Short-term efficacy trial and twenty-four-month follow-up of flunisolide nasal spray in the treatment of perennial rhinitis

Original

articles

Short-term efficacy trial and twenty-four-month follow-up of flunisolide nasal spray in the treatment of perennial rhinitis Donald E. Clayton, M.D., * J. Brent Kooistra, M.D., Mario Geller, M.D., John Ouellette, M.D., Marcus Cohen, M.D., Charles E. Reed, M.D.,** and William Busse, M.D.*** Madison, Wis.

Seventy-eight patients with perennial rhinitis underwent a double-blind, placebo-controlled, 12-wk trial with JIunisolide nasal spray, a new potent topical steroid. Eighteen of these patients were followed in an open study and evaluated at intervals for side effects and dosage of spray used. Baseline and plasma cortisol concentrations were performed before and at the end of the 12-wk, double-blind period. Adrenocorticotropic hormone {ACTH) stimulation testing was performed on six patients after I yr of jlunisolide therapy at 300 pglday or less. Flunisolide was found to be safe and effective over a short period. Over a 2-yr follow-up there were no serious side effects or evidence of adrenal suppression. Ten patients with perennial rhinitis continue to obtain subjective benefit after 2 yr of therapy with flunisolide nasal spray.

Several studies have demonstrated the beneficial effects of topical corticosteroids on the symptoms of allergic rhinitis. 1-5 Flunisolide , a potent topical corticosteroid, has been demonstrated to be effective and safe in the treatment of both seasonal and perennial allergic rhinitis.6-10 Short-term efficacy trials with nasal flumsolide have not been associated with major side effects of adrenal suppressionlO This study asFrom the Allergy-Immunology Section, Department of Internal Medicine, Clinical Science Center, University of WisconsinMadison. This study was supported by a grant from Syntex Research Laboratories. Received for publication March 10, 1980. Accepted for publication June 26, 1980. Reprint requests to: Dr. William Busse, Clinical Science Center H6/360, University of Wisconsin-Madison, 600 Highland Ave., Madison, Wl 53792. *Recipient of a grant from the Asthma and Allergy Foundation of America. Present address: Amett Clinic, Lafayette, Ind. **Resent address: Mayo Clinic, Rochester, Minn. ***Recipient of an Allergic Disease Academic Award from the National Institutes of Allergy and Infectious Disease, Bethesda, Md. (AI 00343-01). Vol. 67, No. 1, pp. 2-7

sesses the efficacy of nasal flunisolide for perennial rhinitis and the safety of long-term treatment. MA=WS FluniaoRde

AN0 METHODS nasal spray

An aqueoussolution containing O-025%flunisolide, 20% propylene glycol, and 15% polyethylene glycol provided by Syntex Corporation (Palo Alto, Calif.) was used for the study. The solution was delivered to the nasal mucosaby a meteredpump spray device from a plastic container. Each spray delivered approximately 25 pg of flunisolide. The patients were instructed to use two sprays into each nostril three times daily for the 12-wk trial period. An identical solution without flunisolide was used for placebo. The patients given flunisolide received a total of 300 pg/day. Pa#ibnt selection Seventy-eight patients, 13 yr of age or older, initially enteredthe study. Selectedpatients had a history of perennial rhinitis for at least2 yr duration except for threepatients in the flunisolide group. Symptoms consisted primarily of nasal stuffiness, rhinorrhea, and sneezing. Excluded from the study were patients with concomitant diseaseprocesses that would potentially obscure the clinical observations

0091-6749/81/010002+06$00.60/0

0 1981 The C. V. Mosby

Co.

Flunisolide

VOLU\‘E 67 NUMHf R 1

made during the study or would possibly be adversely affected by corticosteroids. Seven patients had nasal polyposis three in the flunisolide group and four in the placebo group Fifteen had chronic sinusitis: IO in the flunisolide group and five in the placebo group. Seventy-seven patients had i:ltradermal skin tests at 100 protein nitrogen units (PNI I to tive different extracts. All but eight of these patients had at least one immediate wheal-reacting skin test lo ragwl.ed. grass, trees, mold, or dust. Sixty percent of the patients experienced a seasonal increase in symptoms. All patients had normal screening hematologic, urinary, and bioch%:mical survey findings. Pr; )r to initiation of treatment in the double-blind portion of th. study, each patient was evaluated by a consulting ophth.dmologist. The exam included both slit-lamp examinatio and tonometry. This examination was repeated after 6 mo and I yr of treatment in the open study.

Method

of study

Na;al flunisolide was evaluated as to its effectiveness in a 12-w1, double-blind study, followed by an open study to asses‘ its long-term safety. The double-blind study lasted for a tatal of 14 wk for each patient. The first patient entered in Oc:ober, 1976, and the last completed the double-blind stud:, in April, 1977. The selected patients were evaluated over ‘ 2-wk baseline observation period during which symptom: were recorded. Following this interval, each patient was !iven either the placebo or active drug for a 12-wk period. Patients were allowed to use their usual medication for CI ntrol of nasal symptoms throughout both the baseline and 1: ial periods. Each patient was seen and evaluated every 2 wh throughout the l4-wk period. Sp:cimens for laboratory tests were obtained on one mom.ng of the baseline observation period and again on one mom:ng of the last week of double-blind treatment. These consi *ted of the following: complete blood count (CBC), routire urinalysis, serum alkaline phosphatase, serum sodium serum cholesterol, serum uric acid, serum potassium, total :.erum protein, serum creatinine, total serum calcium, serum. albumin, serum glutamic oxaloacetic transaminase (SCX)T). serum chloride, serum globulin, serum lactic dehydrc,genase (LDH), serum phosphorus, albumin/globulin (A/(11 I ratio, serum TA, blood glucose, blood urea nitrogen (BUT* ), and total serum bilirubin. These were analyzed at ICN ,aboratories (Portland, Ore.). Sp:cimens for plasma cortisol determination were obtaine:! on three separate mornings between 7 A.M. and Y A. M. during the baseline observation period and during the last u, eek of the 3 mo of double-blind treatment. These were analy Led by Syntex Research Laboratories (Palo Alto, Calil ).‘I A open study followed the double-blind period. All patient:, in the open study received active drug and were evaluated by the investigator each month for the first 6 mo. then :very 3 mo thereafter by complete physical examination. -eview of medication use, and side effects. In addition, a record of both subjective symptom severity and condition of naGal mucosa was made.

in perennial

rhinitis

3

Every 3 mo for the first 6 mo, and at 12 mo, patients in the open study had 8 A.M. blood cortisol measurements obtained on three separate mornings along with complete hematologic and biochemical data obtained and analyzed as described previously. After I yr of the open study, adrenocorticotropic hormone (ACTH) stimulation tests were performed on six paplasma cottisol level was drawn tients. Baseline 8 A.M. followed by intramuscular injection of 0.25 mg ACTH. Blood was obtained 1 hr after ACTH administrdtion for plasma cortisol determination. Samples were analyzed by a competitive protein binding method at the University of Wisconsin Center for Health Sciences Clinical I .aboratories (Madison, Wis.).

Evaluation During the 2-wk baseline observation period and each succeeding 2 wk of the double-blind treatment trial, the patients recorded the durations of the following four symptoms: (I) sneezing, (2) stuffy nose, (3) runny nose, and (4) blowing nose. Each of the four symptoms was assigned a “duration score”: 0 = definitely absent, 1 = questionably noted, 2 = definitely present less than 1 hr, 3 = definitely present I hr but less than 2 hr. 4 = definitely present 2 hr but less than 4 hr. 5 = definitely present 4 hr but less than 6 hr, 6 = definitely present 6 hr or more. A daily record of the number of sprays of test drug was kept while all other medications were recorded in terms of “uses” per day. At each 2-wk follow-up visit the investigator evaluated the severity of each of the previously mentioned four symptoms. The severity scores were recorded as either absent (I), mild (2). moderate (3), or severe (4). The overall severity of the nasal symptoms was also assessed as being absent, mild, moderate, or severe. Any side effects in the previous 2 wk were noted and their potential relationship to the test nasal spray recorded. Physical examination of the nasal mucosa was made at admission and at each follow-up visit. The mucosa was graded as being normal or edematous. After completing the l2-wk double-blind trial the patients were evaluated as to the overall efficacy of the test spray during that period. This was defined as total control of nasal symptoms (I), substantial but not complete control (2). minor but definite control (3). no benefit (4), or aggravated nasal symptoms (5). After this evaluation, the drug code was broken. Patients failing to obtain benefit from the placebo were given the opportunity to try the active medication for an additional 6 wk on an open basis. For patients obtaining total or substantial control from flunisolide the opportunity was provided to enroll in a longterm open study. These patients were instructed to use the nasal spray as two sprays in each nostril three times daily or less. An evaluation was performed each month by the investigator for the tirst 6 mo. then every 3 mo thereafter. Evaluation of side effects during the prior interval and physical examination was performed at each patient visit. in addition to any alteration in the dosage of intranasal Hunisolide.

J. ALLERGY

4 Clayton et al. TABLE 1. Summary of symptom 6-wk treatment period

during

comparing

average

changes

Flunisolide

No. patients

from baseline

CLIN. IMMUNOL. JANUARY 1981

period over

Placebo

Average change in symptoms scores during treatment

No. patients

Average change in symptom scores during treatment

Stuffy nose

35

-I .25

32

-0.12

Runny nose

35

-0.61

32

-0.36

Blowing nose

33

-0.73

33

-0.23

Sneezing

32

-0.50

30

+0.10

% days all symptoms lasted no more than 1 hr % days at least one symptom lasted 4 hr or more

35

+17.1%

33

+7.8%

35

-25.9%

33

-4.6%

P

0.0006* (o.ooos)t 0.38 (0.09) 0.61 (0.067) 0.0001 (<0.001) 0.12 (0.082) 0.0014 (0.021)

*Student’s t test. ‘yMann-WhitneyU test.

RESULTS

Sixty-eight of 78 patients starting the study were included in the efficacy analysis. Six patients in the placebo group and four patients in the flunisolide group were excluded because of noncompliance or inappropriate use of the test drugs. The patients assigned to either the flunisolide or placebo group were found to be well matched in regard to age, sex, presence of other atopic diseasessuch as asthma,eczema, and initial physical examination. The patients assigned to the placebo group had a higher proportion of patients with symptomsof 10 or more years in duration (62% placebo vs 41% flunisolide). Severity of symptoms between the two groups during the 2-wk baselineperiod was compared and showed no statistical difference. During the 2-wk baseline observation period more patients assignedto the placebo group used concomitant medications to control nasal symptomsthan did those assignedto the flunisolide treatment group (60% of the flunisolide vs 82% of the placebo group). The duration of the four individual symptoms was similar in both groups except for “stuffy nose,” which was of longer duration in the flunisolide group. The flunisolide and placebo groups were, therefore, comparable except for the placebo group having the highest use of concomitant medication. Analysis

of efficacy

data

An analysis of the efficacy data for average daily duration and severity of each symptom was performed. The average daily duration and severity of

each symptom during the first 6 wk of the doubleblind treatment was analyzed in two ways: (1) the averagescore during the double-blind treatment relative to the samesymptom during the baseline period, and (2) the linear trend during the double-blind period. Analysesof the individual symptomsefficacy data obtained during the double-blind study included only patients in whom the particular symptom was present during the baseline observation period. There was a greater reduction in duration of each symptom in the flunisolide group than the placebo group. In evaluating the symptomsof sneezing, stuffy nose, and percentageof days when at least one symptom was present for 4 hr or more per day, it was found that a significant reduction in duration of symptomsoccurred in the patients treatedwith the active drug (Table I). In addition the averageduration score for each symptom over each2-wk interval ascomparedwith baselinewas analyzed. Comparedwith changesin the control group the duration of the symptom sneezing became significantly different from baselineat 2 wk (p = 0.017), 4 wk (p < O.OOl), and 6 wk (p < 0.001) in the flunisolide-treated group. Also, the percentageof days in which symptomslastedno more than 1 hr, averaged over each 2-wk period, becamesignificantly different from baselineat 2 wk (p = 0.034), 4 wk (p = 0.019), and 6 wk (p = 0.018). At the completion of the 12-wk treatment period it was found that there was significant reduction in the symptom severity of the flunisolide-treated group in regard to sneezing, stuffy nose, blowing nose, and overall severity. Similarly, if these symptoms were

Flunisolide

VOLL’\lE 67 NUMfI iR 1

TABbE II. Open extension

data (24-mo follow-up) Number

-lititial patients Premature withdrawal

(less than

2 yr) b.easons for withdrawal Improvement in rhinitis (no need for medications) Flunisolide ineffective Left community Withdrew under advice of private physician k *valuated flunisolide as effective

(4)

in perennial

rhinitis

5

SNEEZING

(3)

18 8

4

STUFFY NOSE 1 2 1

&---o----o

10

evabtated by linear-trend analysis, the flunisolidetreated patients had a significant improvement for all parameters measured (Fig. 1). The flunisolide-treated group was also able to decrease the use of concomitant medication during the first month of treatment and maintain this decreased use throughout the remainder of the study. In contrast, patients receiving the $acebo required an increase in medication in the first 4 wk. This need for increased medication remairred throughout the 8 wk of study. Fcu-ty-six percent of the patients in the flunisolide grotip vs 9% of the patients in the placebo group achi:ved substantial or total control of nasal symptom.. An additional 29% of the flunisolide-treated group and 22% of the placebo-treated group achieved minlrr but definite control of symptoms. The differencis between the two treatments are statistically significant in favor of flunisolide (p < 0.001). Of the three patients in the flunisolide-treated group wit). negative skin tests, one evaluated the spray as prc.4iding total control and two as providing minor but def rite control. Of the five patients with negative skin test: receiving placebo, four reported no benefit and one reported minor but definite control of symptoms. Lsing a chi-square test, each treatment group was analyzed separately to determine statistically signifrt:ant changes in the condition of the nasal mucosa. The evaluations made at the admission visit were con,pared with the evaluations made at the last visit of the double-blind period. The flunisolide group had sigriticant improvement on examination of nasal mucost over baseline (p = 0.0046), whereas the placebo grotp did not (p = 1.O).

(4) (3)

r

RUNNY NOSE -N

-- *---Q---+..--&---O

(2)

ti,t

I-

-

*-

Loott)

too52 4 I

*

uM;d7l W222) ;=‘d

(4)

NOSE BLOWING (3) q---+--*---Q---~ (2) -

(4)-

OVERALL

RHINITIS

(3)-

.+--*----o----o

(2)-

LOl’36J

(I)-

2

I

I

I

1

I

1

4

6

8

IO

I2

14

STUOY WEEK FIG. 1. Analysis of severity of each symptom obtained at 2-wk intervals during the 12 wk of double-blind treatment period including linear trends. Sever#y scores: 1, Abwnt; 2, mild; 3, moderate; 4, severe. * p value level of significance comparing mean severity score between the two treatment groups (plecebo vs flunioolide) aSa particular visit using the Mann-Whitney

U test (two-sided).

dryness, sore throat, nausea, and headaches. were attributed to the spray rather than the flunisolide.

Side effects

Plasma cortisoi c-h laboratory tests

and

biild nasal burning and stinging was found in 85% of flunisolide-treated and 79% of placebo-treated patients. This was generally of brief duration and tolerabk:. Other infrequent complaints, including nasal

The change in mean cortisol concentrations from baseline observation to the end of the double-blind trial period was analyzed for both the placebo- and flunisolide-treated group. No significant difference in

J. ALLERGY

6 Clayton et al. TABLE III. ACTH stimulation Flunisolide

test-l

yr of therapy

CLIN. IMMUNOL. JANUARY 1981

with flunisolide

dose at time of test

Two One One Two Two Two

sprays each nostril, twice daily spray each nostril, twice daily spray each nostril, once weekly sprays each nostril, three times daily sprayseach nostril, three times daily sprays each nostril, three times daily Mean & SD (SE)

Baseline cortisol* (pg/lOO ml)

1 hr after ACTH cortisol (pg/loO ml)

10.0 13.2 9.0 11.4 8.4 11.8 10.6 * 1.8 (0.74)

19.0 28.0 23.5 27.0 21.0 25.0 23.9 k 3.5 (1.4)

*Normals: Morning cortisol 10 to 25 pg/lOO ml.

changes of mean cortisol concentrations was found between the two groups. No effect was found in either treatment group on routine hematologic, urinary, and biochemical data except for abnormalities noted in two patients. A 36-yr-old woman had SGOT values of 23 SF units at baseline, 24 after placebo treatment, and 61 (normal 5 to 50 SF units) after 12 wk of treatment with flunisolide. No other laboratory abnormalities were noted. A 51-yr-old woman with known alcoholism and use of propranolol and hydrochlorothiazide for hypertension was found to have a rise in SGOT from 29 to 86 SF units after 6 wk of flunisolide followed by a fall to 38 SF units in 2 wk while on flunisolide. Open extension

clinical

data

Thirty of the 39 patients treated with placebo during the double-blind study were entered into a 6-wk open trial on flunisolide. Five patients were dropped becauseof noncompliance and one patient terminated the study becauseof nasal burning and stinging. Of the remaining 24 who completed the 6-wk trial, 19 obtained total or substantial control of their nasal symptoms. No serious side effects occurred. Long-term

open extension

data

Eighteen patients who experiencedan initially good responseto intranasal flunisolide were enteredinto the long-term open study. Four patients withdrew prematurely becauseof overall improvement in their nasal symptoms and absenceof need for continuous medication. Two of these withdrew at less than 6 mo of treatment and the other two at 21 and 24 mo of treatment. One patient with severe allergic rhinitis who initially responded to flunisolide withdrew after 21 mo when the spray failed to control the rhinitis during a seasonalflare. One patient withdrew from the study after switching to dexamethasonenasal spray on the advice of her private physician. Two other patients left the community after 6 mo and were dropped from the study. These two evaluated overall effectiveness

of the spray as adequate in controlling symptoms (Table II). Of the original 18 patients enrolled, 10 have subsequently been followed for a total of 24 mo. Although no statistical analysis of effectivenesshasbeen made in this group, all patients have continued treatment with nasal flunisolide because of overall improvement in their nasal symptoms. Evaluation at 3-mo intervals has revealed only minor side effects reported intermittently, consisting of nasal stinging, nasal dryness, and mild nosebleeds. None of the side effects has been directly responsible for premature withdrawal from the open study. One patient has had recurrent, small, staphylococcal furuncles appearing at the mucocutaneousborder of his naresthat resolve spontaneously without correlation with use of the flunisolide spray. Throughout the first year of open study, no deviation from normal was noted in hematologic or biochemical parameters measured. The 8 A.M. plasma cortisol measurementsremained within normal range. All ACTH stimulation testswere normal with a rise in plasma cortisol to greater than 50% of baseline value (Table III). All patients but one had been using flunisolide daily throughout the preceding year with a range from one spray in eachnostril twice daily to one spray in each nostril three times daily. Ophthalmologic

examination

Prior to initiation in the double-blind study each patient was evaluated by a consulting ophthalmologist. The examination included both a slit-lamp examination and tonometry, which were repeated after 6 mo and 1 yr of the open study. None of the 14 patients studied at 6 and 12 mo had abnormalities noted during ophthalmologic examination that could be attributed to flunisolide spray treatment. DbSCUSSION

The short-term efficacy phaseof this study demonstrated benefit after 12 wk of treatment with flunisolide for perennial rhinitis. To evaluate the treat-

Fiunisolide

VOLL 11E 67 NUMtliR

in perennial

rhtnitis

7

1

merit benefit in any parallel design study, the placebo and treatment groups must be shown to be similar so that variance between the groups does not bias the resul s. The possibility remains that the larger amount of ccncomitant medication used for nasal symptoms in th,: placebo group during the baseline observation period may represent a group of patients with more severe rhinitis than those in the treatment group. If this ‘vere true, spontaneous improvement in patients with less severe rhinitis may have occurred to a greater extent than in those with more severe disease, thus biasing the results to show a beneficial effect from flunisolide. Parameters other than concomitant medication use, such as symptom severity and duration cores, however, did not demonstrate differences in t;c:verity of rhinitis between the two groups. It should be noted that improvement in symptom severity stores did not reach statistical significance in any indi\idual symptom before 6 wk of therapy with flunisolide. Our results are similar to results reported previousi;~ for the treatment of perennial rhinitis with flunisolide. Initial studies demonstrated the effectiveness and safety of flunisolide applied intranasally in the treat nent of ragweed hay fever.“* ’ Subsequent studies nave demonstrated effectiveness in the short-term treat nent of perennial allergic rhinitis with flunisolide in bt:Ith adults and children.8-‘o~ ‘* It does not appear to b: as effective in perennial nonallergic rhinitis’” and may be more effective in those patients who have a gr:ater degree of allergic disease as opposed to nomllergic rhinitis. lo One of three of our patients with negative skin tests had total control of symptoms and two of the three had minor but definite benefit fron flunisolide; therefore, at least some patients with nonallergic rhinitis will benefit from intranasal fluniso ide. Previous reports have established both the efficacy and ;afety of flunisolide administration for periods up to 6 mo. I3 We have followed for 24 mo the effectivenest and safety of intranasal Aunisolide in 10 patients. Thoiigh not double-blinded, all 10 patients continued to hive control of their symptoms with the use of nasa. flunisolide in doses of 300 pg/day or less. In addi ion, prolonged use of this dose of flunisolide did not produce subjective side effects prohibiting its use nor was there the apparent development of nasal men brane abnormalities on examination. Six patients wen given ACTH stimulation tests with normal adrenal I esponse. Rior attempts to control rhinitis with topical administration of dexamethasone resulted in partial but

definite adrenal suppression.‘. I4 Potent topical corticosteroids such as beclomethasone dipropionate and betamethasone- 17-valerate have been used with success in treating allergic rhinitis without development of significant side effects or adrenal suppression.‘, i Flunisolide is another topical steroid which, when administered to the nasal mucosa, is effective in the treatment of seasonal and perennial rhinitis as well as being safe for long-term use without producing adrenal suppression. The authors Rogers statistical assistance. script

thank

of Syntex analysis

Dr. S. Crepea,

Dr. J. Johnson.

and C.

Research

Laboratories for preparing the

and Ann

Smith

We thank

Kathleen

for

Scholes

invaluable for

help

technical in manu-

preparation.

REFERENCES 1.

Norman PS. Winkenwerder WL. Murgatroyd GW Jr, et al: Evidence for the local action of intranasal dexamethasone aerosols in the suppression of hay fever symptoms J AI LFKGY 38~93, 1%6. 2. Czarny D. Brostaff J: Effect of intranasal betamethasone- 17. valerate on perennial rhinitis and adrenal function. Lancet 2: 188, 1968. 3 Godfrey MP. Manusell K: Prednisolone snuff in hay fever: A controlled study. Lancer 1:757, 1957. 4 Aaron TH, Nuttitt ELC: Effect of intranasal dexamethrsone phosphate on the adrenal function of patients with perennial allergic rhinitis. Ann Allergy U: 100. 1965. N: Local effect of intranasal &lomethasone di5 Mygind propionate aerosol in hay fever. Br Med J 4:464. 1973. 6 Turkletaub PC, Norman PS, Crepea S: Treatment of ragweed hay fever with an inaanasal spray containing flunisdide. a new 58~597. synthetic corticostemid. J ALLERGY CL.IN IMMI’NOI 1976. 7 Kammermeyer JK, Rajtora DW. Anuras J. CI al: Clinical evaluation of intranasal topical flunisolide therapy in allergic rhinitis. J ALLERGY CL~ IYMUNOL.5%287. 1977. 8. Horan JD. Johnson JD: Flunisolide nasal spray in lhe treatment of perennial rhinitis. Can Med A.ssoc J 119t334. 1978. trial com9 Schulz JI, Johnson JD, Freedman SO: Double-blind paring flunisolide and placebo for the treatment of perennial rhinitis. Clin Allergy 8:313. 1978. F. et al: intrenasal Hun10 lncaudo G. Schatz M, Yamamoto isolide in the treatment of perennial rhinitis. Correlation with rmmunologic parameters. J AI t ERGY CI.IV IUUUNCM. 65:41, 1980. 11 Murphy BP. Engelberg W, Pattee CJ: Simple method for the determination of plasma corticoids. J Clin Endocrinol 23~293. 1%3. nasal spray for pe12 Scarsfield JK, Thomson GE: Flunisolide rennial rhinitis in children. Br Med J 2:95, 1979. 13. Jones LM, Spector SL, English GM. et al: Treatment of perennial rhinitis with flunisolide corticosteroid spray. Ann Allergy 42: 139. 1979. WL, Agbayani BF. et al: Adrenal 14. Norman PS, Winkenwerder function during the use of dexamethasone aerosols in the treatment of ragweed hay fever. J AI I FRGY 48:57. I%7