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Macitentan in the Treatment of Organ Rejection After Lung Transplantation

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ClinicalTrials.gov Identifier: NCT02893176
Recruitment Status : Unknown
Verified September 2016 by David J. Ross, University of California, Los Angeles.
Recruitment status was:  Not yet recruiting
First Posted : September 8, 2016
Last Update Posted : September 8, 2016
Sponsor:
Information provided by (Responsible Party):
David J. Ross, University of California, Los Angeles

Brief Summary:
Potential therapy with MACITENTAN in the treatment of Chronic Lung Allograft Dysfunction (CLAD) after Lung Transplantation. Pilot Study, Double-blind, "ADD-ON Therapy" with MACITENTAN to "usual standard of care immunosuppressive therapies" after lung transplantation for established BOS Stages I or II versus a "matched control group" who receive "usual standard of care immunosuppressive therapies" alone, results in a decrease in the Primary Endpoint: "rate of decline" in "Forced Expiratory Volume-1 sec (FEV1) versus time" while Secondary Endpoints including: differences in Six minute walk distance (6MWD), BORG Score, corrected single-breath diffusing capacity (DCO corrected) at time intervals of 1, 3, 6 months on therapy. Specific biomarkers for BOS, including inflammatory chemokines, which are routinely collected in the context of post-transplant "surveillance" will be analyzed. Chemokines which our group has previously described in the pathogenesis of the continuum of "acute-to-chronic lung allograft rejection", have included both C-C (CCL2, CCL5) and CXC (CXCL9, CXCL10, CXCL11) chemokines as determined in bronchial-alveolar lavage (BAL).

Condition or disease Intervention/treatment Phase
Lung Transplant Rejection Drug: macitentan Drug: placebo (for macitentan) Phase 4

Detailed Description:

Preliminary studies employing a "rat tracheal allograft transplant model" have demonstrated amelioration of the fibrous airway obliteration associated with blockade of the renin-angiotension and the endothelin system implementing the ERA antagonist, BOSENTAN (100 mg/kg). Clinical studies have indeed demonstrated that the mitogenic and profibrotic peptide, ET-1, may represent a potential biomarker in clinical BOS. Detection of levels of ET-1 mRNA were significantly increased in the lung allografts of those with versus those without BOS at 3 and 12 months post-transplantation while ET-1 concentrations were significantly elevated both in serum and bronchoalveolar lavage fluid (BALF) from patients with BOS. Additional studies have further demonstrated a pronounced inhibitory effect elicited by chronic ET(A) receptor blockade in the absence of immunosuppressive therapy, on both plasma levels and transcriptional regulation of inflammatory chemokines in a rat heterotopic heart transplant model of chronic rejection .

MACITENTAN, a novel, competitive ERA with significantly slower receptor dissociation kinetics than currently approved ERAs, may represent a renewed hope for patients suffering from progressive CLAD post-transplantation. The efficacy of MACITENTAN was not realized in the exploratory Phase II MUSIC Trial for IPF for the primary endpoint measure of forced vital capacity (FVC), nevertheless, mechanistic disparities in the pathobiology of CLAD versus IPF, therefore should not preclude a separate therapeutic trial. Further, in vitro treatment with MACITENTAN and its major metabolite (ACT-132577) decreases alpha smooth muscle actin elaboration by dermal fibroblasts in systemic sclerosis fibrotic skin lesions, therefore offering significant promise for potential disease modulation. Most importantly, the MUSIC Trial has further demonstrated the "clinical safety" of this pharmacologic therapy in 178 patients with IPF with mean drug exposure of approximately 14 months and without statistical differences in incidence of abnormal liver function studies. Recent pharmacokinetic studies of MACITENTAN have suggested no "clinically significant" drug-drug interaction with respect to Cytochrome P4503A4 for concurrent post-transplant immunosuppressive type therapies, such as cyclosporine, tacrolimus and mycophenolate mofetil; while insignificant interaction with the frequently implemented "azole-type antibiotics" was also observed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Potential Therapy With MACITENTAN in the Treatment of Chronic Lung Allograft Dysfunction (CLAD) After Lung Transplantation
Study Start Date : September 2016
Estimated Primary Completion Date : February 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Macitentan

Arm Intervention/treatment
Placebo Comparator: Placebo
10mg will be administered one time daily
Drug: placebo (for macitentan)
Active Comparator: Active
10mg macitentan will be administered one time daily
Drug: macitentan
Other Name: Opsumit




Primary Outcome Measures :
  1. Measure of FEV1 [ Time Frame: Six Months on Therapy ]
    linearized slopes of loss of lung function (FEV1) / month


Secondary Outcome Measures :
  1. Measure of FEV1 [ Time Frame: One, Three, Six and Twelve Months ]
    Absolute change in FEV1

  2. Measure of Six Minute Walk [ Time Frame: One, Three, Six and Twelve Months ]
    Patients' exercise tolerance on six minute walk (6MW) distance

  3. Measure of Pulse Oximetry [ Time Frame: One, Three, Six and Twelve Months ]
    Minimal pulse oximetry saturation (SpO2) during ambulation

  4. Measure of Diffusing Capacity [ Time Frame: One, Three, Six and Twelve Months ]
    Corrected diffusing capacity (DCO)


Other Outcome Measures:
  1. BNP Lab Values [ Time Frame: One, Three, Six and Twelve Months ]
    BNP Values

  2. Creatinine Clearance Lab Values [ Time Frame: One, Three, Six and Twelve Months ]
    Creatinine Clearance

  3. Serum Endothelin-1 Lab Values [ Time Frame: One, Three, Six and Twelve Months ]
    Serum Endothelin-1 Values



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • UCLA unilateral or bilateral lung transplant recipients, ages: 21-65 years.
  • Females of child bearing age who could become pregnant, must implement appropriate contraception per FDA requirement for "ERA medical treatment" with mandatory MONTHLY monitoring of urine or serum pregnancy tests.
  • No concurrent clinically significant chronic liver disease
  • Screening echocardiogram (performed as usual post-transplant standard of care) with LVEF>40%, only "Grade I" or less for "LV diastolic dysfunction".
  • Non-intubated, fully ambulatory patients who can perform respiratory maneuvers for office Spirometry and DCO and 6MWD (no tracheostomy).
  • Total of 20 patients with BOS Stage I or II, randomized double-blind to 'standard of care + placebo" versus "standard of care + MACITENTAN" Groups.
  • Laboratory "safety studies" are already routinely monitored in the context of post-transplant patients' chronic immunosuppressive regimen and include: comprehensive metabolic panel, tacrolimus trough level, B-type natriuretic peptide (BNP), CBC + platelet count.
  • "Physiologic" outcomes for this study are already considered "standard of care" for lung transplant recipients that include: Office-based Spirometry pre- and post-bronchodilator, corrected DCO, six minute walk distances + BORG score assessments (6MWD) at intervals of 1-3 months during routine Lung Transplant Clinic follow-up appointments.

Exclusion Criteria:

  • UCLA unilateral or bilateral lung transplant recipients, ages: over 65 years of age.
  • Females of child bearing age who could become pregnant, refuse to implement appropriate contraception per FDA requirement for "ERA medical treatment" with mandatory MONTHLY monitoring of urine or serum pregnancy tests or become pregnant.
  • Concurrent clinically significant chronic liver disease
  • Intubated patients
  • Patients who cannot perform respiratory maneuvers for office Spirometry and DCO and 6MWD (no tracheostomy).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02893176


Contacts
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Contact: Michaela A Jacquet, CCRC 310-206-4319 mjacquet@mednet.ucla.edu

Locations
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United States, California
University of Califonia, Los Angeles
Los Angeles, California, United States, 90095
Contact: Michaela A Jacquet, CCRC    310-206-4319    mjacquet@mednet.ucla.edu   
Principal Investigator: David J Ross, MD         
Sub-Investigator: Rajan Saggar, MD         
Sub-Investigator: John Belperio, MD         
Sub-Investigator: Abas Ardehali, MD         
Sub-Investigator: S. S Weight, MD         
Sub-Investigator: Michael Shino, MD         
Sub-Investigator: Ariss Derhovanessian, MD         
Sub-Investigator: Joseph P Lynch, III, MD         
Sponsors and Collaborators
University of California, Los Angeles
Investigators
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Principal Investigator: David J Ross, MD University of California, Los Angeles

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Responsible Party: David J. Ross, Clinical Professor of Medicine, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT02893176    
Other Study ID Numbers: 14-001710
First Posted: September 8, 2016    Key Record Dates
Last Update Posted: September 8, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by David J. Ross, University of California, Los Angeles:
Lung Transplant
Macitentan
CLAD
BOS
bronchiolitis obliterans
chronic lung allograft dysfunction
Organ Rejection
Additional relevant MeSH terms:
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Macitentan
Endothelin A Receptor Antagonists
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Endothelin B Receptor Antagonists