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A Study to Assess the Effect of CK-2127107 on Physical Function in Subjects With Chronic Obstructive Pulmonary Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02662582
Recruitment Status : Completed
First Posted : January 25, 2016
Last Update Posted : May 28, 2020
Sponsor:
Collaborator:
Cytokinetics
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:

The purpose of this study is 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 is assessed by a stopwatch and verified from electronic recordings of the cycle ergometer.

This study will also assess 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.


Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease (COPD) Drug: Reldesemtiv Drug: Placebo Phase 2

Detailed Description:
Enrolled participants will be randomly assigned to 1 of 2 treatment sequences and will receive both CK-2127107 and matching placebo over 2 treatment periods.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : June 30, 2016
Actual Primary Completion Date : June 8, 2018
Actual Study Completion Date : June 8, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arm Intervention/treatment
Experimental: CK-2127107 1000 mg, then placebo
Participants will first receive CK-2127107 (500 mg twice daily [1000 mg daily total]) for 14 days. After a washout period of 14 days, participants will then receive matching placebo for 14 days.
Drug: Reldesemtiv
Participants will first receive CK-2127107 as two 250-mg tablets (500 mg twice daily [1000 mg daily total]) orally for 14 days.
Other Name: CK-2127107

Drug: Placebo
Participants will first receive matching placebo orally for 14 days.

Experimental: Placebo, then CK-212710 1000 mg
Participants will first receive placebo for 14 days. After a washout period of 14 days, participants will then receive matching CK-2127107 (500 mg twice daily [1000 mg daily total]) for 14 days.
Drug: Reldesemtiv
Participants will first receive CK-2127107 as two 250-mg tablets (500 mg twice daily [1000 mg daily total]) orally for 14 days.
Other Name: CK-2127107

Drug: Placebo
Participants will first receive matching placebo orally for 14 days.




Primary Outcome Measures :
  1. Change from period baseline in Constant Work Rate (CWR) endurance time [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    The CWR defines how long it takes until the participant reaches symptom limitations while simultaneously being monitored and is called "CWR time to intolerance" which determines the "CWR endurance time".


Secondary Outcome Measures :
  1. Change from period baseline in oxygen uptake (VO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    VO2 is defined as the volume of oxygen (O2) extracted from inspired air in a given period of time.

  2. Change from period baseline in ventilation (VE) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    VE is defined as the volume of gas exhaled from the lungs in 1 minute, also called 'ventilation' or 'minute ventilation.'

  3. Change from period baseline in ventilatory equivalent for carbon dioxide (VE/VCO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    VE/VCO2 is defined as the ratio of VE to VCO2. It is a dimensionless quantity. This ratio indicates how many liters of air exhaled are breathed to eliminate 1 liter of CO2.

  4. Change from period baseline in inspiratory capacity (IC) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    IC is defined as the volume of air that can be inspired after a normal expiration; it is the sum of the tidal volume (VT) and the inspiratory reserve volume (IRV).

  5. Change from period baseline in end-tidal partial pressure of oxygen (PETO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    PETO2 is defined as the partial pressure of oxygen in the expired gas at the end of an exhalation. This represents the mean partial pressure of oxygen in the pulmonary alveoli.

  6. Change from period baseline in end-tidal partial pressure of carbon dioxide (PETCO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    PETCO2 is defined as the partial pressure of carbon dioxide in the expired gas at the end of an exhalation. This represents the mean partial pressure of carbon dioxide in the pulmonary alveoli.

  7. Change from period baseline in VT [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Tidal volume is defined as the volume of gas exhaled in each respiratory cycle. VT is typically measured as an average value over several respiratory cycles.

  8. Change from period baseline in Breathing (or breath) frequency (Bf) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Bf is defined as the number of breaths (i.e., an entire inspiratory and expiratory respiratory cycle) per minute.

  9. Change from period baseline in ventilatory reserve; also called the rate of expired ventilation to the capacity (VE/MVV) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    VE/MVV expresses the rate of expired ventilation to the capacity. Ventilatory capacity is estimated from the MVV, which will be calculated from 40 times the forced expiratory volume in 1 second (FEV1).

  10. Change from period baseline in heart rate (HR) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Vital sign of HR will be derived beat-by-beat from the electrocardiogram (ECG) and recorded to the breath-by-breath record in the Vmax breath-by-breath metabolic measurement system.

  11. Change from period baseline in systolic blood pressure (SBP) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Single measurements of resting SBP will be obtained prior to blood draws. Blood pressure will be measured on the same arm of the participant and preferably in the same position (sitting or supine).

  12. Change from period baseline in diastolic blood pressure (DBP) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Single measurements of resting DBP will be obtained prior to blood draws. Blood pressure will be measured on the same arm of the participant and preferably in the same position (sitting or supine).

  13. Change from period baseline in arterial oxygen saturation from pulse oximetry (SPO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    SPO2 is defined as the noninvasive estimation of arterial hemoglobin (Hb) oxygen saturation, using a device that utilizes the combined principles of spectrophotometry and pulse plethysmography.

  14. Change from period baseline in IRV [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    The Inspiratory reserve volume is equal to VT - IC measured in liters [IRV (L) = VT (L) - IC (L)].

  15. Change from period baseline in carbon dioxide output (VCO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    VCO2 is defined as the volume of CO2 exhaled from the body per unit of time; also called the rate of elimination of CO2.

  16. Change from period baseline respiratory exchange ratio (RER) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    The respiratory exchange ratio is equal to the VCO2 / VO2 [RER = VCO2 (L/min) / VO2 (L/min)].

  17. Change from period baseline in perceived exertion for dyspnea and leg discomfort (Borg CR10) at isotime during CWR [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    The Borg Scale (Borg CR10) is a simple 10-item method of rating perceived exertion (RPE) and collects information on perceived exertion in an individual's rating of exercise intensity. Subjects will be asked to use this scale to rate the intensity of their breathing and leg discomfort before, during, and after exercise. Scores range from 0 (Complete Rest) to 10 (Extremely Hard (almost maximal)).

  18. Change from period baseline in activation of accessory respiratory muscles (by electromyogram (EMG)) at isotime and peak exercise during CWR [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Isotime is the shortest duration of all of the CWR tests performed before and after treatment, not including screening.

  19. Change in resting spirometry [ Time Frame: Baseline and up to Day 14 of each treatment period ]
    Spirometry will measure the volume of air exhaled at specific time points during a forceful and complete exhalation after a maximal inhalation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT02662582


Locations
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United States, California
Site US10001
Torrance, California, United States, 90502
United States, Pennsylvania
Site US10003
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Cytokinetics
Investigators
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Study Director: Senior Medical Director Astellas Pharma Global Development, Inc.
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Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT02662582    
Other Study ID Numbers: 3318-CL-3002
First Posted: January 25, 2016    Key Record Dates
Last Update Posted: May 28, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
Chronic Obstructive Pulmonary Disease
CK-2127107
COPD
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases