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

• ClinicalTrials.gov Identifier: NCT02662582
• Recruitment Status: Completed
• First Posted: January 25, 2016
• Results First Posted: February 5, 2021
• Last Update Posted: March 24, 2021
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborator: Cytokinetics
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information

• First Submitted Date: January 20, 2016
• First Posted Date: January 25, 2016
• Results First Submitted Date: January 16, 2021
• Results First Posted Date: February 5, 2021
• Last Update Posted Date: March 24, 2021
• Actual Study Start Date: June 30, 2016
• Actual Primary Completion Date: June 8, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 16, 2021)

Change From Period Baseline at Week 2 in Constant Work Rate (CWR) Endurance Time Relative to Placebo [ Time Frame: Baseline and week 2 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 determined the "CWR endurance time". Positive change indicates an improvement from baseline (i.e., a favorable outcome).

• Original Primary Outcome Measures (submitted: January 20, 2016): Change from period baseline in Constant Work Rate (CWR) endurance time [ Time Frame: Baseline and up to Day 14 of each treatment period ]

Current Secondary Outcome Measures (submitted: January 16, 2021)

• Change From Period Baseline at Week 2 in Oxygen Uptake (VO2) [ Time Frame: Baseline and week 2 of each treatment period ]
  VO2 was defined as volume of O2 extracted from inspired air in a given period of time. VO2 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Ventilation (VE) [ Time Frame: Baseline and week 2 of each treatment period ]
  VE was defined as volume of gas exhaled from the lungs in 1 minute, also called 'ventilation' or 'minute ventilation. VE was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Ventilatory Equivalent for Carbon Dioxide (VE/VCO2) [ Time Frame: Baseline and week 2 of each treatment period ]
  VE/VCO2 was a ratio of VE to VCO2. It is a dimensionless quantity. This ratio indicates how many liters of air exhaled were breathed to eliminate 1 liter of CO2. VE/VCO2 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Inspiratory Capacity (IC) Change From Peak to Rest [ Time Frame: Baseline and week 2 of each treatment period ]
  IC was 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 IRV.
• Change From Period Baseline at Week 2 in Perceived Exertion for Dyspnea and Leg Discomfort (BORG CR10) [ Time Frame: Baseline and week 2 of each treatment period ]
  The Borg Scale (Borg CR10) is a simple 10-item method of rating perceived exertion and collects information on perceived exertion in an individual's rating of exercise intensity. Participants were 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)). BORG CR10 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Respiratory Exchange Ratio (RER) [ Time Frame: Baseline and week 2 of each treatment period ]
  The respiratory exchange ratio is equal to the VCO2 / VO2 [RER = VCO2 (L/min) / VO2 (L/min)]. RER was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Carbon Dioxide Output (VCO2) [ Time Frame: Baseline and week 2 of each treatment period ]
  VCO2 was defined as volume of CO2 exhaled from the body per unit of time; also called the rate of elimination of CO2. VCO2 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in End-tidal PCO2 (PETCO2) [ Time Frame: Baseline and week 2 of each treatment period ]
  PETCO2 was defined as 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. PETCO2 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in End-tidal PO2 (PETO2) [ Time Frame: Baseline and week 2 of each treatment period ]
  PETO2 was defined as 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. PETO2 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Tidal Volume (VT) [ Time Frame: Baseline and week 2 of each treatment period ]
  VT was defined as tidal volume is the volume of gas exhaled in each respiratory cycle. Tidal volume is typically measured as an average value over several respiratory cycles, and is expressed in liters. VT was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Breathing Frequency (Bf) [ Time Frame: Baseline and week 2 of each treatment period ]
  Bf was defined as the number of breaths (i.e., an entire inspiratory and expiratory respiratory cycle) per minute. Bf was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Inspiratory Capacity (IC) [ Time Frame: Baseline and week 2 of each treatment period ]
  IC was defined as the volume of air that can be inspired after a normal expiration; it is the sum of the VT and the IRV. IC was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline to Week 2 in Inspiratory Reserve Volume (IRV) [ Time Frame: Baseline and week 2 of each treatment period ]
  The Inspiratory reserve volume was equal to VT - IC measured in liters [IRV (L) = VT (L) - IC (L)]. IRV was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Ventilatory Reserve (VE/MVV) [ Time Frame: Baseline and week 2 of each treatment period ]
  VE/MVV provides the rate of expired ventilation to the capacity. VE/MVV was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Heart Rate (HR) [ Time Frame: Baseline and week 2 of each treatment period ]
  HR was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Systolic Blood Pressure (SBP) [ Time Frame: Baseline and week 2 of each treatment period ]
  SBP was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Diastolic Blood Pressure (DBP) [ Time Frame: Baseline and week 2 of each treatment period ]
  DBP was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Arterial Oxygen Saturation From Pulse Oximetry (SpO2) [ Time Frame: Baseline and week 2 of each treatment period ]
  SPO2 was defined as the noninvasive estimation of arterial hemoglobin (Hb) oxygen saturation, using a device that utilizes the combined principles of spectrophotometry and pulse plethysmography. SPO2 was reported at isotime and peak exercise during CWR test.
• Change From Period Baseline at Week 2 in Forced Vital Capacity (FVC) [ Time Frame: Baseline and week 2 of each treatment period ]
  Change From Period Baseline in FVC was reported.
• Change From Period Baseline at Week 2 in Forced Expiratory Volume 1 (FEV1) [ Time Frame: Baseline and week 2 of each treatment period ]
  Change From Period Baseline in FEV1 was reported.
• Change From Period Baseline at Week 2 in FVC/FEV1 Ratio [ Time Frame: Baseline and week 2 of each treatment period ]
  Change From Period Baseline in FVC/FEV1 Ratio was reported.
• Change From Period Baseline at Week 2 in Activation of Accessory Respiratory Muscles [ Time Frame: Baseline and week 2 of each treatment period ]
  Activation of accessory respiratory muscles was assessed by electromyogram. Data was reported at peak and isotime.
• Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From first dose of study drug up to 14 days after last dose of study drug (8 weeks) ]
  TEAEs were defined as any AE that started or worsened in severity after the first dose of study drug up to 14 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participant administered a study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, physical examination) an AE only if the abnormality meets 1 of the following criteria: Induces clinical signs or symptoms, Requires active intervention, Requires interruption or discontinuation of study drug, The abnormality or test value is clinically significant in the opinion of the inves
• Plasma Concentration of CK-2127107 at Day 1 Predose, Day 14 Lowest Concentration (Ctrough), and Day 14 Concentration Predose 6 Hours (C6h) [ Time Frame: Day 1 predose, day 14 Ctrough, day 14 C6h ]
  Plasma concentration of CK-2127107 was reported.
• Plasma Concentration of CK-2127106 (Metabolite of CK-2127107) at Day 1 Predose, Day 14 Ctrough, Day 14 C6h [ Time Frame: Day 1 predose, day 14 Ctrough, day 14 C6h ]
  Plasma concentration of CK-2127106 (metabolite of CK-2127107) was reported.

Original Secondary Outcome Measures (submitted: January 20, 2016)

• Change from period baseline in oxygen uptake (VO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in ventilation (VE) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in ventilatory equivalent for carbon dioxide (VE/VCO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in inspiratory capacity (IC) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in fractions of expired O2 (FeO2 ) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in fractions of expired CO2 (FeCO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in minute ventilation [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in oxygen consumption (VO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline in carbon dioxide production (VCO2) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change from period baseline respiratory exchange ratio (RER) [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• 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)).
• Change from period baseline in activation of accessory respiratory muscles (by electromyogram) at isotime and peak exercise during CWR [ Time Frame: Baseline and up to Day 14 of each treatment period ]
• Change in resting spirometry [ Time Frame: Baseline and up to Day 14 of each treatment period ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Chronic Obstructive Pulmonary Disease (COPD)

Intervention

• Drug: Reldesemtiv
  Oral tablet
  Other Name: CK-2127107
• Drug: Placebo
  Oral tablet

Study Arms

• Experimental: CK-2127107 1000 mg, then placebo
  Participants received CK-2127107 500 milligram (mg), orally, twice daily for 2 weeks in treatment period 1 followed by matching placebo orally, twice daily for 2 weeks in treatment period 2. A washout period of 2 weeks was maintained between the two treatment periods.
  Interventions:

  • Drug: Reldesemtiv
  • Drug: Placebo
• Experimental: Placebo, then CK-212710 1000 mg
  Participants received matching placebo orally, twice daily for 2 weeks in treatment period 1 followed by CK-2127107 500 mg in treatment period 2. A washout period of 2 weeks was maintained between the two treatment periods.
  Interventions:

  • Drug: Reldesemtiv
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 7, 2018): 46
• Original Estimated Enrollment (submitted: January 20, 2016): 40
• Actual Study Completion Date: June 8, 2018
• Actual Primary Completion Date: June 8, 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02662582
• Other Study ID Numbers: 3318-CL-3002
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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."

• Current Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Astellas Pharma Global Development, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Cytokinetics

Investigators

• Study Director: Senior Medical Director; Astellas Pharma Global Development, Inc.

• PRS Account: Astellas Pharma Inc
• Verification Date: February 2021