Efficacy and safety of sublingual tablets of house dust mite allergen extracts: Results of a dose-ranging study in an environmental exposure chamber

Accepted Manuscript Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergen Extracts: Results of a Dose-Ranging Study in an Environmental Exposure Chamber Michel Roux, MD, Philippe Devillier, MD, PhD, William H. Yang, MD, Armelle Montagut, MSc, Kathy Abiteboul, PharmD, Agnès Viatte, MSc, Robert K. Zeldin, MD PII:

S0091-6749(16)30257-3

DOI:

10.1016/j.jaci.2016.03.039

Reference:

YMAI 12098

To appear in:

Journal of Allergy and Clinical Immunology

Received Date: 3 June 2015 Revised Date:

2 February 2016

Accepted Date: 2 March 2016

Please cite this article as: Roux M, Devillier P, Yang WH, Montagut A, Abiteboul K, Viatte A, Zeldin RK, Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergen Extracts: Results of a DoseRanging Study in an Environmental Exposure Chamber, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.03.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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TITLE PAGE

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Original Article

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Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergen Extracts: Results

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of a Dose-Ranging Study in an Environmental Exposure Chamber

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Authors: Michel Roux, MD1, Philippe Devillier, MD, PhD2, William H. Yang, MD3, Armelle

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Montagut, MSc1, Kathy Abiteboul, PharmD1, AgnèsViatte, MSc1, Robert K. Zeldin, MD1

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Stallergenes S.A., Antony, France

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Clinical Research Unit, UPRES EA 220, Foch Hospital, Suresnes, France

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Allergy and Asthma Research Centre, Ottawa, ON, Canada

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11 Corresponding author

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Dr. Robert K. Zeldin

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Stallergenes S.A.

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Global Clinical Development department

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6, rue Alexis de Tocqueville

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92183, Antony, France

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Tel: +33 (0)1 55 59 23 81

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Fax : +33 (0)1 55 59 20 68

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Email: [email protected]

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Declaration of all funding sources

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Michel Roux, Armelle Montagut, Kathy Abiteboul, AgnèsViatte and Robert K. Zeldin are

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employees of Stallergenes S.A. Philippe Devillier has received consulting fees from

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Stallergenes S.A. and has received honoraria for board membership, consultancy, lectures

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and/or manuscript preparation from ALK, Almirall, Astra-Zeneca, Boehringer-Ingelheim,

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Chiesi, CLL Pharma, GlaxoSmithKline, Meda Pharma, Mundipharma, Novartis, Sandoz,

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Stallergenes S.A. and Teva. William Yang has received research grants from Stallergenes

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S.A.

30 Word count: 3185 words

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Number of tables and figures: 3 tables, 5 figures

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Abstract (250 words)

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Background: In a natural field study, sublingual tablets of house dust mite (HDM) allergen

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extracts (STG320) were efficacious in treating HDM-associated allergic rhinitis.

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Objective: To assess the efficacy and safety of three doses of STG320 in an environmental

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exposure chamber (EEC).

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Methods: In this randomized, double-blind study, adults with HDM-associated allergic

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rhinitis were given a daily sublingual tablet containing placebo or STG320 at a dose of 500IR,

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300IR or 100IR (IR=Index of Reactivity) for 6 months. Participants recorded their rhinitis

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symptoms during 4-hour HDM EEC challenges at randomization and months 1, 2, 4, and 6.

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The primary efficacy end point was the change from baseline to end-of-treatment in the area-

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under-the-curve of the rhinitis total symptom score (ChBLAUCRTSS 0-4h). Differences from the

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placebo group were analyzed by ANCOVA. Adverse events (AEs) and routine safety

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parameters were recorded.

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Results: 355 subjects were randomized to one of four groups: 500IR (n=93), 300IR (n=86),

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100IR (n=89), or placebo (n=87). The least squares mean differences from placebo in the

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ChBLAUCRTSS 0-4h for the 500IR, 300IR and 100IR groups indicated a dose-dependent effect

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with reductions in symptom scores of 33%, 29% and 20%, respectively. The most frequent

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AEs were throat irritation and oral pruritus. There were no reports of anaphylaxis or reports

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consistent with severe laryngopharyngeal disorders and no use of epinephrine. AEs leading to

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premature discontinuations were more common in the 500IR group.

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Conclusions: A dose-dependent effect of sublingual HDM immunotherapy was demonstrated

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in this environmental exposure chamber study, supporting further development of this

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treatment.

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Keywords: allergen immunotherapy; allergic rhinitis; house dust mite; sublingual

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immunotherapy tablet; double-blind placebo-controlled trial; environmental exposure

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chamber; dose-ranging.

60 Abbreviations used

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AE: Adverse event

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AIT: Allergen immunotherapy

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ANCOVA: Analysis of covariance

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ARSS: Average Rhinitis Symptom Score

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ARTSS: Average Rhinitis Total Symptom Score

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AUC: Area-under-the-curve

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AVASS: Average Visual Analog Scale Score

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Der f : Dermatophagoides farinae

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Der p: Dermatophagoides pteronyssinus

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EEC: Environmental exposure chamber

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ChBL: Change from baseline

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CI: Confidence interval

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FAS: Full Analysis Set

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FEV: Forced expiratory volume

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HDM: House dust mites

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IR: Index of reactivity

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LS: Least squares

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RTSS: Rhinitis Total Symptom Score

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TEAE: Treatment-emergent adverse event

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VAS: Visual Analog Scale

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82 Clinical Implications (27 words)

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Results of this dose-ranging study are consistent with those of a previous study and support

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further development of this sublingual tablet for patients with HDM-associated allergic

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rhinitis.

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87 Capsule Summary (26 words)

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The results of this placebo-controlled, dose-ranging study conducted in an environmental

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exposure

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immunotherapy tablets of HDM allergen extracts.

demonstrate

a

dose-dependent

effect

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of

STG320

sublingual

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INTRODUCTION

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Among indoor allergies, house dust mite (HDM) allergy is the most prevalent and is

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associated with atopic dermatitis, perennial rhinitis and asthma.1 A diagnostic classification of

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patients with persistent rhinitis showed that 39% had allergic rhinitis and 52% of them were

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sensitized to HDM allergens.2 HDM allergy is strongly associated with development, severity

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and morbidity of asthma.3 Mite avoidance measures are generally not effective.4-6

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Symptomatic medications such as antihistamines and corticosteroids provide partial or

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temporary relief but are not effective in all patients and are not disease-modifying.7 In

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addition, pharmacotherapy may be associated with frequent side effects.

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Recent studies and the GA2LEN meta-analysis have provided evidence of efficacy and safety

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of sublingual immunotherapy in patients with HDM-associated allergic rhinitis and asthma.8

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In a randomized, double-blind, placebo-controlled, one-year phase II/III study conducted

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under natural field conditions, treatment with two doses of sublingual allergen

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immunotherapy (AIT) tablets containing freeze-dried extracts of the two most common

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allergenic mite species, Dermatophagoides pteronyssinus (Der p) and D. farinae (Der f),

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(referred to as STG320) was efficacious and safe.9, 10 In the present study, the dose-dependent

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effect of STG320 was further evaluated with three doses in an environmental exposure

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chamber (EEC) as proposed in the European Medicines Agency’s Guideline on the Clinical

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Development of Products for Specific Immunotherapy for the Treatment of Allergic

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Diseases.11

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The EEC has been used extensively for dose-ranging and assessment of onset of action of

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symptomatic medications.11-13 However, this tool has been underexploited in clinical trials of

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AIT12, 14 and until recently,15 there have been only a few reports on HDM challenge in an EEC

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with small numbers of subjects.16-18 In this multicenter study, HDM allergen challenge in an

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EEC was used to assess dose-dependent effect and safety of AIT.

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METHODS

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Trial design

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This randomized, double blind, placebo-controlled study (Fig. 1) was conducted at eight

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centers in Canada (ClinicalTrials.gov No.: NCT01527188). All allergen challenges in the

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environmental exposure chamber (EEC) were performed at Cetero Research/PRACS Institute

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(Mississauga, Ontario). The study was approved by the appropriate institutional review boards

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and Health Canada and was performed according to Good Clinical Practices guidelines of the

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International Conference on Harmonization. Written informed consent was obtained from all

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subjects before study entry.

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Participants were enrolled between December 2010 and September 2011 for 6 treatment

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months. Using a computer-generated randomization code (see details in this article’s Online

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Repository at www.jacionline.org), eligible subjects were assigned 1:1:1:1 to take a daily dose

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of either placebo or HDM allergen extracts at doses (expressed in IR, the in-house

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standardization unit) of 500IR, 300IR or 100IR. Subjects, investigators, and all other study

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personnel remained blinded for the entire study.

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133 Trial population

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Subjects 18–55 years of age were selected in a 2-step process. First, they had to have at least a

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one-year history of HDM-associated allergic rhinitis uncontrolled despite the use of

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symptomatic treatments, a positive skin prick test (wheal diameter, >3 mm), and HDM-

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specific serum IgE (≥0.7 kU/L). Those with a Rhinitis Total Symptom Score (RTSS) ≥6

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(0-12 scale) for at least 2 of the 12 time points during the baseline allergen challenge were

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eligible for randomization.

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Subjects sensitized to seasonal allergens were permitted to participate if the relevant allergy

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season was outside of the primary evaluation period. Subjects sensitized to other perennial

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allergens were excluded as were those with forced expiratory volume in one second

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(FEV1) <80% of predicted or subjects with asthma requiring treatment other than with inhaled

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beta-2 agonists, which could be used as needed.

146 Investigational treatment and rescue medication

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The investigational products were sublingual tablets containing a 1:1 mixture of standardized

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extracts of Der p and Der f (STG320), at doses of 500IR, 300IR or 100IR, or placebo tablets

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matched for size, shape, color, and taste. Allergen content of the study tablets measured by

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commercial ELISA kit (Indoor Biotechnologies, VA, USA) was 22−23 µg Der p 1 and

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99−102 µg Der f 1 per 500IR tablet, 14–17 µg Der p 1 and 53–62 µg Der f 1 per 300IR tablet,

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and 4–6 µg Der p 1 and 18–21 µg Der f 1 per 100IR tablet. Treatment consisted of sublingual

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administration of a single tablet daily for six months. Subjects were asked to keep the tablet

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under the tongue until complete disintegration. All subjects took the first dose of the

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investigational product under supervision at the trial site. Subsequent doses were

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self-administered at home. In the 500IR and 300IR groups, treatment was initiated with a

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dose-escalation phase, as previously described.10

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Symptomatic treatment of rhinitis was permitted between visits, but predefined washout

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periods were to be respected before allergen challenges (see the Methods section in this

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article’s Online Repository at www.jacionline.org). Outside of the allergen challenges,

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inhaled beta-2 agonists could be used as needed. Rescue medications were not permitted

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during the 4-hour allergen challenges unless prescribed by the investigator to treat an adverse

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event.

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Allergen challenge and trial measurements

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The allergen challenge was carried out in the EEC, a sealed room in which milled whole

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bodies of Der p mites with a particle size range of 15–100 µm were aerosolized and delivered

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at a constant flux via turbulent airflow. The average concentrations of the HDM allergen in

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the chamber were monitored to measure the concentration of allergen particles to which

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subjects were exposed. These concentrations were maintained between 29 and 111 ng

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Der p 1/m3. In the published literature and experience at Cetero Research/PRACS Institute,

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aerosolization of Der p 1 allergen in this concentration range has been shown to induce both

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nasal and non-nasal symptoms in dust mite allergic patients. 19

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Randomized subjects underwent five, 4-hour allergen challenges during the study: at baseline

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and after 1, 2, 4, and 6 treatment months (Fig. 1). During the challenges, participants recorded

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the severity of their four nasal symptoms (rhinorrhea, nasal congestion, sneezing and nasal

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pruritus) on a scale of 0 (no symptoms), 1 (mild), 2 (moderate) to 3 (severe). The Rhinitis

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Total Symptom Score (RTSS) is the sum of these four nasal symptom scores and thus ranges

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from 0 to 12.

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In the EEC, subjects assessed the overall severity of their allergic symptoms on a 10-cm

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Visual Analog Scale (VAS), ranging from “absence of symptoms” to “very severe

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symptoms.”20, 21

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For each challenge, rhinitis symptoms and VAS score were recorded at 13 time points: once

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before entering the EEC, then every 15 minutes for the first 2 hours, and every 30 minutes for

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the last 2 hours. As the intervals between time points were not equal, the area-under-the-curve

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(AUC) of RTSSs was used to analyze the symptom scores in the EEC. In addition, the

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average score of each of the four individual rhinitis symptoms (ARSS), RTSS (ARTSS) and

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VAS score (AVASS) were determined for each allergen challenge. Allergen challenge

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methods are further described in this article’s Online Repository at www.jacionline.org.

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192 The primary efficacy end point was the change from baseline to the end-of-treatment

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(i.e., 6 months) in the AUC of the RTSS over the 4 hours of the challenge (ChBLAUCRTSS 0-4h).

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This variable was also evaluated after 1, 2 and 4 months of treatment. The changes from

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baseline to the end-of-treatment in average RTSS (ChBLARTSS), average individual rhinitis

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scores (ChBLARSS0-4h) and average VAS score (ChBLAVASS0-4h), over the 4 hours of the

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challenge were reported as secondary efficacy end points. Previous studies with grass pollen

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have indicated that symptom scores increase rapidly at the start of an allergen challenge and

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plateau after approximately two hours.14 Hence, the changes from baseline to the end-of-

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treatment for the last 2 hours of the allergen challenges were analyzed for the total rhinitis

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score (AUC of RTSS [ChBLAUCRTSS 2-4h] and ARTSS [ChBLARTSS2-4h]), individual rhinitis

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scores (ARSS [ChBLARSS2-4h]), and VAS score (ChBLAVASS2-4h) as secondary end points.

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Blood samples were collected at baseline and after 2, 4, and 6 treatment months, before the

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allergen challenges. Der p- and Der f-specific serum IgE and IgG4 were determined using the

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ImmunoCap Phadia Laboratory System®.

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Safety variables included adverse events (AEs) which were monitored during the study and

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categorized according to MedDRA dictionary version 14.0. AEs occurring during the

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treatment period and up to 30 days after the last treatment administration are presented here.

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Treatment-emergent adverse events (TEAEs), drug-related TEAEs, and withdrawals due to

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TEAEs were identified in the different study groups. The occurrence of AEs in the peri-EEC

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period (i.e., the day of and the day after an allergen challenge) was compared with that in the

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rest of the study. In addition, changes from baseline in vital signs, lung function, and routine

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laboratory tests were assessed.

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217 Statistical methods

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Assuming a type I error of 5% (2-sided, α=0.05) and a coefficient of variation of the primary

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end point of 45%, a sample size of 71 subjects per treatment group would have a power of

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90% to detect a relative mean difference versus placebo of 22%. A 15% dropout rate was

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assumed. Therefore, the enrollment target was 84 subjects per group. Statistical analyses were

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performed using SAS® software (version 9.1.3), SAS Institute Inc., Cary, NC, USA. The

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threshold of statistical significance was set to a p-value of less than 0.05, and all inferential

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tests were 2-sided.

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Efficacy and safety were evaluated on all randomized subjects who received at least one dose

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of the assigned treatment. In this study, the efficacy set (Full Analysis Set, FAS) and the

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Safety Set were identical, and consistent with the Intent-To-Treat principle. The primary

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efficacy criterion was analyzed using analysis of covariance (ANCOVA) with treatment as

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the main effect and the baseline AUCRTSS 0-4h as covariate. Treatment comparisons were done

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with a step-down approach for the primary end point (first 500IR vs. placebo, then 300IR vs.

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placebo, then 100IR vs. placebo) to maintain the overall type I error rate at 5%. Secondary

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efficacy variables were analyzed as per the primary efficacy criterion.

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RESULTS

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Subject disposition

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A total of 355 subjects were randomized and constituted the FAS: 500IR (n=93), 300IR

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(n=86), 100IR (n=89) and placebo (n=87). 288 (81%) completed the study (Fig. 2).

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Demographics and baseline disease characteristics were similar across the groups (Table I).

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The mean age was 32 years, mean duration of allergic rhinitis was 17 years, about 76% were

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polysensitized, and about 13% had asthma.

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Efficacy analysis

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On the primary end point, the ChBLAUCRTSS 0-4h after six treatment months, a dose-dependent

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effect was observed with relative differences vs. placebo of 33.2% for the 500IR group,

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28.8% for the 300IR group and 19.8% for the 100IR group. The difference between the 500IR

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and placebo groups was statistically significant (p=0.0427) (Fig. 3A). The time course of

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nasal symptoms recorded during the HDM allergen challenge showed a biphasic curve with

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an initial phase of increasing RTSSs (0–2h), followed by a phase where the RTSSs stabilized

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(2–4h), seen as a plateau (Fig. 4 for the baseline challenge and the 6-month challenge). For

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the last two hours of the challenge, when the symptoms were recorded every 30 min by the

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subject, the change from baseline in AUCRTSS (ChBLAUCRTSS 2-4h) and average RTSSs

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(ChBLARTSS2-4h) after 6 treatment months also correlated with dose. For the ChBLAUCRTSS 2-

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4h,

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300IR and 100IR groups, respectively (Fig. 3B). The relative differences from placebo in

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ChBLARTSS2-4h for the 500IR, 300IR, and 100IR groups were 44.7%, 42.3% and 31.3%,

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respectively. The differences were statistically significant for the two higher dose groups

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(Fig. 3D).

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the relative differences vs. the placebo group were 42.0%, 40.9% and 30.5% for the 500IR,

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Also, compared with the placebo group, the relative difference in ChBLARTSS0-4h for the

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500IR group was statistically significant (p=0.0469) after 6 months (Fig. 3C).

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For the primary efficacy variable, the ChBLAUCRTSS 0-4h, the differences between active

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treatment and placebo numerically increased from 1 to 4 months of treatment for all groups

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and demonstrated a trend consistent with a dose-dependent effect, as did the ChBLARTSS0-4h

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(Table E2 in this article’s Online Repository).

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The coefficients of variation of the average RTSS at 6 months (69.5% [500IR] to

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57.6% [Placebo]) were higher than those expected in an EEC.14

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At the end of treatment, results of the changes in the four individual rhinitis symptom scores

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were generally consistent with those of the RTSS. Results for the full 4 hours and the last

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2 hours of the ChBLAUCRTSS, the ChBLARTSS and the changes in the individual rhinitis

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symptom scores are provided in the Online Repository (Table E2 and Table E3).

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Ocular symptoms were also assessed in this study and a positive trend favoring active

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treatment was observed (data not shown).

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For the change from baseline in the average VAS score recorded during the 4 hours of the

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allergen challenge (ChBLAVASS0-4h) after 6 treatment months, the relative differences vs.

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placebo were 25.3%, 23.8% and 14.1% for the 500IR, 300IR and 100IR groups, respectively

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(Table II).

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Immune responses

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At study entry, serum levels of Der p- and Der f-specific IgE and IgG4 were similar across

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treatment groups (Fig. 5). Within the first 2 treatment months, mite-specific serum IgE

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increased 5- to 7-fold in the three active treatment groups, and then gradually decreased,

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while remaining unchanged in the placebo group. Mite-specific serum IgG4 increased over the

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treatment period in the three active treatment groups, and was little changed in the placebo

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group. For both of these markers of immunologic activity, a dose-dependent effect was

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apparent at each time point.

286 Safety analysis

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Overall, the incidences of TEAEs reported by the subjects were higher in the active groups

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(94%, 91% and 97% in the 500IR, 300IR and 100IR groups) compared to the placebo group

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(83%). The most frequent drug-related TEAEs were application site reactions such as oral

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pruritus, mouth edema, throat irritation and ear pruritus (Table III). None of the four serious

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TEAEs reported during the treatment period (meningitis, convulsion, schizoaffective disorder,

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and nephrolithiasis) were considered related to the investigational product. There were no

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reports of anaphylaxis or reports consistent with severe laryngopharyngeal disorders or

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autoimmune disorders and no use of epinephrine.

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The incidence of bronchospasm, asthma and associated symptoms was higher during the peri-

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EEC periods than outside these periods (Table E4). The incidence of these TEAEs both

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during and outside the peri-EEC periods was similar across treatment groups.

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Of the 355 randomized subjects, 20 (6%) withdrew from the study due to TEAEs: 11 in the

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500IR group, 5 in the 300IR group and 4 in the 100IR group. Additionally, 2 subjects in the

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300IR group, 1 in the 100IR group and 6 in the placebo group withdrew because they did not

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tolerate the EEC challenge. The most frequent TEAEs leading to withdrawal were mouth

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edema, dyspnea, and cough. No significant changes were observed in vital signs, laboratory

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tests or spirometry parameters, except for transient decreases in FEV1 during and immediately

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after the allergen challenges.

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DISCUSSION

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This placebo controlled dose-ranging study, conducted using allergen challenges in an

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environmental exposure chamber, was designed to evaluate the effect of treatment with

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500IR, 300IR, and 100IR sublingual tablets of HDM allergen extracts in adults with HDM-

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induced allergic rhinitis. After 6 months of treatment, a dose-dependent effect was observed

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on rhinitis symptoms as evidenced by the changes from baseline in the AUC of the RTSS and

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the average RTSS. This effect was also reflected in the change from baseline in VAS scores,

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which conveys the subjects’ overall assessment of the severity of their allergic symptoms

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during the allergen challenge. Typical symptoms of HDM-associated allergic rhinitis include

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nasal symptoms (rhinorrhea, sneezing, nasal obstruction and pruritus) while ocular symptoms

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are more common in patients allergic to outdoor allergens such as pollens.22 Nevertheless, in

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this study, ocular symptoms were also improved with the active treatment.

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As described in two previous EEC studies conducted with grass pollen allergen (4-hour

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challenges) and HDM allergen (6-hour challenges),14, 15 the RTSS increased rapidly over the

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first two hours and then reached a plateau indicating stabilization of the intensity of the

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allergic symptoms. The plateau period may be more consistent with real life exposure to

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HDM and, therefore, is perhaps more clinically relevant. In the current study, efficacy

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analyses performed on data from the last two hours of each challenge showed larger

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differences between each active treatment group and the placebo group than were observed

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across the full four hours of the challenges. Of note, in the EEC study reported by Nolte et al.,

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the efficacy end points were analyzed during the last 4 hours of the 6-hour challenges (i.e., the

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plateau period).

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Use of an EEC is particularly suitable for dose-ranging studies as it allows assessment of

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symptoms under controlled and uniform exposure to the specific allergen, avoiding the

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variations observed with natural exposure and the confounding effects of other allergens and

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rescue medication usage on symptom scores.11, 12 Differences in the efficacy outcomes of the

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active treatment groups relative to the placebo group were larger in the current study than

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those observed in the natural field study,10 perhaps due to more stringent subject selection

336

including a baseline allergen challenge.

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SC

337

As previously observed in an exposure chamber study with 300IR 5-grass-pollen sublingual

339

tablet,14 subjects in the placebo group displayed a strong and persistent placebo effect at each

340

of the four challenges. Such placebo effect has been attributed to interactions between the

341

EEC trial subjects, and a potential impact of their discussions on symptoms scoring.14 In

342

contrast, in the HDM allergen chamber study conducted by Nolte and colleagues,15 subjects in

343

the placebo group recorded worsening symptoms over the 24 weeks of the trial. This warrants

344

further evaluation in future studies using this model.

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345

A limitation of the study is the variability in rhinitis total symptom score between patients.

347

This variability was higher than that previously reported in an exposure chamber study of

348

sublingual immunotherapy for grass pollen allergy (40–45%).14 It is unclear whether this is

349

due to differences in the allergens being evaluated (i.e., grass pollen and HDM) or between

350

the chambers.23

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351 352

Sensitization to allergens other than the allergen being evaluated is often a confounding factor

353

in natural field studies of AIT. In the present study, more than 75% of the randomized

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subjects were polysensitized. These subjects were eligible to participate in the study if they

355

were not to be exposed to the allergens(s) in question during the time of their participation.

356 Immune responses to treatment with STG320, measured as serum levels of HDM-specific IgE

358

and IgG4, were dose-dependent. The increase in HDM-specific serum IgG4 was apparent at

359

two months, the first measurement after treatment initiation. Trends in these markers were

360

similar to those observed in a natural field study of the same tablets, following the same

361

dosing regimen10 as well as those previously reported in response to treatment with tablets of

362

HDM15 and 5-grass.14

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The favorable safety profile was consistent with that reported in a previous natural field

365

study,10 with application site reactions being the most frequent adverse events. While the

366

incidences of adverse reactions were similar across the active dose groups more subjects

367

receiving the 500IR dose discontinued in both studies.

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Conclusions

370

The dose-dependent effect of STG320 sublingual immunotherapy tablets of HDM allergen

371

extracts in treating HDM-associated allergic rhinitis was demonstrated in this environmental

372

exposure chamber study. Based on the totality of the study results, the 300IR and 500IR doses

373

will be further evaluated in natural field studies.

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374 Acknowledgements

376

We thank all the participants, coordinators, and investigators for their participation. We

377

aknowledge Dr Anne-Marie Salapatek and Dr Peter Couroux’s contribution to the design and

378

execution of the trial, and Anuradha Alahari and Josiane Cognet-Sicé for preparation of the

379

manuscript. This study was funded by Stallergenes S.A., France.

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measures for perennial allergic rhinitis: an updated Cochrane systematic review. Allergy.

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Absence of IgE neosensitization in house dust mite allergic patients following sublingual

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Gaffin JM, Phipatanakul W. The role of indoor allergens in the development of

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Gotzsche PC, Johansen HK. House dust mite control measures for asthma: systematic

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Sheikh A, Hurwitz B, Nurmatov U, van Schayck CP. House dust mite avoidance

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Nathan RA. The burden of allergic rhinitis. Allergy and asthma proceedings : the

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Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual

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Bergmann KC, Demoly P, Worm M, Fokkens WJ, Carrillo T, Tabar AI, et al. Efficacy

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rhinitis. J Allergy Clin Immunol. 2014;133:1608-14 e6.

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Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic

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optimizing the clinical development of pollen immunotherapy. Allergy. 2011;66:163-9.

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Drug Products (Draft guidance). U.S. Department of Health and Human Services, Food and

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Drug Administration, Center for Drug Evaluation and Research (CDER), April 2000.2000.

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onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an

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allergen challenge chamber. J Allergy Clin Immunol. 2009;124:471-7, 7.e1.

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15.

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related efficacy of house dust mite sublingual immunotherapy tablets in an environmental

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exposure chamber. J Allergy Clin Immunol. 2015.

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continuous allergen challenge on clinical symptoms and mediator release in dust-mite-allergic

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placebo-controlled, double-blind trial in house-dust-mite asthma. Allergy. 1997;52:821-8.

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Devillier P, Le Gall M, Horak F. The allergen challenge chamber: a valuable tool for

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FDA. Guidance for Industry. Allergic Rhinitis: Clinical Development Programs for

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Nolte H, Maloney J, Nelson HS, Bernstein DI, Lu S, Li Z, et al. Onset and dose-

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Horak F, Toth J, Hirschwehr R, Marks B, Stubner UP, Jager S, et al. Effect of

Ronborg SM, Mosbech H, Poulsen LK. Exposure chamber for allergen challenge. A

Stubner P, Zieglmayer R, Horak F. A direct comparison of the efficacy of

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Allergic Patients In An Environmental Exposure Chamber Induces Specific Asthma

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Symptoms As Well As Allergic Rhinoconjunctivitis Symptoms. J Allergy Clin Immunol.

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Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World

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Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63 Suppl 86:8-160.

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allergen immunotherapy trials: Current status and clinical validation needs. J Allergy Clin

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Bousquet PJ, Combescure C, Klossek JM, Daures JP, Bousquet J. Change in visual

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Demoly P, Bousquet PJ, Mesbah K, Bousquet J, Devillier P. Visual analogue scale in

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Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic

Rosner-Friese K, Kaul S, Vieths S, Pfaar O. Environmental exposure chambers in

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Patel D, Lee JS, D.Wilson D, N. Camuso N, Salapatek A. Repeated Low-dose

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Table I. Demographics and Baseline characteristics - FAS 300IR

100IR

Placebo

(N = 93)

(N = 86)

(N = 89)

(N = 87)

32.8 (9.33)

32.5 (8.56)

32.4 (10.09)

31.3 (8.75)

44 (47.3)

45 (52.3)

47 (52.8)

47 (54.0)

Duration of AR (years)

19.2 (9.71)

16.6 (9.12)

16.6 (10.28)

15.2 (9.76)

FEV1 (% predicted)

97.0 (13.02)

97.3 (10.94)

96.9 (10.87)

95.0 (11.47)

Asthma, n (%)

12 (12.9)

11 (12.8)

12 (13.5)

10 (11.5)

Polysensitized*, n (%)

69 (74.2)

70 (81.4)

68 (76.4)

64 (73.6)

Baseline ARTSS0-4h

6.21 (2.021)

6.47 (2.092)

6.56 (1.793)

6.81 (2.352)

Baseline AVASS0-4h

4.59 (1.725)

Age (years)

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Women, n (%)

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500IR

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4.78 (1.898)

5.08 (1.662)

5.03 (1.882)

Continuous variables are reported as Mean (SD, Standard Deviation). Categorical variables

454

are reported as n, number of subjects (%, percentage of subjects relative to N, number of

455

participants in each treatment group in the FAS, Full Analysis Set).

456

IR, Index of reactivity; AR, Allergic rhinitis; ARTSS, Average Rhinitis Total Symptom Score

457

(range 0-12); AVASS, Average Visual Analog Scale Score (range 0-10).

458

*Sensitized to HDM allergen(s) and at least one of the other allergens tested based on skin

459

prick testing.

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460

Table II. Change from baseline to end-of-treatment (Month 6) in the average VAS

461

scores for the full 4 hours and the last 2 hours of the allergen challenge - FAS Average VAS scores: Difference from placebo

95% CI

0-4 hours of allergen challenge

P value

Relative LS Mean difference*(%)

.032

25.3

RI PT

LS Mean Treatment no. LS Means (SE) difference

70

−2.64 (0.178)

−0.53

−1.02 to −0.05

300IR

68

−2.61 (0.181)

−0.50

−0.99 to −0.01

.045

23.8

100IR

75

−2.41 (0.172)

−0.30

−0.78 to 0.18

NS

14.1

Placebo

75

−2.11 (0.172)

−

−

−

−

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2-4 hours of allergen challenge

SC

500IR

70

−3.12 (0.239)

−0.75

−1.40 to −0.09

.025

31.5

300IR

68

−3.04 (0.242)

−0.66

−1.32 to 0.00

.049

27.8

100IR

75

−2.87 (0.230)

−0.49

−1.13 to 0.15

NS

20.8

Placebo

75

−2.38 (0.230)

−

−

−

−

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500IR

CI, Confidence interval; FAS, Full Analysis Set; IR, Index of reactivity; LS, Least squares;

464

no., Number of subjects for whom data were available; NS, Not significant; SE, Standard

465

Error

466

* Relative LS mean difference = 100 × (LS mean difference from Placebo/LS mean Placebo)

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Table III. Drug-related treatment-emergent adverse events occurring in at least 5% of

468

population of any treatment group – Safety Set 300IR

100IR

Placebo

(N = 93)

(N = 86)

(N = 89)

(N = 87)

no. (%)

no. (%)

no. (%)

no. (%)

Subjects reporting ≥1 TEAE

87 (93.5)

78 (90.7)

86 (96.6)

72 (82.8)

Subjects reporting ≥1 drugrelated TEAE

66 (71.0)

59 (68.6)

60 (67.4)

38 (43.7)

Gastrointestinal disorders

52 (55.9)

47 (54.7)

40 (44.9)

12 (13.8)

Oral pruritus

29 (31.2)

30 (34.9)

23 (25.8)

7 (8.0)

Oedema mouth

20 (21.5)

19 (22.1)

16 (18.0)

0 (0.0)

Nausea

3 (3.2)

4 (4.7)

7 (7.9)

2 (2.3)

Paraesthesia oral

6 (6.5)

3 (3.5)

3 (3.4)

1 (1.1)

Lip oedema

8 (8.6)

3 (3.5)

1 (1.1)

0 (0.0)

Hypoaesthesia oral

1 (1.1)

1 (1.2)

5 (5.6)

2 (2.3)

45 (48.4)

42 (48.8)

35 (39.3)

24 (27.6)

35 (37.6)

32 (37.2)

28 (31.5)

10 (11.5)

6 (6.5)

6 (7.0)

4 (4.5)

4 (4.6)

Ear and labyrinth disorders

26 (28.0)

21 (24.4)

18 (20.2)

8 (9.2)

23 (24.7)

21 (24.4)

18 (20.2)

8 (9.2)

5 (5.4)

4 (4.7)

7 (7.9)

6 (6.9)

Headache

5 (5.4)

2 (2.3)

4 (4.5)

6 (6.9)

Eye disorders

4 (4.3)

4 (4.7)

7 (7.9)

8 (9.2)

Eye pruritus

3 (3.2)

4 (4.7)

6 (6.7)

5 (5.7)

Throat irritation

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Respiratory, thoracic and mediastinal disorders

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Preferred Term

EP

Oropharyngeal pain

Ear pruritus

Nervous system disorders

469

SC

System Organ Class

RI PT

500IR

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467

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Drug-related TEAEs, Treatment-emergent adverse events (AEs occurring during the treatment

471

period and up to 30 days after the last treatment administration) were classified according to

472

their System Organ Class and Preferred Term (MedDRA version 14.0).

473

IR, Index of reactivity; no., Number of subjects with at least one event in the given preferred

474

term; %, percentage of subjects with at least one event relative to N, number of participants in

475

each treatment group in the Safety Set.

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Figure legends

478 Fig. 1. Trial design. After the primary screening based on clinical history of HDM-associated

480

allergic rhinitis, eligible subjects underwent a baseline HDM allergen challenge in an

481

environmental exposure chamber. Those with symptom scores above the pre-defined

482

threshold were randomized to one of the four treatment arms, and underwent four additional

483

allergen challenges during the 6 treatment months.

484

IR, Index of reactivity.

SC

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479

485 Fig. 2. Subject disposition.

487

*Recorded as withdrawal by subject; †Sponsor’s decision to withdraw the subject; ‡Subject

488

did not tolerate the chamber.

489

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Fig. 3. Treatment efficacy. Change from baseline (ChBL) to end-of-treatment (after

491

6 months) in the area-under-the-curve (AUC) of Rhinitis Total Symptoms Scores (RTSS) for

492

the full 4 hours (0–4h) (A) or the last 2 hours (2–4h) (B) of allergen challenge; Change from

493

baseline in the Average Rhinitis Total Symptoms Scores (ARTSS) for the full 4 hours (0–4h)

494

(C) or the last 2 hours (2–4h) (D) of allergen challenge. NS, Not significant.

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496

Fig. 4. Assessment of Rhinitis Total Symptom Scores during HDM allergen challenge.

497

Subjects were exposed to HDM allergens for 4 hours in the EEC. Rhinitis symptoms were

498

recorded by the subjects at 13 time points, and Rhinitis Total Symptom Scores (RTSS, range

499

0–12) were derived at each time point.

500

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501

Fig. 5. Immunological markers. Serum-specific IgE (top panels) and IgG4 (bottom panels)

502

levels for D. pteronyssinus and D. farinae at baseline and after 2, 4, and 6 months. [Units:

503

kU/L for IgE, mcg/mL for IgG4]

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ACCEPTED MANUSCRIPT Baseline Challenge Primary screening

Month 1 Challenge

Month 2 Challenge

Month 4 Challenge

Month 6 Challenge

Randomization N = 355

Follow-up visit

Placebo, N = 87

300IR, N = 86 500IR, N= 93 Within 8 weeks

~2 weeks

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6 treatment months

RI PT

100IR, N = 89

ACCEPTED MANUSCRIPT Randomized subjects N = 355

500IR N = 93 (100.0%)

300IR N = 86 (100.0%)

100IR N = 89 (100.0%)

Placebo N = 87 (100.0%)

Discontinued N = 18 (20.9%)

Discontinued N = 14 (15.7%)

Discontinued N = 12 (13.8%)

Adverse event (n=11) Non-compliance (n=6) Subject request* (n=4) Lost to follow-up (n=1) Other reasons† (n=1)

Adverse event (n=5) Protocol violation (n=4) Subject request* (n=6) Pregnancy (n=1) Other reasons‡ (n=2)

Adverse event (n=5) Protocol violation (n=1) Non-compliance (n=2) Subject request* (n=3) Pregnancy (n=1) Lost to follow-up (n=1) Other reasons‡ (n=1)

Protocol violation (n=1) Subject request* (n=4) Lost to follow-up (n=1) Other reasons‡ (n=6)

Completed N = 68 (79.1%)

Completed N = 75 (84.3%)

Completed N = 75 (86.2%)

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Completed N = 70 (75.3%)

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Discontinued N = 23 (24.7%)

ACCEPTED MANUSCRIPT B 300IR

500IR

0 n = 75

n = 75

n = 68

n = 70

-250

-500

-750 NS

-1000

NS

p=0.0427

19.8%

28.8%

33.2%

100IR

300IR

500IR

Placebo

100IR

300IR

500IR

n = 75

n = 75

n = 68

n = 70

0

-250

-500

-750

-1000

D Placebo 0 n = 75

n = 75

n = 68

n = 70

-2

-3

-4

n = 75

-1

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-1

Placebo 0

NS

p=0.0376

p=0.0323

30.5%

40.9%

42.0%

100IR

300IR

500IR

n = 75

n = 68

n = 70

SC

C

-2

-3

-4

NS

p=0.0469

NS

p=0.0319

p=0.0233

17.5%

25.8%

31.1%

31.3%

42.3%

44.7%

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NS

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ChBL ARTSS0-4h Least Squares mean ± Standard Error

ChBLAUCRTSS 2-4h Least Squares mean ± Standard Error

100IR

ChBL ARTSS2-4h Least Squares mean ± Standard Error

ChBLAUCRTSS 0-4h Least Squares mean ± Standard Error

Placebo

RI PT

A

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8

7

7

6

6

5

5

4

4

3

3

2

2

1

1

0

RI PT

8

0 0

0.5

1

1.5

2

2.5

3

3.5

4

0

0.5

1

1.5

2

2.5

Time (hours)

100IR

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Placebo

M AN U

Time (hours)

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RTSS Least Squares mean ± Standard Error

After 6 treatment months

9

SC

At baseline

9

300IR

500IR

3

3.5

4

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100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0 2 Months

4 Months

6 Months

Baseline 1.0

0.8

0.8

0.6

0.6

0.4

2 Months

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1.0

4 Months

6 Months

0.4

0.2

0.2

0.0

0.0

Baseline

2 Months

4 Months

6 Months

100IR

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Placebo

AC C

95% CI

Baseline

IgG 4 Geometric mean

RI PT

D. farinae

SC

IgE Geometric mean

95% CI

D. pteronyssinus

Baseline

300IR

2 Months

500IR

4 Months

6 Months

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1

ONLINE REPOSITORY MATERIAL

2 TITLE PAGE

4

Original Article

5

Efficacy and Safety of Sublingual Tablets of House Dust Mite Allergen Extracts: Results

6

of a Dose-Ranging Study in an Environmental Exposure Chamber

7

Authors: Michel Roux, MD1, Philippe Devillier, MD, PhD2, William H. Yang, MD3, Armelle

8

Montagut, MSc1, Kathy Abiteboul, PharmD1, AgnèsViatte, MSc1, Robert K. Zeldin, MD1

SC

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3

9 1

Stallergenes, Antony, France

11

2

Clinical Research Unit, UPRES EA 220, Foch Hospital, Suresnes, France

12

3

Allergy and Asthma Research Centre, Ottawa, ON, Canada

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10

13 Corresponding author

15

Robert K. Zeldin, MD

16

Stallergenes S.A.

17

6, rue Alexis de Tocqueville

18

92183, Antony, France

19

Tel: +33 (0)1 55 59 23 81

20

Email: [email protected]

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METHODS

23

Randomization

24

Eligible subjects were randomized 1:1:1:1 to one of the four treatment groups (500IR, 300IR,

25

100IR or placebo) by using a computer-generated list (block size of 8) created by Cetero

26

Research/PRACS Institute with the SAS System. Treatments were allocated to the study

27

subjects chronologically with the next available treatment number ordered sequentially

28

according to this randomization list.

RI PT

22

SC

29

Wash-out periods for symptomatic medications before an allergen challenge

31

The use of antihistamines, decongestants, intranasal and systemic corticosteroids, and other

32

immunosuppressants was prohibited during predefined washout periods before and during the

33

allergen challenge (Table E1).

34

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Allergen challenge

36

The environmental exposure chamber (EEC) is a specially designed room that provides a

37

standardized, pre-determined level of exposure to the specific allergen in a controlled

38

environment, and the exposure is uniform throughout the chamber. Allergic responses of the

39

study participants to HDM particles were recorded in terms of symptom scores, and

40

treatment-induced changes in symptom severity were assessed during the study period. At

41

each allergen challenge, subjects were exposed for 4 hours to the same concentration range of

42

HDM particles.

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RESULTS

44

Average symptom scores for the four rhinitis symptoms (ARSS)

45

The changes from baseline to the end-of-treatment in the average symptom scores for the four

46

rhinitis symptoms (ARSS) were higher for the active treatment groups, and in general,

47

increased with the dose (Table E3).

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SC

RI PT

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Table E1. Prohibited medications and washout periods before allergen challenge

Prohibited medication

Washout period 3 days

Short-acting antihistamines (ocular/topical/oral/nasal)

3 days

Long-acting antihistamines (ocular/topical/oral/nasal), such as cetirizine, fexofenadine Loratadine, desloratadine

7 days

10 days

Over-the-counter cough and cold preparations or sleep aids containing antihistamines

M AN U

Cromolyn, nedocromil or lodoxamide (intranasal, ocular or oral)

10 days 7 days

Leukotriene receptor antagonists or 5-LO inhibitors

7 days

Inhaled/oral/intranasal anticholinergics

7 days 14 days

All oral steroids

30 days

AC C

EP

TE D

All inhaled, intranasal, ocular, ear administered, and moderate-high dose topical steroids

Anti-IgE therapy 2

RI PT

Decongestants (oral/nasal/ocular)

SC

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Table E2. Change from baseline to treatment months 1, 2, 4 and 6 in the AUCRTSS 0-4h

4

and in the average RTSS0-4h (Summary statistics) – FAS

Average RTSS0-4h

300IR

100IR

Placebo

500IR

Mean (SD)

(N = 93)

(N = 86)

(n = 89)

(N = 87)

(N = 93)

(N = 86)

1602.5 (497.62)

1672.2 1680.4 1753.2 (522.21) (457.82) (576.91)

6.21 (2.021)

6.47 (2.092)

Mean Changes from Baseline

Placebo

(n = 89)

(N = 87)

6.56 (1.793)

6.81 (2.352)

−1.84

−1.58

−1.86

−397.3

−453.8

−378.6

−1.59

Month 2

−547.6

−553.2

−530.9

−480.3

−2.19

−2.22

−2.21

−1.91

Month 4

−710.9

−667.9

−633.3

−523.7

−2.80

−2.64

−2.55

−2.09

Month 6

−738.1

−786.4

−711.9

−639.4

−2.93

−3.10

−2.85

−2.59

TE D

M AN U

Month 1

5

−450.5

300IR

SC

500IR

Baseline

100IR

RI PT

AUCRTSS 0-4h

AUC, Area-under-the-curve; IR, Index of reactivity; N, Number of participants in each

7

treatment group in the FAS, Full Analysis Set; RTSS, Rhinitis Total Symptom Score; SD,

8

Standard Deviation

AC C

EP

6

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Table E3. Change from baseline to Month 6 in the average rhinitis symptom scores (ARSS) for the last 2 hours of the allergen challenge - FAS

Difference from placebo LS Mean (SE)

LS Mean difference

95% CI

500IR

70

−0.92 (0.100)

−0.35

−0.62 to −0.08

300IR

68

−0.88 (0.101)

−0.31

−0.58 to −0.04

100IR

75

−0.85 (0.096)

−0.28

−0.55 to −0.01

Placebo

75

−0.57 (0.096)

M AN U

Nasal congestion

.012

61.1

.027

54.2

.040

49.1

SC

Rhinorrhea

P value

RI PT

no.

Treatment group

Relative LS Mean difference*(%)

70

−1.00 (0.100)

−0.25

−0.52 to 0.03

NS

32.5

300IR

68

−0.99 (0.101)

−0.23

−0.51 to 0.04

NS

30.5

100IR

75

−0.94 (0.096)

−0.19

−0.45 to 0.08

NS

24.7

Placebo

75

−0.76 (0.096)

−0.31

−0.58 to −0.04

.023

48.3

−0.88 (0.099)

−0.23

−0.50 to 0.03

NS

36.3

−0.79 (0.094)

−0.15

−0.41 to 0.11

NS

23.1

−0.95 (0.097)

70

300IR

68

100IR

75

75

−0.64 (0.094)

70

−0.72 (0.100)

−0.23

-0.50 to 0.05

NS

45.9

300IR

68

−0.77 (0.101)

−0.28

-0.55 to 0.00

.049

56.3

100IR

75

−0.67 (0.096)

−0.18

-0.45 to 0.09

NS

37.3

Placebo

75

−0.49 (0.096)

AC C

500IR

EP

Nasal pruritus

TE D

500IR

Placebo

Sneezing 500IR

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CI, Confidence interval; FAS, Full Analysis Set; IR, Index of reactivity; LS, Least squares;

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no., Number of subjects for whom data are available; SE, Standard Error

14

* Relative LS mean difference = 100 × (LS mean difference from Placebo/LS mean Placebo)

AC C

EP

TE D

M AN U

SC

RI PT

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500IR (N = 93)

300IR (N = 86)

100IR (N = 89)

Placebo (N = 87)

no. (%)

no. (%)

no. (%)

no. (%)

39 (44.8)

15 (16.1)

14 (16.3)

19 (21.3)

14 (16.1)

35 (40.2)

14 (15.1)

14 (16.3)

17 (19.1)

14 (16.1)

33 (37.1)

29 (33.3)

1 (1.1)

0 (0.0)

4 (4.5)

4 (4.6)

10 (11.2)

7 (8.0)

7 (7.5)

10 (11.6)

11 (12.4)

9 (10.3)

7 (7.9)

6 (6.9)

7 (7.5)

1 (1.2)

5 (5.6)

4 (4.6)

3 (3.4)

0 (0.0)

0 (0.0)

4 (4.7)

2 (2.2)

1 (1.1)

1 (1.1)

1 (1.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.2)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.1)

1 (1.1)

7 (8.1)

8 (9.0)

5 (5.7)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

7 (8.1)

8 (9.0)

5 (5.7)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

100IR (N = 89)

Placebo (N = 87)

no. (%)

no. (%)

no. (%)

no. (%)

34 (36.6)

38 (44.2)

40 (44.9)

30 (32.3)

32 (37.2)

37 (41.6)

25 (26.9)

22 (25.6)

Cough

4 (4.3)

8 (9.3)

Dyspnea

7 (7.5)

8 (9.3)

Asthma

3 (3.2)

1 (1.2)

Bronchial hyperreactivity

0 (0.0)

0 (0.0)

Wheezing

1 (1.1)

Investigations

4 (4.3)

Respiratory, thoracic and mediastinal disorders Bronchospasm

Forced expiratory volume decreased

4 (4.3)

EP

Subjects reporting ≥1 AE of asthma or associated symptom

SC

300IR (N = 86)

TE D

500IR (N = 93)

System Organ Class Preferred Term

Outside the peri-EEC periods

M AN U

Peri-EEC periods

RI PT

Table E4. Adverse events of asthma and associated symptoms in the peri-EEC periods and outside the peri-EEC periods - Safety Set

AC C

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Chest discomfort

4 (4.3)

6 (7.0)

5 (5.6)

4 (4.6)

4 (4.3)

6 (7.0)

5 (5.6)

4 (4.6)

16

1 (1.1)

RI PT

General disorders and administration site conditions

Roux et al., Online repository, Page 6 of 6

1 (1.1)

0 (0.0)

4 (4.5)

1 (1.1)

0 (0.0)

4 (4.5)

1 (1.1)

AE, Adverse event; EEC, Environmental exposure chamber; IR, Index of reactivity; no., Number of subjects with at least one event in the given

18

Preferred Term; %, percentage of subjects with at least one event relative to N, number of participants in each treatment group in the Safety Set.

AC C

EP

TE D

M AN U

SC

17