A Two-part Study of the Effects of MK-1029 in Allergen-Challenged Asthmatics (MK-1029-003)

Study Overview
=================
Brief Summary
-----------------
This was a 2-part study in participants with allergen-induced asthma. It included a procedural pilot component (Part 1). Part 1 tested the key procedures and timing of Part 2; no study drug was administered during Part 1. Part 2 included a pre-randomization placebo run-in (Period 1) and 3 treatment periods (Periods 2, 3, and 4) during which participants were randomized to receive double-blind placebo, MK-1029 60 mg or MK-1029 500 mg in a crossover design. The treatment periods were followed by a minimum 21-day washout. Part 2 assessed allergen-induced sputum eosinophils and allergen-induced late asthmatic response (LAR) compared to placebo.

Official Title
-----------------
A Two-Part, Multicenter, Randomized, Clinical Trial to Study the Effects of Multiple Doses of MK-1029 on the Late Asthmatic Response to Lung Allergen Challenge in Asthmatics

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: MK-1029 10 mg
* Drug: MK-1029 100 mg
* Drug: Placebo for MK-1029 10 mg
* Drug: Placebo for MK-1029 100 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Parts 1 and 2 Is male or a female of non-childbearing potential Has a history of allergen-induced asthma for at least 6 months Is judged to be in good health (other than asthma) Is able to perform reproducible pulmonary function testing Has a positive methacholine challenge test on Day -1 Has an allergic response to house dust mite allergen as defined by positive skin prick test Is a nonsmoker and/ or has not used nicotine or nicotine-containing products for at least 12 months Has body mass index (BMI) ≥17 kg/m^2, but ≤33 kg/m^2 Part 2 only Must demonstrate a dual airway response to an allergen challenge in Period 1, decrease in FEV1 of at least 20% 0 to 2 hours after allergen challenge for early asthmatic response (EAR) and a positive late asthmatic response (LAR) to an inhaled allergen challenge as defined by a bronchoconstrictive response of at least 15% reduction in FEV1 3 to 8 hours after allergen challenge Can tolerate sputum induction and produce adequate sputum Exclusion Criteria: Parts 1 and 2 Has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses additional risk to the participant Has recent (4 weeks) or ongoing upper or lower respiratory tract infection Is unable to refrain from or anticipates the use of any medication other than the ones permitted in this study Has taken oral, intramuscular, intra-articular, high-potency topical or orally inhaled corticosteroids within 8 weeks Has taken the following medications outside the washout margins: nasal corticosteroids and anti-leukotrienes within 3 weeks; inhaled long-acting β2-agonists, long-acting antihistamines (e.g., loratadine, sustained-release agents), intra-nasal anticholinergics over-the-counter decongestants within 1 week; short-acting oral decongestants, short-acting antihistamines (e.g., chlorpheniramine) within 48 hours Consumes excessive amounts of alcohol or caffeinated beverages Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 3 months Has a history of severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food Is a nursing mother Has a history of receiving anti-immunoglobulin E (IgE) or immunotherapy Has a history of serious allergies to drugs or a history of hypersensitivity to mometasone furoate or any of its inactive ingredients such as lactose, or inhaled salbutamol, antihistamines, or any other potential asthma/anaphylaxis rescue medication Part 2 only - Has a decline in FEV1 of 70% or greater from the post allergen diluent baseline and/or FEV1 <1.0L or has symptomatic drop in FEV1 associated with shortness of breath unresolved with bronchodilators within a reasonable timeframe (60 minutes) after the allergen challenge study in Period 1

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-1029 60 mg<br>Part 2 - Participants will receive 5 days of double-blind, once-daily MK-1029 60 mg followed by a 21-day washout in Period 2, 3, or 4 in a crossover design | Drug: MK-1029 10 mg<br>* Six capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design<br>Drug: Placebo for MK-1029 10 mg<br>* Six capsules once daily for 5 days in Period 1, and the same in Period 2, 3, or 4 in a crossover design.<br>|
| Experimental: MK-1029 500 mg<br>Part 2 - Participants will receive 5 days of double-blind, once-daily MK-1029 60 mg followed by a 21-day washout in Period 2, 3, or 4 in a crossover design | Drug: MK-1029 100 mg<br>* Five capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design<br>Drug: Placebo for MK-1029 100 mg<br>* Five capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design<br>|
| Placebo Comparator: Placebo<br>Part II - Participants will receive 5 days of double-blind, once-daily MK-1029 60 mg followed by a 21-day washout in Period 2, 3, or 4 in a crossover design | Drug: Placebo for MK-1029 10 mg<br>* Six capsules once daily for 5 days in Period 1, and the same in Period 2, 3, or 4 in a crossover design.<br>Drug: Placebo for MK-1029 100 mg<br>* Five capsules once daily for 5 days in Period 2, 3, or 4 in a crossover design<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Percent (%) Eosinophils in Induced Sputum At 8 Hours Post Allergen | The effect of MK-1029 on the reduction of percent (%) sputum eosinophils following allergen challenge with standardized cat pelt or hair (CPH) allergen extract was assessed. Baseline % eosinophils were measured before treatment (and pre-allergen challenge) on Day -1. The change from baseline in allergen-induced % sputum eosinophils at 8 hr post allergen challenge testing on Day 5 was analyzed using a repeated measures linear mixed effects model with treatment, period, time, time-by-treatment interaction as fixed factors, and participant as a random factor. Outcome Measure 6 shows % eosinophil values at baseline. | Baseline (Day -1) and Day 5 (8 hours after allergen challenge in each treatment period) | 
| Forced Expiratory Volume in One Second (FEV1) From 3 to 8 Hours Postdose (AUC3-8hr) During the Late Asthmatic Response (LAR) | The effect of MK-1029 on the FEV1 AUC(3-8hr) during LAR was assessed. The unit of measure for an FEV1 AUC value is L*hr. The effect of treatment on LAR was assessed as the percent-fall in FEV1 AUC(3-8hr), evaluated by spirometry following allergen challenge on Day 5. The FEV1 AUC(3-8hr) during LAR was analyzed using a linear mixed effects model with treatment and period as fixed factors and participant as a random factor. | From 3 to 8 hours after allergen challenge on Day 5 of each treatment period | 
| Number of Participants With an Adverse Event (AE) | 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. | Up to 26 days in each treatment period | 
| Number of Participants Discontinuing Treatment Due to an AE | 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 5 days in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Inhibition of the Expression of Cluster of Differentiation (CD)11b on Blood Eosinophils | The concentration of CD11b in whole blood samples was assessed. The percent-inhibition of CD11b (a cell-surface biomarker on activated eosinophils) was assessed following inhaled allergen challenge on Day 5. Inhibition of CD11b expression was assessed by analyzing the % inhibition of CD11b expression from baseline (Day -1) using a linear mixed-effects model with period, treatment, time, and treatment by time as fixed terms and subject as a random term. Outcome Measure 7 shows CD11b expression values at baseline. | Baseline (Day -1, predose), 24 hours after allergen challenge on Day 5 in each treatment period |