Allergic Rhinitis, Allergic Rhinoconjunctivitis
Conditions
Brief summary
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.
Interventions
BIOLOGICALMK-8237
A single tablet of MK-8237 with 12 DU, administered sublingually, at approximately the same time each day for 84 days (+/- 5 days)
OTHERPlacebo
A single placebo tablet administered sublingually, at approximately the same time each day for 84 days (+/- 5 days)
BIOLOGICALNAC
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
Sponsors
ALK-Abelló A/S
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in D. Farinae HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | Baseline and 12 weeks | 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. |
| Change From Baseline in D. Pteronyssinus HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | Baseline and 12 weeks | 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. |
| Change From Baseline in HDM-specific IgE Blocking Factor (IgE-BF) in Serum at 12 Weeks | Baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Baseline and 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 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. |
| Change From Baseline in 6.5 Hours Post-NAC Nasal Epithelial Eosinophil-related Messenger RNA (mRNA) Signature Following 12 Weeks of Treatment (Part 2) | Baseline and 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 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. |
| 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) | Baseline and 12 weeks | 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. |
Participant flow
Recruitment details
In Part 1, healthy participants aged 18-55 years were enrolled; In Part 2, participants with house dust mite (HDM)-induced allergic rhinitis or rhinoconjunctivitis, aged 18-55, were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| NAC + MK-8237 (Part 2) 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) | 16 |
| NAC + Placebo (Part 2) 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) | 7 |
| NAC (Part 1) Nasal Allergen Challenge (NAC) treatment 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 | 3 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | NAC + MK-8237 (Part 2) | NAC + Placebo (Part 2) | NAC (Part 1) |
|---|---|---|---|---|
| Age, Continuous | 31.9 Years STANDARD_DEVIATION 9.9 | 31.3 Years STANDARD_DEVIATION 8.6 | 36.1 Years STANDARD_DEVIATION 13.2 | 25.7 Years STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 12 Participants | 8 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 14 Participants | 8 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 14 / 16 | 6 / 7 |
| serious Total, serious adverse events | 0 / 3 | 0 / 16 | 0 / 7 |
Outcome results
Primary
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.
Time frame: Baseline and 12 weeks
Population: All randomized participants from Part 2 who are compliant with the study procedures and have available data from at least one treatment. Participants from Part 1 were not analyzed because they were not treated with MK-8237 or placebo.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| NAC + MK-8237 (Part 2) | Change From Baseline in D. Farinae HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | 0.392 Fold Change |
| NAC + Placebo (Part 2) | Change From Baseline in D. Farinae HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | 0.166 Fold Change |
Comparison: The hypothesis is supported if the lower bound of the two-sided 90% confidence interval for the Week 12 geometric mean fold difference is \>1.0.p-value: 0.00390% CI: [1.515, 3.661]Constrained Longitudinal Data Analysis
Primary
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.
Time frame: Baseline and 12 weeks
Population: All randomized participants from Part 2 who are compliant with the study procedures and have available data from at least one treatment. Participants from Part 1 were not analyzed because they were not treated with MK-8237 or placebo.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| NAC + MK-8237 (Part 2) | Change From Baseline in D. Pteronyssinus HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | 0.619 Fold Change |
| NAC + Placebo (Part 2) | Change From Baseline in D. Pteronyssinus HDM-specific IgG4 Antibodies in Serum at 12 Weeks (Part 2) | 0.284 Fold Change |
Comparison: The hypothesis is supported if the lower bound of the two-sided 90% confidence interval for the Week 12 geometric mean fold difference is \>1.0.p-value: 0.0190% CI: [1.364, 3.49]Constrained Longitudinal Data Analysis
Primary
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.
Time frame: Baseline and 12 weeks
Population: All randomized participants from Part 2 who are compliant with the study procedures and have available data from at least one treatment. Participants from Part 1 were not analyzed because they were not treated with MK-8237 or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAC + MK-8237 (Part 2) | Change From Baseline in HDM-specific IgE Blocking Factor (IgE-BF) in Serum at 12 Weeks | 0.097 Ratio |
| NAC + Placebo (Part 2) | Change From Baseline in HDM-specific IgE Blocking Factor (IgE-BF) in Serum at 12 Weeks | -0.141 Ratio |
Comparison: The hypothesis is supported if the lower bound of the 1-tailed 95% CI around the mean difference in change from baseline excludes zerop-value: 0.02790% CI: [0.066, 0.41]Constrained Longitudinal Data Analysis
Secondary
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.
Time frame: Baseline and 12 weeks
Population: All randomized participants from Part 2 who are compliant with the study procedures and have available data from at least one treatment. Participants from Part 1 were not analyzed because they were not treated with MK-8237 or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAC + MK-8237 (Part 2) | 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) | 9.444 Fold change |
| NAC + Placebo (Part 2) | 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) | 8.843 Fold change |
p-value: 0.93590% CI: [0.272, 4.19]Constrained Longitudinal Data Analysis
Secondary
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.
Time frame: Baseline and 12 weeks
Population: All randomized participants from Part 2 who are compliant with the study procedures and have available data from at least one treatment. Participants from Part 1 were not analyzed because they were not treated with MK-8237 or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAC + MK-8237 (Part 2) | Change From Baseline in 6.5 Hours Post-NAC Nasal Epithelial Eosinophil-related Messenger RNA (mRNA) Signature Following 12 Weeks of Treatment (Part 2) | 2.618 Fold change |
| NAC + Placebo (Part 2) | Change From Baseline in 6.5 Hours Post-NAC Nasal Epithelial Eosinophil-related Messenger RNA (mRNA) Signature Following 12 Weeks of Treatment (Part 2) | 0.981 Fold change |
p-value: 0.29690% CI: [0.605, 8.066]Constrained Longitudinal Data Analysis
Secondary
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.
Time frame: Baseline and 12 weeks
Population: All randomized participants from Part 2 who are compliant with the study procedures and have available data from at least one treatment. Participants from Part 1 were not analyzed because they were not treated with MK-8237 or placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAC + MK-8237 (Part 2) | 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) | 53.065 Score on a scale |
| NAC + Placebo (Part 2) | 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) | 114.180 Score on a scale |
p-value: 0.01490% CI: [-100.185, -22.045]Constrained Longitudinal Data Analysis