A Dose-Ranging Study of MK-1029 in Adults With Persistent Asthma (MK-1029-012)

Study Overview
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Brief Summary
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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; and (2) To determine the dose-related safety and tolerability of MK-1029 as monotherapy and as concomitant dosing with montelukast over 12 weeks. The primary hypothesis is: MK-1029 is superior to placebo in a dose-related fashion in the average change from baseline in FEV1 over the last 6 weeks of the 12-week active-treatment period.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled, Multicenter, Parallel-Group, Adaptive-Design, Dose-Ranging Study of MK-1029 in Adult Subjects With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: MK-1029
* Drug: Montelukast 10 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: not pregnant or breastfeeding, and not planning to become pregnant during the study history of symptoms of persistent asthma for at least one year current use of acceptable asthma treatments and willingness to taper or discontinue these treatments; acceptable asthma treatments: use of inhaled SABAs (e.g., albuterol/salbutamol) only as-needed with no use of asthma controller medications; OR use of stable doses of low- or medium-dose inhaled corticosteroids (ICS), alone, or in combination with either a long-acting beta-agonist (LABA) or other asthma controller medications (including leukotriene receptor antagonists) and can tolerate tapering or discontinuation no history of smoking OR no smoking within <1 year with a smoking history of ≤10 pack-years ability to maintain a constant day/night, awake/sleep cycle agreement to not change habitual consumption of beverages or food containing caffeine throughout the study Body Mass Index (BMI) of 15 to 40 kg/m^2 Exclusion Criteria: myocardial infarction, congestive heart failure, or uncontrolled cardiac arrhythmia within past ≤3 months hospitalization within past ≤4 weeks major surgical procedure within past ≤4 weeks participation in a clinical study involving an investigational drug within past ≤4 weeks current regular use or recent (within past ≤5 years) past abuse of alcohol (>14 drinks/week) or illicit drugs donation of a unit of blood within past ≤2 weeks or intention to donate a unit of blood during the study evidence of another clinically significant, active pulmonary disorder such as chronic obstructive pulmonary disease (COPD) emergency room treatment for asthma within past ≤4 weeks or hospitalization for asthma within past ≤8 weeks respiratory tract infection requiring antibiotic treatment within past ≤8 weeks evidence of active, clinically significant sinus disease within past ≤1 week history of a clinically significant psychiatric disorder, other than stable depression, within past ≤12 weeks history of HIV hypersensitivity or intolerance to inhaled beta-agonists, leukotriene antagonists, leukotriene synthesis inhibitors, or any of their ingredients, including lactose and galactose clinically unstable disease of the ophthalmologic, neurological, hepatic, renal, connective tissue, genitourinary, gastrointestinal, cardiovascular or hematologic systems current cancer or history (within past ≤5 years) of cancer (except for successfully treated basal and squamous cell carcinomas of the skin); if cancer-free for >5 years, study participation may be allowed evidence of uncontrolled hypertension

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-1029 10 mg<br>Participants receive MK-1029 10 mg tablets once daily (QD) for 12 weeks | Drug: MK-1029<br>* MK-1029 10 mg, 30 mg or 150 mg oral tablets taken QD at bedtime, based on randomization.<br>|
| Experimental: MK-1029 30 mg<br>Participants receive MK-1029 30 mg tablets QD for 12 weeks | Drug: MK-1029<br>* MK-1029 10 mg, 30 mg or 150 mg oral tablets taken QD at bedtime, based on randomization.<br>|
| Experimental: MK-1029 60 mg<br>Participants will receive MK-1029 two 30 mg tablets QD for 12 weeks | Drug: MK-1029<br>* MK-1029 10 mg, 30 mg or 150 mg oral tablets taken QD at bedtime, based on randomization.<br>|
| Experimental: MK-1029 150 mg<br>Participants will receive MK-1029 150 mg tablets QD for 12 weeks | Drug: MK-1029<br>* MK-1029 10 mg, 30 mg or 150 mg oral tablets taken QD at bedtime, based on randomization.<br>|
| Active Comparator: Montelukast 10 mg<br>Participants will receive Montelukast 10 mg tablets QD for 12 weeks | Drug: Montelukast 10 mg<br>* Parts I-II: Participants will receive Montelukast 10 mg tablets QD<br>* Other names: SINGULAIR®;|
| Placebo Comparator: Placebo<br>Participants will receive Placebo tablets QD for 12 weeks | Drug: Placebo<br>* Parts I-II: Participants will receive Placebo tablets QD<br>|
| Experimental: MK-1029 1 mg or 3 mg<br>Participants will receive either MK-1029 1 mg or 3 mg tablets (dose to be determined based on results of interim analysis from Part I) QD. | Drug: MK-1029<br>* MK-1029 10 mg, 30 mg or 150 mg oral tablets taken QD at bedtime, based on randomization.<br>|
| Experimental: Montelukast 10 mg + MK-1029<br>Participants will receive Montelukast 10 mg tablets QD and MK-1029 tablets (dose to be determined based on results of interim analysis from Part I) QD | Drug: Montelukast 10 mg<br>* Parts I-II: Participants will receive Montelukast 10 mg tablets QD<br>* Other names: SINGULAIR®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | FEV1 is the amount of air (in liters) forcibly exhaled in one second. Repeated measurements of FEV1 were collected at visits during the 12 week active treatment period and the average change from baseline in FEV1 over the last 6 weeks of the 12-week-treatment period (visits at Week 6, Week 8, Week 10 and Week 12) was estimated using a constrained longitudinal data analysis (cLDA) model. In the cLDA analysis, baseline was the average FEV1 during the placebo run-in period and the post-baseline value was the average FEV1 over Week 6 to Week 12. | Baseline and last six weeks of treatment (visits at Week 6, Week 8, Week 10 and Week 12) | 
| Percentage of Participants Who Experience Adverse Events (AEs) | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of the study drug, is also an AE. | Up to 14 weeks | 
| Percentage of Participants Who Discontinue Study Due to AEs | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of the study drug, is also an AE. | Up to 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Asthma Exacerbation Days | An asthma exacerbation day was defined as a day with ANY of the following: a decrease from Baseline in morning (AM) Peak Expiratory Flow (PEF) of more than 20%, an AM PEF of less than 180 liters (L)/min, an increase in Short Acting Beta2 Agonist (SABA) use of more than 70% (and a minimum increase of at least 2 puffs), an increase from Baseline in Daytime Asthma Symptom Score of more than 50%, an overnight asthma symptom of: Awake all night, or an asthma attack. Information on asthma exacerbation days was recorded throughout the study in the participant's electronic diary (e-Diary), and an Analysis of Variance (ANOVA) was used to calculate the average percentage of days with asthma exacerbations over Week 6 to Week 12. | Week 6 to Week 12 | 
| Average Change From Baseline in Daytime Symptom Score (DSS) | The Daytime Symptom Score assessed daytime asthma symptoms. In the evening just before going to bed, participants scored their asthma symptoms for the period since arising by answering the following 4 questions in eDiaries: 1) How often did you experience asthma symptoms today?, 2) How much did your asthma symptoms bother you?, 3) How much activity could you do today? and 4) How often did your asthma affect your activities today? The 4 questions were scored on a 7-point scale (0=best to 6=worst) and averaged for a single score. The average change from baseline in DSS over the last 6 weeks of the 12-week-treatment period (visits at Week 6, Week 8, Week 10 and Week 12) was estimated using a cLDA model. In the cLDA analysis, baseline was the average DSS score during the placebo run-in period and the post-baseline value was the average DSS Score over Week 6 to Week 12. | Baseline and last six weeks of treatment (visits at Week 6, Week 8, Week 10 and Week 12) | 
| Average Change From Baseline in Use of Short-Acting Beta-Agonists (SABAs) | Twice daily (upon arising and before going to sleep), participants recorded the total number of puff (actuations) of SABA used for asthma symptoms in their eDiaries. The number of SABA puffs used in one day was calculated based on eDiary entries as the sum of daytime and nighttime number of puffs of SABA. The average change from baseline over the last 6 weeks of the 12-week-treatment period (visits at Week 6, Week 8, Week 10 and Week 12) in the daily number of SABA puffs was estimated using a cLDA model. In the cLDA analysis, Baseline was the average number of SABA puffs used in one day during the placebo run-in period and the post-baseline value was calculated as the average number of SABA puffs used in one day over Week 6 to Week 12. | Baseline and last six weeks of treatment (visits at Week 6, Week 8, Week 10 and Week 12) | 
| Average Change From Baseline in Number of Nocturnal Awakenings | The number of nights per week (between consecutive visits) that a participant awakened with asthma was based on eDiary entries and was calculated by dividing the number of nights a participant awakened with asthma (positive responses of once, more than once, awake all night) by the total number of nights (all responses) and then multiplying by 7 (standardized to a 7-day period). The average change from baseline in number of nocturnal awakenings over the last 6 weeks of the 12-week-treatment period (visits at Week 6, Week 8, Week 10 and Week 12) was estimated using a cLDA model. In the cLDA analysis, baseline was the average number of nocturnal awakenings during the placebo run-in period and the post-baseline value was calculated as the average number of nocturnal awakenings over Week 6 to Week 12. | Baseline and last six weeks of treatment (visits at Week 6, Week 8, Week 10 and Week 12) | 
| Average Change From Baseline in Morning/Evening Peak Expiratory Flow (AM/PM PEF) | PEF was defined as a person's maximum speed (rate) of expiration as measured with a peak flow meter in liters per minute. Participants performed triplicate PEF measurements twice daily using a PEF meter, in the AM upon rising and in the PM immediately before study drug administration at bedtime. All three values were recorded and the average of the best morning PEF and the best evening PEF for each day (AM/PM) was determined through the e-Diary. The average change from Baseline in AM/PM PEF over the last 6 weeks of a 12-week treatment period (visits at Week 6, Week 8, Week 10 and Week 12) was estimated using a cLDA model. In the cLDA analysis, baseline was the average AM/PM PEF value during the placebo run-in period and the post-baseline value was calculated as the average AM/PM PEF over Week 6 to Week 12. | Baseline and last six weeks of treatment (visits at Week 6, Week 8, Week 10 and Week 12) | 
| Change From Baseline in Asthma Quality of Life Questionnaire With Standardised Activities [AQLQ(S)] Overall and Domain Scores | The AQLQ(S) is a 32-item questionnaire with questions on 4 domains (asthma symptoms, activity limitation, emotional function and environmental stimuli) over the previous 2 weeks. Responses were scored on a 7-point scale (1=worst to 7=best). Each domain score is defined as the average score of all answered questions in that domain. The AQLQ(S) Overall Score is defined as the average of all available item scores (1=worst to 7=best). The changes from baseline are presented for the overall scores and the individual domain scores. Baseline was the last measurement taken prior to the first double-blind study drug. The ending values were calculated as the average AQLQ(S) Overall Score and domain scores at Week 12 of a 12-week treatment period. Statistical analyses are provided for the AQLQ(S) Overall Scores only. | Baseline and Week 12 | 
| Percentage of Participants With a ≥0.5 Change From Baseline in AQLQ(S) Overall and Domain Scores | The AQLQ(S) is a 32-item questionnaire with questions on 4 domains (asthma symptoms, activity limitation, emotional function and environmental stimuli) over the previous 2 weeks. Responses were scored on a 7-point scale (1=worst to 7=best). Each domain score is defined as the average score of all answered questions in that domain. The AQLQ(S) Overall Score is defined as the average of all available item scores (1=worst to 7=best). The percentage of participants who experienced a ≥0.5 increase in AQLQ(S) Overall and Domain Scores at Week 12 compared to baseline was calculated using the Miettinen and Nurminen (MN) method. Statistical analyses are provide for the AQLQ(S) Overall Score response rate only. | Baseline and Week 12 | 
| Change From Baseline in Asthma Control Questionnaire (ACQ) Score | The ACQ is a validated 6-item measure of asthma control to evaluate asthma control in response to therapy. Participants evaluate their asthma over the previous week by answering 6 questions: How often were you woken by your asthma during the night? How bad were your asthma symptoms when you woke up in the morning? How limited were you in your activities because of your asthma? How much shortness of breath did you experience because of your asthma? How much of the time did you wheeze? How many puffs/inhalations of short-acting bronchodilator have you used each day? Each response to a question was scored on a 7-point scale (0=best to 6=worst). The ACQ score is the average of the scores for the 6 items. Change from baseline to Week 12 in ACQ was estimated using a cLDA model. In the cLDA analysis, the Baseline value was the last measurement taken prior to the first double-blind study drug and the post-baseline value was calculated as the average ACQ Score at Week 12. | Baseline and Week 12 | 
| Percentage of Participants With a ≥0.5 Change From Baseline in ACQ Score | The ACQ is a validated 6-item measure of asthma control to evaluate asthma control in response to therapy. Participants evaluate their asthma over the previous week by answering 6 questions: How often were you woken by your asthma during the night? How bad were your asthma symptoms when you woke up in the morning? How limited were you in your activities because of your asthma? How much shortness of breath did you experience because of your asthma? How much of the time did you wheeze? How many puffs/inhalations of short-acting bronchodilator have you used each day? Each response to a question was scored on a 7-point scale (0=best to 6=worst). The ACQ score is the average of the scores for the 6 items. The percentage of participants who experienced a ≥0.5 decrease in ACQ Score at Week 12 compared to Baseline was calculated using the MN method. | Baseline and Week 12 | 
| Percentage of Asthma Attack Days | An asthma attack was defined as asthma symptoms during the previous 24 hours requiring one or more of the following: corticosteroid use (systemic), unscheduled visit to the doctor or urgent care clinic, unscheduled visit to the emergency department or hospitalization. Information on asthma attacks was recorded throughout the study in the participant's e-Diary, and an Analysis of Variance (ANOVA) was used to calculate the average percentage of asthma attack days over Week 6 to Week 12 of a 12-week treatment period. | Week 6 to Week 12 |