Efficacy and safety of moguisteine in comparison with levodropropizine in patients with cough associated with chronic obstructive pulmonary disease, lung cancer, or pulmonary fibrosis

CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 3, MARCH1994

EFFICACY AND SAFETY OF MOGUISTEINE IN COMPARISON WITH LEVODROPROPIZINE IN PATIENTS WITH COUGH ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE, LUNG CANCER, OR PULMONARY FIBROSIS G. FASCIOLO,1 A. NICOLINI,2 N. VACCA,3 AND P. VIGLIERCHIO3 ~Pneumology Centre, USL XII, Genoa, 2Department of Pneumology, Chiavari Hospital, Chiavari (GE), and ZDepartment of General Medicine, S. Paolo Hospital, Savona, Italy

ABSTRACT The purpose of this study was to compare the efficacy and safety of moguisteine, a new antitussive drug with a peripheral mechanism of action, with levodropropizine, a reference antitussive compound. A randomized, single-blind, parallel-group, multicenter trial was conducted in 104 adult patients with persistent cough associated with chronic obstructive pulmonary disease, lung cancer, or pulmonary fibrosis. The drug regimen was 200 mg TID moguisteine and 60 mg TID levodropropizine, each given orally for 6 days. The primary efficacy variable was the sum of daytime and nighttime cough frequency scores assigned by the patients according to a 0 to 10 ladder scale. Secondary efficacy variables were the number of coughs in the morning at baseline and on the third day of treatment, rated by hospitalized patients with manual counters and tape recorders for a period of 2 hours; the scores were separately assigned by patients to daytime and nighttime cough frequency; and the patients' final evaluation of the antitussive treatment received. Safety variables were the clinical laboratory test values and the adverse events reported by the patients or observed by the investigators. Both drugs were highly effective and significantly reduced daytime and nighttime cough frequency scores. Patients receiving moguisteine showed a significantly greater reduction in these scores than those receiving levodropropizine on the third and fourth days of treatment. The cough count significantly decreased after both treatments--the number of baseline coughs recorded for patients receiving moguisteine and levodropropizine was 44 and 43, respectively; on the third day of treatment it dropped to 17 in both groups. Both drugs were well tolerated; adverse events were reported by only 2 patients receiving moguisteine (moderate epigastric pain for both patients) and 3 patients receiving levodropropizine (2 patients reported epigastric pain, I moderate and I mild in intensity; I patient presented with moderate anxiety and insomnia). No event was serious, but treatment was stopped for the patient in the levodropropizine group who presented with anxiety and insomnia. The results of this study suggest that moguisteine, 200 mg TID, is at least as effective and safe an antitussive agent as levodropropizine, 60 mg TID. Address correspondenceto: Dr. G. Fasciolo,PneumotogyCentre, USL XII,Via Assarotti 35, 1621Genoa, Italy. Receivedfor publication on December2, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 251

0011-393x/94/$3.50

EFFICACY AND SAFETY OF MOGUISTEINE VERSUS LEVODROPROPIZINE

INTRODUCTION

Cough, in cooperation with mucus hypersecretion, mucociliary clearance, and bronchoconstriction, is an important defense mechanism of the tracheobronchial tree in response to noxious stimuli. 1-3 It may also be an important symptom of many respiratory diseases. 4 When coughing is nonproductive and becomes an annoying reflex that debilitates patients and worsens their pathologic condition, antitussive drugs may be required. 5'6 Among the available antitussive compounds, nonnarcotic drugs that act directly on peripheral receptors of cough are generally preferable, because they can produce cough reflex suppression with minimal or no harmful side effects, v Compounds that act with either antitussive or anti-inflammatory mechanisms, ameliorating the condition that led to the symptom, represent a useful clinical approach to cough treatment. Moguisteine [(R,S)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl-l,3-thiazolidine] is a new, peripherally acting, nonnarcotic antitussive drug synthesized by Boehringer Mannheim Italia S.p.A., Milan, Italy. Moguisteine does not interact with central opiate receptorsS; instead, it probably exerts its action by interacting with the airway's rapidly adapting receptors (J. G. Widdicombe, 1992, unpublished animal data). Previous toxicologic, pharmacologic, and clinical studies have demonstrated that moguisteine is well tolerated and highly effective in subjects with experimentally induced cough, s-ll A few placebo-controlled studies have shown the efficacy of moguisteine in patients with persistent cough associated with various respiratory disorders. 12'13 Furthermore, moguisteine displayed anti-inflammatory properties in guinea pig airways, preventing allergen-induced cellular infiltration 14 and reducing hyperreactivity, cell recruitment, and plasma exudation induced by tobacco-smoke exposure. 9 These data suggest that moguisteine could be an attractive pharmacologic alternative to currently available antitussive drugs. We conducted a randomized, single-blind, multicenter trial in patients with persistent cough associated with chronic obstructive pulmonary disease (COPD), lung cancer, or pulmonary fibrosis to compare the antitussive activity and safety of moguisteine with that of levodropropizine, a commonly used, peripherally acting antitussive drug. 15 PATIENTS

AND METHODS

Screening procedures were conducted on the basis of medical history, physical examination, and the following baseline clinical laboratory tests: hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) total and differential counts, platelets, erythrocyte sedimentation rate 252

G. FASCIOLO ET AL.

(ESR), protein electrophoresis, lactate dehydrogenase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, blood urea nitrogen (BUN), creatinine, gamma-glutamyl transpeptidase, glucose, uric acid, and urinalysis. Patients were included in the study if they were between the ages of 18 and 75 years and had a dry or slightly productive cough associated with COPD, lung cancer, or pulmonary fibrosis that persisted for at least 7 days. The degree of cough severity had to be equal to or higher than II according to the following scale: 0 = no cough; I = occasional cough, not troublesome; II = frequent cough, but not limiting normal activities and/or sleep; III = frequent cough, limiting normal activities and/or sleep; and IV = continuous cough, throughout 24 hours. The following patients were excluded from the study: pregnant women and nursing mothers, patients with a life expectancy of less than 3 months, and patients with renal or hepatic failure or other severe conditions that might complicate participation in the study. Antitussives were not permitted for 3 days prior to baseline assessment and antitussives other than the study drug were not permitted throughout the study. Any other concomitant medication was permitted, provided that it was already stabilized by visit 1 and not modified during the study. The study was performed according to a randomized, single-blind, multicenter design with parallel groups and was controlled with levodropropizine, a standard reference compound. At visit I (baseline), medical history, physical examination, evaluation of cough severity rank, cough frequency scores, and clinical laboratory tests were performed and, only for hospitalized patients, a cough count was performed. Eligible patients were enrolled and randomized through assignment of a consecutive identification number. On the basis of their identification number, patients were assigned to a treatment, according to the randomization list. All patients enrolled in the trial were given a diary card for the subjective recording of cough throughout the study. Hospitalized patients were also supplied with a manual counter for monitoring their cough. The number of coughs was recorded for 2 hours in the morning, from 8 AM to 10 AM, at baseline and on the third day of treatment, immediately after drug administration. In addition, a tape recording was obtained throughout the observation time, using a cassette recorder, in order to verify, if necessary, the data reported by the patients. The subjective evaluation of cough began at baseline and continued during the 6-day treatment period until the day after the last dose of study drug, when the final evaluations were carried out (visit 2). These procedures included physical examination, clinical laboratory tests, and collec253

EFFICACY AND SAFETY OF MOGUISTEINE VERSUS LEVODROPROPIZINE

tion of the patients' diaries. The occurrence of any adverse event was also reviewed. Since the study-drug formulations were different, double-blinding would have only been possible through a double-dummy technique, which was felt to be at high risk of making patients noncompliant. The singleblind condition (patient blinded) was therefore chosen as appropriate to avoid bias in this setting; in addition, an objective variable (number of coughs during a fixed period) was also recorded. Containers of moguisteine suspension and of levodropropizine syrup were different in appearance. They were nevertheless packed in anonymous boxes so that the patients did not know which drug they were taking. The treatment (moguisteine or levodropropizine) was allocated according to the randomization list and was identified in a sealed envelope bearing the patient's identification number on the outside. This envelope was opened by the investigating physician at the end of visit 1, and it was the physician who gave the drug to the patient in accordance with the information in the envelope. Moguisteine, 20 mg/ml ready-to-use suspension, was administered in oral doses of 10 ml (200 mg). The treatment started the day after baseline and lasted for 6 complete days during which moguisteine was administered in three daily doses, at 8 AM, 2 PM, and 8 PM. Levodropropizine, 6 mg/ml syrup, was administered in three oral doses of 10 ml (60 mg) over 6 days according to the same schedule. The sum of the cough frequency scores assigned by patients during the day and during the night was considered the primary efficacy variable. The number of coughs recorded with manual counters and recorders during the monitoring period, the cough frequency scores separately assigned by patients during the day and during the night, and the final evaluation by patients of the antitussive treatment received were considered secondary efficacy variables. Safety variables were represented by the clinical laboratory test values and by the adverse events that were spontaneously reported by the patients or observed by the investigators. An adverse event was defined as any undesired, noxious, or pathologic change (indicated by changes in clinical symptoms and/or laboratory values) that occurred in association with the use of drug whether or not it was considered to be drug related. An adverse event was considered to be serious when the event was fatal or life-threatening, hospitalization was required or prolonged, or the patient was permanently disabled. Heart rate and blood pressure measurements were also performed at baseline and at the end of the study. Cough frequency scores were assigned by patients during the day and during the night (the time intervals considered for the day were approximately 8 AM to 8 PM and for the night were approximately 8 PM to 8 A M ) . 254

G. FASCIOLO ET AL.

Patients were asked to fill in a diary card when evaluating cough frequency. This was done by assigning an arbitrary score to cough frequency using a scale of 0 to 10. According to this scale, 0 indicated absence of cough, 1 through 9 represented gradually increasing cough, and 10 corresponded to continuous cough. A final evaluation of the antitussive treatment received was made by each patient at the end of the study. This final evaluation consisted of two questions in the diary card--the first one regarding the efficacy of the drug received (three answers: yes, a lot; yes, a little; no) and the second one the possibility, if necessary, of using the same drug again (yes; no). The protocol of this study was approved by a central ethics committee of the Istituto Scientifico Medicina Domani, Genoa, and the authorization to perform the study was granted locally to individual centers by the appropriate health authorities and scientific committees. The trial was conducted in accordance with the provisions of the Declaration of Helsinki 1974 and its amendments. Each subject was informed about the specific effect and risk of treatment and the special trial procedures. Oral informed consent, in the presence of a witness, was obtained from each patient.

Statistical Analysis The population size was not calculated on a statistical basis. An inferential analysis was performed to evaluate the comparability of the study groups in relation to demographic data (sex, age, weight, etc). The differences between groups with regard to efficacy variables were calculated using the Mann-Whitney test, and the differences between baseline and final values with regard to efficacy and safety variables were performed using the Friedman test. The chi-square test was used to compare the final evaluation by the patients of the antitussive treatment received. The statistical evaluation of adverse events was a standardized tabulation of the frequency rate of all observed adverse events. A descriptive analysis was performed for the other parameters observed. RESULTS

Three centers participated in the study; a total of 104 patients, 53 receiving moguisteine and 51 receiving levodropropizine, were enrolled. Thirtyone of these patients were hospitalized. The study was completed by 103 patients; 1 patient in the levodropropizine group withdrew before completion of the study because of an adverse event. 255

EFFICACY AND SAFETY OF MOGUISTEINE VERSUS LEVODROPROPIZINE

Details of patient characteristics are summarized in Table I. There were no noteworthy differences between the two treatment groups with respect to demographic data, cough severity, and diagnosis on entry. Concomitant diseases were mainly related to the cardiovascular or digestive systems and were present to the same extent in both groups. Concomitant medications, most of all cardiovascular drugs, beta2-adrenergic receptor agonists, and theophyllinics, were distributed homogeneously between the two t r e a t m e n t groups (15 patients in the moguisteine group and 11 patients in the levodropropizine group). The patient who withdrew from the study was excluded from efficacy analysis; thus a total of 103 patients, 53 receiving moguisteine and 50 receiving levodropropizine, were evaluated. Cough counts were performed by 29 of the 31 hospitalized patients (16 treated with moguisteine and 13 with levodropropizine). Counts at baseline but not on the third day of treatment were obtained in the remaining 2 cases. All 104 patients were evaluated for safety.

Efficacy Variables The mean values of the sum of daytime and nighttime cough frequency scores during the study period are shown in the figure. All data were reported as mean -+ SD. The scores at baseline were similar in both groups: 15.79 -+ 2.08 for patients receiving moguisteine and 15.76 -+ 2.02 for patients receiving levodropropizine, and the treatment was associated with a score reduction in both the moguisteine, 0.45 -+ 1.07, and levodro-

Table I. P a t i e n t characteristics.

Enrolled and randomized Withdrawn before completion of the study Sex Male Female Age (yr) Body weight (kg) Height (cm) Rank of cough severity II III IV Diagnosis COPD Lung cancer Pulmonary fibrosis

Moguisteine

Levodr0propizine

53 0

51 1

36 17 65 + 8.1 72 + 10.7 168 +_ 6.6

36 15 64 _+ 8.1 72 _+ 13.6 167 _+ 8.2

11 30 12

7 38 6

27 15 11

36 9 6

Age, body weight, and height are reported as mean -- SD, where SD = standard deviation. COPD = chronic obstructive pulmonary disease. 256

G. FASCIOLOET AL.

16

14

12

10 ® i,= 0

8

6 ¸

4¸

2¸

Study

Per iod

F i g u r e . M o g u i s t e i n e v e r s u s tevodropropizine, s u m of d a y t i m e a n d n i g h t t i m e c o u g h f r e q u e n c y scores a s s i g n e d b y p a t i e n t s a c c o r d i n g to a 0 to 10 l a d d e r scale.

propizine, 0.36 -+ 0.85, groups at the end of the study. Moguisteine displayed an antitussive activity significantly greater than levodropropizine on the third day of treatment (5.83 -+ 3.85 for moguisteine versus 7.27 -+ 2.88 for levodropropizine [P = 0.0061]), and on the fourth day of t r e a t m e n t (3.47 -+ 3.39 for moguisteine versus 4.60 -+ 2.47 for levodropropizine [P = 0.0076]). Secondary efficacy variables are shown in Table II. Mean values of daytime cough frequency scores were similar in both groups at baseline, 7.86 -+ 1.20 for patients in the moguisteine group and 7.92 -+ 1.09 for patients in the levodropropizine group; the treatment was associated with a score reduction, 0.23 -+ 0.52 for patients in the moguisteine group and 0.21 -+ 0.52 for patients in the levodropropizine group at the end of treatment. Nighttime cough frequency scores were also comparable at baseline, 7.93 -+ 1.16 for patients receiving moguisteine and 7.84 +- 1.19 for patients receiving levodropropizine, and at the end of the study, 0.23 +- 0.57 and 0.14 -+ 0.42, respectively. Moguisteine exhibited greater antitussive activity than levodropropizine on the third and fourth days of treatment. This difference was not statistically significant. 257

EFFICACY AND SAFETY OF MOGUISTEINE VERSUS LEVODROPROPIZINE

Table II. Daytime and nighttime cough frequency scores. Moguisteine (n = 53) Day of Treatment Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Final

Daytime 7.86 6.32 4.45 2.79 1.62 0.91 0.60 0.23

+- 1.20 +- 2.06 _+ 1.99 -+ 1.81 -+ 1.77 _+ 1.24 -+ 1.51 -+ 0.52

Levodropropizine (n = 50) Nighttime 7.93 6.60 4.68 3.04 1.85 1.08 0.67 0.23

-+ 1.16 _+ 2.22 _+ 2.19 +_ 2.27 -+ 1.84 -+ 1.49 -+ 1.35 -+ 0.57

Daytime 7.92 6.63 4.96 3.57 2.16 1.16 0.55 0.21

Nighttime

-+ 1.09 -+ 1.89 - 1.75 _+ 1.82 ___1.58 _+ 1.21 -+ 0.97 _+ 0.52

7.84 6.41 5.04 3.71 2.39 1.31 0.73 0.14

+-- 1.19 +- 2.00 - 1.61 _+ 1.46 - 1.31 _+ 1.07 _+ 1.15 -+ 0.42

All data are presented as mean - SD, where SD = standard deviation.

The mean values (SD) of the number of coughs counted by hospitalized patients, at baseline and on the third day of treatment, were similar for moguisteine and levodropropizine and are reported in Table III. The treatment reduced the number of coughs in both groups from 44 + 13 to 17 -+ 6 for patients receiving moguisteine and from 43 -+ 11 to 17 - 5 for patients receiving levodropropizine. Although the population size was small, the decrease in coughs was statistically significant with both drugs (moguisteine, P = 0.0004; levodropropizine, P = 0.0019). No significant differences were found between treatments. The patient's final assessment of drug efficacy was favorable in 89% of patients treated with moguisteine and 90% of patients treated with levodropropizine; a large percentage of patients (85% with moguisteine and 94% with levodropropizine) would use the same drug again. No statistically significant differences in the final evaluation of the antitussive treatment received were found between groups, according to the chi-square test.

Safety Evaluations No serious adverse events occurred. Possible drug-related adverse events were reported in 2 (3.77%) of 53 patients receiving moguisteine

Table III. Number of coughs counted by hospitalized patients.

Baseline Third day of treatment

Moguisteine (n = 16)

Levodropropizine (n = 13)

44 -+ 13 17 -+ 6

43 -+ 11 17 -+ 5

Data are presented as mean -+ SD, where SD = standard deviation.

258

G. FASCIOLO ET AL.

(both patients presented with moderate epigastric pain) and in 3 (5.88%) of 51 patients receiving levodropropizine (2 patients reported epigastric pain, 1 moderate and 1 mild in intensity; the third patient presented with a moderate state of anxiety and insomnia). Treatment was discontinued for the patient who presented with anxiety and insomnia, although the adverse event was not considered to be serious. With regard to clinical laboratory tests, a statistically significant difference between the baseline and final values measured was only found for ESR and leukocyte counts both in patients treated with moguisteine and in those treated with levodropropizine. In the moguisteine and levodropropizine groups, ESR decreased from 33.96 +- 23.54 mm/hr at baseline to 31.21 -+ 23.08 mm/hr at the end of the study and from 23.76 -+ 18.23 mm/hr to 20.82 -+ 16.15 mm/hr, respectively. Leukocyte numbers were reduced from 8.23 -+ 2.04 103/ml to 7.47 -+ 1.52 103/ml in patients receiving moguisteine and from 8.23 -+ 2.30 103/ml to 7.43 -+ 1.64 103/ml in patients receiving levodropropizine. These changes were not considered to be of clinical relevance but instead related to the normal course of the illness. No trends in laboratory tests were observed that indicated functional or toxic effects of the study drugs on specific organs. Blood pressure and heart rate were unchanged at the end of the study compared with the baseline values. Ninety-six percent of patients in both groups were fully compliant with the study protocol and the schedule of drug administration. DISCUSSION Cough is an important mechanism for the protection and clearance of the airways. 1 When coughing performs no useful function, and it is annoying or its complications represent a real or potential hazard, antitussive therapy is indicated. 4 In this single-blind, parallel-group, multicenter clinical trial we evaluated the efficacy and safety of moguisteine, a new antitussive agent with a peripheral mechanism of action, compared with levodropropizine, a standard antitussive drug. The enrolled patients presented with a dry or slightly productive cough, persistent for at least 7 days, and associated with COPD, lung cancer, or pulmonary fibrosis. Both drugs induced significant cough relief, and the cough reduction achieved was similar. At the end of the observation period, there were no statistically significant differences between the two groups. The primary variable of the study was the sum of the daytime and nighttime cough frequency scores assigned by the patients. The two treatments appeared to be highly effective; in particular, moguisteine showed a significantly higher antitussive activity than levodropropizine on the third and fourth days of treatment. 259

EFFICACYANDSAFETYOFMOGUISTEINEVERSUSLEVODROPROPIZINE

Secondary efficacy variables (cough frequency scores during the day, cough frequency scores during the night, the number of coughs counted during monitored periods by hospitalized patients, and the final judgment by patients of the antitussive treatment received) showed noteworthy improvements in symptoms in both groups, without any remarkable difference between treatments. Possible drug-related adverse events were reported in 2 of 53 patients receiving moguisteine and in 3 of 51 patients receiving levodropropizine. No adverse event was serious; however, it was necessary to discontinue treatment in one of the patients in the levodropropizine group. In either drug group, routine clinical laboratory tests did not show any clinically relevant data that might indicate toxic effects. Since the patients involved in this study were enrolled on the basis of persistent cough related to chronic diseases, the symptom improvement observed with both drugs can be ascribed to their antitussive action rather than to a spontaneous resolution. We conclude that treatment with moguisteine is associated with a clinically important antitussive effect at least equal to that of a standard, currently used antitussive drug; furthermore, the compound appears to be safe and well tolerated. These data, in addition to moguisteine's peripheral mechanism of action and anti-inflammatory activity in animal models, 9'14 make moguisteine a useful, new antitussive agent.

Acknowledgments The authors gratefully acknowledge Istituto Scientifico Medicina Domani, Genoa, Italy, and Dr. M. Reali for their valuable assistance with this project. This study was supported in part by Boehringer Mannheim Italia S.p.A., Monza, Italy. References: 1. Leith DE. Cough. In: Brain JD, Proctor DF, Reid L, eds. Respiratory defense mechanism. Part III. New York: Marcel Dekker, 1977:545-592. 2. Pavia D, Agnew JE, Clarke SW. Cough and mucociliary clearance. Clin Respir Physiol 1987; 23(Suppl 10):41-45. 3. Del Donno M, D'Ippolito R, Olivieri D. Mucociliary clearance in humans as physiologic lung defense mechanism. In: Junoud A, Olivieri D, Pozzi E, eds. Endothelial and mucus secreting cells. Milan: Masson, 1991:247-260. 4. Irwin RS, Curley FJ. The treatment of cough: A comprehensive review. Chest 1991; 99:1477-1484. 5. Hughes DTD. Cough suppressants, expectorants, and mucolytic agents. BMJ 1978; 1: 1202-1203. 260

G. FASCIOLOETAL.

6. Eddy NB, Friebel H, Hahn KJ, Halbach H. Codeine and its alternatives for pain and cough relief. Part 3. Bull WHO 1969; 40:425-454. 7. Banner AS. Cough: Physiology, evaluation and treatment. Lung 1986; 164:79-92. 8. Gallico L, Borghi A, Dalla Rosa C, et al. BBR 2173, a new nonnarcotic antitussive agent. (Abstract) Pharmacol Res Commun 1988; 20(Suppl III):lT1. 9. Gallico L, Borghi A, Dalla Rosa C, et al. Moguisteine: A new drug effective in experimental cough and hyperreactivity. Am Rev Respir Dis 1990; 141(N4, Part II):A654. 10. Sestini P, Refini RM, Pieroni MG, et al. Protective effect of the new antitussive drug moguisteine on citric acid-induced cough. (Abstract) EurRespirJ 1990; 3(Suppl 10):160s. 11. Moscato G, Dellabianca A, Carlesi RM, et al. Preliminary clinical experience with moguisteine in acetylcholine induced cough. (Abstract) Eur Respir J 1990; 3(Suppl 10): 93s. 12. Morrone L, Pizza A, Martinelli A, et at. Pilot study on efficacy and safety of a new antitussive drug, moguisteine: A double-blind placebo-controlled trial. Adv Ther 1993; 10(N2):67-73. 13. Aversa C, Cazzola M, Clini V, et al. A double-blind, placebo-controlled, parallel group clinical trial on efficacy and safety of moguisteine in patients with cough associated to chronic respiratory diseases. Drugs Exp Clin Res (in press). 14. Gallico L, Borghi A, Dalta Rosa C, et al. Effect of dexamethasone and moguisteine on allergen-induced early broncho-constrictionand late phase airway leucocyte recruitment in sensitized guinea-pigs. (Abstract) Br J Pharmacol 1992; 106:75P. 15. Allegra L, Bossi R. Clinical trials with the new antitussive levodropropizine in adult bronchitic patients. Arzneim-Forsch Drug Res 1988; 38(N8, Part II):1163-1166.

261