Safety and Efficacy of Itacitinib in Participants With Bronchiolitis Obliterans Syndrome Following Lung Transplantation

Phase 2TerminatedNCT03978637

Incyte Corporation23 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

ItacitinibDRUG

Itacitinib administered orally at the specified dose.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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. Exclusion Criteria: * 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.

Locations (9)

University of California, Los Angeles - David Geffen School of Medicine

Los Angeles, California, United States

Brigham and Women'S Faulkner Hospitals Inc

Boston, Massachusetts, United States

Duke University Health System

Durham, North Carolina, United States

Outcomes

Primary Outcomes

Number of Participants With Any Treatment-emergent Adverse Event (TEAE)

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.

Time frame: up to approximately 162 weeks

Number of Participants With Any Grade 3 or Higher TEAE

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.

Time frame: up to approximately 162 weeks

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at 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.

Time frame: Baseline; Week 12

Phase 2: FEV1 Response Rate

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Phase 1: Duration of FEV1 Response

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.

Time frame: up to 34.9 months

Phase 2: Duration of FEV1 Response

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.

Time frame: up to 24 months

Phase 1: Time to Progression

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.

Time frame: up to 36.4 months

Phase 2: Time to Progression

Time frame: up to 24 months

Phase 1: Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score

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.

Time frame: Baseline; up to 158.4 weeks

Phase 2: Change From Baseline in the SGRQ Total Score

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.

Time frame: up to 24 months

Phase 1: Change From Baseline in the Quality of Life-Short Form-12 (QOL-SF-12) Questionnaire Scores

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.

Time frame: Baseline; up to 158.4 weeks

Phase 2: Change From Baseline in QOL-SF-12 Questionnaire Scores

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.

Time frame: up to 24 months

Phase 1: Number of Participants With the Indicated Responses on the EQ-5D-3L Questionnaire Regarding Their Health State

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.

Time frame: Baseline; up to 158.4 weeks

Phase 2: Number of Participants With the Indicated Responses on the EQ-5D-3L Questionnaire Regarding Their Health State

Time frame: up to 24 months

Phase 1: Cmax of Itacitanib

Cmax was defined as the maximum observed concentration of itacitanib.

Time frame: pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4

Phase 2: Cmax of Itacitanib

Cmax was defined as the maximum observed concentration of itacitanib.

Time frame: pre-dose and 1, 2, and 5 hours post-dose at Week 4

Phase 1: AUC0-24h of Itacitanib

AUC0-24h was defined as the area under the plasma concentration-time curve over the last 24-hour dosing interval.

Time frame: pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4

Phase 2: AUC0-24h of Itacitanib

AUC0-24h was defined as the area under the plasma concentration-time curve over the last 24-hour dosing interval.

Time frame: pre-dose and 1, 2, and 5 hours post-dose at Week 4

Phase 1: Tmax of Itacitanib

tmax was defined as the time to the maximum observed concentration of itacitanib.

Time frame: pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4

Phase 2: Tmax of Itacitanib

tmax was defined as the time to the maximum observed concentration of itacitanib.

Time frame: pre-dose and 1, 2, and 5 hours post-dose at Week 4

Phase 1: Ctau of Itacitanib

Ctau was defined as the observed itacitanib concentration at the end of the dosing interval.

Time frame: pre-dose and 1, 2, and 5 hours post-dose on Day 1 (Baseline) and at Week 4

Phase 2: Ctau of Itacitanib

Ctau was defined as the observed itacitanib concentration at the end of the dosing interval.

Time frame: pre-dose and 1, 2, and 5 hours post-dose at Week 4

Phase 2: Time to Retransplantation or Death

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.

Time frame: up to 24 months