Back to resultsThe Safety and Tolerability of Pirfenidone for BOS After HCT (STOP-BOS)
Primary Purpose
Bronchiolitis Obliterans, Graft Vs Host Disease
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pirfenidone 267 MG [Esbriet]
Sponsored by
About this trial
This is an interventional treatment trial for Bronchiolitis Obliterans focused on measuring Bronchiolitis obliterans syndrome
Eligibility Criteria
Inclusion Criteria:
- Age > 18 years at randomization
- Clinical symptoms (e.g., dyspnea or cough) consistent with BOS of ≥ 2 months duration
- Presence of cGVHD in an organ other than lung
Subjects must have had recent pulmonary function test (PFTs) measured for at least 3 months prior to study enrollment that show:
- A decrease in %FVC and/or %FEV1 ≥ 20% at Screening compared with pre-transplant baseline.
- Bronchodilator response on PFT testing that results in an FEV1 < 75%
Diagnosis of BOS by one of the following criteria:
- Transbronchial or surgical lung biopsy demonstrating the obliterative bronchiolitis lesion
- Volumetric CT scan with lung density analysis with ≥ 28% air trapping (1).
- NIH-based PFT criteria for the diagnosis of BOS: FEV1/FVC <0.7 and FEV1 < 75%
- Evidence of clinical improvement after treatment for BOS has been initiated.
- No features supporting an alternative diagnosis by transbronchial biopsy, bronchoalveolar lavage (BAL), surgical lung biopsy, culture and non-culture based data, if performed
- Adequate organ and marrow function including: liver function as defined by a total bilirubin below the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; AST/SGOT or ALT/SGPT < 3 x ULN; alkaline phosphatase < 2.5 x ULN; renal function as defined by a CrCl > 30 mL/min, calculated using the Cockcroft-Gault formula; cardiac electrophysiologic stability as defined by an electrocardiogram (ECG) with a QTc interval < 500 msec at Screening; and bone marrow function as defined by a white blood cell count > 3 K/µL, an absolute neutrophil count > 15 K/µL and a platelet count > 20 K/µL
- Life expectancy > 6 months
- Participants must be able to understand and sign a written informed consent form and understand the importance of adherence to study treatment and protocol. In addition, participants must demonstrate a willingness to follow all study requirements, including the concomitant medication restrictions, throughout the study
Exclusion Criteria:
- Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone e.g., presence of active GVHD of the gastrointestinal tract as manifested by rising liver function tests (LFTs) prior to initiation of study treatment
- Uncontrolled infection
- Major surgery within the past 2 months
- The use of another investigational drug within the previous 30 days.
- Inability to attend scheduled clinic visits
- Inability to perform pulmonary function testing
- Significant clinical change in health in the past 30 days
- Body mass index (BMI) < 17.5
- Life expectancy < 6 months due to any condition other than BOS that, in the opinion of the investigator, is likely to result in the death of the patient.
History of unstable or deteriorating cardiac or pulmonary disease (other than BOS) within the previous 6 months, including but not limited to the following:
- Unstable angina pectoris or myocardial infarction
- Congestive heart failure requiring hospitalization
- Uncontrolled clinically significant arrhythmias
- Pregnancy or lactation.
- Family or personal history of long QT syndrome
- Investigational therapy, defined as any drug that has not been approved for marketing for any indication in cGVHD will be restricted from the study
- The following medications may significantly increase the level of Pirfenidone and should not be taken concurrently including: fluvoxamine, ciprofloxacin > 500mg twice daily, systemically administered aminolevulinic acid, vemurafenib and enoxacin. Any other strong inhibitors of P450 isoenzymes CYP1A2, CYP2C9, 2C19, 2D6, and 2E1 should be avoided. Participants that cannot take alternative medications to those listed above will be excluded from this study.
Laboratory Exclusions
- Any of the following LFT criteria above specified limits: total bilirubin above the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >3 × ULN; alkaline phosphatase >2.5 × ULN
- Creatinine clearance (CrCl) <30 mL/min, calculated using the Cockcroft-Gault formula
- Electrocardiogram (ECG) with a QTc interval >500 msec at Screening
Medication Exclusions
1. Prior use of pirfenidone or known hypersensitivity to any of the components of study treatment.
Sites / Locations
- Stanford University School of Medicine
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Patient centered approach
Arm Description
Drug titration of maximum dose over 3-8 weeks
Outcomes
Primary Outcome Measures
The number of participants that do not require a reduction in drug dose for more than 21 days due to adverse events.
We will count the number of participants that do not require a reduction in drug dose of more than 21, non-continuous days due to adverse events. Tolerability will be assessed during continuous treatment. If the medication dosage increase results in the reoccurrence of a moderate adverse event or serious adverse event, lasting more than 21 days, then the event would be defined as "not tolerated". If adverse events resolve before 21 days, then participants will attempt to again up-titrate the Pirfenidone dose, as tolerated. If at least 25% of participants tolerate the drug, then investigators will deem that this study demonstrates adequate tolerability to proceed to a larger trial to examine drug efficacy.
Secondary Outcome Measures
The number of participants that permanently discontinue drug due to adverse events.
We will count the number of patients that permanently discontinue Pirfenidone due to adverse events. A permanent discontinuation of drug is defined as discontinuation of the drug for more than 42 days.
The number of participants that temporarily discontinue drug due to adverse events.
We will count the number of participants that temporarily discontinue Pirfenidone due to adverse events. A temporary discontinuation of drug is defined as discontinuation of the drug for less than or equal to 42 days.
The number of patients that experience treatment-emergent adverse events
Treatment emergent events are defined as those that start or worsen after the start of study treatment and up to 28 days after the last dose of study treatment. AEs will be summarized by treatment group, system organ class, and preferred term, and also by the event's relationship to study treatment. At each level of summation, patients will be counted only once, under the greatest severity and strongest study-drug relationship (as reported by the investigator).
The number of patients that experience treatment-emergent serious adverse events (SAEs)
Serious adverse events (SAEs) are defined as those that result in: (i) death or are life threatening; (ii) result in hospitalization or prolong hospitalization; or (iii) result in disability (disruption of the participant's ability to conduct normal daily activities). Serious adverse events will be summarized by treatment group, system organ class, and preferred term, and also by the event's relationship to study treatment. At each level of summation, patients will be counted only once, under the greatest severity and strongest study-drug relationship (as reported by the investigator).
The number of patients that experience treatment-emergent deaths during the study period and for 28 days after the last dose of study treatment.
Treatment emergent deaths are defined as those that occur after the start of study treatment and up to 28 days after the last dose of study treatment and are deemed by the investigator to be related to study treatment.
All-cause mortality
We will count the total number of deaths during the study period and for 28 days after the last dose of study treatment
The number of patients that experience treatment-emergent changes in complete blood counts.
The complete blood count measures the number white blood cells (WBCs) per liter (L) including differential counts of the type of WBCs, hemoglobin concentration (g/dL), and platelet count per liter.
The number of patients that experience treatment-emergent changes in liver function testing.
We will assess treatment related changes in total bilirubin (mg/dL), AST/SGOT (units/L) or ALT/SGPT (units/L), alkaline phosphatase (units/L)
The number of patients that experience treatment-emergent changes in serum chemistries panel.
We will assess treatment related changes in potassium (mEq/L), blood urea nitrogen (mg/dL) and serum creatinine (mg/dL).
The number of patients that experience treatment-emergent changes in the corrected QT-interval on electrocardiogram.
We will evaluate changes in the interval from ventricular depolarization (Q-wave) to ventricular repolarization (T-wave) corrected for by heart rate
Body mass index
We will measure changes in the participant's height (meters) and weight (kg) to determine changes in body mass index (kg/m^2)
Oxygen saturation
We will measure the participant's oxygen saturation (%) at rest on room air.
Heart rate
We will measure the participant's resting heart rate (beats per minute)
Chronic GVHD assessment
Chronic GVHD symptoms will be assessed according to NIH cGVHD global severity score. The global cGVHD severity score evaluates the severity of cGVHD in eight sites including the skin, mouth, eyes, gastrointestinal track, liver, lungs, joints and fascia, and genital track. Each organ is assigned a severity score and composite scores are calculated based on the number of organs involved and the severity score within each affected organ.
Full Information
NCT ID
NCT03315741
First Posted
October 5, 2017
Last Updated
June 8, 2022
Sponsor
Stanford University
Collaborators
Genentech, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT03315741
Brief Title
The Safety and Tolerability of Pirfenidone for BOS After HCT
Acronym
STOP-BOS
Official Title
The Safety and Tolerability of Pirfenidone for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
March 1, 2018 (Actual)
Primary Completion Date
February 27, 2022 (Actual)
Study Completion Date
April 27, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Stanford University
Collaborators
Genentech, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a phase 1, non-randomized, single-arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant.
Detailed Description
This is a phase 1, non-randomized, single-arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant (HCT). Such a trial is a necessary step prior to an evaluation of efficacy, as pirfenidone is known to be associated with adverse events (AEs) of the liver, gastrointestinal system and skin, organs frequently affected in GVHD. Approximately 30 patients will be enrolled, all patients will follow the same drug titration approach. The primary endpoint will be drug tolerability as measured by: the number of patients that are able to maintain the recommended dose of pirfenidone (2403 mg/d) without dose reduction lasting more than 21 days, due to adverse events (AEs). Changes from Baseline to Week 52 will be studied using validated health-related quality of life scales. Eligible patients aged > 18 years must have a diagnosis of BOS according to pre-specified criteria. Patients will be required to have an %FEV1 or %FVC decline >20% from pre-transplant baseline and symptoms of dyspnea, or cough. Eligible patients will enter the Screening Period, which may last up to 28 days. The dose of pirfenidone will be titrated over 3-8 weeks. Patients will have a telephone assessment at Week 1 and 2. An in-clinic assessment will occur every 1-3 months as part of their usual clinical care in the Stanford University Lung GVHD clinic. Patients will complete an AE and dosing compliance diary. If patients discontinue study treatment early for any reason, they will continue with all scheduled study procedures through Week 52. All deaths will be reviewed by a Mortality Assessment Committee (MAC). An external Data Safety Monitoring Board (DSMB) will monitor patient safety during the study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiolitis Obliterans, Graft Vs Host Disease
Keywords
Bronchiolitis obliterans syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
This is a phase 1, non-randomized, single arm, open label, single center clinical trial to determine the tolerability and safety of pirfenidone in patients with BOS associated with lung GVHD after hematopoietic cell transplant (HCT). Approximately 30 patients will be enrolled. All patients will follow the 'patient-centered' drug titration approach.
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Patient centered approach
Arm Type
Experimental
Arm Description
Drug titration of maximum dose over 3-8 weeks
Intervention Type
Drug
Intervention Name(s)
Pirfenidone 267 MG [Esbriet]
Intervention Description
Tolerability of drug
Primary Outcome Measure Information:
Title
The number of participants that do not require a reduction in drug dose for more than 21 days due to adverse events.
Description
We will count the number of participants that do not require a reduction in drug dose of more than 21, non-continuous days due to adverse events. Tolerability will be assessed during continuous treatment. If the medication dosage increase results in the reoccurrence of a moderate adverse event or serious adverse event, lasting more than 21 days, then the event would be defined as "not tolerated". If adverse events resolve before 21 days, then participants will attempt to again up-titrate the Pirfenidone dose, as tolerated. If at least 25% of participants tolerate the drug, then investigators will deem that this study demonstrates adequate tolerability to proceed to a larger trial to examine drug efficacy.
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
The number of participants that permanently discontinue drug due to adverse events.
Description
We will count the number of patients that permanently discontinue Pirfenidone due to adverse events. A permanent discontinuation of drug is defined as discontinuation of the drug for more than 42 days.
Time Frame
52 weeks
Title
The number of participants that temporarily discontinue drug due to adverse events.
Description
We will count the number of participants that temporarily discontinue Pirfenidone due to adverse events. A temporary discontinuation of drug is defined as discontinuation of the drug for less than or equal to 42 days.
Time Frame
52 week
Title
The number of patients that experience treatment-emergent adverse events
Description
Treatment emergent events are defined as those that start or worsen after the start of study treatment and up to 28 days after the last dose of study treatment. AEs will be summarized by treatment group, system organ class, and preferred term, and also by the event's relationship to study treatment. At each level of summation, patients will be counted only once, under the greatest severity and strongest study-drug relationship (as reported by the investigator).
Time Frame
56 week
Title
The number of patients that experience treatment-emergent serious adverse events (SAEs)
Description
Serious adverse events (SAEs) are defined as those that result in: (i) death or are life threatening; (ii) result in hospitalization or prolong hospitalization; or (iii) result in disability (disruption of the participant's ability to conduct normal daily activities). Serious adverse events will be summarized by treatment group, system organ class, and preferred term, and also by the event's relationship to study treatment. At each level of summation, patients will be counted only once, under the greatest severity and strongest study-drug relationship (as reported by the investigator).
Time Frame
56 week
Title
The number of patients that experience treatment-emergent deaths during the study period and for 28 days after the last dose of study treatment.
Description
Treatment emergent deaths are defined as those that occur after the start of study treatment and up to 28 days after the last dose of study treatment and are deemed by the investigator to be related to study treatment.
Time Frame
56 week
Title
All-cause mortality
Description
We will count the total number of deaths during the study period and for 28 days after the last dose of study treatment
Time Frame
56 week
Title
The number of patients that experience treatment-emergent changes in complete blood counts.
Description
The complete blood count measures the number white blood cells (WBCs) per liter (L) including differential counts of the type of WBCs, hemoglobin concentration (g/dL), and platelet count per liter.
Time Frame
52 week
Title
The number of patients that experience treatment-emergent changes in liver function testing.
Description
We will assess treatment related changes in total bilirubin (mg/dL), AST/SGOT (units/L) or ALT/SGPT (units/L), alkaline phosphatase (units/L)
Time Frame
52 week
Title
The number of patients that experience treatment-emergent changes in serum chemistries panel.
Description
We will assess treatment related changes in potassium (mEq/L), blood urea nitrogen (mg/dL) and serum creatinine (mg/dL).
Time Frame
52 week
Title
The number of patients that experience treatment-emergent changes in the corrected QT-interval on electrocardiogram.
Description
We will evaluate changes in the interval from ventricular depolarization (Q-wave) to ventricular repolarization (T-wave) corrected for by heart rate
Time Frame
52 week
Title
Body mass index
Description
We will measure changes in the participant's height (meters) and weight (kg) to determine changes in body mass index (kg/m^2)
Time Frame
52 week
Title
Oxygen saturation
Description
We will measure the participant's oxygen saturation (%) at rest on room air.
Time Frame
52 week
Title
Heart rate
Description
We will measure the participant's resting heart rate (beats per minute)
Time Frame
52 week
Title
Chronic GVHD assessment
Description
Chronic GVHD symptoms will be assessed according to NIH cGVHD global severity score. The global cGVHD severity score evaluates the severity of cGVHD in eight sites including the skin, mouth, eyes, gastrointestinal track, liver, lungs, joints and fascia, and genital track. Each organ is assigned a severity score and composite scores are calculated based on the number of organs involved and the severity score within each affected organ.
Time Frame
56 week
Other Pre-specified Outcome Measures:
Title
Pulmonary function testing: spirometric change from baseline to week 52.
Description
We will measure the participant's Forced Expiratory Volume in 1 second (FEV1: L, % predicted), and Forced Vital Capacity (FVC: L, % predicted)
Time Frame
52 week
Title
Pulmonary function testing: diffusion capacity for carbon monoxide (DLCO) change from baseline to week 52.
Description
We will measure DLCO (ml/min/mmHg)
Time Frame
52 week
Title
Change from Baseline to Week 52 in % air trapping as measured by volumetric CT thorax with lung density analysis
Description
We will use lung density analysis to radiographically quantify the percent air trapping between an inspiratory and expiratory CT scan.
Time Frame
52 week
Title
BOS-related mortality
Description
We will count the number of participant deaths that are attributable to BOS.
Time Frame
52 week
Title
Change from Baseline to Week 24 and 52 in dyspnea, as measured by the University of California at San Diego Shortness-of-Breath Questionnaire (UCSD SOBQ) score
Description
Changes in dyspnea, as measured by UCSD SOBQ score, from Baseline to Week 26 and 52 will be analyzed using the same methods described in Section 5.4.2.1. Baseline UCSD SOBQ score will be the average of the measurements recorded at the Screening and Day 1 visits. The UCSD SOBQ score will be repeated at Week 26 and 52. The magnitude of the treatment effect of pirfenidone will be presented as the distribution (number and percentage) of patients across two categories of change from Baseline:
Increase of ≥ 25 points in the UCSD SOBQ score at Week 26 and 52 or death before Week 52
Decrease of ≥ 0
Time Frame
24 and 52 week
Title
Change from Baseline to Week 24 and 52 in Chronic GVHD (cGVHD) response
Description
The Lee cGVHD symptom scale contains 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy and psychological), using a 5-point Likert scale. Scores are linearly transformed to a 0-100 scale with higher values representing more severe symptoms. A summary score also is calculated if 4 or more subscales are available for scoring. Change in GVHD symptoms as measured by the Lee GVHD-symptom scale from Baseline to Week 26 and 52 will be evaluated.
Time Frame
24 and 52 week
Title
Cumulative systemic corticosteroid exposure
Description
We will calculate the cumulative Prednisone dose (mg, or its corticosteroid equivalent) used by each participant over the trial period.
Time Frame
52 week
Title
Use of other immunosuppressive medications
Description
We will calculate the type and the cumulative dose (mg) of other immune suppressive medications used by each participant over the trial period.
Time Frame
52 week
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age > 18 years at randomization
Clinical symptoms (e.g., dyspnea or cough) consistent with BOS of ≥ 2 months duration
Presence of cGVHD in an organ other than lung
Subjects must have had recent pulmonary function test (PFTs) measured for at least 3 months prior to study enrollment that show:
A decrease in %FVC and/or %FEV1 ≥ 20% at Screening compared with pre-transplant baseline.
Bronchodilator response on PFT testing that results in an FEV1 < 75%
Diagnosis of BOS by one of the following criteria:
Transbronchial or surgical lung biopsy demonstrating the obliterative bronchiolitis lesion
Volumetric CT scan with lung density analysis with ≥ 28% air trapping (1).
NIH-based PFT criteria for the diagnosis of BOS: FEV1/FVC <0.7 and FEV1 < 75%
Evidence of clinical improvement after treatment for BOS has been initiated.
No features supporting an alternative diagnosis by transbronchial biopsy, bronchoalveolar lavage (BAL), surgical lung biopsy, culture and non-culture based data, if performed
Adequate organ and marrow function including: liver function as defined by a total bilirubin below the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; AST/SGOT or ALT/SGPT < 3 x ULN; alkaline phosphatase < 2.5 x ULN; renal function as defined by a CrCl > 30 mL/min, calculated using the Cockcroft-Gault formula; cardiac electrophysiologic stability as defined by an electrocardiogram (ECG) with a QTc interval < 500 msec at Screening; and bone marrow function as defined by a white blood cell count > 3 K/µL, an absolute neutrophil count > 15 K/µL and a platelet count > 20 K/µL
Life expectancy > 6 months
Participants must be able to understand and sign a written informed consent form and understand the importance of adherence to study treatment and protocol. In addition, participants must demonstrate a willingness to follow all study requirements, including the concomitant medication restrictions, throughout the study
Exclusion Criteria:
Any condition that, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone e.g., presence of active GVHD of the gastrointestinal tract as manifested by rising liver function tests (LFTs) prior to initiation of study treatment
Uncontrolled infection
Major surgery within the past 2 months
The use of another investigational drug within the previous 30 days.
Inability to attend scheduled clinic visits
Inability to perform pulmonary function testing
Significant clinical change in health in the past 30 days
Body mass index (BMI) < 17.5
Life expectancy < 6 months due to any condition other than BOS that, in the opinion of the investigator, is likely to result in the death of the patient.
History of unstable or deteriorating cardiac or pulmonary disease (other than BOS) within the previous 6 months, including but not limited to the following:
Unstable angina pectoris or myocardial infarction
Congestive heart failure requiring hospitalization
Uncontrolled clinically significant arrhythmias
Pregnancy or lactation.
Family or personal history of long QT syndrome
Investigational therapy, defined as any drug that has not been approved for marketing for any indication in cGVHD will be restricted from the study
The following medications may significantly increase the level of Pirfenidone and should not be taken concurrently including: fluvoxamine, ciprofloxacin > 500mg twice daily, systemically administered aminolevulinic acid, vemurafenib and enoxacin. Any other strong inhibitors of P450 isoenzymes CYP1A2, CYP2C9, 2C19, 2D6, and 2E1 should be avoided. Participants that cannot take alternative medications to those listed above will be excluded from this study.
Laboratory Exclusions
Any of the following LFT criteria above specified limits: total bilirubin above the upper limit of normal (ULN), excluding patients with Gilbert's syndrome; aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >3 × ULN; alkaline phosphatase >2.5 × ULN
Creatinine clearance (CrCl) <30 mL/min, calculated using the Cockcroft-Gault formula
Electrocardiogram (ECG) with a QTc interval >500 msec at Screening
Medication Exclusions
1. Prior use of pirfenidone or known hypersensitivity to any of the components of study treatment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joe L Hsu, MD, MPH
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35641662
Citation
Matthaiou EI, Sharifi H, O'Donnell C, Chiu W, Owyang C, Chatterjee P, Turk I, Johnston L, Brondstetter T, Morris K, Cheng GS, Hsu JL. The safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome after hematopoietic cell transplant (STOP-BOS) trial. Bone Marrow Transplant. 2022 Aug;57(8):1319-1326. doi: 10.1038/s41409-022-01716-4. Epub 2022 May 31.
Results Reference
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The Safety and Tolerability of Pirfenidone for BOS After HCT
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