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

PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2023-04-18

    Primary completion: 2025-01-31

    Study completion finish: 2025-01-31

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

    trial

    Trial ID

    NCT05501574

    Intervention or treatment

    DRUG: Tacrolimus Inhalation Powder

    Conditions

    • Lung Transplant Rejection

    Find a site

    Closest Location:

    The Alfred Hospital

    Research sites nearby

    Select from list below to view details:

    • The Alfred Hospital

      Melbourne, Victoria, Australia

    • St Vincent's Hospital

      Darlinghurst, New South Wales, Australia

    • Prince Charles Hospital

      Brisbane, Queensland, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Tacrolimus Inhalation Powder
    • Single arm open label
    DRUG: Tacrolimus Inhalation Powder
    • Tacrolimus powder for inhalation to prevent acute allograft rejection

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Number of participants experiencing Adverse Events, Serious Adverse Events, and withdrawals due to Adverse EventsNumber of AEs, SAEs, and discontinuation due to AEsBaseline through end of study (up to 2 years)
    Number of participants who experience laboratory test abnormalitiesNumber of participants with potentially clinically significant lab test valuesBaseline through end of study (up to 2 years)
    Number of participants who experience physical examination abnormalitiesNumber of participants with potentially clinically significant physical examination abnormalitiesBaseline through end of study (up to 2 years)
    Number of participants who experience pulse oximetry abnormalitiesNumber of participants with potentially clinically significant pulse oximetry valuesBaseline through end of study (up to 2 years)
    Number of participants who experience vital sign abnormalitiesNumber of participants with potentially clinically significant vital sign valuesBaseline through end of study (up to 2 years)
    Mean change from baseline in chest radiologyNumber of participants with potentially clinically significant changes in chest radiologyBaseline through end of study (up to 2 years)
    Mean change from baseline in blood serum creatinineNumber of participants with potentially clinically significant changes in blood serum creatinineBaseline 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 eGFRBaseline through end of study (up to 2 years)
    Mean change from baseline in forced expiratory volume (FEV1)Spirometry used to measure FEV1 lung functionBaseline through end of study (up to 2 years)
    Mean change from baseline in forced vital capacity (FVC)Spirometry used to measure FVC lung functionBaseline through end of study (up to 2 years)
    Mean change from baseline in FEV1/FVC ratioSpirometry used to measure FEV1 and FVC lung functionBaseline through end of study (up to 2 years)
    Number of participants meeting treatment stopping rules of acute allograft rejectionNumber of participants meeting treatment stopping rules of acute allograft rejectionBaseline through end of study (up to 2 years)

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Change from baseline in FEV1 percent predictedSpirometry used to measure FEV1 lung functionBaseline through end of study (up to 2 years)
    PK of tacrolimus in whole blood AUC0-6PK of tacrolimus in whole blood: Area under the plasma-concentration time curve (AUC0-6) from time 0 through 6 hours after dosingBaseline through week 12
    PK of tacrolimus in whole blood AUClastPK of tacrolimus in whole blood: Area under the plasma-concentration time curve (AUClast) from time of dosing to the last measurable concentrationBaseline through week 12
    PK of tacrolimus in whole blood CmaxPK of tacrolimus in whole blood: Maximum observed concentration (Cmax)Baseline through week 12
    PK of tacrolimus in whole blood TmaxPK of tacrolimus in whole blood: Time to maximal observed concentration (Tmax)Baseline through week 12
    Incidence of all-cause mortalityIncidence of all-cause mortalityBaseline through end of study (up to 2 years)
    Incidence of allograft-related mortalityIncidence of allograft-related mortalityBaseline through end of study (up to 2 years)
    Incidence of all-cause hospitalizationsIncidence of all-cause hospitalizationsBaseline through end of study (up to 2 years)
    Incidence of acute allograft-related hospitalizationsIncidence of acute allograft-related hospitalizationsBaseline through end of study (up to 2 years)

    Frequently Asked Questions

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    References

    Clinical Trials Gov: An Open Label Trial Evaluating Tacrolimus Inhalation Powder in Adult Lung Transplant Recipients

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