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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-005621-70 | EudraCT Number |
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| Name | Class |
|---|---|
| ALK-Abelló A/S | INDUSTRY |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| NAC + MK-8237 (Part 2) | Experimental | 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) |
|
| NAC + Placebo (Part 2) | Placebo Comparator | 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) |
|
| NAC (Part 1) | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MK-8237 | Biological | A single tablet of MK-8237 with 12 DU, administered sublingually, at approximately the same time each day for 84 days (+/- 5 days) |
|
| 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. |
| 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. |
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Inclusion Criteria:
Part 1:
Part 2:
Exclusion Criteria:
Parts 1 and 2:
Part 2 only:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28911971 | Result | Gunawardana NC, Zhao Q, Carayannopoulos LN, Tsai K, Malkov VA, Selverian D, Clarke G, Mant T, Butts BD, Lund K, Hansel TT, Nolte H. The effects of house dust mite sublingual immunotherapy tablet on immunologic biomarkers and nasal allergen challenge symptoms. J Allergy Clin Immunol. 2018 Feb;141(2):785-788.e9. doi: 10.1016/j.jaci.2017.08.016. Epub 2017 Sep 11. No abstract available. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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) |
| FG001 | 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) |
| FG002 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | Fold Change | Baseline and 12 weeks |
Part 1: Up to 17 days after treatment; Part 2: Up to 101 days after treatment
All participants who received at least one dose of the investigational drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear pruritus | Ear and labyrinth disorders | MedDRA 18.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D065631 | Rhinitis, Allergic |
| ID | Term |
|---|---|
| D012220 | Rhinitis |
| D009668 | Nose Diseases |
| D012140 | Respiratory Tract Diseases |
| D012130 | Respiratory Hypersensitivity |
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| Placebo | Other | A single placebo tablet administered sublingually, at approximately the same time each day for 84 days (+/- 5 days) |
|
| NAC | Biological | 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 |
|
| Baseline and 12 weeks |
| 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 |
| 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) |
| BG002 | 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 |
| BG003 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID | Title | Description |
|---|
| OG000 | 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) |
| OG001 | 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) |
| OG002 | 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 |
|
|
|
| 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | Fold Change | Baseline and 12 weeks |
|
|
|
|
| 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | Ratio | Baseline and 12 weeks |
|
|
|
|
| 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | Fold change | Baseline and 12 weeks |
|
|
|
|
| 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | Fold change | Baseline and 12 weeks |
|
|
|
|
| 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | Score on a scale | Baseline and 12 weeks |
|
|
|
|
| 0 |
| 3 |
| 0 |
| 3 |
| EG001 | 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) | 0 | 16 | 14 | 16 |
| EG002 | 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) | 0 | 7 | 6 | 7 |
| Conjunctivitis allergic | Eye disorders | MedDRA 18.1 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Hypoaesthesia oral | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Lip pain | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Lip swelling | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Mouth swelling | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Oral pruritus | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Paraesthesia oral | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Swollen tongue | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Tongue pruritus | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA 18.1 | Systematic Assessment |
|
| Hypersensitivity | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Seasonal allergy | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Conjunctivitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Burns first degree | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
| Blood iron decreased | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Dry throat | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Nasal dryness | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
|
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.
| D010038 |
| Otorhinolaryngologic Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |