Effectiveness and Safety of Intranasal Ipratropium Bromide in Common Colds

Rhinorrhea, nasal congestion, and sneezing are the cardinal symptoms of common colds. The pathogenesis of these symptoms is incompletely understood, and currently available therapies are largely ineffective in ameliorating rhinorrhea [1]. Because histologic studies have indicated that rhinoviral infection causes little direct damage to the nasal mucosa, it has been hypothesized that the pathogenesis of cold symptoms is related to host responses and involves the release of inflammatory mediators and neurogenic reflexes [2-5]. The rhinorrhea associated with common colds is multifactorial and involves both transudation of plasma proteins and increased secretion by the submucosal glands of the nose [6]; secretion by the submucosal glands increases after the intranasal application of cholinergic agents [7] and through parasympathetic nervous system reflex mechanisms. The intranasal administration of anticholinergic agents, particularly ipratropium bromide and atropine methonitrate, has been associated with reduced nasal mucus production during experimentally induced rhinovirus colds [8-10]. In addition, methacholine-induced rhinorrhea can be prevented by the topical application of ipratropium [11] or atropine [12]. Initial clinical trials [13, 14] found that intranasal sprays of ipratropium bromide (84 g per nostril three or four times daily) also reduced the rhinorrhea associated with naturally occurring colds. However, excessive drying related to the topical application of anticholinergic agents may worsen certain symptoms, such as nasal obstruction, without providing an overall clinical benefit. Consequently, we did this study to determine the efficacy and tolerability of intranasal ipratropium bromide for the treatment of common colds with regard to the effect of this therapy on the patient's overall perception of well-being and on subjective and objective measures of rhinorrhea. Methods Study Design This was a multicenter, double-blind, randomized, placebo-controlled trial. For the purposes of comparison, it incorporated a group of untreated patients that was monitored in the same way as the ipratropium and control groups. The trial involved 411 persons who had self-diagnosed common colds and were enrolled at one of three study centers. To avoid the autumn and spring allergy seasons, patients were enrolled between 1 November 1993 and 29 March 1994. Study Participants Patients were recruited by advertisement and were compensated for participation. Male and female patients 12 to 70 years of age who had had rhinorrhea associated with a common cold for no more than 36 hours were eligible. The rhinorrhea had to be scored as at least moderate in severity (a score of 5 or more on a visual analogue scale), and the severity had to be confirmed by the recovery of at least 1.5 g of nasal discharge over a 1-hour baseline observation period. For each participant, a medical history was taken and nasal and limited physical assessments, which included measurement of vital signs, were done at the time of study entry. Persons with a history of asthma or chronic respiratory disease, allergic or perennial rhinitis, nasal polyps, seasonal allergic rhinitis with allergen in season, or frequent complications associated with upper respiratory infections (such as sinusitis or bronchitis) were excluded, as were pregnant and lactating women. Patients with a positive result on a streptococcal antigen screening test (Q-Test-Strep, Becton-Dickinson, Cockeysville, Maryland), signs of lower respiratory tract disease, or an oral temperature greater than 102 F were also excluded from participation. Written informed consent was obtained from each patient in a form approved by the institutional review board of each study institution. Treatment Administration Patients who met the entrance criteria were randomly assigned by a computer-generated randomization sequence to one of three groups: that receiving ipratropium bromide nasal spray 0.06% in a buffered salt solution (two sprays per nostril, administered with a metered pump spray bottle designed to deliver a total dose of 84 g per nostril); that receiving control nasal spray, which contained the same excipients as the ipratropium bromide spray but did not contain ipratropium bromide; or that receiving no treatment. The patients were instructed to clear their noses and administer two sprays in each nostril three times daily for 4 days at equally spaced intervals during waking hours. The protocol allowed patients to use their medication four times daily if rhinorrhea was not adequately controlled or fewer than three times daily if nasal dryness occurred. The patients were consecutively enrolled at each study center, and randomization was done in blocks of six. The treatments were administered under double-blind conditions; the untreated group was not blinded. The ipratropium and control spray bottles were identical in appearance. To minimize unintentional bias in assigning patients to receive no treatment, empty bottles were used as place holders for these patients. The bottles were placed in sequence with the filled bottles and were labeled Do Not Dispense to Patient. Throughout the study, patients were instructed to take no other medications (such as antihistamines, decongestants, nasal decongestants or steroids, or saline nose drops) to relieve their nasal symptoms. Analgesics (including acetaminophen, aspirin, and ibuprofen) and antitussives (Robitussin or Robitussin-DM; A.H. Robbins Co., Richmond, Virginia) were allowed for the relief of disabling symptoms. Clinical Monitoring After baseline monitoring and the administration of the first nasal spray treatment, patients remained at the study center for 6 hours. During this period, they provided hourly evaluations of the severity of their rhinorrhea and hourly collections of expelled nasal mucus. A visual analogue scale was used to evaluate symptom severity. This scale ranged from 0 to 10 and included five descriptions of severity: very mild (doubtful, trivial, or just noticeable), mild (present but not uncomfortable), moderate (present and somewhat uncomfortable or annoying), severe (present and definitely uncomfortable or annoying), and unbearable (necessitating additional treatment). On study day 2, the patients returned to the study center before taking their first dose of medication or at least 4 hours after taking any dose. After receiving ipratropium, control spray, or no treatment, they evaluated the severity of their rhinorrhea and provided expelled nasal mucus every hour for 3 hours. On the evenings of study days 1 through 4, all patients completed daily symptom record forms evaluating the overall severity of runny nose, nasal congestion, and sneezing for that day. On each of the 2 testing days, the patients were asked a single global question: Compared to when you came into the clinic this morning, how was your cold over today's testing period? One of four categorical responses (much better, better, no difference, or worse) was recorded. On study days 3 and 4, the patients continued their treatment on an outpatient basis and then returned to the study center on study day 5 for follow-up examination, collection of study records and spray devices, and completion of final global assessments. On study day 5, patients were asked, Overall, how do you think being in this study helped your cold? and Overall, how was this treatment in the relief of your symptoms? Data Analysis The data for all patients who were randomly assigned to treatment groups and who received at least one dose of their treatment were included in the analysis [410 of 411 patients]. The primary end point used to determine efficacy was the patient's global assessment of overall improvement obtained on study days 1, 2, and 5. Secondary measures of efficacy included 1) quantitation of nasal discharge weights and subjective assessments of rhinorrhea severity on the first 2 study days and 2) assessment of the severity of cold symptoms made using the visual analogue scale on the evening of each of the first 4 study days. The distribution of responses to each global question by study group was assessed. The stratified Wilcoxon test was the primary method of analysis used for the global assessments. To assess rhinorrhea using the visual analogue scale, we subtracted the hourly scores after treatment from the baseline values and determined the hourly average change from baseline. The end points were the average change from baseline for each of the first two study days and the average change from baseline for the first 3 hours on each of these 2 days combined. These data were analyzed using an analysis of variance that incorporated the centers and treatment-by-center interactions as factors. Baseline nasal mucus weights were used as a covariate in the analysis of discharge weights. The daily visual analogue scale assessments of rhinorrhea, nasal congestion, and sneezing were analyzed in a similar way but without a baseline covariate. Adverse events were recorded as they occurred, but we did not specifically ask about them. Staff members asked each patient how he or she had felt since the previous visit. Nasal examinations were done and vital signs were obtained on study day 1 and at the final study visit. The sample size for this trial was determined on the basis of global assessments that required the patients to choose one of four ordinal categories (much better, better, no difference, or worse) to describe the amelioration or lack of amelioration of their cold. By comparing the percentage of patients in the ipratropium group who chose either much better or better with the percentage of patients in the control group who chose these responses, we determined that a sample size of 130 patients per group would be sufficient to detect 20% differences in proportions ranging from 20% versus 40% to 70% versus 90% between the control and ipratropium groups, respectively, with a 90% powe