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, BA 679 BR Title of study: Effect of tiotropium on exercise tolerance and static and dynamic lung volumes in COPD patients (a randomized, double-blind, placebo controlled, parallel group study) Investigator: Study centres: Publication (reference): Clinical phase: Objectives: Methodology: Multi-centre study Data of this study has not been published IIIb To investigate whether treatment with tiotropium improves exercise tolerance in COPD patients. Randomized, Double-Blind, Placebo Controlled, Parallel Group Study No. of subjects: planned: entered: 160 (original); 260 (revised, Amendment 3, dated 11 June 2001 ) actual: Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Duration of treatment: Reference therapy: dose: mode of admin.: batch no.: : entered: 131 treated: 131 analysed (for primary endpoint): 131 Placebo: entered: 130 treated: 130 analysed (for primary endpoint): 117 Outpatients of either sex, between 40 and 75 years old (Amendment 2, dated 25 June 2002), inclusive, with a diagnosis of chronic obstructive pulmonary disease and the presence of static lung hyperinflation. 18 mcg Powder inhalation via the HandiHaler 002506 (original); 103115 (re-supply) 6 weeks (43 days) Placebo Not applicable Powder inhalation via the HandiHaler 9806002 (original); 009586 (re-supply)
, BA 679 BR Criteria for evaluation: Efficacy: Safety: Statistical methods: SUMMARY CONCLUSIONS: Efficacy results: Constant work rate exercise endurance time, exertional dyspnea during constant work rate exercise, inspiratory capacity during constant work rate exercise, spirometric parameters (FEV 1, FVC, SVC), body plethysmographic parameters (TGV(FRC), IC, TLC, RV, R aw, SG aw ), single breath inert gas dilution parameters (V A ), COPD symptom scores, Physician Global Assessment, rescue medication use Adverse events, physical examination, ECGs, vital signs ANCOVA with baseline as covariate The primary endpoint for the trial was the endurance time (ET) during a constant work rate cycle ergometry test performed 2 hours and 15 minutes after trial medication administration on Day 42 of treatment. The results of the pre-specified primary parametric treatment comparison for ET (sec, imputed), based on an ANCOVA model with terms treatment and centre and using baseline as a covariate, are presented below: Placebo Difference N AdjMean (SE) N AdjMean (SE) AdjMean (SE) P-value (95% CI) d-5 534.9# 534.9# d0 2h15m post 131 668.3 (24.0) 117 597.5 (25.4) 70.7 (35.1) 0.045 (1.5, 139.9) d21 2h15m post 131 791.4 (35.0) 117 563.4 (37.1) 228.0 (51.2) 0.0000 (127.1, 328.9) d42 2h15m post 131 803.2 (39.5) 117 567.6 (41.8) 235.6 (57.7) 0.0001 (122.0, 349.3) d42 8h post 131 664.9 (39.7) 117 493.7 (42.0) 171.1 (57.9) 0.0035 (57.0, 285.3) #: common mean across groups at day -5 (baseline) Source Data: Appendix 16.1.9.2 StatDoc 6.1.2; Program=tETmain; 03APR03 Skewness was observed throughout the trial for ET and was generally more apparent in the tiotropium group. In addition, two outliers were evident in the tiotropium group for ET at Day 42, 2 hours 15 minutes post-dose (ET >3,000 seconds). These observations suggested that a non-parametric analysis of ET would be a more appropriate analysis. The results of a
, BA 679 BR non-parametric analysis of change in ET from baseline (Wilcoxon Rank Sum test stratified by Investigator) is presented below: Treatment N Mean SD Med P-value d0 2h15m post 131 127.6 312.2 50.0 0.0138 Placebo 117 69.0 261.7 16.0 d21 2h15m post 131 250.3 488.1 113.0 0.0000 Placebo 117 35.3 326.7 8.0 d42 2h15m post 131 260.0 592.0 110.0 0.0003 Placebo 117 41.9 289.3 10.0 d42 8h post 131 122.9 572.5 12.0 0.0343 Placebo 117-33.4 278.0-26.0 Source Data: Appendix 16.1.9.2 StatDoc 6.1.2; Program=tETwilc; 03APR03 The non-parametric analysis identified a statistically significant improvement in ET for tiotropium compared with placebo. These results were consistent with the results of the primary parametric analysis, i.e., significant increases in ET at all timepoints during the treatment period in the tiotropium group compared with the placebo group. In order to examine the influence of the outliers on the treatment difference, the primary parametric analysis (based on an ANCOVA model with terms treatment and centre and using baseline as a covariate) was repeated following removal of the two outliers with ET >3000 secs at Day 42, 2 hrs 15 mins post-dose: Placebo Difference N AdjMean (SE) N AdjMean (SE) AdjMean (SE) P-value (95% CI) d-5 536.5# 536.5# d42 2h15m post 129 740.8 (29.7) 117 577.2 (31.2) 163.6 (43.3) 0.0002 (78.2, 248.9) #: common mean across groups at day -5 (baseline) Source Data: Appendix 16.1.9.2 StatDoc 6.1.3; Program=tETmain; 03APR03 A quantitative interaction between treatment and baseline was observed with respect to absolute changes in ET, with subjects with a higher baseline ET
, BA 679 BR having a greater increase in ET following treatment with tiotropium. Treatment with tiotropium resulted in a reduction in the intensity of dyspnea (as rated by the subject using the Borg scale) at rest (immediately prior to exercise), a reduced rate of increase in dyspnea during exercise and a reduction in the intensity of dyspnea at peak exercise compared with placebo during the constant work rate exercise tests. The treatment comparisons (based on an ANCOVA model with terms treatment and centre and using baseline as a covariate) for the summary measures of dyspnea during the constant work rate exercise tests are presented below: Placebo Difference N AdjMean (SE) N AdjMean (SE) AdjMean (SE) P-value (95% CI) Rest d-5 base 0.49# 0.49# d0 2h15m 131 0.42 (0.04) 117 0.53 (0.05) -0.11 (0.06) 0.0767 (-0.24, 0.01) d21 2h15m 131 0.28 (0.05) 117 0.49 (0.05) -0.21 (0.07) 0.0034 (-0.34,-0.07) d42 2h15m 131 0.35 (0.05) 117 0.57 (0.06) -0.22 (0.08) 0.0048 (-0.37,-0.07) d42 8h 131 0.45 (0.06) 117 0.67 (0.06) -0.22 (0.08) 0.0069 (-0.39,-0.06) Peak d-5 base 7.02# 7.02# d0 2h15m 131 6.54 (0.13) 117 7.02 (0.13) -0.48 (0.18) 0.0096 (-0.84,-0.12) d21 2h15m 131 6.39 (0.14) 117 7.03 (0.14) -0.64 (0.20) 0.0016 (-1.04,-0.24) d42 2h15m 131 6.28 (0.15) 117 6.97 (0.16) -0.69 (0.22) 0.0019 (-1.12,-0.26) d42 8h 131 6.62 (0.14) 117 7.03 (0.15) -0.41 (0.21) 0.0521 (-0.82, 0.00) Slope d-5 base 0.97# 0.97# d0 2h15m 131 0.76 (0.03) 117 0.93 (0.03) -0.17 (0.05) 0.0005 (-0.27,-0.08) d21 2h15m 131 0.77 (0.05) 117 1.00 (0.05) -0.23 (0.07) 0.0010 (-0.36,-0.09) d42 2h15m 131 0.82 (0.05) 117 0.97 (0.06) -0.15 (0.08) 0.0552 (-0.30, 0.00) d42 8h 131 1.00 (0.06) 117 1.16 (0.06) -0.15 (0.09) 0.0825 (-0.33, 0.02) #: common mean across groups at Day -5 (baseline) Source Data: Appendix 16.1.9.2 StatDoc 6.2.1; Program=tDHmain; 04APR03 Treatment with tiotropium resulted in a reduction in lung hyperinflation at rest and during exercise compared with placebo, as indicated by decreases in TGV(FRC) measured by body plethysmography, and increases in IC at rest (immediately prior to exercise), and throughout exercise up to the point of symptom limitation. The treatment comparisons for TGV(FRC) (based on an ANCOVA model with main effect terms treatment and centre and using baseline as a covariate) are presented below:
, BA 679 BR Placebo Difference N AdjMean (SE) N AdjMean(SE) AdjMean(SE) P-value (95% CI) d0 pre-dose 5.55# 5.55# d0 2h post 131 5.07 (0.03) 117 5.42 (0.04) -0.35 (0.05) 0.0000 (-0.45,-0.25) d42 40m pre 131 5.24 (0.04) 117 5.41 (0.04) -0.17 (0.06) 0.0035 (-0.29,-0.06) d42 2h post 131 4.95 (0.05) 117 5.35 (0.05) -0.41 (0.07) 0.0000 (-0.55,-0.27) #: common mean across groups at Day 0 (baseline) Source Data: Appendix 16.1.9.2 StatDoc 6.2.3; Program=tPLETmain; The treatment comparisons (based on an ANCOVA model with terms treatment and centre and using baseline as a covariate) for the summary measures of IC during the constant work rate exercise tests, are presented below: Placebo Difference N AdjMean (SE) N AdjMean (SE) AdjMean (SE) P-value (95% CI) Rest d-5 2202# 2202# d0 2h15m 131 2389 (25) 117 2200 (27) 189 (37) 0.0000 (116,262) d21 2h15m 131 2442 (26) 117 2189 (27) 253 (38) 0.0000 (178,327) d42 2h15m 131 2405 (29) 117 2186 (30) 219 (42) 0.0000 (137,302) d42 8h 131 2314 (26) 117 2160 (28) 154 (39) 0.0001 (78,230) Peak d-5 1803# 1803# d0 2h15m 131 1915 (24) 117 1766 (25) 149 (35) 0.0000 (80,218) d21 2h15m 131 1950 (26) 117 1794 (28) 155 (38) 0.0001 (80,230) d42 2h15m 131 1922 (28) 117 1780 (30) 142 (41) 0.0007 (61,223) d42 8h 131 1857 (24) 117 1733 (26) 124 (35) 0.0006 (54,194) ISOV1 d-5 1831# 1831# d0 2h15m 130 1985 (21) 117 1806 (23) 179 (31) 0.0000 (117,241) d21 2h15m 130 2020 (24) 117 1803 (25) 216 (35) 0.0000 (147,285) d42 2h15m 130 2008 (26) 117 1786 (28) 222 (38) 0.0000 (147,298) d42 8h 130 1883 (25) 117 1739 (26) 144 (36) 0.0001 (73,215) ISOV1 (value at isotime) obtained at the minimum ET among baseline and all post-baseline tests #: common mean across groups at Day -5 (baseline) Source Data: Appendix 16.1.9.2 StatDoc 6.2.2; Program=tDHmain;
, BA 679 BR Treatment with tiotropium also resulted in the following: - significant decreases in TLC, RV, and Raw and significant increases in FEV 1, FVC, SVC, SGaw and V A compared with placebo; - significant decreases in shortness of breath, tightness of chest, and wheezing, significant improvements in physician global evaluation, and significant decreases in mean weekly salbutamol use compared with placebo. Safety results: A total of 261 patients were randomized and received at least one dose of trial medication. One hundred thirty one (131) subjects received tiotropium (18μg/day) and 130 subjects received placebo. One subject (0.8%) in the tiotropium group and 19 subjects (14.6%) in the placebo group withdrew from the trial prior to completion. The most common adverse events ( 3% of subjects receiving tiotropium) that were proportionately higher in the tiotropium group compared with the placebo group were: dry mouth (tiotropium 6.1% vs. placebo 3.8%), headache (tiotropium 6.1% vs. placebo 3.8%), cough (tiotropium 3.8% vs. placebo 1.5%) and upper respiratory tract infections (tiotropium 3.8% vs. placebo 1.5%). No deaths occurred during the treatment period. One patient who received placebo died during the post-study period, approximately 4.5 months after conclusion of participation in the trial. Two (1.5%) patients in the tiotropium group experienced a Serious Adverse Event during the treatment period (hospitalization for neck pain; hospitalization for uterine fibroids). Two (1.5%) patients in the placebo group experienced a Serious Adverse Event during the treatment period (hospitalization for shoulder pain; hospitalization for aggravation of osteoarthritis).
, BA 679 BR Conclusions: The present trial provides information regarding the characterisation of the clinical efficacy of tiotropium at the impairment-disability interface in patients with COPD. The study has shown that previously observed improvements in measures of resting pulmonary function such as FEV 1 and FVC following once daily treatment with tiotropium are translated into significant reductions in lung hyperinflation at rest and during exercise, with concomitant reductions in exertional dyspnea and increases in symptom-limited endurance time during constant work rate cycle ergometry at 75% of maximal work capacity (Wcap), which persist for at least 8 hours post-dosing. The safety assessment from this trial was generally consistent with the overall safety database from previous tiotropium clinical trials. The trial did not identify any previously unsuspected important adverse reaction to tiotropium.