| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult subjects 18 to 75 years of age with persistent asthma |
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| E.1.1.1 | Medical condition in easily understood language |
| Adults with chronic asthma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001705 |
| E.1.2 | Term | Allergic asthma |
| E.1.2 | System Organ Class | 100000004855 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| This adaptive design, dose-ranging study of MK-1029 will assess the dose-related efficacy and safety of MK-1029 compared with placebo using measures of lung function (forced expiratory volume in 1 second (FEV1). The primary objectives are (1) To demonstrate that MK-1029, compared with placebo, results in dose-related improvements in FEV1 over the last 6 weeks of the 12-week active-treatment period; (2) To determine the dose-related safety and tolerability of MK-1029 as monotherapy and as concomitant dosing with monteulkast over 12 weeks. |
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| E.2.2 | Secondary objectives of the trial |
1)Demonstrate co-administration of MK-1029 & montelukast (ML), compared with ML alone results in FEV1 improvement over last 6 wks treatment; ASSESS:
2)Dose-related efficacy of MK-1029, compared with placebo, on % days with asthma exacerbations, daytime symptom score, as-needed SABA use, night awakening AM & PM PEF over last 6 wks treatment; AQLQ(S) total & each domain scores, ACQ score at wk 12 treatment & asthma attacks over entire treatment
3)Efficacy of MK-1029 & ML co-administration compared with ML alone on same endpoints in Obj. 2
4)Efficacy of MK-1029 & ML co-administration compared with MK-1029 alone, on FEV1 change from baseline over last 6 wks treatment & on same endpoints n Obj. 2
5)Efficacy of MK-1029 compared with ML on FEV1 change from baseline over last 6 wks treatment & on same endpoints as described in Obj. 2
6) Determine relationship between change from baseline in efficacy endpoints & genetic polymorphisms that may predict responsiveness to treatment |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A Sputum Substudy will be conducted at selected sites, to analyze sputum of subjects with asthma. The objectives include evaluating the distribution of sputum biomarkers at baseline; Evaluating the effect of MK-1029, compared with placebo, on change from baseline in sputum biomarkers after 12 weeks of treatment; and to explore the relationship between baseline and change from baseline sputum biomarker measurements and baseline and change form baseline primary, secondary, and exploratory efficacy endpoints in the main study. |
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| E.3 | Principal inclusion criteria |
• Subject is a female or male subject between 18 and 75 years of age
• Subject has a consistent clinical history, for at least one year, of symptoms of persistent asthma that may include, but are not limited to, dyspnea, wheezing, chest tightness, cough, and/or sputum production
• While withholding SABAs for at least 6 hours and long-acting β-agonists (LABAs) for at least 12 hours, subject has a FEV1 ≥60% and ≤85% of the predicted value (≥65% and ≤90% of the predicted value if subject is receiving asthma controller medications)
• While withholding SABAs for at least 6 hours and LABAs for at least 12 hours (at Visit 1 only), subject has evidence of reversibility of airway obstruction defined as an increase of FEV1 of 12% or greater, and at least 200 mL, 10 to 30 minutes after SABA administration, documented once during the screening period
• Subject’s asthma treatment must fall into one of two categories:
o The subject must have been using only “as-needed” inhaled SABAs (e.g., albuterol/salbutamol) and not using asthma controller medications; OR
o The subject must have been receiving stable doses of low- or medium-dose ICS, combination ICS/LABA, and/or other asthma controller medications, including leukotriene receptor antagonists, and can tolerate tapering of these controllers (e.g., ICS) or discontinuing them (e.g., montelukast), during the run-in period
• Subject has never smoked or is a non-smoker for at least 1 year, with a smoking history of no more than 10 pack-years
• Subject has a Body Mass Index (BMI) between 15 and 40 kg/m2 inclusive (BMI = weight in kg/[height in meters]2
• Subject provides written informed consent for the study. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main study without participating in Future Biomedical Research
• Subject has an ACQ-6 of ≥1.5 at the Randomization visit
• Subject has a total daytime and nocturnal SABA administration average ≥1 puff per day, as recorded on the subject’s e-Diary for the last 7 days prior to Randomization visit
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| E.4 | Principal exclusion criteria |
• Subject is, in the opinion of the investigator, mentally or legally incapacitated preventing informed consent from being obtained, unable to read or comprehend written material, or unable to comply with the study procedures or protocol
• Subject has a recent history (≤3 months) of myocardial infarction, congestive heart failure, or uncontrolled cardiac arrhythmia prior to Visit 1
• Subject is hospitalized or has been hospitalized in the 4 weeks prior to Visit 1
• Subject has undergone any major surgical procedure within the 4 weeks prior to Visit 1
• Subject has evidence of another clinically significant, active pulmonary disorder such as bronchiectasis or chronic obstructive pulmonary disease (COPD) documented by history, physical examination, or chest x-ray
• Subject has been treated in an emergency room for asthma within the 4 weeks prior to Visit 1 or has been hospitalized for asthma within the 8 weeks prior to Visit 1
• Subject has had a respiratory tract infection which necessitated treatment with antibiotics within the 8 weeks prior to Visit 1
• Subject has evidence of active, clinically significant sinus disease within 1 week prior to Visit 1
• Subject is hypersensitive to inhaled β-agonists, leukotriene antagonists, leukotriene synthesis inhibitors, or any of their formulation components
• Subject has evidence of uncontrolled hypertension, defined as systolic >160 mmHg and/or diastolic >100 mmHg, during at least 2 of the first 3 study visits
• The electrocardiogram (ECG) obtained at Visit 1 demonstrates clinically significant or unexplained abnormality, that may include but is not limited to: a clinically significant conduction disturbance (e.g., second or third degree AV block), clinically significant tachycardia, active cardiac ischemia, or a QTc > 460 msec
• Subject has used any medication with a narrow therapeutic index (e.g., warfarin, coumadin, dicoumarol, digoxin, digitoxin) within the 2 weeks prior to Visit 1 or plans to take such medications during the study
• Subject is unable to comply with the study procedures or protocol, including completion of the e-Diary and compliance with study medication
• Subject experiences a clinically significant worsening of their asthma between Visits 1 and 3.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this study is the average change from baseline in FEV1 over the last 6 weeks of the 12-week active treatment period |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The last 6 weeks of the 12-week active treatment period ( weeks 8, 10, and 12) |
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| E.5.2 | Secondary end point(s) |
• percentage of days with asthma exacerbations
• daytime symptom score
• as-needed SABA use
• nocturnal awakenings
• AM and PM PEF
• Asthma Quality of Life Questionnaire with Standardised Activities [AQLQ(S)] total and individual domain scores
• Asthma Control Questionnaire-6 (ACQ-6) score
• asthma attacks
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The various time points include daily or every 2 weeks of the 12-week active treatment period; Week 12 of the 12-week active period and over the entire 12-week active treatment period. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Italy |
| Japan |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 39 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 39 |
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