Study to Evaluate the Effectiveness and Safety of MK-1029 in the Treatment of Persistent Asthma That is Not Controlled With Montelukast (ML) in Adults (MK-1029-011)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of MK-1029 on lung function in the treatment of adults who have persistent asthma that is uncontrolled with the use of montelukast (ML). Participants will use randomized study drug (either MK-1029 or placebo) for two separate 4-week treatment periods. All participants will also use ML during the treatment periods. The primary hypothesis is that MK-1029 is superior to placebo in change from baseline in forced expiratory volume in one second (FEV1) at the end of the 4-week treatment period.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled, Multicenter, Crossover Study of MK-1029 in Adult Subjects With Persistent Asthma Who Remain Uncontrolled While Being Maintained on Montelukast

Conditions
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Asthma

Intervention / Treatment
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* Drug: MK-1029
* Drug: Placebo
* Drug: Montelukast (ML)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: not pregnant or breastfeeding and does not plan to become pregnant for the duration of the study; symptoms of persistent asthma for at least one year; current use of asthma treatments: 1) as-needed inhaled SABAs (albuterol/salbutamol) and no asthma controller for at least 4 weeks prior to Screening Visit OR 2) stable dose of ICS, combination ICS/LABA and/or oral asthma controller(s) for at least 4 weeks prior to Screening Visit and able to tolerate discontinuing all controllers while receiving ML; no history of smoking OR no smoking for at least 1 year, with a smoking history of no more than 10 pack-years; able to maintain a constant day/night, awake/sleep cycle; agrees to not change habitual consumption of beverages or foods containing caffeine throughout the study; Body Mass Index (BMI) of 15 kg/m^2 to 40 kg/m^2. Exclusion Criteria: history of myocardial infarction, congestive heart failure, or uncontrolled cardiac arrhythmia within 3 months prior to Screening Visit; hospitalized or hospitalization within 4 weeks prior to Screening Visit; intention of moving or anticipation of missing any study visits; any major surgical procedure(s) within 4 weeks prior to Screening Visit; participation in a clinical trial involving an investigational drug within 4 weeks prior to Screening Visit; current regular use or a recent past abuse (within past 5 years) of alcohol (>14 drinks/week) or illicit drugs; donation of a unit of blood within 2 weeks prior to Screening Visit or intention of donating a unit of blood during the study; evidence of another active pulmonary disorder such as bronchiectasis or COPD; treatment in an emergency room for asthma within 4 weeks prior to Screening Visit or hospitalization for asthma within 2 months prior to Screening Visit; respiratory tract infection which required treatment with antibiotics within 2 months prior to Screening Visit; evidence of active sinus disease within 1 week prior to Screening Visit; history of a psychiatric disorder, other than stable depression, within 3 months prior to Screening Visit; history of human immunodeficiency virus (HIV); hypersensitivity or intolerance to inhaled beta-agonists and/or leukotriene inhibitors or any of their ingredients, including lactose and galactose; unstable disease of the ophthalmologic, neurological, hepatic, renal, connective tissue, genitourinary, gastrointestinal, cardiovascular or hematologic systems; cancer (except for successfully treated basal and squamous cell carcinomas of the skin) or history of cancer within 5 years prior to Screening Visit; 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-1029/Placebo<br>Participants received 4 weeks treatment with MK-1029 150 mg once daily (QD) + ML 10 mg QD in Period III and Placebo QD + ML 10 mg QD in Period V. Period IV was a 4-week wash-out period during which participants received single-blind Placebo QD and open-label ML 10 mg QD. | Drug: MK-1029<br>* MK-1029 150 mg tablets taken QD<br>Drug: Placebo<br>* Placebo tablets (matching the MK-1029 150 mg tablets) QD<br>Drug: Montelukast (ML)<br>* ML 10 mg tablets QD<br>|
| Experimental: Placebo/MK-1029<br>Participants received 4 weeks treatment with Placebo QD + ML 10 mg QD in Period III and MK-1029 150 mg QD + ML 10 mg QD in Period V. Period IV was a 4-week wash-out period during which participants received single-blind Placebo QD and open-label ML 10 mg QD. | Drug: MK-1029<br>* MK-1029 150 mg tablets taken QD<br>Drug: Placebo<br>* Placebo tablets (matching the MK-1029 150 mg tablets) QD<br>Drug: Montelukast (ML)<br>* ML 10 mg tablets QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at Week 4 | The change from baseline in FEV1 at Week 4 following treatment with MK-1029 + ML or placebo + ML was assessed. The pre-bronchodilator FEV1 was evaluated to assess the response to treatment for asthma. The primary efficacy evaluation period was the last week of each treatment period: Period III (Initial Therapy, Week 4) and Period V (Crossover Therapy, Week 4). The change from baseline in FEV1 was evaluated using a longitudinal data analysis (LDA) model with repeated measurements of FEV1, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. Baseline FEV1 is defined as the measurement taken before dosing in each treatment period (i. e., at Visit 3 [Week 0], prior to Period III and at Visit 6 [Week 8], prior to Period V). The Baseline Characteristics section shows FEV1 values at baseline. | The week before the first dose in Period III or V (Baseline) and the last week of Period III or V | 
| Adverse Events During Treatment and Follow-up | The number of participants who had at least one adverse event (AE) during study treatment and follow-up was assessed. 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 SPONSOR's product, whether or not considered related to the use of the product. The number of participants with at least one AE was assessed. The number of participants in any treatment group with at least one AE was assessed. | Up to 14 days after the last dose in Period III or Period V (up to 6 weeks) | 
| Discontinuation of Treatment Due to An Adverse Event | The number of participants who discontinued study treatment due to an AE was assessed. 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 SPONSOR's product, whether or not considered related to the use of the product. | Up to the last dose in Period III or Period V (up to 4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daytime Symptom Score (DSS) at Week 4 | The change from baseline in DSS at Week 4 following treatment was assessed. Participants used an electronic diary (e-Diary) to enter their asthma symptom scores every evening. Participants scored daily symptoms (chest discomfort, wheezing, shortness of breath, and cough) by responding to 4 questions: 1) Symptom frequency (0 = None of the time, 6 = All of the time); 2) Bothersomeness (0 = Not bothered, 6 = Severely bothered); 3) Activity limitation (0 = Not limited, 6 = Totally limited); 4) Frequency of activity limitation (0 = None of the time, 6 = All of the time). The average of the 4 scores for overall DSS ranges from 0 to 6 where a higher average indicates greater symptom severity. The average overall DSS was calculated over the week-long assessment periods. The change from baseline in DSS was evaluated using the LDA model with repeated measurements of DSS, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. | The week before the first dose in Period III or V (Baseline) and the last week of Period III or V | 
| Change From Baseline in Short-Acting Beta Agonist (SABA) Use at Week 4 | The change from baseline in SABA use at Week 4 after treatment with MK-1029 + ML or placebo + ML was assessed. Participants used the e-Diary upon arising and before going to sleep to enter the total number of SABA puffs used for asthma relief. The number of SABA puffs recorded was the number of canister actuations (e. g., when SABA use was required and 3 puffs were inhaled, this was recorded as 3). Participants also recorded the number of nebulizer treatments (1 nebulized SABA use = 3 puffs). The average daily number of puffs for an individual participant was calculated over the week-long assessment periods. The change from baseline in SABA use was evaluated using the LDA model with repeated measurements of SABA use, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. | The week before the first dose in Period III or V (Baseline) and the last week of Period III or V | 
| Change From Baseline in Nocturnal Awakenings at Week 4 | The change from baseline in nocturnal awakenings due to asthma at Week 4 after treatment with MK-1029 + ML or placebo + ML was assessed. The participant scored nocturnal awakenings by answering the question, Did you wake up with asthma symptoms in the middle of the night or upon awakening in the morning? (No or Yes). Participants recorded in the e-Diary the number of nights per week in which they awakened with asthma, as determined by dividing the number of nights of awakening with asthma by the total number of nights and then multiplying by 7 (standardized to a 7-day period). The change from baseline in nocturnal awakenings was evaluated using the LDA model with repeated measurements of nocturnal awakenings, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. | The week before the first dose in Period III or V (Baseline) and the last week of Period III or V | 
| Change From Baseline in Morning (AM) Peak Expiratory Flow (PEF) at Week 4 | The change from baseline in AM PEF at Week 4 after treatment with MK-1029 + ML or placebo + ML was assessed in 97 participants. Participants performed triplicate AM PEF measurements in the morning upon rising. Participants entered all 3 measurements and the greatest AM PEF value was recorded by the e-Diary. Participants refrained from SABA use within the 4 hours prior to performing PEF measurements. The average AM PEF for an individual participant was calculated over the week-long assessment periods. The change from baseline in AM PEF was evaluated using the LDA model with repeated measurements of AM PEF, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. | The week before the first dose in Period III or V (Baseline) and the last week of Period III or V | 
| Change From Baseline in Evening (PM) PEF at Week 4 | The change from baseline in PM PEF at Week 4 after treatment with MK-1029 + ML or placebo + ML was assessed. Participants performed triplicate PM PEF measurements in the evening, immediately before study drug administration, at bedtime. Participants entered all 3 measurements and the greatest PM PEF value was recorded by the e-Diary. Participants refrained from SABA use within the 4 hours prior to performing PEF measurements. The average PM PEF for an individual participant was calculated over the week-long assessment periods. The change from baseline in PM PEF was evaluated using the LDA model with repeated measurements of PM PEF, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. | Baseline (Week 0 and Week 8), Last week of the 4-week treatment period | 
| Change From Baseline in Asthma Control Questionnaire (ACQ) Score at Week 4 | The change from baseline in the ACQ score at Week 4, after treatment, was assessed in 97 participants. Participants completed 6 items of the ACQ (i. e., ACQ-6) and provided the average of responses over the past week: 1) Frequency of nocturnal awakenings (0 = Never, 6 = Unable to sleep); 2) Symptom severity (0 = None, 6 = Very severe); 3) Activity limitations (0 = Not limited, 6 = Totally limited); 4) Breathlessness (0 = None, 6 = Very great deal); 5) Wheezing (0 = Not at all, 6 = All the time); 6) Daily SABA use (0 = None, 6 = More than 16 puffs on most days). The ACQ score ranges from 0 to 6 where a lower score indicates greater performance. The investigator reviewed the participant-completed ACQ-6 to ensure its completeness. The change from baseline in the ACQ score was evaluated using the LDA model with repeated measurements of the ACQ score, with treatment, visit, treatment-by-visit interaction, and period as fixed effects, and participant as random effect. | The week before the first dose in Period III or V (Baseline) and the last week of Period III or V |