Clinical trial NCT02662582: A Study to Assess the Effect of CK-2127107 on Physical Function in Subjects With Chronic Obstructive Pulmonary Disease
Official title: A Phase 2a, Randomized, Double-blind, Placebo-controlled, Two Period, Crossover Study to Assess the Effect of CK-2127107 on Physical Function in Subjects With Chronic Obstructive Pulmonary Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Chronic Obstructive Pulmonary Disease
CK-2127107
COPD
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Cytokinetics
First posted: 2016-01-25
Enrollment: 46
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to assess the effect of CK-2127107 relative to placebo on cycle ergometer exercise tolerance, assessed as change from period baseline in constant work rate (CWR) endurance time, utilizing a breath-by-breath metabolic measurement system with integrated electrocardiogram (ECG). The time to intolerance was assessed by a stopwatch and verified from electronic recordings of the cycle ergometer.

This study assessed cardiopulmonary and neuromuscular effects of CK-2127107 relative to placebo; the effect of CK-2127107 on resting spirometry relative to placebo; the safety and tolerability of CK-2127107 as well as the pharmacokinetics of CK-2127107.

Detailed description: Enrolled participants were randomly assigned to 1 of 2 treatment sequences and received both CK-2127107 and matching placebo over 2 treatment periods.

Eligibility criteria: Inclusion Criteria:

* Subject has a body mass index (BMI) of 18-35 kg/m2 inclusive.
* Subject must have all of the following:

  * Clinical diagnosis of moderate to severe COPD, with a postbronchodilator FEV1/FVC ratio \< 70% and 30% ≤ FEV1 \< 65% predicted at screening. The predicted values for normal spirometry will be those recommended by the American Thoracic Society (ATS) / European Respiratory Society (ERS) \[Miller et al, 2005\].
  * General stable health with no change in medication (including non-COPD agents and dietary aids/food supplements) within 2 weeks prior to screening, no systemic corticosteroid administration (topical or inhaled corticosteroids are allowed) within 6 weeks prior to screening, no exacerbations or hospitalization within 6 weeks prior to screening.
  * Current or ex-smokers with a smoking history of at least 10 pack years.
  * Grade of 2 or 3 on the Modified Medical Research Council (mMRC) Dyspnea Scale at screening:

    1. Grade 2: walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level.
    2. Grade 3: stops for breath after walking about 100 meters or after a few minutes on the level.
* Subject is able to complete technically acceptable respiratory muscle strength tests, spirometry, physical performance test and exercise tests.
* Female subject must either:

  * Be of non-child bearing potential: Postmenopausal (defined as at least 1 year without any menses) prior to screening, or documented surgically sterile.
  * Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 28 days after the last dose, and have a negative serum pregnancy test at screening, and, if heterosexually active, agree to consistently use 2 forms of highly-effective birth control (at least 1 of which must be a barrier method) starting at screening, throughout the study, and for 28 days after the last dose.
* Female subject must agree not to breastfeed starting at screening and throughout the study and for 28 days after the last dose.
* Female subject must not donate ova starting at screening, throughout the study and for 28 days after the last dose.
* Male subject and their female spouse/partners who are of childbearing potential must be using highly effective form of contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method) starting at screening, and continuing throughout the study and for 90 days after the last dose.
* Male subject must not donate sperm starting at screening, throughout the study and for 90 days after the last dose.
* Subject agrees not to participate in another interventional study from screening through the follow-up visit (FUV) of the study.

Exclusion Criteria:

* Subject has previously enrolled in a clinical study of CK-2127107.
* Subject has any clinically significant abnormality following the investigator's review of the physical examination, ECG and protocol-defined clinical laboratory tests at screening. A significant abnormality is defined as an abnormality which, in the opinion of the investigator, may (i) put the subject at risk because of participation in the study, (ii) influence the results of the study or (iii) cause concern regarding the subject's ability to participate in the study.
* Subject has any of the liver function tests (LFTs; i.e., aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase \[ALP\], γ-glutamyl transferase \[GGT\] and/or total bilirubin \[TBL\]) above 1.5 times the upper limit of normal (ULN) at screening. These assessments may be repeated once at the investigator's discretion (within the screening window).
* Subject has an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 by the Cockcroft-Gault equation at screening.
* Subject has a serious cardiovascular disease, including a current New York Heart Association (NYHA) class III or IV congestive heart failure or clinically significant valvular disease, history of cardiac arrest, uncontrolled angina or arrhythmia, untreated serious conduction disorder (e.g., third-degree heart block), or acute myocardial ischemic condition suspected on the ECG at screening (e.g., ST-segment elevation, ST-segment depressions \> 2 mm).
* Subject has had a myocardial infarction or other acute coronary syndrome, major heart surgery (i.e., valve replacement or bypass surgery), stroke, deep vein thrombosis or pulmonary embolus in the 6 months prior to screening.
* Subject has known active tuberculosis.
* Subject has undergone thoracotomy with pulmonary resection (except for sub-lobar resection).
* Subject has resting pulse \< 40 bpm or \> 100 bpm; resting systolic blood pressure \> 160 mm Hg or \< 90 mm Hg; resting diastolic blood pressure \> 100 mm Hg at screening. These assessments may be repeated once at the investigator's discretion (within the screening window).
* Subject desaturates to SpO2 \< 85% for at least 1 minute on screening IET.
* Subject has a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnea/shortness of breath (considered to be due to COPD), such as arthritis in the leg, angina pectoris, heart failure, claudication or morbid obesity.
* Subject has a CWR cycle ergometry endurance time less than 4 or greater than 8 minutes after WR adjustment procedures.
* Subject has used the following drugs within 14 days prior to day -1:

  * Strong cytochrome P450 (CYP)3A4 inhibitor (e.g., itraconazole, clarithromycin).
  * Strong CYP3A4 inducer (e.g., barbiturates, rifampin).
* Subject has hemoglobin (Hb) concentration below 10.0 g/dL at screening.
* Subject has a cancer requiring treatment currently or in the past 3 years (except primary nonmelanoma skin cancer, carcinoma in situ or cancers that have an excellent prognosis such as early stage breast or prostate cancer).
* Subject giving a history of asthma, allergic rhinitis or atopy shall be evaluated by the investigator to determine whether the subject's predominant diagnosis is COPD rather than asthma.
* Subject has neurological conditions or neuromuscular diseases that are causing impaired muscle function or mobility.
* Subject has a current diagnosis of schizophrenia, other psychotic disorders or bipolar disorder.
* Subject in the active phase of pulmonary rehabilitation or had completed pulmonary rehabilitation or exercise training within the 13 weeks prior to screening.
* Subject has severe and/or uncontrolled medical conditions that could interfere with the study (e.g., severe neurological deficit after stroke, developed diabetic peripheral neuropathy, respiratory diseases requiring daytime supplemental oxygen, infection, gastrointestinal disorder, uncontrolled pain or any other non-stable illness) as judged by the medical investigator.
* Subject has a known history of positive test for hepatitis B surface antigen (HBsAg) or hepatitis C antibody or history of a positive test for human immunodeficiency virus (HIV) infection.
* Subject has a history of alcoholism or drug/chemical substance abuse within 2 years prior to screening.
* Subject has used any medications known to affect physical function or muscle mass including androgen supplements, anti-androgens (such as luteinizing hormone-releasing hormone \[LHRH\] agonists), anti-estrogen (tamoxifen, etc.), recombinant human growth hormone (rhGH), insulin, oral beta adrenergic agonists, megestrol acetate, dronabinol, metformin or other drugs which, in the opinion of the investigator, might influence physical function or muscle mass within 6 weeks prior to screening.
* Subject has participated in any interventional clinical study or has been treated with any investigational drugs within 28 days or 5 half-lives whichever is longer, prior to the initiation of screening.
* Subject has any other condition that in the opinion of the investigator precludes the subject's participation in the trial.

Primary outcomes:
measure: Change From Period Baseline at Week 2 in Constant Work Rate (CWR) Endurance Time Relative to Placebo
timeFrame: Baseline and week 2 of each treatment period
Secondary outcomes:
measure: Change From Period Baseline at Week 2 in Oxygen Uptake (VO2)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Ventilation (VE)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Ventilatory Equivalent for Carbon Dioxide (VE/VCO2)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Inspiratory Capacity (IC) Change From Peak to Rest
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Perceived Exertion for Dyspnea and Leg Discomfort (BORG CR10)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Respiratory Exchange Ratio (RER)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Carbon Dioxide Output (VCO2)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in End-tidal PCO2 (PETCO2)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in End-tidal PO2 (PETO2)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Tidal Volume (VT)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Breathing Frequency (Bf)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Inspiratory Capacity (IC)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline to Week 2 in Inspiratory Reserve Volume (IRV)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Ventilatory Reserve (VE/MVV)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Heart Rate (HR)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Systolic Blood Pressure (SBP)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Diastolic Blood Pressure (DBP)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Arterial Oxygen Saturation From Pulse Oximetry (SpO2)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Forced Vital Capacity (FVC)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Forced Expiratory Volume 1 (FEV1)
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in FVC/FEV1 Ratio
timeFrame: Baseline and week 2 of each treatment period
measure: Change From Period Baseline at Week 2 in Activation of Accessory Respiratory Muscles
timeFrame: Baseline and week 2 of each treatment period
measure: Number of Participants With Treatment Emergent Adverse Events
timeFrame: From first dose of study drug up to 14 days after last dose of study drug (8 weeks)
measure: Plasma Concentration of CK-2127107 at Day 1 Predose, Day 14 Lowest Concentration (Ctrough), and Day 14 Concentration Predose 6 Hours (C6h)
timeFrame: Day 1 predose, day 14 Ctrough, day 14 C6h
measure: Plasma Concentration of CK-2127106 (Metabolite of CK-2127107) at Day 1 Predose, Day 14 Ctrough, Day 14 C6h
timeFrame: Day 1 predose, day 14 Ctrough, day 14 C6h
Other outcomes:
Locations:
city: Torrance
country: United States
facility: Site US10001
state: California
city: Pittsburgh
country: United States
facility: Site US10003
state: Pennsylvania
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Senior Medical Director
role: STUDY_DIRECTOR
References: