Gary Berman

Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus on diagnosis and treatment.

Sinus headache is a widely accepted clinical diagnosis, although many medical specialists consider it an uncommon cause of recurrent headaches. The inappropriate diagnosis of sinus headache can lead to unnecessary diagnostic studies, surgical interventions, and medical treatments. Both the International Headache Society and the American Academy of Otolaryngology-Head and Neck Surgery have attempted to define conditions that lead to headaches of rhinogenic origin but have done so from different perspectives and in isolation of each other. An interdisciplinary ad hoc committee convened to discuss the role of sinus disease as a cause of headache and to review recent epidemiological studies that suggest sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. This committee reviewed available scientific evidence from multiple disciplines and concluded that considerable research and clinical study are required to further understand and delineate the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, this group agreed that greater diagnostic and therapeutic attention needs to be given to patients with sinus headaches.

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults.

BACKGROUND Ragweed is an important cause of allergic rhinitis with or without conjunctivitis (AR/C) in North America and elsewhere. Allergen immunotherapy enabling safe patient self-administration is considered an unmet clinical need. Allergy immunotherapy tablet (AIT) treatment has shown promising efficacy and safety for grass allergy but has not been assessed for ragweed allergy. OBJECTIVE To evaluate efficacy and safety of 2 short ragweed AIT doses in patients with AR/C. METHODS Adults with ragweed pollen-induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season (approximately 52 weeks). Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events. RESULTS A total of 565 patients were randomized. During peak season, the 6- and 12-Amb a 1 unit ragweed AIT doses showed 21% (-1.76 score) and 27% (-2.24 score) improvement in TCS vs placebo (P < .05). The 6- and 12-Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo (P < .05). Peak and entire season efficacy were comparable. The 12-Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6-Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema. CONCLUSION In this trial, ragweed AIT was effective and well tolerated in ragweed-allergic North American adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00783198.

An Otolaryngology, Neurology, Allergy, and Primary Care Consensus on Diagnosis and Treatment of Sinus Headache:

While “sinus” headache is a widely accepted clinical diagnosis, many medical specialists consider it to be an uncommon cause of recurrent headaches. Unnecessary diagnostic studies, surgical interventions, and medical treatments are often the result of the inappropriate diagnosis of sinus headache. Both the International Headache Society and the American Academy of Otolaryngology–Head and Neck Surgery have attempted to characterize conditions leading to headaches of rhinogenic origin. However, they have done so from different perspectives and in isolation from the other specialty groups. An interdisciplinary ad hoc committee recently convened to discuss the role of sinus disease and the nose in the etiology of headache and to review recent epidemiologic studies suggesting that sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. Clinical trial data are presented which clearly indicate that the majority of sinus headaches can actually be classified as migraines. This committee reviewed scientific evidence available from multiple disciplines and concludes that considerable research and clinical study are needed to further understand and explain the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, there was a consensus from this group that greater diagnostic and therapeutic attention needs to be given to patients complaining of sinus headache that may indeed be due to the nose.

Safety and tolerability of a short ragweed sublingual immunotherapy tablet

BACKGROUND MK-3641 is a short ragweed sublingual tablet under investigation for immunotherapy of ragweed pollen-induced allergic rhinitis. OBJECTIVE To characterize the safety and tolerability of a ragweed sublingual tablet (Merck/ALK-Abelló) in ragweed-allergic adults with or without conjunctivitis. METHODS Data from 4 randomized, double-blinded, placebo-controlled trials of MK-3641 (2 28-day and 2 52-week trials) were evaluated. Pooled analyses examined short-term safety over 28 days from all 4 trials and long-term safety from the 52-week trials. RESULTS Across all studies, 757, 198, 454, and 1,058 subjects were randomized to placebo or 1.5, 6, or 12 Amb a 1-U of MK-3641, respectively. Treatment-related adverse events were more frequent in the 6- and 12-Amb a 1-U MK-3641 groups than in the placebo group and were primarily local application-site reactions occurring in the first few days of treatment. There was no treatment-associated loss of asthma control or worsening of asthma associated with treatment. No swellings led to airway obstruction or respiratory compromise. No treatment-related anaphylactic shock, life-threatening, or serious treatment-related adverse events were reported for any MK-3641 dose. Of the 1,707 MK-3641-treated subjects, 1 systemic (anaphylactic) reaction was reported (0.06%). The 52-week long-term assessment was generally similar to the safety profile based on the 28-day assessment. CONCLUSION MK-3641 doses up to and including 12 Amb a 1-U were well tolerated, with no unexpected safety findings. Sublingual immunotherapy risks such as worsening asthma or airway swellings that could cause airway obstruction were not observed. Systemic reactions and use of epinephrine were uncommon. In these studies, after the first dose was administered in a health care setting, self-administration was well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT01469182, NCT00783198, NCT00770315, and NCT00978029.

Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites

BACKGROUND Sublingual immunotherapy (SLIT) tablets could be an important alternative to subcutaneous immunotherapy for house dust mite (HDM) allergy in children. OBJECTIVE To characterize the safety, tolerability, and duration of local adverse events (AEs) of an HDM SLIT tablet (MK-8237; Merck, ALK Abellò, and Torii) in North American children 12 to 17 years old with HDM allergic rhinitis with and without conjunctivitis and with or without asthma. METHODS In this phase 1, multicenter, double-blinded, randomized trial (NCT01678807), children received placebo, HDM SLIT tablet 6 standardized quality (SQ) HDM, or 12 SQ-HDM once daily for 28 days. The primary end point was the proportion of subjects with treatment-emergent AEs receiving active treatment vs placebo. The secondary end point was the proportion of subjects who discontinued owing to AEs. RESULTS In total 195 subjects were randomized. The 2 HDM SLIT tablet doses were well tolerated. No anaphylactic reactions, systemic allergic reactions, AEs requiring epinephrine, serious AEs, or local swellings in the mouth or throat assessed as severe were reported. The proportion of subjects with treatment-emergent AEs was 54% with 6 SQ-HDM and 57% with 12 SQ-HDM (nonsignificant vs 43% with placebo). Local AEs were the most commonly reported treatment-emergent AEs. On day 1, the median duration of individual local AEs ranged from 1 to 43 minutes. The proportion of subjects who discontinued owing to AEs was 0%, 6.2%, and 6.2%, and who experienced treatment-related AEs was 25%, 45%, and 52% for the placebo, 6 SQ-HDM, and 12 SQ-HDM groups, respectively. CONCLUSION The 6 and 12 SQ-HDM doses of the HDM SLIT tablet MK-8237 were well tolerated, and local AEs were of short duration. TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01678807.

Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated.

BACKGROUND Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. OBJECTIVE To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. METHODS This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. RESULTS No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. CONCLUSIONS In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated.

The effect of the ragweed sublingual immunotherapy tablet MK-3641 on rescue medication use

Background Allergic rhinitis with/without conjunctivitis (AR/C) sufferers often rely on pharmacotherapy to relieve symptoms. Although the main goal of immunotherapy is long-term disease modification, reducing or eliminating the need for pharmacotherapy is also an important and desirable treatment goal. Methods Data were pooled from two trials that evaluated the efficacy and safety of short-ragweed sublingual immunotherapy tablet (SLIT-T), MK-3641 (Ambrosia artemisiifolia; Merck/ALK-Abello). Subjects with ragweed-pollen– induced AR/C were randomized ~16 weeks before the 2010 pollen season to once-daily MK-3641 (6 or 12 Amb a 1-U doses; one trial also included a no-effect dose of 1.5 Amb a 1-U) or placebo. During the trial, all subjects, whether taking MK-3641 or placebo, could use AR/C rescue medication, including oral/ocular antihistamines and intranasal/oral corticosteroids. We examined rescue medication use in all groups.