Lung Transplant RejectionPhase 4NCT02893176
Macitentan in the Treatment of Organ Rejection After Lung Transplantation
A Phase 4 study testing macitentan in people with Lung Transplant Rejection, run by University of California, Los Angeles at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 21 to 65 years
- Conditions the study is for
- Lung Transplant Rejection
- What is being tested?
- macitentan
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2016to 19 Sep 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Califonia, Los Angeles
Los Angeles, California, 90095
About this study
Official title: Potential Therapy With MACITENTAN in the Treatment of Chronic Lung Allograft Dysfunction (CLAD) After Lung Transplantation
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).
Read the 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.
- Conditions
- Lung Transplant Rejection
- Being tested
- macitentan, placebo (for macitentan)
- Keywords
- Lung Transplant, Macitentan, CLAD, BOS, bronchiolitis obliterans, chronic lung allograft dysfunction, Organ Rejection
- Medical subject headings
- Bronchiolitis Obliterans
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
macitentanDrug
Also called Opsumit
placebo (for macitentan)Drug
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | 10mg will be administered one time daily Receives: Drug: placebo (for macitentan) |
| Active | Active comparator | 10mg macitentan will be administered one time daily Receives: Drug: macitentan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Measure of FEV1
linearized slopes of loss of lung function (FEV1) / month
Measured: Six Months on Therapy
Secondary outcomes (4)
Measure of FEV1
Absolute change in FEV1
Measured: One, Three, Six and Twelve Months
Measure of Six Minute Walk
Patients' exercise tolerance on six minute walk (6MW) distance
Measured: One, Three, Six and Twelve Months
Measure of Pulse Oximetry
Minimal pulse oximetry saturation (SpO2) during ambulation
Measured: One, Three, Six and Twelve Months
Measure of Diffusing Capacity
Corrected diffusing capacity (DCO)
Measured: One, Three, Six and Twelve Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Sep 2016 (estimated)
- Study startSep 2016 (estimated)
- Primary completion19 Sep 2019
- Study completion19 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Lung Transplant RejectionStudies of the same condition, open and under way.
- More trials run by University of California, Los AngelesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, Los Angeles
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- David J Ross, MD, Principal investigator, University of California, Los Angeles
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02893176
- Sponsor's protocol ID
- 14-001710
- Status last verified
- Dec 2020
- First submitted
- 9 Mar 2016
- Last updated
- 11 Dec 2020
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Potential Therapy With MACITENTAN in the Treatment of Chronic Lung Allograft Dysfunction (CLAD) After Lung Transplantation
- ClinicalTrials.gov ID
- NCT02893176
- Acronym / sponsor ID
- 14-001710
- Conditions
- Lung Transplant Rejection
- Keywords
- Lung Transplant, Macitentan, CLAD, BOS, bronchiolitis obliterans, chronic lung allograft dysfunction, Organ Rejection
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of California, Los AngelesUniversity, hospital or other
- Study start
- Sep 2016 (estimated)
- Primary completion
- 19 Sep 2019 (actual)
- Study completion
- 19 Sep 2019 (actual)
- First posted
- 8 Sep 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: placebo (for macitentan)10mg will be administered one time daily |
| Active | Active comparator | Drug: macitentan10mg macitentan will be administered one time daily |
Who may qualify
- Ages
- 21 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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).
Key exclusion criteria (5 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| macitentanAlso: Opsumit | Drug | Active |
| placebo (for macitentan) | Drug | Placebo |
Primary outcome
Measure of FEV1
Time frame: Six Months on Therapy
linearized slopes of loss of lung function (FEV1) / month
4 secondary outcomes
Measure of FEV1
Time frame: One, Three, Six and Twelve Months
Measure of Six Minute Walk
Time frame: One, Three, Six and Twelve Months
Measure of Pulse Oximetry
Time frame: One, Three, Six and Twelve Months
Measure of Diffusing Capacity
Time frame: One, Three, Six and Twelve Months
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2020.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David J Ross, MD principal investigator
University of California, Los Angeles
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing macitentan in people with Lung Transplant Rejection, run by University of California, Los Angeles at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 11 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Measure of FEV1 (time frame: Six Months on Therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Dec 2020.