MK-8237 (SCH900237) Biomarker Study in Participants With Allergic Rhinitis or Rhinoconjunctivitis (MK-8237-009)

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect on various biomarkers of treatment with MK-8237 in participants with allergic rhinitis or rhinoconjunctivitis. In Part 1 of the study healthy participants undergo nasal allergen challenge (NAC) with house dust mite (HDM) extract in order to verify the operational performance of NAC and associated sample collection methods. Part 2, the main study, is a placebo controlled, double blind study of participants with HDM-induced allergic rhinitis or rhinoconjunctivitis. The primary hypotheses are that the changes from baseline in post-allergen challenge HDM-specific Immunoglobulin G4 (IgG4) and Immunoglobulin E blocking factor (IgE-BF) are greater after treatment with MK-8237 than after treatment with placebo.

Official Title
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A Two Part, Randomized Clinical Trial to Study Biomarkers of MK-8237 (SCH 900237) Treatment in Subjects With House Dust Mite Induced Allergic Rhinitis or Rhinoconjunctivitis

Conditions
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Allergic Rhinitis, Allergic Rhinoconjunctivitis

Intervention / Treatment
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* Biological: MK-8237
* Other: Placebo
* Biological: NAC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: healthy participants has a Body Mass Index (BMI) =< 30 kg/m^2 female of reproductive potential remains abstinent or uses two acceptable methods of birth control from 2 weeks before first allergen challenge to 2 weeks after last allergen challenge; alternatively hormonal contraception may be used. Part 2: has a Body Mass Index (BMI) =< 38 kg/m^2 has a clinical history of allergic rhinitis/rhinoconjunctivitis to HDM for at least one year, and used medication to relieve symptoms within the last year does not have asthma, or has mild controlled asthma not requiring regular use over the 12 months prior to screening of any corticosteroids female of reproductive potential remains abstinent or use two acceptable methods of birth control from 2 weeks before first allergen challenge to at least 2 weeks after last allergen challenge or last dose of study drug, whichever is longer has not smoked or used tobacco for the prior 6 months, and agrees not to during study Exclusion Criteria: Parts 1 and 2: is experiencing at the first NAC visit, symptoms from an upper or lower respiratory tract infection (viral or bacterial) has participated within the prior 3 months in another investigational study (that included an investigational drug or agent) is directly associated with the administration of the study or is related to the investigational study staff is mentally or legally incapacitated, has significant emotional problems or has a history of clinically significant psychiatric disorder within the past 5 years has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases has a history of cancer has a history of significant intolerability to drugs or food is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV had major surgery or lost 1 unit (500 mL) of blood within the prior 4 weeks has a clinical history of chronic sinusitis during the prior 2 years has any nasal condition (e.g. nasal polyposis) that could confound efficacy or safety assessments is pregnant or expects to conceive during the study period is a nursing mother consumes more than 3 glasses of alcoholic beverages per day regularly uses any illicit drug, or has a history of drug or alcohol abuse within the prior 6 months Part 2 only: is experiencing allergic rhinoconjunctivitis exacerbation at Screening NAC consumes excessive daily amounts of caffeinated beverages has a known history of allergy, hypersensitivity or intolerance to investigational medicines is sensitized and regularly exposed to animal dander and molds in the home or workplace in a manner that might interfere with the study in the opinion of the investigator is sensitized and regularly exposed to seasonal allergens such as Birch or grass pollen (sensitized but out of season is acceptable however) has a history of chronic urticaria and/or angioedema within the prior 2 years has had previous immunotherapeutic treatment with any HDM allergen for more than 1 month during the prior 3 years is receiving any specific immunotherapy within prior 60 days has a history of anaphylaxis with cardiorespiratory symptoms with prior immunotherapy due to an unknown cause or an inhalant allergen

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAC + MK-8237 (Part 2)<br>Nasal Allergen Challenge (NAC) treatment consisting of 1800 Biological Units (BU) of HDM extract on Days -14, 56 and 84; starting on Day 1 a single tablet of MK-8237 with 12 Development Units (DUs), administered sublingually, at approximately the same time each day for 84 days (+/- 5 days) | Biological: MK-8237<br>* A single tablet of MK-8237 with 12 DU, administered sublingually, at approximately the same time each day for 84 days (+/- 5 days)<br>Biological: NAC<br>* 0.1 mL fixed volume of 10,000 BU/mL of HDM extract is delivered with a Pfeiffer Bidose Nasal Delivery System (or equivalent) to each nostril for a total dose of 1800 BU at the start of Part 1; and in Part 2 on Days -14, 56 and 84<br>|
| Placebo Comparator: NAC + Placebo (Part 2)<br>NAC treatment consisting of 1800 BU of HDM extract on Days -14, 56 and 84; starting on Day 1 a single placebo tablet administered sublingually, at approximately the same time each day for 84 days (+/- 5 days) | Other: Placebo<br>* A single placebo tablet administered sublingually, at approximately the same time each day for 84 days (+/- 5 days)<br>Biological: NAC<br>* 0.1 mL fixed volume of 10,000 BU/mL of HDM extract is delivered with a Pfeiffer Bidose Nasal Delivery System (or equivalent) to each nostril for a total dose of 1800 BU at the start of Part 1; and in Part 2 on Days -14, 56 and 84<br>|
| Experimental: NAC (Part 1)<br>Nasal Allergen Challenge (NAC) consisting of 100 µl fixed volume of 10,000 biological units (BU) of HDM extract delivered with a Pfeiffer Bidose Nasal Delivery System (or equivalent) to each nostril for a total dose of 1800 BU at the start of Part 1 | Biological: NAC<br>* 0.1 mL fixed volume of 10,000 BU/mL of HDM extract is delivered with a Pfeiffer Bidose Nasal Delivery System (or equivalent) to each nostril for a total dose of 1800 BU at the start of Part 1; and in Part 2 on Days -14, 56 and 84<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in D. Farinae HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | Blood was collected from participants treated with Dermatophagoides (D.) farinae HDM and then with MK-8237 or placebo, and the amount of HDM-specific IgG4 antibodies in serum at baseline and at week 12 were measured. Fold change from baseline was evaluated based on constrained longitudinal data analysis (cLDA) method with log transformed data. The model included time (categorical variable), treatment, and time by treatment interaction as fixed effects and participants as random effect. Least squares geometric means are presented. It is hypothesized that the change from baseline is statistically greater with MK-8237 treatment than with placebo. This hypothesis is supported if the lower bound of the two-sided 90% confidence interval for the geometric mean fold difference is >1.0. | Baseline and 12 weeks | 
| Change From Baseline in D. Pteronyssinus HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | Blood was collected from participants treated with D. pteronyssinus HDM, and then with MK-8237 or placebo, and the amount of HDM-specific IgG4 antibodies in serum at baseline and at week 12 were measured. Fold change from baseline was evaluated based on cLDA method with log transformed data. The model included time (categorical variable), treatment, and time by treatment interaction as fixed effects and participants as random effect. Least squares geometric means are presented. It is hypothesized that the change from baseline is statistically greater with MK-8237 treatment than with placebo. This hypothesis is supported if the lower bound of the two-sided 90% confidence interval for the geometric mean fold difference is >1.0. | Baseline and 12 weeks | 
| Change From Baseline in HDM-specific IgE Blocking Factor (IgE-BF) in Serum at 12 Weeks | Blood was collected from participants treated with D. pteronyssinus and D.farinae HDM and then with either MK-8237 or placebo, and the amount of IgE-BF in serum was measured based on an Ordinary IgE measurement and an assay in the presence of Competitors; with IgE-BF = 1 - (Competitive IgE/Ordinary IgE). This ranges from 0 (no IgE blocked) to 1 (all IgE blocked); and as it is based on a ratio there are no units. Change from baseline (12 weeks minus baseline) was evaluated based on cLDA method, and was analyzed based on the original scale. The model included time (categorical variable), treatment, and time by treatment interaction as fixed effects and participants as random effect. It is hypothesized that the change from baseline is statistically greater with MK-8237 treatment than with placebo. This hypothesis is supported if the lower bound of the 1-tailed 95% CI around the 12 week mean difference in change from baseline in HDM-specific IgE blocking factor response excludes zero. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 6.5 Hours Post-NAC Interleukin-5 (IL-5) Protein Concentration in Nasal Exudates Following 12 Weeks of Treatment (Part 2) | Blood was collected from participants treated with D. pteronyssinus and D.farinae HDM and then with either MK-8237 or placebo, and the levels of Il-5 protein 6.5 hours after NAC in serum at baseline and at week 12 were measured. Fold change from baseline and between-treatment comparison was evaluated based on cLDA method with log transformed data. IL-5 protein concentration was measured in nasal exudates collected both pre- and post-nasal challenge. Least squares geometric means are presented. | Baseline and 12 weeks | 
| Change From Baseline in 6.5 Hours Post-NAC Nasal Epithelial Eosinophil-related Messenger RNA (mRNA) Signature Following 12 Weeks of Treatment (Part 2) | Blood was collected from participants treated with D. pteronyssinus and D.farinae HDM and then with either MK-8237 or placebo, and the levels of nasal epithelial eosinophil-related mRNA signature 6.5 hours after NAC in serum at baseline and at week 12 were measured. The mRNA signature is derived from nine gene transcripts which were measured using the NanoString nCounter Gene Expression Assay. Positive control and pre-specified housekeeping gene normalization methods recommended by nSolver were used to normalize the transcripts. The average of the expression level of the nine genes was used to describe the eosinophil mRNA signature. Fold change from baseline and between-treatment comparison was evaluated based on cLDA method with log transformed data. Least squares geometric means are presented. | Baseline and 12 weeks | 
| Change From Baseline in Time Weighted Average (TWA) Over 1 Hour Pre-NAC Through 1 Hour Post-NAC Visual Analog Score (VAS) for Sneezing, Rhinorrhea, Congestion and Nasal Itch Following 12 Weeks of Treatment (Part 2) | A visual analog scale (VAS) representing the spectrum of symptoms from absent (0) to extremely severe (100) for each of rhinorrhea, nasal blockage, sneezing and nasal itch were summed to obtain an overall score. The range of VAS overall score is 0 - 400, with higher numbers representing worse symptoms. The models for the time-weighted mean (TWA) of the summed scores over 1 hour pre-NAC through hour 1 following NAC were constructed at the original scale. | Baseline and 12 weeks |