Lung Transplantation Clinical Trial
— INSPO-BOSOfficial title:
A Randomized, Placebo-controlled Phase 2 Study to Demonstrate the Safety and Efficacy of the Addition of LAM-001 to Standard Immunosuppression Therapy for Chronic Lung Allograft Dysfunction (BOS).
The goal of this clinical trial is to learn about the safety and effectiveness of LAM-001 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 LAM-001 safe in these patients? - Is LAM-001 effective in slowing BOS progression? Participants will: - Be randomly assigned to inhale either LAM-001 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 LAM-001 versus placebo to see if LAM-001 is safely tolerated and to assess the effectiveness of LAM-001 on slowing BOS progression.
Status | Recruiting |
Enrollment | 30 |
Est. completion date | December 2025 |
Est. primary completion date | December 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
United States | University of California, San Francisco | San Francisco | California |
Lead Sponsor | Collaborator |
---|---|
Steven Hays, MD | OrphAI Therapeutics |
United States,
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Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Change in Quality of Life | 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. | 48 weeks | |
Other | Change in six-minute walk distance (6MWD) | Change in 6MWD from baseline | 48 weeks | |
Other | Donor-derived cell-free DNA: Ongoing lung injury | 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. | 52 weeks | |
Other | % Reduced donor-derived cell-free DNA | Determine whether the LAM-001 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 LAM-001 and placebo groups. | 48 weeks | |
Other | CLAD signature gene profiling | 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. | 3 months post randomization | |
Other | mTOR pathway activation | 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. | 3 months post randomization | |
Other | Blood sirolimus levels | Measured blood sirolimus levels | Assessed pre-inhalation at in-person study visits over 48 weeks and post-inhalation at 3 months post randomization | |
Other | Bronchioalveolar lavage fluid sirolimus levels | Measured bronchioalveolar lavage fluid sirolimus levels | 12 weeks | |
Other | Airway Hypersensitivity to Treatment | Measurement of FEV1 pre-inhalation and 4 hours following study drug inhalation to determine whether a subject has airway hyperreactivity to the study drug. | Baseline Study Visit (Week 0) | |
Other | Adverse events | Incidence and severity of treatment emergent adverse events (AE) and serious adverse events (SAE). | 52 weeks | |
Primary | Time to Progression Free Survival (PFS), Level 1 | 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 |
52 weeks | |
Secondary | Change in FEV1 | Change in FEV1 from baseline | 48 weeks | |
Secondary | Change in forced expiratory volume in one second/forced vital capacity (FEV1/FVC) | Change in FEV1/FVC from baseline | 48 weeks | |
Secondary | Time to Progression Free Survival (PFS), Level 2 | 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 |
52 weeks |
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