Safety and Efficacy of Itacitinib in Participants With Bronchiolitis Obliterans Syndrome Following Lung Transplantation
- Registration Number
- NCT03978637
- Lead Sponsor
- Incyte Corporation
- Brief Summary
The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of itacitinib in participants with post-lung transplant bronchiolitis obliterans syndrome (BOS).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 23
-
Double lung transplantation ≥ 1 year before informed consent. Confirmed BOS progression to Grade 1, 2, or 3 diagnosed within 1 year of screening
*Confirmed BOS progression to Grade 1, 2, or 3 diagnosed within 2 years of screening AND:
-
A ≥ 200 mL decrease in FEV1 in the previous 12 months
OR
*A ≥ 50 mL decrease in FEV1 in the last 2 measurements.
• Willingness to avoid pregnancy or fathering children.
- History of a single lung transplant
- FEV1 decline attributable to cause(s) other than BOS.
- Participants who have had any significant change (eg, addition of new agents) in an immunosuppressive regimen in the 4 weeks before screening.
- Untreated and/or symptomatic gastroesophageal reflux disease.
- Significant infectious comorbidities including invasive fungal disease, B. Cepacia, non TB mycobacteria, or TB.
- Receipt of JAK inhibitor therapy after lung transplant for any indication. Treatment with a JAK inhibitor before lung transplant is permitted.
- Laboratory values at screening outside the protocol-defined ranges.
- Active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (ie, positive HBsAg).
- Known HIV infection.
- History of active malignancy within 3 years of screening.
- Women who are pregnant or breastfeeding.
- Treatment with an investigational agent, procedure, or device within 30 days of enrollment, or within 5 half-lives of the investigational product, whichever is longer.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Itacitinib 300 mg Itacitinib Phase 1: Itacitinib 300 mg twice daily. There can be required dose adjustments in the protocol for concurrent CYP3A administration. Itacitinib 400 mg Itacitinib Phase 1: Itacitinib 400 mg once daily. There can be required dose adjustments in the protocol for concurrent CYP3A administration. Itacitinib 600 mg Itacitinib Phase 1: Itacitinib 600 mg once daily. There can be required dose adjustments in the protocol for concurrent CYP3A administration Itacitinib Itacitinib Phase 2: Itacitinib administered orally at the recommended dose from Phase 1.
- Primary Outcome Measures
Name Time Method Number of Participants With Any Treatment-emergent Adverse Event (TEAE) up to approximately 162 weeks An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as either an AE reported for the first time or the worsening of a pre-existing condition after the first dose of itacitinib until 30 days after the last dose of itacitinib.
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 12 Baseline; Week 12 FEV1 was defined as the volume of air exhaled in 1 second. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Phase 2: FEV1 Response Rate Baseline through Week 12 FEV1 response rate was defined as the percentage of participants demonstrating a ≥10% absolute increase in FEV1 compared with Baseline, confirmed by 2 consecutive spirometric assessments ≥1 week apart.
Number of Participants With Any Grade 3 or Higher TEAE up to approximately 162 weeks An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. A TEAE was defined as either an AE reported for the first time or the worsening of a pre-existing condition after the first dose of itacitinib until 30 days after the last dose of itacitinib. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events v5.0. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
- Secondary Outcome Measures
Name Time Method Phase 1: Duration of FEV1 Response up to 34.9 months Duration of FEV1 response was defined as the interval between the onset of response and the earliest of bronchiolitis obliterans syndrome (BOS) progression, loss of clinical benefit as determined by the investigator, or death.
Phase 2: Duration of FEV1 Response up to 24 months Duration of FEV1 response was defined as the interval between the onset of response and the earliest of bronchiolitis obliterans syndrome progression, loss of clinical benefit as determined by the investigator, or death.
Phase 1: Time to Progression up to 36.4 months Time to progression was defined as defined as the interval between the start of treatment and bronchiolitis obliterans syndrome progression (≥10% absolute decrease in FEV1 compared to baseline), or death.
Phase 2: Time to Progression up to 24 months Time to progression was defined as defined as the interval between the start of treatment and bronchiolitis obliterans syndrome progression (≥10% absolute decrease in FEV1 compared to baseline), or death.
Phase 2: Time to Retransplantation or Death up to 24 months Time to retransplantation or death was defined as the interval between the start of treatment and the date of retransplantation or death due to any cause.
Phase 1: Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score Baseline; up to 158.4 weeks The SGRQ is a disease-specific instrument designed to measure the impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. It consists of 50 items covering 3 domains: symptoms (8 items), activity (16 items), and impacts (26 items). A component score is calculated for each of the 3 domains. One total score is calculated if none of the component scores is missing. All scales (both domain and total) have a score ranging between 0 and 100, with higher scores indicating a worse quality of life. Change from (CFB) Baseline was calculated as the post-Baseline value minus the Baseline value.
Phase 2: Change From Baseline in the SGRQ Total Score up to 24 months The SGRQ is a disease-specific instrument designed to measure the impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. It consists of 50 items covering 3 domains: symptoms (8 items), activity (16 items), and impacts (26 items). A component score is calculated for each of the 3 domains. One total score is calculated if none of the component scores is missing. All scales (both domain and total) have a score ranging between 0 and 100, with higher scores indicating a worse quality of life. Change from Baseline was to be calculated as the post-Baseline value minus the Baseline value.
Phase 1: Change From Baseline in the Quality of Life-Short Form-12 (QOL-SF-12) Questionnaire Scores Baseline; up to 158.4 weeks The QOL-SF-12 v2 is a 12-item subset of the QOL-SF-36 v2 scale that assesses 8 health concepts related to limitations in physical activities, social activities (SA), bodily pain, general mental and physical health, and vitality. Participants answered each question by selecting pre-specified choices. Score ranges are specified for each item; higher scores indicate better health. Assessment of health score: poor (1) to excellent (5). Moderate activities and climbing stairs score: limited a lot (1) to not limited at all (3). Accomplished less because of physical health (PH) or emotional problems (EP)/limited in work/did work less carefully score: all of the time (1) to none of the time (5). Pain interfered with work score: extremely (1) to not at all (5). Felt calm/peaceful, had a lot of energy, felt depressed, PH or EP interfered with SA score: none of the time (1) to all of the time (6). Change from Baseline (BL) was calculated as the post-BL value minus the BL value.
Phase 2: Change From Baseline in QOL-SF-12 Questionnaire Scores up to 24 months The QOL-SF-12 v2 is a 12-item subset of the QOL-SF-36 v2 scale that assesses 8 health concepts related to limitations in physical activities, social activities (SA), bodily pain, general mental and physical health, and vitality. Participants answered each question by selecting pre-specified choices. Score ranges are specified for each item; higher scores indicate better health. Assessment of health score: poor (1) to excellent (5). Moderate activities and climbing stairs score: limited a lot (1) to not limited at all (3). Accomplished less because of physical health (PH) or emotional problems (EP)/limited in work/did work less carefully score: all of the time (1) to none of the time (5). Pain interfered with work score: extremely (1) to not at all (5). Felt calm/peaceful, had a lot of energy, felt depressed, PH or EP interfered with SA score: none of the time (1) to all of the time (6). Change from Baseline (BL) was to be calculated as the post-BL value minus the BL value.
Phase 1: Number of Participants With the Indicated Responses on the EQ-5D-3L Questionnaire Regarding Their Health State Baseline; up to 158.4 weeks The EQ-5D-3L essentially consists of 2 components: the EQ-5D descriptive scale and the EQ-VAS. The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. Each dimension has 3 levels: no problems, some problems, and extreme problems. At each specific visit (starting on Day 1), the participant was asked to indicate their health state. BL=Baseline; EOT=end of treatment.
Phase 2: Number of Participants With the Indicated Responses on the EQ-5D-3L Questionnaire Regarding Their Health State up to 24 months The EQ-5D-3L essentially consists of 2 components: the EQ-5D descriptive scale and the EQ-VAS. The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. Each dimension has 3 levels: no problems, some problems, and extreme problems. At each specific visit (starting on Day 1), the participant was asked to indicate their health state.
Phase 1: Cmax of Itacitanib pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4 Cmax was defined as the maximum observed concentration of itacitanib.
Phase 2: Cmax of Itacitanib pre-dose and 1, 2, and 5 hours post-dose at Week 4 Cmax was defined as the maximum observed concentration of itacitanib.
Phase 1: AUC0-24h of Itacitanib pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4 AUC0-24h was defined as the area under the plasma concentration-time curve over the last 24-hour dosing interval.
Phase 2: AUC0-24h of Itacitanib pre-dose and 1, 2, and 5 hours post-dose at Week 4 AUC0-24h was defined as the area under the plasma concentration-time curve over the last 24-hour dosing interval.
Phase 1: Tmax of Itacitanib pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4 tmax was defined as the time to the maximum observed concentration of itacitanib.
Phase 2: Tmax of Itacitanib pre-dose and 1, 2, and 5 hours post-dose at Week 4 tmax was defined as the time to the maximum observed concentration of itacitanib.
Phase 1: Ctau of Itacitanib pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4 Ctau was defined as the observed itacitanib concentration at the end of the dosing interval.
Phase 2: Ctau of Itacitanib pre-dose and 1, 2, and 5 hours post-dose at Week 4 Ctau was defined as the observed itacitanib concentration at the end of the dosing interval.
Trial Locations
- Locations (9)
Brigham and Women'S Faulkner Hospitals Inc
🇺🇸Boston, Massachusetts, United States
Temple University Department of Thoracic Medicine and Surgery
🇺🇸Philadelphia, Pennsylvania, United States
Universitaire Ziekenhuis Leuven - Gasthuisberg
🇧🇪Leuven, Belgium
UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Duke University Health System
🇺🇸Durham, North Carolina, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
University of California, Los Angeles - David Geffen School of Medicine
🇺🇸Los Angeles, California, United States
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University Health Network Toronto General Hospital
🇨🇦Toronto, Ontario, Canada