A Dose-Ranging Study of the Safety and Effectiveness of MK-8237 in the Treatment of House Dust Mite (HDM) Induced Allergic Rhinitis/Rhinoconjunctivitis in Adults (MK-8237-003/P07627)

A Phase IIb, Randomized, Placebo-Controlled, Dose-Finding Clinical Trial to Study the Safety and Efficacy of MK-8237 Using an Environmental Exposure Chamber in Subjects With House Dust Induced Allergic Rhinitis/Rhinoconjunctivitis

The purpose of this study is to evaluate the dose-related effectiveness, the safety and the tolerability of MK-8237, compared to placebo, in the treatment of house dust mite (HDM)-induced allergic rhinitis/rhinoconjunctivitis in adults. The primary hypothesis is that administration of MK-8237, compared to placebo, results in dose-related improvement in the average total nasal symptom score (TNSS) determined during environmental exposure chamber (EEC) challenge.

Study Overview

• Status: Completed
• Conditions: Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Nonseasonal
• Intervention / Treatment: Drug: Placebo; Drug: MK-8237 6 DU; Drug: MK-8237 12 DU

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• History of allergic rhinitis/rhinoconjunctivitis to house dust of 1 year duration or more (with or without asthma)
• If female of childbearing potential, has a negative urine pregnancy test at screening and agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control within the projected duration of the study.

Exclusion Criteria:

• Sensitized and regularly exposed to animal dander and molds, (e.g. present in the home, job, etc.)
• Sensitized and regularly exposed to seasonal allergens (i.e., birch or grass pollen)
• Immunosuppressive treatment within 3 months prior to screening (except steroids for allergic and asthma symptoms)
• History of chronic urticaria and/or angioedema within 2 years prior to screening
• Previous immunotherapy treatment with any HDM allergen for more than 1 month within 3 years prior to screening
• Ongoing treatment with any specific immunotherapy
• History of anaphylaxis with cardiorespiratory symptoms with prior immunotherapy, due to an unknown cause or to an inhalant allergen
• Unstable uncontrolled/partially controlled or severe asthma, or life-threatening asthma attack or an occurrence of any clinical deterioration of asthma that resulted in emergency treatment, hospitalization due to asthma, or treatment with systemic corticosteroids (but allowing short-acting beta agonists [SABA]) within 3 months prior to screening
• Asthma requiring medium- or high-dose inhaled corticosteroid (ICS) within 12 months prior to screening
• Chronic sinusitis within 2 years prior to screening
• Nasal condition that could confound the efficacy or safety assessments (e.g., nasal polyps)
• Pregnant, breastfeeding or planning to become pregnant during the study
• Participation in a different investigational study at any site during the same time frame of this study
• Direct association with the administration of the study or a family member of the study staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo rapidly dissolving tablet administered sublingually once daily (q.d.), at approximately the same time each day, for 24 weeks	Drug: Placebo; Placebo rapidly dissolving tablets administered sublingually once daily
Experimental: MK-8237 6 Developmental Units (DU); MK-8237 6 DU rapidly dissolving tablet administered sublingually q.d., at approximately the same time each day, for 24 weeks	Drug: MK-8237 6 DU; MK-8237 6 DU rapidly dissolving tablets administered sublingually once daily; Other Names: SCH 900237
Experimental: MK-8237 12 DU; MK-8237 12 DU rapidly dissolving tablet administered sublingually q.d., at approximately the same time each day, for 24 weeks	Drug: MK-8237 12 DU; MK-8237 12 DU rapidly dissolving tablets administered sublingually once daily; Other Names: SCH 900237

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Total Nasal Symptom Score (TNSS) During Environmental Exposure Chamber (EEC) Challenge Session at Week 24	The average total TNSS included the evaluation of 4 nasal symptoms: itchy nose, blocked nose, runny nose, and sneezing. The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 24. TNSS was the total of scores for the 4 nasal symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TNSS ranged from 0 to 12 points. The 24-week TNSS was analyzed using the analysis of covariance (ANCOVA) model with treatment and baseline TNSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TNSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average TNSS During EEC Challenge Session at Week 16	The average total TNSS included the evaluation of 4 nasal symptoms: itchy nose, blocked nose, runny nose, and sneezing. The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 16. TNSS was the total of scores for the 4 nasal symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TNSS ranged from 0 to 12 points. The Week 16 TNSS was analyzed using the ANCOVA model with treatment and baseline TNSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TNSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 16
Average TNSS During EEC Challenge Session at Week 8	The average total TNSS included the evaluation of 4 nasal symptoms: itchy nose, blocked nose, runny nose, and sneezing. The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 8. TNSS was the total of scores for the 4 nasal symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TNSS ranged from 0 to 12 points. The Week 8 TNSS was analyzed using the ANCOVA model with treatment and baseline TNSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TNSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 8
Average Total Symptom Score (TSS [TNSS + TOSS]) During EEC Challenge Session at Week 24	The average total TSS included the evaluation of the 4 nasal symptoms of the TNSS (itchy nose, blocked nose, runny nose, and sneezing) plus the 2 ocular symptoms of the TOSS (gritty/feeling/red/itchy eyes and watery eyes). The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 24. TSS was the total of scores for the 4 nasal symptoms and 2 ocular symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TSS ranged from 0 to 18 points. The Week 24 TSS was analyzed using the ANCOVA model with treatment and baseline TSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 24
Average TSS (TNSS + TOSS) During EEC Challenge Session at Week 16	The average total TSS included the evaluation of the 4 nasal symptoms of the TNSS (itchy nose, blocked nose, runny nose, and sneezing) plus the 2 ocular symptoms of the TOSS (gritty/feeling/red/itchy eyes and watery eyes). The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 16. TSS was the total of scores for the 4 nasal symptoms and 2 ocular symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TSS ranged from 0 to 18 points. The Week 16 TSS was analyzed using the ANCOVA model with treatment and baseline TSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 16
Average TSS (TNSS + TOSS) During EEC Challenge Session at Week 8	The average total TSS included the evaluation of the 4 nasal symptoms of the TNSS (itchy nose, blocked nose, runny nose, and sneezing) plus the 2 ocular symptoms of the TOSS (gritty/feeling/red/itchy eyes and watery eyes). The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 8. TSS was the total of scores for the 4 nasal symptoms and 2 ocular symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TSS ranged from 0 to 18 points. The Week 8 TSS was analyzed using the ANCOVA model with treatment and baseline TSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 8
Average Total Ocular Symptom Score (TOSS) During EEC Challenge Session at Week 24	The average total TOSS included the evaluation of 2 ocular symptoms: gritty/feeling/red/itchy eyes and watery eyes. The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 24. TOSS was the total of scores for the 2 ocular symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TOSS ranged from 0 to 6 points. The Week 24 TOSS was analyzed using the ANCOVA model with treatment and baseline TOSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TOSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 24
Average TOSS During EEC Challenge Session at Week 16	The average total TOSS included the evaluation of 2 ocular symptoms: gritty/feeling/red/itchy eyes and watery eyes. The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 16. TOSS was the total of scores for the 2 ocular symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TOSS ranged from 0 to 6 points. The Week 16 TOSS was analyzed using the ANCOVA model with treatment and baseline TOSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TOSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 16
Average TOSS During EEC Challenge Session at Week 8	The average total TOSS included the evaluation of 2 ocular symptoms: gritty/feeling/red/itchy eyes and watery eyes. The endpoint was based on participant diary entries over the last 4 hours of the EEC challenge session at Week 8. TOSS was the total of scores for the 2 ocular symptoms, each scored on a 4-point rating scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). The total TOSS ranged from 0 to 6 points. The Week 8 TOSS was analyzed using the ANCOVA model with treatment and baseline TOSS as covariates and expressed as a least squares mean with 95% confidence interval. A decrease in TOSS for participants receiving either dose of MK-8237 compared to placebo indicated an improvement in symptoms.	Week 8
HDM-specific Immunoglobulin E (IgE) Levels at Week 8	Dermatophagoides pteronyssinus (D. pteronyssinus) and Dermatophagoides farinae (D. farinae) serum IgE levels were measured using the Immunocap® assay at Week 8. IgE levels were expressed in Log 10 scale kilo units/Liter (kU/L). Analysis was based on the analysis of variance parametric (ANOVA) model with treatment as the fixed effect and reported as mean IgE with a standard deviation.	Week 8
HDM-specific Immunoglobulin G4 (IgG4) Levels at Week 8	D. pteronyssinus and D. farinae serum IgG4 levels were measured using the Immunocap® assay at Week 8. IgG4 levels were expressed in Log 10 scale milligrams/Liter (mg/L). Analysis was based on the ANOVA model with treatment as the fixed effect and reported as mean IgG4 with a standard deviation.	Week 8
Change From Baseline in HDM-specific IgE Levels at Week 8	D. pteronyssinus and D. farinae serum IgE levels were measured using the Immunocap® assay at baseline and Week 8. IgE levels were expressed in Log 10 scale kU/L. Mean Week 8 IgE levels were compared to the mean IgE levels at baseline. Analysis was based on the ANOVA model with treatment as the fixed effect and reported as a least squares mean with 95% confidence interval.	Baseline and Week 8
Change From Baseline in HDM-specific IgG4 Levels at Week 8	D. pteronyssinus and D. farinae serum IgG4 levels were measured using the Immunocap® assay at baseline and Week 8. IgG4 levels were expressed in Log 10 scale mg/L. Mean Week 8 IgG4 levels were compared to the mean IgG4 levels at baseline. Analysis was based on the ANOVA model with treatment as the fixed effect and reported as a least squares mean with 95% confidence interval.	Time Frame: Baseline and Week 8
Percentage of Participants Who Experienced At Least One Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A serious adverse event (SAE) was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event.	From first dose to last dose of treatment plus 2 weeks of follow-up (Up to 26 weeks)
Percentage of Participants Who Discontinued Study Drug Due to an AE	The percentage of participants who had study treatment stopped due to an AE. Discontinuations were reported for all randomized participants who received ≥1 dose of study treatment.	From first dose to last dose of treatment (Up to 24 weeks)

Collaborators and Investigators

• Sponsor: ALK-Abelló A/S
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Nolte H, Maloney J, Nelson HS, Bernstein DI, Lu S, Li Z, Kaur A, Zieglmayer P, Zieglmayer R, Lemell P, Horak F. Onset and dose-related efficacy of house dust mite sublingual immunotherapy tablets in an environmental exposure chamber. J Allergy Clin Immunol. 2015 Jun;135(6):1494-501.e6. doi: 10.1016/j.jaci.2014.12.1911. Epub 2015 Jan 27.
• Fortescue R, Kew KM, Leung MST. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2020 Sep 14;9(9):CD011293. doi: 10.1002/14651858.CD011293.pub3.
• Roth-Walter F, Schmutz R, Mothes-Luksch N, Lemell P, Zieglmayer P, Zieglmayer R, Jensen-Jarolim E. Clinical efficacy of sublingual immunotherapy is associated with restoration of steady-state serum lipocalin 2 after SLIT: a pilot study. World Allergy Organ J. 2018 Oct 1;11(1):21. doi: 10.1186/s40413-018-0201-8. eCollection 2018.
• Bernstein DI, Kleine-Tebbe J, Nelson HS, Bardelas JA Jr, Sussman GL, Lu S, Rehm D, Svanholm Fogh B, Nolte H. SQ house dust mite sublingual immunotherapy tablet subgroup efficacy and local application site reaction duration. Ann Allergy Asthma Immunol. 2018 Jul;121(1):105-110. doi: 10.1016/j.anai.2018.04.007. Epub 2018 Apr 12.
• Zieglmayer P, Nolte H, Nelson HS, Bernstein DI, Kaur A, Jacobi H, Lemell P, Schmutz R, Zieglmayer R, Horak F. Long-term effects of a house dust mite sublingual immunotherapy tablet in an environmental exposure chamber trial. Ann Allergy Asthma Immunol. 2016 Dec;117(6):690-696.e1. doi: 10.1016/j.anai.2016.10.015.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: July 17, 2012
• First Submitted That Met QC Criteria: July 17, 2012
• First Posted (Estimate): July 19, 2012

Study Record Updates

• Last Update Posted (Actual): September 15, 2017
• Last Update Submitted That Met QC Criteria: September 14, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Otorhinolaryngologic Diseases; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Rhinitis; Rhinitis, Allergic; Rhinitis, Allergic, Perennial
• Other Study ID Numbers: P07627; 2012-001855-38 (EudraCT Number); 8237-003 (Other Identifier: Merck Registration Number)