The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SLMF 4010 Title: Multicentre, randomised, parallel group, placebo-controlled, double-blind, study, stratified on tobacco status at enrollment, evaluating during 6 months the efficacy of salmeterol powder for inhalation, 50 µg two times per day for the reduction of thoracic distension in subjects with chronic obstructive pulmonary disease (COPD) Rationale: Thoracic CT-scan associated with spirometry shows structure details on bronchial and parenchymatous lesions and on bronchial dynamics during respiratory movements. The negative expiratory pressure (NEP) technique provides a simple and reliable method for detection of expiratory flow limitation. In subjects with chronic obstructive pulmonary disease (COPD), dynamic overinflation is seen when breathing demand increases and, in the most severe subjects, even at rest. The increase in total lung capacity (TLC) and functional residual capacity (FRC) and the decrease in inspiratory capacity (IC) reflects this overinflation, IC being directly correlated to the overinflation improvement. Bronchodilators are used to relieve symptoms in obstructive lung disease, such as asthma or COPD. After salbutamol inhalation in COPD subjects, the dyspnoea improvement is correlated to the IC increase and overinflation reduction. At the time of the study, there were no data on the long-term effects of salmeterol on overinflation. Phase: IV Study Period: 16 August 2001 to 01 October 2002 Study Design: Multicentre, randomised, parallel-group, placebo-controlled, double-blind study, stratified by tobacco status at enrolment. Centres: 9 centres in France Indication: Chronic Obstructive Pulmonary Disease (COPD) Treatment: meterol 50µg Diskus () and matching placebo Diskus (), with administration of one inhalation morning and evening during 24 weeks, then use of immediate bronchodilators during the 8-week follow-up period. Objectives : The objectives were: to evaluate, long term, the action of salmeterol on thoracic overinflation, to verify correlation between IC and FRC and the evolution of dyspnoea after immediate administration of salbutamol and during chronic use of salmeterol (treatment period of 24 weeks) and after stopping salmeterol during the 8 weeks follow-up period in COPD subjects with thoracic distension, to verify parallel variations of IC and FRC after 6 months of administration, to evaluate improvement of exercise capacity under salmeterol, due to a decrease of thoracic distension, to evaluate the action of salmeterol on expiratory limitation of expiratory flow with the quantified NEP, to evaluate the action of salmeterol on gasometric parameters, to evaluate the quality of life (QoL) under salmeterol, to verify correlation between QoL and thoracic distension, to explore bronchial tree with spiro CT-scan in order to argue the structural hypothesis of distension reduction mechanism in COPD subjects receiving salmeterol on long term to evaluate the safety of salmeterol Primary Outcome/Efficacy Variable: Variation of IC (in ml) before salbutamol inhalation, between visit 1 and visit 4. Secondary Outcome/Efficacy Variables: Variation in ml of IC before salbutamol inhalation, from visit 1 to visit 2, and from visit 4 to visit 6; Variation in ml of the IC difference (post salbutamol - pre salbutamol); Variation in ml of FRC measured by plethysmography before salbutamol inhalation ; Variation in ml of FRC difference (post salbutamol - pre salbutamol), FRC measured by plethysmography ; Variation in ml and in percentage of theoretical value of forced expiratory volume in one second (FEV1) before salbutamol inhalation; Variation in ml and in percentage of theoretical value of FEV1 difference (post salbutamol - pre salbutamol); Variation in ml of forced inspiratory volume in one second (FIV1) before salbutamol inhalation ; Variation in ml of FIV1 difference (post salbutamol - pre salbutamol) ; Variation in ml of Total Lung Capacity (TLC) measured by plethysmography before salbutamol inhalation Variation in ml of residual volume (RV) measured by plethysmography before salbutamol inhalation ; Dyspnoea evaluated by EEC scale at each visit ; Blood gasometry: PaO2, PaCO2, ph, HCO3-, SaO2 ; Follow-up of tobacco status through questioning and measure of expired CO at each visit ; 1
Follow-up of rescue medication use measured by the percentage of days with no short-acting bronchodilator use ; Qualitative and quantified NEP at each visit (depending on centre, optional): expiratory flow induced by NEP (in L/sec) and measured between 25 and 75%, at 25% and at 50% respectively of tidal volume before application of NEP (DEMNEP25-75%, DEMNEP50% and DEMNEP25%), measures were performed before and after salbutamol inhalation ; Evaluation of exercise capacity during an exercise test limited by symptoms at 50% of the maximum theoretical power (depending on centre, optional) : dyspnoea evaluated by Visual analogical scale (VAS) and IC at rest, during test, then end of test, and duration of the test, testing done before and after salbutamol inhalation ; Spiro-tomodensitometry scan (depending on centre, optional) at visit 1 and visit 4 ; Follow-up of exacerbations, including those leading to hospitalization and collection of hospital length of stay; Safety Improvement during treatment evaluated by variation of QoL measured by Saint-George s Respiratory Questionnaire (SGRQ)validated in the French language. Statistical Methods: Pre-salbutamol IC, IC difference (post salbutamol - pre salbutamol); FRC measured before salbutamol inhalation, FRC difference (post salbutamol - pre salbutamol), FEV1 before salbutamol inhalation, FEV1 difference (post salbutamol - pre salbutamol), FIV1 before salbutamol inhalation, FIV1 difference (post salbutamol - pre salbutamol), TLC before salbutamol inhalation, TLC before salbutamol inhalation, dyspnea score and Saint George questionnaire total score were tested by a repeated-measures model with treatment group and time (visit) as qualitative covariates and age, sex and smoking status as explicative covariates, interactions analyses were time (visit) and treatment, age, sex and smoking status. Adjusted mean changes were calculated by LS means. Percentage of days with no short-acting bronchodilator use was tested by a covariance analysis (ANCOVA) with treatment group, age, sex and smoking status at inclusion as covariates. No formal statistical analysis was performed for PaO2, PaCO2, ph, HCO3-, SaO2, smoking status, expired CO, COPD exacerbations which were described by mean and standard deviation for quantitative data and frequency for qualitative data. NEP, exercise test data and CT-scan data were not analyzed and were listed per subject. The ITT population included all randomised subjects having received at least one dose of study medication and for whom the assessment data for at least one assessment criterion was available and was analysed based on treatment allocated. Safety population consisted of all randomised subjects having received at least one dose of study medication and was analysed based on treatment really received. Study Population: Subjects aged more than 40 years, with tobacco habit more than 20 pack-years, with a diagnosis of COPD confirmed by a pneumologist with questioning and functional respiratory explorations and at visit 1 FEV1 > 60% of theoretical value, FEV1/TLC ratio > 75% in absolute value and > 85% of theoretical value, FEV1 reversibility >12% and >200 ml twenty minutes after 400µg of salbutamol, with an inflation defined by a FRC >110% of theoretical value. Subjects were not included with asthma and/or history of allergy including non respiratory signs, with other respiratory pathologies (bronchial cancer, interstitial pneumopathy, history of thoracic surgery, tuberculosis sequelae, pleural or parietal pathology), subjects requiring chronic oxygen therapy, subjects with severe cardiovascular disease, subjects treated within 4 weeks before enrolment with inhaled or systemic corticosteroids, β2 long-acting agonists and/or theophyllines, subjects who have presented with a COPD exacerbation and/or other acute respiratory disease within 4 weeks before enrolment, breast-feeding or potentially pregnant female. Number of Subjects: nned, N 16 16 Randomised, N 17 17 Completed, n (%) 10 10 Total Number Subjects Withdrawn, N (%) 7 7 Withdrawn due to Adverse Events n (%) 0 2 Withdrawn due to Lack of Efficacy n (%) 1 0 Withdrawn for other reasons n (%) 6 5 Demographics N (ITT) 17 17 Females: Males 1 :16 3 :14 Mean Age, years (SD) 62.9 (10.0) 64.6 (12.1) Caucasian, n (%) 17 (100) 17 (100) Primary Efficacy Results: (ITT population) Variation of inspiratory capacity (in ml) before salbutamol inhalation, between visit 1 and visit 4 2
Median Baseline (SE) NA NA (SE) -193 (185) 95% Confidence Interval (CI) -570; 184 p-value 0.304 Secondary Outcome Variables: (ITT population) Variation (in ml) of IC before salbutamol inhalation, between -158 (158) 41 (146) (SE) -199 (215) 95% CI -639; 241 Variation (in ml) of IC before salbutamol inhalation, between 99 (123) 60 (119) (SE) 40 (171) 95% CI -570; 184 Variation (in ml) of the IC difference (post salbutamol - pre 131 (80) -32 (87) salbutamol), between visit 1 and visit 4 (SE) (SE) 163 (116) 95% CI -76; 401 Variation (in ml) of the IC difference (post salbutamol - pre 13 (134) 30 (134) salbutamol), between (SE) -17 (190) 95% CI -406; 371 Variation (in ml) of the IC difference (post salbutamol - pre -308 (109) -88 (116) salbutamol), between (SE) -220 (160) 95% CI -546. 107 Variation (in ml) of the FRC measured by plethysmography 150 (321) -160 (287) before salbutamol inhalation, between visit 1 and visit 4 (SE) (SE) 475 (430) 95% CI -406; 1357 Variation (in ml) of the FRC measured by plethysmography 315 (320) -160 (287) before salbutamol inhalation, between (SE) 475 (430) 95% CI -406; 1357 Variation (in ml) of the FRC measured by plethysmography -214 (221) 265 (209) before salbutamol inhalation, between (SE) -479 (303) 95% CI -1100; 142 Variation (in ml) of the difference post-salbutamol FRC presalbutamol -240 (257) -157 (253) FRC (FRC measured by plethysmography), between visit 1 and visit 4 (SE) (SE) -84 (370) 95% CI -841 ;673 Variation (in ml) of the difference post-salbutamol FRC presalbutamol -376 (253) -54 (240) FRC (FRC measured by plethysmography), between (SE) -321 (357) 95% CI -1052; 409 Variation (in ml) of the difference post-salbutamol FRC presalbutamol 201 (213) -417 (253) FRC (FRC measured by plethysmography), between (SE) 618 (329) 95% CI -57; 1292 Variation (in ml) of FEV1 before salbutamol inhalation, between visit 1 and visit 4 (SE) -94 (58) -30 (57) 3
(SE) -64 (81) 95% CI -230; 102 Variation (in ml) of FEV1 before salbutamol inhalation, between -107 (55) -76 (51) (SE) -30 (75) 95% CI -183; 122 Variation (in ml) of FEV1 before salbutamol inhalation between -40 (66) -124 (67) (SE) 84 (94) 95% CI -108; 275 Variation (in ml) of difference post salbutamol FEV1 - pre -29 (38) 17 (42) salbutamol FEV1, between visit 1 and visit 4 (SE) (SE) -46 (57) 95% CI -163; 70 Variation (in ml) of difference post salbutamol FEV1 - pre -14 (30) 41 (27) salbutamol FEV1, between (SE) -56 (40) 95% CI -138; 27 Variation (in ml) of difference post salbutamol FEV1 - pre 14 (28) 59 (32) salbutamol FEV1, between (SE) -45 (43) 95% CI -134; 43 Variation (in ml) of FIV1 before salbutamol inhalation, between -517 (230) 25 (185) visit 1 and visit 4 (SE) (SE) -542 (294) 95% CI -1157; 72 Variation (in ml) of FIV1 before salbutamol inhalation, between -128 (288) 119 (202) (SE) -248 (353) 95% CI -986; 490 Variation (in ml) of FIV1 before salbutamol inhalation between 338 (262) -318 (191) (SE) 657 (319) 95% CI -12; 1325 Variation (in ml) of difference post salbutamol FIV1- pre 245 (282) -102 (251) salbutamol FIV1, between visit 1 and visit 4 (SE) (SE) 347 (385) 95% CI -461; 1155 Variation (in ml) of difference post salbutamol FIV1- pre -159 (334) 167 (258) salbutamol FIV1, between (SE) -327 (420) 95% CI -1208; 555 Variation (in ml) of difference post salbutamol FIV1- pre -357 (247) 492 (232) salbutamol FIV1, between (SE) -848 (342) 95% CI -1566; -130 Variation (in ml) of TLC measured by plethysmography before 270 (454) 251 (431) salbutamol inhalation, between visit 1 and visit 4 (SE) (SE) 18 (625) 95% CI -1262; 1299 Variation (in ml) of TLC measured by plethysmography before 373 (490) -197 (444) salbutamol inhalation, between (SE) 570 (661) 95% CI -785; 1925 Variation (in ml) of TLC measured by plethysmography before salbutamol inhalation, between 353 (351) 239 (339) 4
(SE) 114 (487) 95% CI -884; 1111 Variation (in ml) of RV measured by plethysmography before -288 (403) -189 (395) salbutamol inhalation, between visit 1 and visit 4 (SE) (SE) -100 (564) 95% CI -1252; 1053 Variation (in ml) of RV measured by plethysmography before -152 (405) -531 (384) salbutamol inhalation, between (SE) 379 (558) 95% CI -761; 1519 Variation (in ml) of RV measured by plethysmography before -463 (431) 246 (433) salbutamol inhalation, between (SE) -709 (610) 95% CI -1955; 537 Dyspnoea evaluated by EEC scale at visit 1, mean (SD) 2.9 (0.9) 3.0 (0.9) Dyspnoea evaluated by EEC scale at visit 2, mean (SD) 3.0 (1.0) 2.6 (0.9) Dyspnoea evaluated by EEC scale at visit 3, mean (SD) 2.3 (1.0) 2.3 (0.8) Dyspnoea evaluated by EEC scale at visit 4, mean (SD) 2.7 (1.2) 2.6 (0.7) Dyspnoea evaluated by EEC scale at visit 5, mean (SD) 2.4 (1.0) 2.5 (1.2) Dyspnoea evaluated by EEC scale at visit 6, mean (SD) 2.7 (1.2) 2.9 (1.4) Blood gasometry : PaO2 (in mmhg) at visit 1, mean (SD) 75.5 (10.0) 72.3 (7.9) Blood gasometry : PaO2 (in mmhg) at visit 4, mean (SD) 72.5 (8.8) 72.3 (7.9) Blood gasometry : PaO2 (in mmhg) at visit 6, mean (SD) 71.7 (6.5) 76.7 (11.9) Blood gasometry : PaCO2 (in mmhg) at visit 1, mean (SD) 39.7 (4.5) 40.6 (4.2) Blood gasometry : PaCO2 (in mmhg) at visit 4, mean (SD) 39.0 (3.6) 40.1 (5.8) Blood gasometry : PaCO2 (in mmhg) at visit 6, mean (SD) 39.3 (3.4) 38.2 (6.0) Blood gasometry : ph at visit 1, mean (SD) 7.143 (0.023) 7.401 (0.020) Blood gasometry : ph at visit 4, mean (SD) 7.423 (0.033) 7.395 (0.026) Blood gasometry : ph at visit 6, mean (SD) 7.402 (0.033) 7.394 (0.052) Blood gasometry : HCO3- (in mmol/l) at visit 1, mean (SD) 24.9 (2.5) 24.5 (2.9) Blood gasometry : HCO3- (in mmol/l) at visit 4, mean (SD) 24.8 (1.9) 24.7 (2.8) Blood gasometry : HCO3- (in mmol/l) at visit 6, mean (SD) 24.1 (1.9) 23.1 (4.7) Blood gasometry : SaO2 (in %) at visit 1, mean (SD) 94.9 (1.7) 94.3 (1.5) Blood gasometry : SaO2 (in %) at visit 4, mean (SD) 94.5 (2.6) 94.0 (2.5) Blood gasometry : SaO2 (in %) at visit 6, mean (SD) 93.9 (2.0) 94.8 (2.1) Smoking status at inclusion (current smokers/former smokers), 7/10 7/10 n Smoking status during study N=15 Stopped smoking 1 1 Start again smoking 0 1 No change of smoking status 14 15 Measure of expired CO (in ppm) at visit 1, mean (SD) 7.3 (7.3) 7.2 (6.5) Measure of expired CO (in ppm) at visit 2, mean (SD) 7.9 (7.2) 5.1 (5.1) Measure of expired CO (in ppm) at visit 3, mean (SD) 7.5 (7.3) 6.4 (7.2) Measure of expired CO (in ppm) at visit 4, mean (SD) 6.2 (5.3) 5.5 (5.3) Measure of expired CO (in ppm) at visit 5, mean (SD) 7.5 (8.0) 7.8 (5.5) Measure of expired CO (in ppm) at visit 6, mean (SD) 6.5 (7.2) 5.3 (4.2) Percentage of days with no short-acting bronchodilator use 41.9 (10.2) 36.2 (10.2) from week 1 to week 24, adjusted mean (SE) (SE) 5.7 (14.5) 95% CI -24.0; 35.5 5
Short-acting bronchodilator use (in puff/day) from week 1 to 2.0 (2.2) 2.6 (2.9) week 24, mean (SD) Short-acting bronchodilator use (in puff/day) from week 25 to 2.7 (1.9) 4.0 (3.4) week 32, mean (SD) DEMNEP25-75%, measures performed before and after salbutamol inhalation, in Litres per second (L/s) 95% CI DEMNEP50%, measures performed before and after salbutamol inhalation, (L/s) 95% CI DEMNEP25%, measures performed before and after salbutamol inhalation, (L/s) 95% CI Evaluation of exercise capacity during an exercise test limited by symptoms at 50% of the maximal theoretical power (depending on centre, optional) : dyspnoea evaluated by VAS (Visual analogical scale) and inspiratory capacity at rest, during test, then end of test, and duration of the test, testing done before and after salbutamol inhalation 95% CI Spiro-tomodensitometry at visit 1 95% CI Spiro-tomodensitometry at visit 4 95% CI Number of exacerbations, including those leading to hospitalization, adjusted mean 0.58 0.75 Ratio meterol/placebo 0.75 95% CI 0.3; 1.85 Change in QoL measured by SGRQ total score from visit 1 to visit 4-7.1 (3.7) 2.7 (3.9) -9.7 (4.6) 95% CI -20.7; 1.2 Change in QoL measured by SGRQ total score from visit 4 to 5.8 (3.0) 3.3 (3.4) visit 6 2.4 (4.6) 95% CI -6.9; 11.8 Safety Results: An on-therapy adverse event/ serious adverse event (AE/SAE) was defined as an AE/SAE with onset on or after the start date of study medication but no later than the last date of study medication. Most Frequent Adverse Events (AEs) On-Therapy Subjects with any AE(s), n (%) 4 (24) 11 (65) n (%) n (%) Bronchitis 1 (6) 3 (18) Lower respiratory failure 0 2 (12) Serious Adverse Events (SAEs) - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 1 (6) 3 (18) 6
n (%) [related] n (%) [related] Lower respiratory failure 0 2 (12) [0] Cardiac failure 0 1 (6) [0] Embolisms 0 1 (6) [0] Tachyarrhythmias 0 1 (6) [0] Fractures 0 1 (6) [0] Abdominal discomfort & Pain 1 (6) [0] 0 Colitis 1 (6) [0] 0 Gastrointestinal polyps of uncertain behaviour 1 (6) [0] 0 Nausea & vomiting 1 (6) [0] 0 Subjects with fatal SAEs, n (%) 0 0 Conclusion: No statistical evidence of a reduction of thoracic distension was demonstrated in subjects with COPD treated during 6 months with salmeterol 50µg twice daily. Four subjects presented AEs and one subject an SAE when receiving salmeterol versus 11 and 3, respectively, when receiving placebo. No deaths were reported. Publications: No Publication Date Updated: 16-Nov-2005 7