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A Phase 2a Study to Assess Safety, Daily Symptoms, Pharmacokinetics (PK), and Biomarkers of YPL-001 in Chronic Obstructive Pulmonary Disease (COPD) Patients

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ClinicalTrials.gov Identifier: NCT02272634
Recruitment Status : Recruiting
First Posted : October 23, 2014
Last Update Posted : August 22, 2017
Sponsor:
Information provided by (Responsible Party):
Yungjin Pharm. Co., Ltd.

Brief Summary:
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, double dummy, 3-treatment, parallel study, with low and high YPL 001 doses (low dose and high dose twice daily [BID]) and a placebo control in moderate to severe Chronic Obstructive Pulmonary Disease (COPD) patients.

Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Drug: YPL-001 low dose Drug: YPL-001 high dose Drug: placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 61 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker Variations After Administration of Either YPL-001, or Placebo in Patients With Moderate-to-Severe Chronic Obstructive Pulmonary Disease
Actual Study Start Date : June 4, 2015
Estimated Primary Completion Date : October 31, 2017
Estimated Study Completion Date : October 31, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arm Intervention/treatment
Experimental: YPL-001 low dose
Active arm including patients who receive the YPL-001 low dose
Drug: YPL-001 low dose
twice daily [BID]

Experimental: YPL-001 high dose
Active arm including patients who receive the YPL-001 high dose
Drug: YPL-001 high dose
twice daily [BID]

Placebo Comparator: placebo
Control arm including patients who receive the placebo drug
Drug: placebo
twice daily [BID]




Primary Outcome Measures :
  1. Safety and tolerability of multiple doses of YPL-001 as assessed by number of adverse events (AEs) [ Time Frame: Up to Day 70 ]
    An AEs means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. The number of AEs will be collected until the follow-up contact.

  2. Safety and tolerability of multiple doses of YPL-001 as assessed by clinical laboratory tests [ Time Frame: Up to Day 56 ]
    Clinical laboratory assessments will perform hematology, serum chemistry, serology, serum pregnancy test, urinalysis, and urine drug and alcohol screen. Hematology, chemistry, and urinalysis will be collected at baseline and on days 29 and 55.

  3. Safety and tolerability of multiple doses of YPL-001 as assessed by vital signs [ Time Frame: Up to Day 56 ]
    Measurements of vital signs (body temperature, respiratory rate, blood pressure, and heart rate) will be measured as schedule. When performed prior to the morning dose, blood pressure and heart rate will be measured within 2 hours prior to dosing. When scheduled, post dose vital signs readings will be performed within approximately 10 minutes of the scheduled time point. When performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood pressure, and heart rate) will be monitored continuously until the end of the procedure.

  4. Safety and tolerability of multiple doses of YPL-001 as assessed by 12-lead electrocardiogram (ECG) [ Time Frame: Up to Day 56 ]
    Standard 12-lead ECG will be performed at the time points. Patients will be required to lie quietly in a supine position for at least 1 minute prior to ECG measurements. ECG parameters will be included pulse rate (PR), QT, and QT duration corrected for heart rate by Bazett's formula (QTcB intervals).

  5. Safety and tolerability of multiple doses of YPL-001 as assessed by physical examination [ Time Frame: Up to Day 56 ]
    All full physical examinations will include, at a minimum, assessment of the following systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular system, gastrointestinal system, neurological condition, blood and lymphatic systems, and the musculoskeletal system.

  6. Safety and tolerability of multiple doses of YPL-001 as assessed by pulse oximetry [ Time Frame: Up to Day 56 ]
    Oxygen levels, saturation [%], and heart rate will be assessed using a pulse oximeter and measured with 2 hours of bronchoscopy procedures.


Secondary Outcome Measures :
  1. Change From Baseline in Peak Expiratory Flow (PEF) [ Time Frame: Up to Day 56 ]
    The PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period to Day 56 of the Treatment Period. Three measurements will be made at each time point using a hand held PEF meter. Readings not performed in the clinical research unit (CRU) will be recorded in the patient e-diary. All PEF assessments should be performed before administration of a bronchodilator where possible.

  2. Change From Baseline in Symptoms of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation [ Time Frame: Up to Day 56 ]
    Patient will be asked to record the major (sputum quality, color, consistency) and minor (cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation via the e-diary before each dosing.

  3. Change From Baseline in Dyspnea (Modified Borg Dyspnea Scale) [ Time Frame: Up to Day 56 ]
    Severity level of patient's dyspnea will be accessed via the modified Borg dyspnea scale programmed within the e-diary. The modified Borg dyspnea scale is a self-administered categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) corresponds to the sensation of normal breathing (absence of dyspnea) and 10 corresponds to the patient's maximum possible sensation of dyspnea.

  4. Change From Baseline in Duke Activity Status Index (DASI) [ Time Frame: Up to Day 56 ]
    Patient's functional capacity and activity status will be accessed via the DASI programmed within the e-diary. DASI is a self-administered 12-item questionnaire that assesses daily activities such as personal care, ambulation, household tasks, sexual function and recreation with respective metabolic costs. Each item has a specific weight based on the metabolic cost. The final score ranges between 0 and 58.2 points.


Other Outcome Measures:
  1. Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Baseline (Day -1), Day 15, 29, 43, 55 ]
    Forced expiratory volume in 1 second (FEV1) is the amount of air that can be exhaled in one second. FEV1 will be measured by spirometry performed at approximately the same time of day on each visit to avoid diurnal variation. A positive change from baseline in FEV1 will indicate improvement in lung function.

  2. Change From Baseline in Forced Vital Capacity (FVC) [ Time Frame: Baseline (Day -1), Day 15, 29, 43, 55 ]
    Forced vital capacity (FVC) is the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC will be measured by spirometry performed at approximately the same time of day on each visit to avoid diurnal variation. A positive change from baseline in FVC will indicate improvement in lung function.

  3. Change From Baseline in Inspiratory Capacity (IC) [ Time Frame: Baseline (Day -1), Day 15, 29, 43, 55 ]
    Inspiratory capacity (IC) is the maximum volume of air that can be inhaled into the lungs from the normal resting position after breathing out normally. IC will be measured by spirometry performed at approximately the same time of day on each visit to avoid diurnal variation.

  4. Change From Baseline in Forced Expiratory Volume in 1 Second/Forced Vital Capacity (FEV1/FVC) Ratio [ Time Frame: Baseline (Day -1), Day 15, 29, 43, 55 ]
    The ratio is calculated as the amount of air expelled from the lungs in one second after a full inspiration (FEV1) divided by the volume of air that can forcibly be blown out after a full inspiration (FVC).

  5. Change From Baseline in Dyspnea (Baseline Dyspnea Index/Transition Dyspnea Index [BDI/TDI]) [ Time Frame: Baseline (Day -1), Day 15, 29, 43, 55 ]
    Dyspnea at baseline (Day -1) will be assessed with the Baseline Dyspnea Index (BDI). This instrument has 3 domains (functional impairment, magnitude of task and magnitude of effort) with the values added for a combined focal score. Functional impairment determines the impact of breathlessness on the ability to carry out activities; magnitude of task determines the type of task that causes breathlessness, magnitude of effort establishes the level of effort that results in breathlessness. The BDI scores range from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal score consisting of the sum of each domain (0 to 12). Dyspnea throughout the study will be performed at the time points. The change from baseline is measured by the Transition Dyspnea Index (TDI) score which ranges from -3 (major deterioration) to +3 (major improvement) for each domain with the TDI focal score consisting in the sum of each domain (-9 to +9).

  6. Change From Baseline in Chronic Obstructive Pulmonary Disease Assessment Test (CAT) [ Time Frame: Baseline (Day -1), Day 15, 29, 43, 55 ]
    The chronic obstructive pulmonary disease assessment test (CAT) is a short and simple questionnaire of 8 items completed by patients to be performed at the time points. Scores for each of the 8 items are summed to give a single, final score ranging from 0 (no impact on daily activities) to 40 (very high impact on daily activity).

  7. Change in Percentage of Total Cells in Bronchoalveolar Lavage (BAL) [ Time Frame: Baseline (Day -1) and Day 55 ]
    The bronchoalveolar lavage (BAL) samples will be collected at baseline and again at the completion of the study for pharmacodynamics (PD) assessments of biomarkers. BAL samples will be at analyzed for total cell count (cells/mL) of macrophages, lymphocytes, and eosinophils as a percentage of total cells.

  8. Change in Absolute Number of Total Cells in Bronchoalveolar Lavage (BAL) [ Time Frame: Baseline (Day -1) and Day 55 ]
    The bronchoalveolar lavage (BAL) samples will be collected at baseline and again at the completion of the study for pharmacodynamics (PD) assessments of biomarkers. BAL samples will be analyzed for total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils as absolute inflammatory cell numbers.

  9. Change in Concentrations of Cytokines in Bronchoalveolar Lavage (BAL) [ Time Frame: Baseline (Day -1) and Day 55 ]
    The bronchoalveolar lavage (BAL) samples will be collected at baseline and again at the completion of the study for pharmacodynamics (PD) assessments of biomarkers. BAL samples will be analyzed for concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, Myeloperoxidase (MPO), neutrophil elastase, monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9).

  10. Change in Inflammatory Markers in Blood [ Time Frame: Day 1, 15, 29, 43, 56 ]
    The blood samples will be collected at the the time points of the study for pharmacodynamics (PD) assessments of biomarkers. The blood samples will be analyzed for inflammatory markers (total and differential cell counts as absolute and percentage for neutrophils, macrophages, eosinophils and lymphocytes).

  11. Change in Concentrations of Cytokines in Blood [ Time Frame: Day 1, 15, 29, 43, 56 ]
    The blood samples will be collected at the the time points of the study for pharmacodynamics (PD) assessments of biomarkers. The blood samples will be analyzed for concentrations of C-reactive protein (CRP), fibrinogen, TNF-alpha, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and MMP-9.

  12. Pharmacokinetic (PK) Parameters for YPL-001 [ Time Frame: Day 1, 15, 29, 43, 56 ]
    PK parameters, including area under the drug concentration-time curve (AUC) values, maximum plasma concentration (Cmax), concentration at the end of a dosing interval [C(trough)], time of the maximum drug concentration (tmax), oral clearance (CL/F), total body clearance estimated at steady-state after oral administration (CLss/F), apparent volume of distribution at the terminal phase (Vz/F), and apparent elimination half-life (t1/2), as appropriate, will be calculated from plasma concentrations. Samples will be collected prior to the initial dosing and through 12 hours following dosing at pre-dose, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours on Days 1 and 56 to determine concentrations in plasma. Pre-dose samples will also be collected in the morning of Days 15, 29, 43 and 56 for concentration at the end of a dosing interval [C(trough)], determination.



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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult males and/or females, 40 to 80 years of age (inclusive).
  • History of COPD for at least 12 months prior to screening.
  • Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at least 12 months prior to screening.
  • Classified as moderate to severe COPD based on the current severity classification GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening
  • etc.

Exclusion Criteria:

  • History of life-threatening COPD including respiratory arrest, intensive care unit admission and/or requiring intubation.
  • History of more than 2 hospitalizations for COPD within 12 months prior to screening.
  • Presentation of an acute exacerbation of COPD that will be associated with increase sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in Period.
  • Evidence of pulmonary heart disease, or clinically significant pulmonary hypertension.
  • etc.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02272634


Contacts
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Contact: Gerard J Criner, MD 1-215-707-8113

Locations
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United States, Alabama
UAB Lung Health Center Recruiting
Birmingham, Alabama, United States, 35249
Contact: Mark T Dransfield, MD, Ph.D.    205-934-5555    mdrans99@uab.edu   
Contact: James M Wells, MD, Ph.D.    205-934-6047    jmwells@uab.edu   
United States, Florida
Florida Pulmonary Research Institute, LLC Recruiting
Winter Park, Florida, United States, 32789
Contact: Faisal Fakih, MD    407-740-8078      
United States, Ohio
Aventiv Research Inc. Recruiting
Columbus, Ohio, United States, 43213
Contact: Samir Arora, MD    614-501-6164      
United States, Pennsylvania
Temple Lung Center, Temple University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 191140
Contact: Gerard J Criner, MD, Ph.D.    215-707-8113    Gerard.Criner@tuhs.temple.edu   
Contact: Victor Kim, MD, Ph.D.    215-707-3336    victor.kim@tuhs.temple.edu   
Sponsors and Collaborators
Yungjin Pharm. Co., Ltd.
Investigators
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Principal Investigator: Gerard J Criner, MD Temple University
Principal Investigator: Mark T Dransfield, MD The Kirklin Clinic of UAB Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Yungjin Pharm. Co., Ltd.
ClinicalTrials.gov Identifier: NCT02272634     History of Changes
Other Study ID Numbers: YPL-001_YJP-130403
First Posted: October 23, 2014    Key Record Dates
Last Update Posted: August 22, 2017
Last Verified: August 2017

Keywords provided by Yungjin Pharm. Co., Ltd.:
COPD

Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases