Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 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.: SMS40298 Title: A multi-centre, randomized, double-blind, parallel group study to evaluate the impact on Quality of Life (QOL) of adding Serevent 50ug bid via MDI to patients existing therapy in patients with chronic obstructive pulmonary disease (COPD). Rationale: A new QOL measure specifically for COPD has been developed, consisting of the generic health status measure Short Form 36 (SF-36) and a COPD-specific module. This study explored the impact on quality of life of adding salmeterol to existing COPD therapy using the St. George s Respiratory Questionnaire, and the new COPD quality of life measure in a Phase IV study with a naturalistic design reflecting fewer protocol-driven clinic visits. Phase: IV Study Period: November 1999 September 2001 Study Design: This study was a randomized, double-blind, parallel, placebo controlled design. Centres: 27 centres in Canada Indication: COPD Treatment: At Assessment 1 (clinic visit), upon satisfying the inclusion/exclusion criteria, eligible subjects were randomized (1:1) to receive salmeterol (2 puffs twice daily (bid), 25 µg per puff) or placebo bid. Subjects were treated for 16 weeks. All inhaled short-acting β2-agonists were discontinued, and replaced with inhaled study salbutamol for use as rescue medication throughout the study. Subjects remained on all other existing medications as prescribed by their physician for concurrent disease(s), including COPD. Objectives: The primary objective of this study was to evaluate the effect of salmeterol in conjunction with regular medication on quality of life of COPD subjects. Primary Outcome/Efficacy Variable: The primary variable was the Total score of the St. George s Respiratory Questionnaire (SGRQ), and the primary endpoint was the change in the score from baseline to end of treatment. Secondary Outcome/Efficacy Variables: Spirometric measurements at clinic visit 1 and 5 consisting of Forced Expiratory Volume in 1 second (FEV1), Forced Vital Capacity (FVC), Forced Expiratory Flow (FEF25-75%), and Peak Expiratory Flow (PEF). FEV1/FVC was calculated. Inspiratory capacity (IC) was also measured. Day- and night-time symptom scores. Rescue salbutamol usage. COPD QOL scores: Symptoms, Activity, and Impacts scores from the SGRQ, the scores from the 8 scales and 2 summary measures of the SF-36, and the score of the new COPD-specific module. COPD Exacerbations Statistical Methods: Four point changes from baseline in the SGRQ score have been identified as clinically significant, and the standard deviation of the change from baseline was estimated to be 12 points. Therefore, the number of subjects required to detect a 4 point difference between the treatment groups with a power of 80% at the 5% significance level was 145 per group. If 90% of subjects met the criteria and provided data at both assessments, an enrolment of 320 subjects provided the required 290 evaluable subjects. All statistical tests were carried out at the two sided, 5% significance level. The estimate of treatment effect and the 95% confidence interval of the treatment effect were calculated. Treatment differences for QOL and spirometry measures were compared by Analysis of Covariance (ANCOVA). Symptom scores and salbutamol usage were compared using the Wilcoxon rank sum test. The Intent-to-Treat (ITT) population consisted of all randomized subjects who received at least one dose of study medication, and for whom corresponding data exists. The safety data were analyzed using the same population. 1

2 Study Population: Diagnosis and main criteria for inclusion: Males/females aged 40 to 79 years inclusive with an established clinical history of COPD in accordance with the American Thoracic Society (ATS) definition. (A disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible.) Current or previous smokers with a smoking history of 10 pack years. Previous smokers were defined as those who stopped smoking for at least 6 months prior to assessment 1. Subjects already receiving short-acting bronchodilators (may be anticholinergics and/or short-acting β2-agonists) as part of their current therapy. FEV1: 85% of predicted and FEV1/FVC: 70% Subjects with a documented poor reversibility of airway obstruction, defined as an increase of less than 10% of the normal predicted FEV1 within the last 12 months of Assessment 1. Study Population Results: Number of Subjects Randomized Number of Subjects (ITT): Completed, n (%) 140 (80) 134 (78) Total Number Subjects Withdrawn, n (%) 36 (20) 37 (22) Withdrawn due to Adverse Events n (%) 18 (10)18 (50) 17 (10) Withdrawn due to Lack of Efficacy n (%) 1 (<1) 1 (<1) Withdrawn for other reasons n (%) 17(10) 19 (11) Demographics Mean age, years (SD) 66.7 (8.6) 67.0 (8.0) Age Range Female: Male, n 68:108 75: 96 Caucasian, n (%) 173 (98) 166 (97) Primary Efficacy Results: Total of St. George s Respiratory Questionnaire (SGRQ) Clinic Visit 1, [n] mean (SD) [157] 46.8 (16.6) [150] 46.2 (18.0) Clinic Visit 5 1 [139] 44.7 (18.6) [124] 41.6 (19.0) Change in Total 1 [157] -1.3 (10.3) [150] -2.9 (11.1) Statistical Analysis of Change in Total SGRQ : vs 95% Confidence Interval p-value 2 Total SGRQ (-4.0, 0.7) Notes: 1 Questionnaire data collected at early withdrawal and unscheduled assessments are included here; 2 Analysis of covariance, controlling for baseline, age, sex and centre cluster Secondary Outcome Variables: Summary of St. George Respiratory Questionnaire (SGRQ) Symptom, Activity, Impacts s Symptom Clinic Visit 1, [n] mean (SD) [157] 56.7 (19.6) [150] 59.6 (18.4) Clinic Visit 5 1 [139] 57.3 (21.6) [124] 55.4 (19.7) Change in Symptom 1 [157] 1.4 (15.5) [150] -3.0 (15.8) Activity Clinic Visit 1, [n] mean (SD) [157] 62.7 (18.9) [150] 61.6 (21.9) Clinic Visit 5 1 [139] 59.7 (22.4) [124] 53.3 (23.8) Change in Activity 1 [157] -3.0 (15.0) [150] -5.9 (15.4) Impacts Clinic Visit 1, [n] mean (SD) [157] 34.8 (18.9) [150] 33.5 (20.7) 2

3 Clinic Visit 5 1 [139] 32.4 (20.3) [124] 30.6 (20.0) Change in Impacts 1 [157] -1.2 (11.5) [150] -1.2 (13.6) Summary of Results of Statistical Analysis of Change in SGRQ vs. Symptom (-7.1, -0.4) Activity (-6.1, 0.5) Impacts (-3.0, 2.4) Notes: 1 Questionnaire data collected at early withdrawal and unscheduled assessments are included here Spirometry Summary of FEV1 (L) Clinic Visit 1 [n] mean (SD) [176] (0.660) [171] (0.481) Clinic Visit 5 3 [167] (0.542) [164] (0.537) Change [167] (0.493) [164] (0.215) Summary of FVC (L) Clinic Visit 1 [n] mean (SD) [176] (0.760) [171] (0.795) Clinic Visit 5 3 [167] (0.783) [164] (0.845) Change [167] (0.369) [164] (0.361) Summary of FEF(25-75%) (L/sec) Clinic Visit 1 [n] mean (SD) [176] (0.352) [170] (0.331) Clinic Visit 5 3 [165] (0.442) [163] (0.492) Change [165] (0.250) [162] (0.283) Summary of FEV1/FVC Clinic Visit 1 [n] mean (SD) [176] (0.746) [170] (0.481) Clinic Visit 5 3 [167] (0.361) [163] (0.358) Change [167] (0.467) [163] (0.098) Summary of PEF (L/min) Clinic Visit 1 [n] mean (SD) [175] (100.2) [169] (99.6) Clinic Visit 5 3 [166] (112.3) [162] (102.2) Change [165] 8.8 (60.9) [160] 22.8 (49.7) Summary of Inspiration Capacity (L) Clinic Visit 1 [n] mean (SD) [41] (0.721) [46] (0.560) Clinic Visit 5 3 [39] (0.684) [44] (0.628) Change [36] (0.291) [42] (0.552) Notes: 3 Spirometry data collected at early withdrawal is included here Statistical Analysis of Change in Spirometry Data Measure vs FEV1 FVC FEF (25-75%) FEV1/FVC (-0.0, 0.1) (-0.0, 0.1) (-0.0, 0.1) (-0.0, 0.1) 3

4 PEF Inspiratory Capacity (2.2, 25.2) (-0.0, 0.3) Symptoms Summary of Daytime Symptom s Weeks 1-2, [n] mean (SD) [168] 1.2 (1.0) [160] 1.2 (1.1) Weeks [140] 1.1 (1.0) [133] 1.1 (1.1) Summary of Night-time Symptom s Weeks 1-2, [n] mean (SD) [167] 0.4 (0.7) [161] 0.4 (0.7) Weeks [142] 0.3 (0.7) [133] 0.4 (0.7) Summary of Percentage of Symptom-Free Days Weeks 1-2, [n] mean (SD) [168] 23.8 (35.8) [160] 29.0 (38.4) Weeks [140] 29.0 (42.4) [133] 30.5 (41.5) Summary of Percentage of Symptom-Free Nights Weeks 1-2, [n] mean (SD) [167] 68.5 (37.8) [161] 72.6 (36.3) Weeks [142] 74.6 (37.4) [133] 71.1 (39.9) Summary of Daytime Salbutamol Use Weeks 1-2, [n] mean (SD) [168] 1.8 (2.0) [160] 1.4 (1.8) Weeks [140] 1.9 (2.5) [132] 1.3 (1.8) Summary of Night-time Salbutamol Use Weeks 1-2, [n] mean (SD) [168] 0.4 (0.8) [161] 0.3 (0.7) Weeks [142] 0.5 (1.0) [133] 0.3 (0.7) Summary of Percentage of Salbutamol-Free Days Weeks 1-2, [n] mean (SD) [168] 33.6 (39.8) [160] 47.8 (42.6) Weeks [140] 35.1 (43.2) [132] 48.0 (43.5) Summary of Salbutamol-Free Nights Weeks 1-2, [n] mean (SD) [168] 70.4 (39.0) [161] 78.7 (34.2) Weeks [142] 69.5 (40.5) [133] 78.1 (35.0) Summary of SF-36 Questionnaire s Physical Functioning Clinic Visit 1, [n] mean (SD) [166] 46.8 (24.7) [161] 48.2 (24.8) Clinic Visit 5 1 [144] 47.1 (25.9) [131] 52.0 (27.2) Change in Physical Functioning [166] -0.7 (15.7) [161] 2.6 (15.1) Role - Physical Clinic Visit 1, [n] mean (SD) [164] 36.1 (42.1) [157] 39.4 (42.6) Clinic Visit 5 1 [144] 39.4 (43.0) [131] 41.2 (44.0) Change in Role-Physical [164] 0.2 (33.4) [157] 3.1 (43.2) Bodily Pain Clinic Visit 1, [n] mean (SD) [168] 65.6 (25.6) [158] 65.0 (25.7) Clinic Visit 5 1 [144] 71.6 (25.7) [131] 66.3 (25.1) Change in Bodily Pain [168] 2.9 (22.0) [158] 1.5 (23.3) General Health Clinic Visit 1, [n] mean (SD) [166] 48.7 (22.3) [154] 48.4 (21.8) Clinic Visit 5 1 [144] 51.2 (23.3) [131] 47.8 (22.3) Change in General Health [166] 1.5 (14.5) [154] -0.9 (16.2) Vitality Clinic Visit 1, [n] mean (SD) [166] 49.1 (19.9) [157] 50.3 (19.0) Clinic Visit 5 1 [144] 53.6 (20.8) [131] 53.3 (20.9) Change in Vitality [166] 2.9 (18.2) [157] 2.8 (18.4) Social Functioning 4

5 Clinic Visit 1, [n] mean (SD) [167] 69.9 (26.8) [158] 71.0 (25.6) Clinic Visit 5 1 [144] 72.2 (25.8) [131] 73.2 (27.3) Change in Social Functioning [167] 0.7 (23.3) [158] 2.5 (24.2) Role-Emotional Clinic Visit 1, [n] mean (SD) [162] 55.1 (42.6) [153] 58.6 (42.8) Clinic Visit 5 1 [144] 58.6 (44.6) [131] 59.8 (43.5) Change in Role-Emotional [162] 1.0 (40.9) [153] 2.6 (44.0) Mental Health Clinic Visit 1, [n] mean (SD) [166] 72.2 (18.6) [157] 71.0 (18.8) Clinic Visit 5 1 [144] 74.3 (17.2) [131] 73.5 (19.5) Change in Mental Health [166] 1.3 (13.3) [157] 2.9 (16.7) Physical Health Summary Clinic Visit 1, [n] mean (SD) [156] 36.1 (9.5) [146] 36.5 (10.0) Clinic Visit 5 1 [144] 36.8 (10.3) [131] 37.1 (10.5) Change in Physical Health Summary [156] 0.1 (6.4) [146] 0.3 (7.7) Mental Health Summary Clinic Visit 1, [n] mean (SD) [156] 48.8 (11.0) [146] 49.3 (10.8) Clinic Visit 5 1 [144] 50.3 (10.6) [131] 50.0 (10.5) Change in Mental Health Summary [156] 1.1 (9.1) [146] 1.1 (10.0) Notes: 1 Questionnaire data collected at early withdrawal and unscheduled assessments are included here Summary of Statistical Analysis of Change in SF-36 Questionnaire s Measure vs Physical Functioning Role-Physical Bodily Pain General Health Vitality Social Functioning Role-Emotional Mental Health Physical Health Summary Mental Health Summary Summary of COPD-Specific Questionnaire s (0.1, 6.7) (-3.3, 11.8) (-6.1, 2.9) (-5.9, 0.5) (-3.3, 4.0) (-2.9, 6.4) (-5.8, 10.7) (-1.9, 4.0) (-1.3, 1.9) (-1.9, 1.9) Symptoms Clinic Visit 1, [n] mean (SD) [153] 13.3 (3.1) [150] 13.5 (3.1) Clinic Visit 5 1 [144] 13.7 (3.3) [130] 14.1 (3.6) Change in Symptoms [153] 0.2 (2.6) [150] 0.6 (2.7) Social and Emotional Clinic Visit 1, [n] mean (SD) [136] 40.1 (8.5) [143] 40.0 (8.7) 5

6 Clinic Visit 5 1 [144] 41.2 (8.8) [130] 41.2 (9.5) Change in Social and Emotional [136] 0.6 (6.4) [143] 0.6 (6.8) Physical Function Clinic Visit 1, [n] mean (SD) [133] 55.4 (12.5) [117] 55.7 (12.0) Clinic Visit 5 1 [140] 56.0 (12.4) [128] 56.8 (12.8) Change in Physical Function [133] 0.4 (6.2) [117] 1.4 (5.9) Summary of Results of Statistical Analysis of Change in COPD-Specific Module Questionnaire s Measure vs Symptoms (-0.2, 0.9) Social and (-1.5, 1.4) Emotional Physical Function (-0.4, 2.6) Notes: 1 Questionnaire data collected at early withdrawal and unscheduled assessments are included here Summary of COPD Exacerbations Number of subjects with COPD exacerbations n (%) 41 (23) 39 (23) Total number of exacerbations for all subjects Severity of Exacerbation, n (%) Mild 7 (13) 15 (28) Moderate 39 (70) 32 (59) Severe 10 (18) 7 (13) Length of Exacerbation (days) [n] mean (SD) [55] 14.9 (17.1) [54] 10.3 (10.4) Percentage of exacerbation-free days [n] mean (SD) [175] 94.5 (15.1) [171] 96.8 (8.1) Safety Results: Most Frequent Adverse Events (AEs): AEs include pre- or post-treatment events that occurred as a result of protocolmandated procedures. Subjects with any AE(s), n (%) 112 (64) 110 (64) Headaches 23 (13) 29 (17) Upper Respiratory Tract Infection 17(10) 17 (10) Chronic Obstructive Airways Disease Exacerbation 16 (9) 0 Breathing Disorders 14(8) 7 (4) Musculoskeletal Pain 9 (5) 8 (5) Cough 7 (4) 15 (9) Dizziness 7 (4) 17 (10) Throat Irritation 7 (4) 0 Chest Symptoms 7 (4) 8 (5) Pneumonia 6 (3) 0 Viral Respiratory Infections 6 (3) 13 (8) Malaise and Fatigue 6 (3) O Nausea and Vomiting 0 11 (6) Bronchitis 0 7 (4) Muscle Cramps and Spasms 0 6 (4) Serious Adverse Events (SAEs) - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs: 15 (9) 9 (5) 6

7 n (%) [related] n (%) [related] Chronic Obstructive Airways Disease Exacerbation 9 (5) [2] 2 (1) [0] Pneumonia 2 (1) [0] 1 (<1) [0] Breathing Disorders 0 1 (<1) [0] Bronchitis 1 (<1) [0] 0 Lower Respiratory Infections 1 (<1) [0] 0 Angina Pectoris 2 (1) [1] 0 Artery Disorders 0 1 (<1) [0] Myocardial Ischemia 1 (<1) [0] 0 Tachyarrhythmias 1 (<1) [0] 0 Duodenal Ulcers 1 (<1) [0] 0 Gastroenteritis 1 (<1) [0] 0 Gastrointestinal Fistula 0 1 (<1) [0] Gastrointestinal Obstructions 0 1 (<1) [0] Nausea And Vomiting 0 1 (<1) [0] Diabetes Mellitus 1 (<1) [0] 0 Electrolyte Disturbances 1 (<1) [0] 0 Infections 0 1 (<1) [0] Viral Infections 1 (<1) [0] 0 Fractures 1 (<1) [0] 0 Cholangitis 0 1 (<1) [0] Cholecystitis 0 1 (<1) [0] Convulsions 0 1 (<1) [0] Urinary Retention 0 1 (<1) [0] Renal Insufficiency 1 (<1) [0] 0 n (%) [related] n (%) [related] Subjects with fatal SAEs: 1(1) 0 Lower Respiratory Failure 1 (<1) [0] 0 Conclusion: There was no statistical difference between salmeterol and placebo in the change in total SGRQ score. Adverse events were reported in 112 (64%) subjects in the placebo group, and 110 (64%) of the salmeterol group. The most frequently reported events in both groups were headache and upper respiratory tract infection. Serious adverse events were reported in 15 (9%) subjects in the placebo group, and 9 (5%) subjects in the salmeterol group; COPD exacerbation was reported in two subjects in the placebo group, and was the only serious adverse event reported by more than one subject in a group. One fatality was reported in the placebo group. Publications: No Publication Date Updated: 21-Dec