation of the mammalian target of rapamycin (mTOR) pathway by measuring chronic lung allograft dysfunction signature gene profiling and mTOR pathway activation in bronchoalveolar lavage fluid
To determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. % ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups.
To determine the levels of sirolimus in the blood and bronchoalveolar lavage (BAL) fluid, the BAL as a surrogate for levels in the lung.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, Placebo-controlled Phase 2 Study to Demonstrate the Safety and Efficacy of the Addition of Inhaled Sirolimus to Standard Immunosuppression Therapy for Chronic Lung Allograft Dysfunction (BOS).

Actual Study Start Date :

Aug 17, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sirolimus 100 ug sirolimus capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.	Drug: Sirolimus Inhaled sirolimus administered via dry powder inhaler Other Names: LAM-001
Placebo Comparator: Placebo Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.	Drug: Placebo Inhaled lactose administered via dry powder inhaler

Arm

Intervention/Treatment

Experimental: Sirolimus

100 ug sirolimus capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.

Drug: Sirolimus

Inhaled sirolimus administered via dry powder inhaler

Other Names:

LAM-001

Placebo Comparator: Placebo

Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.

Drug: Placebo

Inhaled lactose administered via dry powder inhaler

Outcome Measures

Primary Outcome Measures

Time to Progression Free Survival (PFS), Level 1 [52 weeks]
Time to Progression Free Survival (PFS) Level 1, defined as the earliest of the following: Absolute decrease in FEV1 from baseline of > 10% Death from respiratory failure

Secondary Outcome Measures

Change in FEV1 [48 weeks]
Change in FEV1 from baseline
Change in forced expiratory volume in one second/forced vital capacity (FEV1/FVC) [48 weeks]
Change in FEV1/FVC from baseline

Other Outcome Measures

Time to Progression Free Survival (PFS), Level 2 [52 weeks]
Time to Progression Free Survival (PFS) Level 2, defined as the earliest of the following: Absolute decrease in the FEV1 from baseline of >20% Death from respiratory failure
Change in Quality of Life [48 weeks]
Change in Quality of Life as measured by St. George's Respiratory Questionnaire -COPD (SGRQ-C). The range of scores is 0-100, with the higher scores representing more limitation in quality of life.
Change in six-minute walk distance (6MWD) [48 weeks]
Change in 6MWD from baseline
Donor-derived cell-free DNA: Ongoing lung injury [52 weeks]
Determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. %ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups.
% Reduced donor-derived cell-free DNA [48 weeks]
Determine whether the inhaled sirolimus group will have a salutary effect on allograft injury in terms of reduced %ddcfDNA compared to standard therapy by measuring %ddcfDNA values at determined time points and comparing values between the inhaled sirolimus and placebo groups.
CLAD signature gene profiling [3 months post randomization]
Utilizing the endobronchial brush, we will quantify a metagene, or normalized sum of gene expression, from our previously published airway inflammation gene set, as described in our publication (PMID: 32885581). The metagene expression will be compared between randomized groups.
mTOR pathway activation [3 months post randomization]
Utilizing the bronchioalveolar lavage fluid, we will quantify pS6S235/235 in lymphocytes using flow cytometry, to quantify mTORC1 activity, as previously published (PMID: 36066491). We will compare pS6S235/235 between randomized groups.
Serum sirolimus levels [Assessed pre-inhalation at in-person study visits over 48 weeks and post-inhalation at 3 months post randomization]
Measured serum sirolimus levels
Tolerability of inhaled therapy [Baseline Study Visit (Week 0)]
Measurement of FEV1 pre-inhalation and 4 hours following study drug inhalation.
Adverse events [52 weeks]
Incidence and severity of treatment emergent adverse events (AE) and serious adverse events (SAE).
Adverse events of special interest [52 weeks]
Incidence of local and systemic adverse events of special interest (AESI) including oral or dental lesions, pharyngeal soreness, cough, and dyspnea associated with inhalation will be recorded using a specific case report form and standard examination
White blood cell (WBC) count [52 weeks]
WBC will be monitored and compared between randomized groups
Hemoglobin [52 weeks]
Hemoglobin will be monitored and compared between randomized groups
Platelet count [52 weeks]
Platelet count will be monitored and compared between randomized groups
Aspartate Aminotransferase (AST) [52 weeks]
AST will be monitored and compared between randomized groups
Alanine Aminotransferase (ALT) [52 weeks]
ALT will be monitored and compared between randomized groups
Alkaline Phosphatase [52 weeks]
Alkaline Phosphatase will be monitored and compared between randomized groups
Total Bilirubin [52 weeks]
Total Bilirubin will be monitored and compared between randomized groups
Triglycerides [52 weeks]
Triglycerides will be monitored and compared between randomized groups
Creatinine [52 weeks]
Creatinine will be monitored and compared between randomized groups
Urine protein/creatinine ratio [52 weeks]
Urine protein/creatinine ratio will be monitored and compared between randomized groups
Mortality [52 weeks]
Overall mortality in each group will be compared
Infections [52 weeks]
Incidence of infections including pneumonia, bronchitis, viral infections (including COVID-19) in each group will be compared
Malignancies [52 weeks]
Incidence of malignancies in each group will be compared
Wound healing complications [52 weeks]
Wound healing complications in each group will be compared
Hospitalization rates [52 weeks]
Hospitalization rates in each group will be compared
Interstitial pneumonitis [52 weeks]
Incidence of interstitial pneumonitis in each group will be compared

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age > 18 years old
Recipient of a double pulmonary allograft at least 12 months before study entry
Subjects with clinically diagnosed CLAD-BOS phenotype (all 3 required)
BOS defined as screening FEV1 between 85-51% of the baseline as defined by the 2 highest FEV1 measures at least 3 weeks apart.
Diagnosis within 12 months of screening visit.
FEV1 decline is persistent as defined by decline sustained for > 30 days.
Currently receiving Standard Immunosuppression. This is defined as a combination of 3 medications including Prednisone, Mycophenolate or Azathioprine, and Tacrolimus or Cyclosporine. The dosing should be stable for 4 weeks prior to screening.
Absence of oral sirolimus or everolimus treatment for at least 4 weeks prior to screening based on the half-life and resolution of the tissue effects
Stable enough to enable routine post-transplant bronchoscopy with BAL and biopsy when indicated
Capable of understanding the purposes and risks of the study
Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.
Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry
Women of childbearing potential if sexually active must agree to using highly effective contraception during study and for 90 days after discontinuation of study treatment
Women of childbearing potential must refrain from breast feeding or donating eggs for the duration of the study and for 90 days after the last dose of study treatment
Male participants must agree to use a condom during sexual contact with a female of childbearing potential while participating in the study and for 90 days following discontinuation of investigational product use
Male participants must refrain from donating sperm for the duration of the study and for 90 days after the last dose of study treatment

Exclusion Criteria:

Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
Patients with re-transplantation or currently listed for re-transplantation
Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see Protocol Specific Definition), etc.
Patients with acute antibody-mediated rejection at Screening. In this context, clinically stable patients (as judged by the Investigator) with detectable donor-specific antibodies (DSA) levels at the Screening Visit are eligible for the study
Active acute bacterial, viral, or fungal infection that has not successfully resolved in at least 4 weeks prior to the Screening Visit. Patients with chronic infection or colonization who are clinically stable as per judgement of the investigator are eligible.
Mechanical ventilation within 12 weeks prior to the randomization
Patient has baseline resting oxygen saturation of < 89% on room air or use of supplemental oxygen at rest at screening
Evidence of functional airway stenosis (i.e., bronchomalacia/ tracheomalacia, airway stents, or airways requiring balloon dilatations to maintain patency) with onset after the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit
Known hypersensitivity to sirolimus or everolimus
Currently enrolled in another investigational trial for obstructive chronic lung allograft dysfunction (BOS)
Patients with chronic renal failure, defined as serum creatinine > 2.5 mg/dL at screening, or requiring chronic dialysis
Patients with liver disease and serum bilirubin > 3-fold upper limit of normal range or transaminases > 2.5 upper limit of normal range
Patients with active malignancy within the previous 2 years, including post-transplant lymphoproliferative disorder, except for treated, localized basal and squamous cell carcinomas
Any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months. This does not include minor surgical procedures for localized skin cancer.
History of severe allergic reaction to lactose (patients with lactose intolerance are eligible)
Patients with uncontrolled hypertension