An Open Label Trial Evaluating Tacrolimus Inhalation Powder in Adult Lung Transplant Recipients

Study Overview
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Brief Summary
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This is an open label, multicenter, safety and PK study comparing safety, efficacy, and pharmacokinetic (PK) levels of Tacrolimus Inhalation Powder in lung transplant patients that require reduced tacrolimus blood levels due to kidney toxicity. Part A of the study will consist of a 12 week safety, efficacy, and PK study. Part B of the study will be an optional safety extension following successful completion of the 12 week safety, efficacy, and PK study. Patients would have the option to continue Tacrolimus Inhalation Powder for up to 1 year, with a possibility to extend to 2 years depending on the results from Part A.

Detailed Description
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This is an open label, single-arm study that will evaluate the safety and PK of Tacrolimus Inhalation Powder in lung transplant patients who require reduced blood levels of tacrolimus due to kidney toxicity. Tacrolimus Inhalation Powder is being developed as an alternative to oral tacrolimus in adult lung transplant recipients. Patients enrolled in this study will have been receiving an oral dose of tacrolimus after a successful lung transplant that is resulting in kidney toxicity. During Part A, the patients will be transferred into the study with the anticipation of switching to inhaled tacrolimus with the goal of reducing blood levels to stabilize or minimize kidney toxicity while maintaining sufficiently high lung tacrolimus levels to prevent allograft rejection. Once the study patients are enrolled, they will return to the clinic on a regular basis to allow for dose adjustment. Therapeutic tacrolimus drug concentrations will be measured at every clinic visit under trough conditions (i.e., pre-dose). Kidney function testing will also be monitored on a regular basis. Part B of this study is an optional safety extension following successful completion of Part A. Patients would have the option to continue Tacrolimus Inhalation Powder for up to 1 year, with a possibility to extend to 2 years pending analysis of Part A data. Participants would return to clinic periodically for safety assessments, dose adjustments, and to receive more Tacrolimus Inhalation Powder. After 2 years, if the drug is still under development, the subject will be invited to continue receiving tacrolimus inhalation powder under a special access program.

Official Title
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An Open Label Trial Evaluating the Safety and PK Profile of Tacrolimus Inhalation Powder in Adult Lung Transplant Recipients

Conditions
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Lung Transplant Rejection

Intervention / Treatment
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* Drug: Tacrolimus Inhalation Powder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent to participate and is willing and able to participate in the study and abide by study restrictions in the judgement of the Investigator. Males or females aged 18 or over, at time of screening. Continuous non-smoker who has not used nicotine-containing products (including e-vaping) for at least 3 months prior to the first dosing and throughout the study, based on patient's self-reporting and urine cotinine levels at screening and Day 1. Have undergone bilateral allograft lung transplantation prior to enrolment and meet all of the following': Receiving oral immediate-release (not intravenous [IV], extended release or sublingual) tacrolimus immunosuppression at a stable dose for 3 weeks prior to first dosing according to institutional standards as part of an immunosuppressive regimen along with mycophenolate mofetil (MMF) or azathioprine and corticosteroids- Demonstrating elevated markers of renal dysfunction: blood serum creatinine > 124 μmol/L (0.14 mg/dL) or estimated glomerular filtration rate (eGFR) < 45 Is able to undergo routine bronchoscopy with BAL and biopsy Screening forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) values ≥ 40% predicted (to assure viable graft) Agree to use acceptable contraception or are not able to bear children. Able to successfully perform spirometry, use the inhalation device, and comply with study restrictions and visit schedule. Body mass index (BMI) ≤ 34.0kg/m2 at screening, and a maximum weight of 120.0kg at screening Exclusion Criteria: Active antibody-mediated rejection (AMR) or any other evidence of acute rejection. Active bacterial, viral or fungal infection not successfully resolved at least 4 weeks prior to study entry. Patients on prophylactic anti-fungal treatment may be enrolled. Presence of uncontrolled gastro-esophageal reflux disease (GERD) History or presence of hypersensitivity or idiosyncratic reaction to tacrolimus or any calcineurin inhibitor. Received a treatment with other investigational drug within 5 times the elimination half-life, if known (e.g., a marketed product) or within 30 days (if the elimination half-life is unknown), whichever is longer, prior to Study Day 1 dosing. Positive for hepatitis B surface antigen (HBsAg) PCR, hepatitis C PCR, and human immunodeficiency virus (HIV) I and II antibodies, tuberculosis (TB), or COVID-19 at Screening. Patients who have taken any of the following prohibited medications within 30 days of the first dose or who are expected to require these medications during the study: Cyclosporin Any form of sirolimus or everolimus Allergy or sensitivity to lactose or milk products Clinically significant hepatic impairment defined as 2.5 times the upper limit of normal (ULN) Active post-transplant lymphoproliferative disorder (PTLD) related to Epstein-Barr Virus (EBV) infection Subjects with significant electrocardiogram (ECG) abnormalities at screening, including a QT interval corrected by the Fridericia correction formula that is ≥ 440 msec in men and ≥ 460 msec in women Demonstrates an inability to operate the inhalation device after training

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus Inhalation Powder<br>Single arm open label | Drug: Tacrolimus Inhalation Powder<br>* Tacrolimus powder for inhalation to prevent acute allograft rejection<br>* Other names: Tacrolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants experiencing Adverse Events, Serious Adverse Events, and withdrawals due to Adverse Events | Number of AEs, SAEs, and discontinuation due to AEs | Baseline through end of study (up to 2 years) | 
| Number of participants who experience laboratory test abnormalities | Number of participants with potentially clinically significant lab test values | Baseline through end of study (up to 2 years) | 
| Number of participants who experience physical examination abnormalities | Number of participants with potentially clinically significant physical examination abnormalities | Baseline through end of study (up to 2 years) | 
| Number of participants who experience pulse oximetry abnormalities | Number of participants with potentially clinically significant pulse oximetry values | Baseline through end of study (up to 2 years) | 
| Number of participants who experience vital sign abnormalities | Number of participants with potentially clinically significant vital sign values | Baseline through end of study (up to 2 years) | 
| Mean change from baseline in chest radiology | Number of participants with potentially clinically significant changes in chest radiology | Baseline through end of study (up to 2 years) | 
| Mean change from baseline in blood serum creatinine | Number of participants with potentially clinically significant changes in blood serum creatinine | Baseline through end of study (up to 2 years) | 
| Mean change from baseline in estimated glomerular flow rate (eGFR) | Number of participants with potentially clinically significant changes in eGFR | Baseline through end of study (up to 2 years) | 
| Mean change from baseline in forced expiratory volume (FEV1) | Spirometry used to measure FEV1 lung function | Baseline through end of study (up to 2 years) | 
| Mean change from baseline in forced vital capacity (FVC) | Spirometry used to measure FVC lung function | Baseline through end of study (up to 2 years) | 
| Mean change from baseline in FEV1/FVC ratio | Spirometry used to measure FEV1 and FVC lung function | Baseline through end of study (up to 2 years) | 
| Number of participants meeting treatment stopping rules of acute allograft rejection | Number of participants meeting treatment stopping rules of acute allograft rejection | Baseline through end of study (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in FEV1 percent predicted | Spirometry used to measure FEV1 lung function | Baseline through end of study (up to 2 years) | 
| PK of tacrolimus in whole blood AUC0-6 | PK of tacrolimus in whole blood: Area under the plasma-concentration time curve (AUC0-6) from time 0 through 6 hours after dosing | Baseline through week 12 | 
| PK of tacrolimus in whole blood AUClast | PK of tacrolimus in whole blood: Area under the plasma-concentration time curve (AUClast) from time of dosing to the last measurable concentration | Baseline through week 12 | 
| PK of tacrolimus in whole blood Cmax | PK of tacrolimus in whole blood: Maximum observed concentration (Cmax) | Baseline through week 12 | 
| PK of tacrolimus in whole blood Tmax | PK of tacrolimus in whole blood: Time to maximal observed concentration (Tmax) | Baseline through week 12 | 
| Incidence of all-cause mortality | Incidence of all-cause mortality | Baseline through end of study (up to 2 years) | 
| Incidence of allograft-related mortality | Incidence of allograft-related mortality | Baseline through end of study (up to 2 years) | 
| Incidence of all-cause hospitalizations | Incidence of all-cause hospitalizations | Baseline through end of study (up to 2 years) | 
| Incidence of acute allograft-related hospitalizations | Incidence of acute allograft-related hospitalizations | Baseline through end of study (up to 2 years) |