Rhinitis, sinusitis, and upper airway disease
A proof-of-concept study of the effect of a novel H3-receptor antagonist in allergen-induced nasal congestion

Presented at the European Histamine Research Society, Durham, United Kingdom, July 13-17, 2010; the Japan Histamine Society Meeting, Morioka, Japan, October 20-21, 2011; and the American Society for Pharmacology and Experimental Therapeutics meeting, April 22, 2012.
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Background

H1-receptor inverse agonists are used effectively for treating several symptoms of allergic rhinitis, including nasal itching, rhinorrhea, and sneezing, although most agents are not very effective in treating nasal congestion.

Objective

This study evaluated the relative efficacy of a novel selective H3-receptor antagonist, JNJ-39220675, in preventing nasal congestion induced by exposing participants with ragweed allergy to ragweed allergen in an environmental exposure chamber model.

Methods

In this single-dose, patient-blind, double-dummy, placebo- and active-controlled, phase IIa cross-over study, 53 participants were randomized to JNJ-39220675 plus placebo, placebo plus pseudoephedrine, or only placebo. The primary efficacy assessment was change in nasal patency assessed by measuring the minimal cross-sectional area of the nasal cavity by using acoustic rhinometry. Secondary assessment included total nasal symptom scores (TNSSs) over the 8-hour environmental exposure chamber exposure period.

Results

Smaller decreases in minimal cross-sectional area were observed after JNJ-39220675 (least square mean difference, −0.126; P = .06) and pseudoephedrine (least square mean difference, −0.195; P = .004) treatment compared with placebo. The means for the baseline-adjusted area under the curve of TNSSs were significantly smaller for JNJ-39220675 (P = .0003) and pseudoephedrine (P = .04) versus placebo. JNJ-39220675 was significantly effective in treating all 4 individual symptoms (P ≤ .05 for all scores) compared with placebo, whereas pseudoephedrine only showed a trend for improvement in individual symptom scores of the TNSS. Insomnia was the most frequent adverse event (17.3%) associated with JNJ-39220675 treatment.

Conclusion

Prophylactic treatment with the H3-antagonist JNJ-39220675 relieved allergen-induced nasal congestion by using standard nasal symptom scoring; however, in contrast to pseudoephedrine, it only showed a trend for increasing nasal patency by using objective measures.

Section snippets

Study population

Men and women aged 18 to 65 years (inclusive) with a body mass index of between 18 and 32 kg/m2 (inclusive) and a body weight of 50 kg or greater and in good health were enrolled. Participants were required to have a clinical history of SAR with a seasonal onset and offset of nasal allergy symptoms during each of the last 2 ragweed allergy seasons and a positive skin prick test response to ragweed allergen (defined as a wheal diameter ≥3 mm larger than that elicited by the negative control) or

Participant disposition

The study was conducted from November 10, 2008, to February 8, 2009, at Cetero Research, Mississauga, Ontario, Canada. Of the 147 participants screened, 53 were randomized to one of 6 treatment sequences (Fig 1) and included in the safety and intent-to-treat analysis. The majority (72%) were men and 49% were white, with a mean age of 42 (SD, 12) years (Table I). Four participants discontinued the study (Fig 1).

Efficacy

Carryover effects of active treatments on MCA and nasal symptom scores in periods 2

Discussion

Both JNJ-39220675 and pseudoephedrine resulted in a smaller decrease in the MCA (less of a decrease in nasal patency or less congestion) versus placebo in participants with ragweed allergy exposed to ragweed in an EEC. A statistically significant difference was observed with pseudoephedrine versus placebo in reducing the baseline-adjusted MCA. JNJ-39220675 showed a strong trend in the same direction (P = .06). On the basis of these data, the hypothesis that H3-receptor inhibition would result

References (29)

  • F.M. Baroody et al.

    Oxymetazoline adds to the effectiveness of fluticasone furoate in the treatment of perennial allergic rhinitis

    J Allergy Clin Immunol

    (2011)
  • S.D. Reed et al.

    The economic burden of allergic rhinitis: a critical evaluation of the literature

    Pharmacoeconomics

    (2004)
  • H. Xie et al.

    Roles of histamine and its receptors in allergic and inflammatory bowel diseases

    World J Gastroenterol

    (2005)
  • R.L. Thurmond et al.

    The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines

    Nat Rev Drug Discov

    (2008)
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    Supported by Janssen Research & Development, LLC (formerly Johnson and Johnson Research and Development, LLC).

    Disclosure of potential conflict of interest: W. T. Barchuk is employed by and owns stock/stock options in Janssen Research & Development. A. M. Salapatek and P. D'Angelo have been supported by one or more grants from Cetero Research at the time of the study, which was sponsored by Janssen Research & Development. T. Ge and X. Liu are employed by Janssen Research & Development.

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