Chronic Lung Allograft Dysfunction, Disorder Related to Lung Transplantation
Conditions
Keywords
CLAD, Chronic Rejection, Lung Transplant
Brief summary
Greater than 50% of lung transplant recipients show signs of chronic lung allograft dysfunction (CLAD) by 5 years post-transplantation.Therapies to prevent or slow CLAD are lacking. Anti-fibrotic therapies may offer an avenue to prevent progression of CLAD and prolong allograft survival. This study investigates if Pirfenidone therapy will stabilize lung function decline and slow progression of Functional small airways disease (fSAD) in lung transplant recipients with CLAD.
Detailed description
The study aimed to enroll lung transplant recipients with an established diagnosis of CLAD. The patients were randomized to receive an anti-fibrotic drug Pirfenidone or Placebo pills for 6 month period. High-resolution CT scan of the chest was utilized to measure the primary endpoint of change in functional small airway disease (fSAD). Pulmonary function testing and spirometry were utilized to measure the secondary endpoint of change in FEV1 and FVC.
Interventions
Dosing: Days 1 through 7, 267 mg three times daily; Days 8 through 14, 534 mg three times daily; Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks
DRUGPlacebo Capsule
Dosing: * Days 1 through 7, 267 mg three times daily; * Days 8 through 14, 534 mg three times daily; * Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks
Sponsors
Genentech, Inc.
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Lung transplant recipients 18 years of age or older * Greater than 6 months after single or bilateral lung transplantation * Baseline FEV1 and FVC values (mean of two highest value measured 3 weeks apart) \> 50% predicted (to assure viable graft) * Diagnosis of CLAD (two consecutive spirometric values of FEV1 alone or both FEV1 and FVC \< 80% of baseline)
Exclusion criteria
* Acute Rejection (AR) diagnosis by biopsy in the 28 days prior to enrollment * Treatment with pulse steroids, Anti-thymocyte Globulin (ATG), extracorporeal photopheresis (ECP), plasmapheresis, or Immunoglobulin therapy aimed at CLAD within the 28 days prior to enrollment * If the subject is receiving chronic Azithromycin therapy, the dose must be stable for the 28 days prior to enrollment * Presence of active pulmonary infection at the time of enrollment as determined by an investigator in consultation with the treating pulmonologist * Diagnosis of bronchial stenosis either a) requiring stenting, or b) thought to be responsible for the spirometric decline by principal investigator * Abnormal liver function tests (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2 x upper limit of normal (ULN), Alkaline phosphatase \> 2.5 x ULN, total bilirubin \> ULN) or known cirrhosis (\>2 times upper limit of normal of AST/ALT/AP) * Total white blood cell (WBC) \< 3.0 K/uL * Moderate to Severe Renal insufficiency (CrCl \<15 mL/min calculated by the Cockcroft-Gault equation) * Use of any medication known to cause significant interactions with pirfenidone (strong CYP1A2 inhibitors such as Fluvoxamine or Enoxacin or inducers) * Pregnancy or lactation. Women of child-bearing potential will have a pregnancy test at enrollment and must agree to maintain highly effective contraception with two methods of birth control from the date of consent through the end of the study. * Tobacco use within 6 months * History of alcohol abuse in the past 1 year as determined by the treating pulmonologist * Any condition other than CLAD that will likely result in death in the next 1 year * Any condition in the judgement of the principal investigator that would preclude participation in this study * EKG with QTc interval \> 500 msec at screening * Listed for repeat lung transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Baseline, 24 weeks | Evaluate if pirfenidone compared to placebo will stabilize progression of fSAD by comparison of inspiratory and expiratory high resolution computed tomography (HRCT) images through co-registration to provide quantitative measures of fSAD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | Baseline, 24 weeks | Measured by spirometry |
| Change in Forced Vital Capacity (FVC) Over 24 Weeks | Baseline, 24 weeks | Measured by spirometry |
| Number of Adverse Events Related to Study Treatment | 28 weeks | Safety of pirfenidone will be measured by adverse events determined to be related to the study drug through review of medical history, physical exam and laboratory findings. |
| Number of Subjects With Treatment Intolerance | 24 weeks | Subjects permanently discontinuing study medication before 24 weeks |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pirfenidone Capsule Method of Administration: Oral (capsule)
Dosing:
* Days 1 through 7, 267 mg three times daily;
* Days 8 through 14, 534 mg three times daily;
* Days 15 through end of treatment (24 weeks), 801 mg three times daily
Pirfenidone Capsule: Dosing:
Days 1 through 7, 267 mg three times daily; Days 8 through 14, 534 mg three times daily; Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks | 13 |
| Placebo Capsule Method of Administration: Oral (capsule)
Dosing:
* Days 1 through 7, 267 mg three times daily;
* Days 8 through 14, 534 mg three times daily;
* Days 15 through end of treatment (24 weeks), 801 mg three times daily
Placebo Capsule: Dosing:
* Days 1 through 7, 267 mg three times daily;
* Days 8 through 14, 534 mg three times daily;
* Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks | 11 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Follow up not possible due to COVID restrictions | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Pirfenidone Capsule | Placebo Capsule | Total |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 11.6 | 57.5 years STANDARD_DEVIATION 13.5 | 58.6 years STANDARD_DEVIATION 12.3 |
| CLAD Phenotype Concurrent FEV1 and FVC Decline | 8 Participants | 7 Participants | 15 Participants |
| CLAD Phenotype FEV1 First Decline | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 11 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Lung Function FEV 1, FVC, FEV1 | 1.400769 liters STANDARD_DEVIATION 0.5887057 | 1.410909 liters STANDARD_DEVIATION 0.4713906 | 1.41 liters STANDARD_DEVIATION 0.527 |
| Lung Function FEV 1, FVC, FVC | 2.544615 liters STANDARD_DEVIATION 0.8378904 | 2.517273 liters STANDARD_DEVIATION 0.7226353 | 2.53 liters STANDARD_DEVIATION 0.77 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 11 Participants | 23 Participants |
| Region of Enrollment United States | 13 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Female | 10 Participants | 2 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 11 |
| other Total, other adverse events | 11 / 13 | 9 / 11 |
| serious Total, serious adverse events | 0 / 13 | 4 / 11 |
Outcome results
Primary
Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping
Evaluate if pirfenidone compared to placebo will stabilize progression of fSAD by comparison of inspiratory and expiratory high resolution computed tomography (HRCT) images through co-registration to provide quantitative measures of fSAD.
Time frame: Baseline, 24 weeks
Population: Baseline measures taken from all participants. Post treatment percentage measurements taken only from participants who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone Capsule | Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Baseline percentage fSAD | 14.21 percentage of change of fsad | Standard Deviation 8.8 |
| Pirfenidone Capsule | Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Post treatment percentage fSAD | 17.10 percentage of change of fsad | Standard Deviation 6.43 |
| Pirfenidone Capsule | Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Net change | -5.8620625 percentage of change of fsad | Standard Deviation 6.636287 |
| Placebo Capsule | Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Baseline percentage fSAD | 11.90 percentage of change of fsad | Standard Deviation 13.08 |
| Placebo Capsule | Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Post treatment percentage fSAD | 10.62 percentage of change of fsad | Standard Deviation 9.25 |
| Placebo Capsule | Change in Percent of Functional Small Airways Disease (fSAD) as Measured by Parametric Response Mapping | Net change | 0.4497328 percentage of change of fsad | Standard Deviation 10.91197 |
Comparison: P-Value provided is for net change only.p-value: 0.17697507t-test, 2 sided
Secondary
Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1)
Measured by spirometry
Time frame: Baseline, 24 weeks
Population: Baseline measures taken from all participants. Post treatment percentage measurements taken only from participants with available FEV1 results at 24-week mark.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone Capsule | Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | 24 week FEV1 | 1.36 liters | Standard Deviation 0.57 |
| Pirfenidone Capsule | Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | Change in FEV1 | -0.12 liters | Standard Deviation 0.13 |
| Pirfenidone Capsule | Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | Baseline FEV1 | 1.40 liters | Standard Deviation 0.59 |
| Placebo Capsule | Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | Baseline FEV1 | 1.41 liters | Standard Deviation 0.47 |
| Placebo Capsule | Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | 24 week FEV1 | 1.35 liters | Standard Deviation 0.54 |
| Placebo Capsule | Change in Forced Expiratory Volume 1 Over 24 Weeks (FEV1) | Change in FEV1 | -0.09 liters | Standard Deviation 0.3 |
Comparison: P-Value provided is for net change only.p-value: 0.77367872Welch Two Sample t-test
Secondary
Change in Forced Vital Capacity (FVC) Over 24 Weeks
Measured by spirometry
Time frame: Baseline, 24 weeks
Population: Baseline measures taken from all participants. Post treatment percentage measurements taken only from participants with available FVC results at 24-week mark.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone Capsule | Change in Forced Vital Capacity (FVC) Over 24 Weeks | Baseline FVC | 2.54 liters | Standard Deviation 0.84 |
| Pirfenidone Capsule | Change in Forced Vital Capacity (FVC) Over 24 Weeks | 24-week FVC | 2.52 liters | Standard Deviation 0.87 |
| Pirfenidone Capsule | Change in Forced Vital Capacity (FVC) Over 24 Weeks | Change in FVC | -0.06 liters | Standard Deviation 0.25 |
| Placebo Capsule | Change in Forced Vital Capacity (FVC) Over 24 Weeks | Baseline FVC | 2.52 liters | Standard Deviation 0.72 |
| Placebo Capsule | Change in Forced Vital Capacity (FVC) Over 24 Weeks | 24-week FVC | 2.36 liters | Standard Deviation 0.86 |
| Placebo Capsule | Change in Forced Vital Capacity (FVC) Over 24 Weeks | Change in FVC | -0.12 liters | Standard Deviation 0.4 |
Comparison: P-Value provided is for net change only.p-value: 0.68595748t-test, 2 sided
Secondary
Number of Adverse Events Related to Study Treatment
Safety of pirfenidone will be measured by adverse events determined to be related to the study drug through review of medical history, physical exam and laboratory findings.
Time frame: 28 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirfenidone Capsule | Number of Adverse Events Related to Study Treatment | AE Probably Related | 4 Adverse Events |
| Pirfenidone Capsule | Number of Adverse Events Related to Study Treatment | AE Unlikely to be Related | 8 Adverse Events |
| Pirfenidone Capsule | Number of Adverse Events Related to Study Treatment | AE Possibly Related | 15 Adverse Events |
| Pirfenidone Capsule | Number of Adverse Events Related to Study Treatment | AE Definitely Not Related | 1 Adverse Events |
| Pirfenidone Capsule | Number of Adverse Events Related to Study Treatment | AE Definitely Related | 0 Adverse Events |
| Placebo Capsule | Number of Adverse Events Related to Study Treatment | AE Definitely Not Related | 12 Adverse Events |
| Placebo Capsule | Number of Adverse Events Related to Study Treatment | AE Definitely Related | 0 Adverse Events |
| Placebo Capsule | Number of Adverse Events Related to Study Treatment | AE Probably Related | 0 Adverse Events |
| Placebo Capsule | Number of Adverse Events Related to Study Treatment | AE Possibly Related | 10 Adverse Events |
| Placebo Capsule | Number of Adverse Events Related to Study Treatment | AE Unlikely to be Related | 10 Adverse Events |
p-value: 0.00127634Fisher Exact
Secondary
Number of Subjects With Treatment Intolerance
Subjects permanently discontinuing study medication before 24 weeks
Time frame: 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pirfenidone Capsule | Number of Subjects With Treatment Intolerance | Drug Discontinued | 1 Participants |
| Pirfenidone Capsule | Number of Subjects With Treatment Intolerance | Drug Not Discontinued, but Held or Dose Reduced | 5 Participants |
| Pirfenidone Capsule | Number of Subjects With Treatment Intolerance | Drug Tolerated | 4 Participants |
| Placebo Capsule | Number of Subjects With Treatment Intolerance | Drug Discontinued | 1 Participants |
| Placebo Capsule | Number of Subjects With Treatment Intolerance | Drug Not Discontinued, but Held or Dose Reduced | 3 Participants |
| Placebo Capsule | Number of Subjects With Treatment Intolerance | Drug Tolerated | 6 Participants |
p-value: 0.80904544Fisher Exact