Double-blind, placebo-controlled study of
`azelastine and fluticasone in a single nasal spray
`delivery device
`Frank C. Hampel, MD*; Paul H. Ratner, MD†; Julius Van Bavel, MD‡; N. J. Amar, MD§;
`Pramila Daftary, MD储; William Wheeler, PhD¶; and Harry Sacks, MD¶
`
`Background: A proof-of-concept study suggested that combination therapy with commercial azelastine hydrochloride nasal
`spray and fluticasone propionate nasal spray significantly improved nasal symptoms of seasonal allergic rhinitis compared with
`either agent alone.
`Objective: To compare an azelastine-fluticasone combination nasal spray administered in a single-delivery device with a
`commercially available azelastine nasal spray and fluticasone nasal spray.
`Methods: This 14-day, multicenter, randomized, double-blind study was conducted during the Texas mountain cedar season.
`After a 5-day placebo lead-in, 610 patients with moderate-to-severe nasal symptoms were randomized to treatment with (1)
`azelastine nasal spray, (2) fluticasone nasal spray, (3) combination azelastine and fluticasone nasal spray, or (4) placebo nasal
`spray. All treatments were given as 1 spray per nostril twice daily. The primary efficacy variable was the change from baseline
`in the total nasal symptom score (TNSS), consisting of nasal congestion, runny nose, itchy nose, and sneezing.
`Results: All 3 active groups were statistically superior (P ⱕ .02) to placebo, and the combination was statistically superior
`(P ⱕ .003) to either agent alone. The TNSS improved by 28.4% with combination azelastine-fluticasone, 20.4% with fluticasone,
`16.4% with azelastine, and 11.2% with placebo. All 3 treatments were well tolerated.
`Conclusions: The combination azelastine-fluticasone nasal spray provided statistically significant improvement in the TNSS
`and additive clinical benefit compared with either agent alone in patients with moderate-to-severe seasonal allergic rhinitis.
`Trial Registration: clinicaltrials.gov Identifier: NCT00660517.
`
`Ann Allergy Asthma Immunol. 2010;105:168 –173.
`
`INTRODUCTION
`In a proof-of-concept study, the combination of azelastine hy-
`drochloride nasal spray and fluticasone propionate nasal spray
`administered concomitantly significantly improved nasal symp-
`toms of seasonal allergic rhinitis in patients with an allergy to
`Texas mountain cedar (Juniperus ashei).1 The Joint Task Force
`on Practice Parameters for the diagnosis and management of
`rhinitis recognizes that intranasal antihistamines are appropriate
`for use as first-line treatment for symptoms of allergic rhinitis,
`and their use in combination with nasal corticosteroids may
`provide added benefit.2,3 The Allergic Rhinitis and its Impact on
`Asthma guidelines and other expert panels also provide algo-
`
`Affiliations: * Central Texas Health Research, New Braunfels, Texas;
`† Sylvana Research, San Antonio, Texas; ‡ Allergy and Asthma Associates
`Research, Austin, Texas; § Allergy and Asthma Research Institute, Waco,
`Texas; 储 Allergy and Asthma Care of Waco, Waco, Texas; and ¶ Meda
`Pharmaceuticals Inc, Somerset, New Jersey.
`Disclosures: Dr Wheeler is the director of medical communications at Meda
`Pharmaceuticals. Dr Sacks is the chief medical officer of Meda Pharmaceuticals.
`Funding/Support: Funding for this study was provided by MedPointe
`Pharmaceuticals, Somerset, New Jersey.
`Previous Presentation: Presented at the American Academy of Allergy
`Asthma and Immunology Annual Meeting; March 2, 2009; New Orleans,
`Louisiana.
`© 2010 American College of Allergy, Asthma & Immunology.
`Published by Elsevier Inc. All rights reserved.
`doi:10.1016/j.anai.2010.06.008
`
`rithms that include combination therapy with intranasal antihis-
`tamines and intranasal corticosteroids.4,5
`The economic burden of allergic rhinitis is substantial and
`includes both direct medical costs of physician visits and
`medications and indirect costs related to reductions in pro-
`ductivity due to rhinitis symptoms or the effects of treatment.
`Although methods vary, the total treatment cost of rhinitis has
`been estimated to be as much as $7.3 billion.6 With allergic,
`nonallergic, and mixed rhinitis affecting up to 60 million
`people in the United States annually, the costs of treatment
`must be viewed in light of the potential clinical benefit.2,7
`Ineffective treatment leads to patient frustration, dissatisfac-
`tion, and poor compliance. Physicians may likewise become
`frustrated that patients do not adhere to their prescribed
`treatment regimens despite their efforts to educate them.
`Patients may benefit from the availability of a combination
`azelastine and fluticasone product in a single-delivery nasal
`spray device due to potential additive effects that may result
`from the different primary mechanisms of action of each drug
`and the possible improvement in adherence to therapy by deliv-
`ering the 2 agents in a single device.
`
`METHODS
`Patients
`The study population included males and females 12 years
`and older with a minimum 2-year history of allergy to Texas
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`mountain cedar pollen (J ashei), as confirmed by a positive
`prick-puncture skin test result
`to mountain cedar pollen
`within the past 12 months. Before study entry, all patients or
`their guardians (if younger than 18 years) signed an institu-
`tional review board–approved informed consent agreement
`(Sterling Institutional Review Board, Atlanta, Georgia). At
`screening, eligible patients had to have a 12-hour reflective
`total nasal symptom score (TNSS) of at least 8 of a possible
`12 and a congestion score of 2 or 3; by randomization,
`patients had to have a TNSS of at least 8 on 3 separate
`symptom assessments (1 of which was within 2 days of day
`1 and could include the morning of day 1) during the placebo
`lead-in period. Patients were also required to be in general
`good health and free of any disease or concomitant treatment
`that could interfere with the interpretation of the study results
`as determined by the study investigator.
`Key exclusion criteria included the following: (1) the pres-
`ence of any nasal mucosal erosion, nasal ulceration, or nasal
`septal perforation (grade 1b-4) at either screening or random-
`ization; (2) other nasal disease(s) likely to affect deposition of
`intranasal medication, such as sinusitis, rhinitis medicamen-
`tosa, clinically significant polyposis, or nasal structural ab-
`normalities; (3) nasal surgery or sinus surgery within the
`previous year; or (4) more than 3 episodes per year of chronic
`sinusitis.
`Study Design
`This randomized, double-blind, placebo-controlled, parallel-
`group study was conducted at 6 investigational sites during
`January and February 2007 (clinicaltrials.gov identifier:
`NCT00660517). The study consisted of a 5-day, single-blind,
`placebo lead-in period during which patients were required to
`have a minimum symptom severity score to be eligible for
`double-blind treatment. The placebo lead-in period was fol-
`lowed by a 14-day, double-blind treatment period in which
`qualified patients were randomized by a computer-generated
`randomization schedule to treatment with (1) combination
`azelastine 0.1% and fluticasone, 1 spray per nostril twice
`daily (each metered spray of azelastine-fluticasone delivers
`137 ␮g of azelastine hydrochloride and 50 ␮g of fluticasone
`propionate; therefore, a dosage of 1 spray per nostril twice
`daily delivers 548 ␮g of azelastine hydrochloride and 200 ␮g
`of fluticasone propionate); (2) azelastine 0.1% (Astelin;
`Meda Pharmaceuticals Inc, Somerset, New Jersey), 1 spray
`per nostril twice daily (each metered spray of Astelin delivers
`137 ␮g of azelastine hydrochloride; therefore, a dosage of 1
`spray per nostril twice daily delivers 548 ␮g of azelastine);
`(3) fluticasone (Flonase; GlaxoSmithKline, Research Trian-
`gle Park, North Carolina), 1 spray per nostril twice daily
`(each metered spray of Flonase delivers 50 ␮g of fluticasone
`propionate; therefore, a dosage of 1 spray per nostril twice
`daily delivers 200 ␮g of fluticasone); or (4) azelastine-fluti-
`casone vehicle placebo, 1 spray per nostril twice daily.
`Symptom severity was assessed by the 12-hour reflective
`TNSS, consisting of nasal congestion, runny nose, itchy nose,
`and sneezing, and the instantaneous TNSS recorded twice
`
`daily (morning and evening) in diary cards. The 12-hour
`reflective and instantaneous TNSS assessments were made
`before the morning and evening doses of study medication.
`Symptoms were scored on a scale of 0 to 3 (0 indicating
`no symptoms; 1, mild symptoms; 2, moderate symptoms; and
`3, severe symptoms), such that the maximum daily symptom
`severity score was 24.
`On the first day of the placebo lead-in period, patients were
`required to have a 12-hour reflective TNSS of at least 8, to
`have a nasal congestion score of 2 or 3, and to meet all
`specified study inclusion and exclusion criteria. Qualified
`patients then recorded 12-hour reflective and instantaneous
`TNSS twice daily (morning and evening) during the 5-day
`placebo lead-in period.
`To be eligible for double-blind treatment, patients were
`required to have a minimum 12-hour reflective TNSS of 8 for
`at least 3 symptom assessments (either morning or evening)
`during the placebo lead-in period and have a 12-hour reflec-
`tive nasal congestion score of 2 or 3 for at least 3 symptom
`assessments (either morning or evening). For both TNSS and
`nasal congestion, 1 of the 3 assessments must have occurred
`within 2 days of day 1.
`On days 1 through 14, patients recorded 12-hour reflective
`and instantaneous TNSS daily (morning and evening) in
`diaries. Patients also recorded the severity of postnasal drip
`and the 12-hour reflective and instantaneous total ocular
`symptom score (TOSS), consisting of itchy eyes, watery
`eyes, and red eyes, twice daily (morning and evening) in
`diaries, such that the maximum daily score was 18. In addi-
`tion, patients 18 years and older completed the Adult Rhino-
`conjunctivitis Quality of Life Questionnaire (RQLQ) on days
`1 and 14.
`The primary efficacy variable was the change from base-
`line (day 1) to day 14 in 12-hour reflective TNSS, consisting
`of nasal congestion, runny nose, itchy nose, and sneezing.
`Baseline was the average of the combined (morning and
`evening) TNSS during the entire placebo lead-in period.
`Secondary efficacy variables included the following: (1)
`change from baseline to day 14 in individual symptom scores,
`(2) change from baseline in TNSS on each study day, (3)
`change from baseline to day 14 in TOSS, (4) change from
`baseline to day 14 in individual ocular symptom scores, and
`(5) change from baseline to day 14 on the RQLQ, including
`overall score and individual domains. Safety was assessed by
`patient-reported adverse events and vital sign assessments,
`including body temperature, blood pressure, pulse, and res-
`piration rate, performed at baseline and study end.
`Statistical Analysis
`The primary efficacy variable was evaluated for the intent-
`to-treat population, consisting of all randomized patients with
`at least 1 postbaseline efficacy assessment. For each evalua-
`tion, the treatment groups were compared using an analysis of
`covariance model with baseline as a covariate. Missing TNSS
`values were imputed using the last observation carried for-
`ward method. Analyses of TOSS were performed in a manner
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`identical to that for TNSS. The change from day 1 to day 14
`in the RQLQ score was summarized according to the method
`described by Juniper et al.8 On the basis of this method, a
`change in the RQLQ of 0.5 units is considered clinically
`important. All inferential statistics were calculated at P ⬍ .05
`level of significance.
`
`RESULTS
`Patient Disposition
`A total of 610 patients were randomized to double-blind
`treatment. Of the 610 randomized patients, 607 had postbase-
`line diary data and were included in the efficacy analysis.
`Data for 609 randomized patients were included in the safety
`analysis. A total of 577 patients completed all 14 days of
`double-blind treatment, and 33 discontinued participation in
`the study. Completion rates were similar in all treatment
`groups. One patient in the combination group, 3 in the azelas-
`tine group, 1 in the fluticasone group, and 1 in the placebo
`group discontinued participation in the study because of an
`adverse event. The most common reason for study with-
`drawal was noncompliance, followed by “other,” withdrawal
`of consent, and adverse events.
`Demographic and Clinical Characteristics
`The treatment groups were comparable with regard to demo-
`graphic and baseline clinical characteristics (Table 1). The
`patients had a mean age of 39.3 years (range, 12–75 years),
`most patients were female (65.2%), and the average duration
`of allergy to Texas mountain cedar was 18.6 years (range,
`2– 64 years). Of the 607 patients included in the efficacy
`analysis, 87.0% identified themselves as white or Caucasian,
`10.4% as black or African American, 1.5% as Asian or
`Pacific Islander, and 1.1% as other.
`Efficacy
`Change from baseline to day 14 in TNSS. Figure 1 shows
`the mean improvement in the TNSS for each treatment group.
`All 3 active treatment groups resulted in a statistically sig-
`nificant (P ⬍ .001) improvement from baseline. The mean
`
`Figure 1. Mean improvement from baseline in the total nasal symptom
`score (TNSS) during the 14-day study period (negative values indicate
`improvement).
`
`(SD) improvement from baseline TNSS was ⫺3.25 (4.16)
`with azelastine, ⫺3.84 (4.76) with fluticasone, and ⫺5.31
`(5.08) with azelastine and fluticasone in combination. The
`TNSS improved from baseline by 16.4% with azelastine, by
`20.4% with fluticasone, and by 28.4% with the 2 agents in
`combination (P ⬍ .01 vs placebo and either agent alone).
`Both azelastine and fluticasone alone significantly improved
`the TNSS compared with placebo (P ⱕ .02).
`Change from baseline to day 14 in individual symptoms.
`Combination therapy significantly (P ⬍ .05) improved the
`individual TNSS symptoms of nasal congestion, itchy nose,
`and sneezing compared with azelastine, fluticasone, or pla-
`cebo (Figure 2). Combination therapy significantly (P ⬍ .01)
`improved the individual TNSS symptoms of runny nose
`compared with azelastine or placebo but not fluticasone.
`Change from baseline to day 14 in TNSS on individual
`study days. Figure 3 shows the mean daily improvement in
`TNSS in each treatment group. The combination of azelastine
`
`Table 1. Demographic and Baseline Clinical Characteristics (Intent-to-Treat Population)
`Azelastine 0.1% and
`Azelastine 0.1%
`fluticasone (n ⴝ 153)
`(n ⴝ 152)
`
`Characteristic
`
`Fluticasone
`(n ⴝ 151)
`
`Placebo
`(n ⴝ 151)
`
`Age, mean (range), y
`Sex, No. (%)
`Male
`Female
`Race, No. (%)
`White
`Black
`Asian
`Other
`TNSS, mean (range)a
`Duration of SAR, mean (range), y
`
`39.5 (12–73)
`
`39.5 (12–74)
`
`38.1 (12–74)
`
`39.9 (12–75)
`
`56 (36.6)
`97 (63.4)
`
`132 (86.3)
`15 (9.8)
`4 (2.6)
`2 (1.3)
`18.8 (9–24)
`18.7 (3–64)
`
`55 (36.2)
`97 (63.8)
`
`135 (88.8)
`15 (9.9)
`0 (0.0)
`2 (1.3)
`18.1 (10–24)
`19.0 (2–61)
`
`51 (33.8)
`100 (66.2)
`
`130 (86.1)
`16 (10.6)
`3 (2.0)
`2 (1.3)
`18.3 (8–24)
`18.4 (3–57)
`
`49 (32.5)
`102 (67.5)
`
`131 (86.8)
`17 (11.3)
`2 (1.3)
`1 (0.7)
`18.7 (10–24)
`18.1 (3–56)
`
`Abbreviations: SAR, seasonal allergic rhinitis; TNSS, Total Nasal Symptom Score.
`a Mean baseline TNSS during 5-day lead-in period, including the morning of day 1.
`
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`Figure 2. Mean improvement from baseline in the severity of individual
`nasal symptoms. TNSS indicates total nasal symptom score.
`
`and fluticasone was statistically superior (P ⱕ .01) compared
`with azelastine or placebo on each day of the study, and the
`combination was statistically superior (P ⱕ .01) to flutica-
`sone on every study day except days 10 and 11.
`Change from baseline to day 14 in TOSS. Combination
`therapy significantly (P ⬍ .01) improved the overall TOSS
`compared with either fluticasone or placebo but not azelastine
`(Figure 4). The percentage improvement in TOSS was 21.2%
`for azelastine, 17.5% for fluticasone, 26.6% for the combi-
`nation, and 10.5% for placebo.
`Change from baseline to day 14 in individual ocular
`symptoms. Combination therapy significantly (P ⬍ .05) im-
`proved all individual ocular symptoms compared with azelas-
`
`Figure 4. Mean improvement from baseline in the total ocular symptom
`score (TOSS) during the 14-day study period.
`
`tine, fluticasone, or placebo, with the exception of azelastine
`for watery eyes (Figure 5). In addition, each component of the
`combination was significantly (P ⬍ .05) better than placebo
`for each individual symptom of the TOSS.
`Change from baseline to day 14 in RQLQ scores. All 3
`treatments produced a statistically significant (P ⬍ .001)
`improvement from baseline, both for overall score and for
`each individual domain of the RQLQ. The mean change from
`baseline in the overall RQLQ score was 1.17 with azelastine,
`1.43 with fluticasone, 1.60 with azelastine-fluticasone com-
`bination therapy, and 1.01 with placebo. The combination of
`azelastine and fluticasone significantly improved the overall
`RQLQ score compared with azelastine (P ⫽ .005) and pla-
`cebo (P ⬍ .001) but not fluticasone (P ⫽ .29). The change
`from day 1 to day 14 in the overall RQLQ score was clini-
`
`Figure 3. Mean improvement from baseline in the total nasal symptom
`score (TNSS) on individual study days.
`
`Figure 5. Mean improvement from baseline in the severity of individual
`ocular symptoms. TOSS indicates total ocular symptom score.
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`Table 2. Commonly Reported Adverse Events (Safety Population)a
`
`Adverse event
`
`Dysgeusia (bitter taste)
`Epistaxis
`Headache
`Pharyngolaryngeal pain
`Nasal discomfort
`Nausea
`Mucosal erosion
`Somnolence
`
`Azelastine 0.1% and
`fluticasone (n ⴝ 153)
`
`Azelastine 0.1%
`(n ⴝ 152)
`
`Fluticasone
`(n ⴝ 153)
`
`Placebo
`(n ⴝ 151)
`
`Adverse events, No. (%)
`
`11 (7.2)
`6 (3.9)
`4 (2.6)
`2 (1.3)
`2 (1.3)
`1 (0.7)
`1 (0.7)
`1 (0.7)
`
`3 (2.0)
`4 (2.6)
`2 (1.3)
`1 (0.7)
`0 (0.0)
`2 (1.3)
`1 (0.7)
`1 (0.7)
`
`0 (0.0)
`6 (3.9)
`6 (3.9)
`0 (0.0)
`1 (0.7)
`0 (0.0)
`1 (0.7)
`1 (0.7)
`
`0 (0.0)
`5 (3.3)
`2 (1.3)
`1 (0.7)
`0 (0.0)
`2 (1.3)
`0 (0.0)
`0 (0.0)
`
`a A patient with multiple adverse events is counted only once in any row. Adverse events were coded using the Medical Dictionary for Regulatory
`Activities.
`
`cally important (⬎0.5 units) in the combination group com-
`pared with the placebo group.
`Safety and Tolerability
`All 3 treatments were well tolerated (Table 2). The most
`common adverse event was bitter taste (2.0% with azelastine,
`0.0% with fluticasone, and 7.2% with combination therapy).
`There were no significant findings based on assessment of
`vital signs.
`
`DISCUSSION
`Allergic rhinitis is a global problem that is increasing in
`prevalence. It is 1 of the most common illnesses in the
`general population, with prevalence estimates ranging from
`3% to 19% in the population of the United States.3 Untreated
`rhinitis has been shown to significantly reduce work and
`school productivity (P ⬍ .05),
`impair sleep, and reduce
`quality of life and cognitive function and should not be
`underestimated as a health care problem.9
`There is still a need for effective rhinitis therapy, especially
`for patients with severe or difficult-to-treat symptoms. A
`nationwide survey indicated that a significant proportion of
`patients with rhinitis experience poor symptom control with
`either an intranasal antihistamine or an intranasal steroid.10
`The combination of azelastine and fluticasone in a single-
`delivery device should benefit a proportion of patients with
`symptoms that are not controlled by either agent alone.
`Patients who cannot avoid allergen exposure and/or do not
`adequately respond to multiple pharmacologic interventions
`may be offered the option of allergen immunotherapy. Im-
`munotherapy is an important
`treatment option; however,
`many patients refuse this avenue for various reasons, includ-
`ing inconvenience, cost, lack of efficacy, and adverse ef-
`fects.11,12 For example, immunotherapy patients are recom-
`mended to undergo treatment for at
`least 5 years, and
`although some patients may remain in sustained remission
`after treatment, others may relapse. There are no specific tests
`or clinical markers that will distinguish between patients who
`will relapse compared with those who will remain in long-
`term clinical remission.13
`
`Virtually all patients seen in allergy specialty practice have
`tried at least 1 allergy medication without success, and many
`patients require more than 1 medication to achieve a satis-
`factory degree of symptom control. Although combination
`therapy is frequently prescribed, there are a relatively small
`number of published clinical studies that have evaluated
`combination therapies for allergic rhinitis. Nielsen and Dahl14
`analyzed pertinent medical literature published between 1966
`and 2001 and reported no difference in efficacy among the
`intranasal steroids for treating allergic rhinitis and no clinical
`evidence to support the practice of combining an intranasal
`steroid with an oral antihistamine. Review articles by Aker-
`lund et al15 and Howarth et al16 also reported no evidence to
`suggest that a clinical benefit can be achieved by combining
`an intranasal steroid and an oral antihistamine in the treat-
`ment of allergic rhinitis.
`In the current study, combination therapy with azelastine
`and fluticasone provided significantly greater improvement in
`the TNSS compared with placebo. All of the individual
`symptoms of the TNSS were improved with combination
`therapy when compared with either azelastine or fluticasone.
`This improvement
`in TNSS with combination therapy
`reached statistical significance compared with each individ-
`ual agent on day 2 and continued during the 14-day study
`period. In addition to the TNSS improvements seen in this
`study, the ocular symptom complex was also significantly
`improved with combination therapy compared with flutica-
`sone and placebo. The difference in improvement with com-
`bination therapy compared with azelastine monotherapy was
`not significant. The antihistaminic effect of azelastine may
`provide more relief of ocular symptoms than fluticasone;
`however, no definitive conclusion with regard to this out-
`come can be made without a direct comparative study. Al-
`though it is speculation, the original azelastine (Astelin) la-
`beling included data from studies in which the administration
`technique for the nasal spray was not uniform. Some patients
`appeared to have inhaled and swallowed substantial amounts
`of medication such that the incidence of bitter taste and
`somnolence was substantially higher than in subsequent stud-
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`ies in vasomotor rhinitis17 and several published postmarket-
`ing studies.18 –21 In addition, compliance, which was assessed
`by patient diary entries and confirmed by bottle weights
`measured before and after the double-blind treatment period,
`was greater than 98% in each treatment group.
`The high baseline symptom scores reported by the patients
`are indicative of the severity of rhinitis symptoms that can be
`caused by Texas mountain cedar pollen. In this patient pop-
`ulation, azelastine nasal spray in combination with flutica-
`sone nasal spray provided additive relief of nasal symptoms
`of seasonal allergic rhinitis relative to azelastine or flutica-
`sone nasal spray alone. Combination therapy began to im-
`prove symptoms within 24 hours compared with the individ-
`ual agents, and increasing improvement was observed
`throughout the 14-day study period. The azelastine-flutica-
`sone combination was well tolerated in this study. In addition
`to the small increase in the incidence of bitter taste in the
`combination group, only epistaxis and headache were re-
`ported by more than 3 patients in any treatment group. In
`particular, there was no increase in the incidence of nasal
`irritation or epistaxis with azelastine nasal spray and flutica-
`sone nasal spray in combination. There were no significant
`changes from baseline to end of study in vital signs.
`The use of intranasal azelastine in combination with intra-
`nasal fluticasone produced an additive improvement in rhi-
`nitis symptoms among patients with an allergy to Texas
`mountain cedar pollen. Azelastine nasal spray and fluticasone
`nasal spray used in combination may provide a substantial
`clinical benefit for patients with seasonal allergic rhinitis
`compared with therapy with either agent alone.
`
`ACKNOWLEDGMENTS
`We thank Carrie D’Andrea, MS (MedPointe Pharmaceuti-
`cals, Somerset, New Jersey), for clinical trial management
`and i3 Statprobe (Ann Arbor, Michigan) for statistical anal-
`ysis of the data.
`
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`
`Requests for reprint should be addressed to:
`William Wheeler, PhD
`Meda Pharmaceuticals Inc
`265 Davidson Ave
`Suite 300
`Somerset, NJ 08873
`E-mail: WWheeler@medapharma.us
`
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