UPLIFT Understanding Potential Long-term Impacts on Function with Tiotropium Adapted from Tashkin et al. NEJM 2008: 359: Please be advised that some of the information included may go beyond the existing product labelling as this information represents currently available medical information.

UPLIFT Objective: To assess whether Tiotropium 18  g once daily is associated with a decrease in the rate of decline of FEV 1 over time in patients with COPD. Design: randomized, double-blind, placebo-controlled* Duration: 4 years # Randomized Patients: 5,993 Outcomes: Rate of decline in pre- & post-bronchodilator FEV 1 & FVC SGRQ, exacerbations, mortality *Patients were allowed to continue all previously prescribed respiratory meds except anticholinergics Adapted from Tashkin et al. NEJM 2008: 359:

Major Inclusion/exclusion Criteria Inclusion criteria Exclusion criteria Outpatients with clinical diagnosis of COPD* Post-bronchodilator † FEV 1 ≤70% predicted ‡ Post-bronchodilator † FEV 1 /FVC ratio ≤70% Male or female, ≥40 years old Smoking history ≥10 pack-years Asthma, cystic fibrosis, bronchiectasis, interstitial lung disease, pulmonary thromboembolic disease, or significant disease other than COPD Use of oxygen therapy for >12 hours/day Respiratory infection or exacerbation of COPD within 4 weeks of screening or during the run-in period Recent history of myocardial infarction, arrhythmia, heart failure History of thoracotomy with pulmonary resection * ATS criteria † Post-bd = spirometry measured 90 minutes after initial 4 inhalations of ipratropium followed after 60 minutes with 4 inhalations of albuterol ‡ ECSC criteria Adapted from Tashkin et al. NEJM 2008: 359:

Clinic Visit Spirometry Pre dose Spirometry Ipratropium Salbutamol Day 30 and every 6 months during 4 year study Post dose Spirometry 1 hour30 min Study drug followed by Maximizing bronchodilation Time Pre dose Spirometry Ipratropium (total 80 µg) Salbutamol (total 400 µg) Day 1, Randomization Post dose Spirometry 1 hour30 min Time

Co-Primary End Points Yearly rate of decline in trough (pre-bronchodilator) FEV 1 from steady state until end of the treatment period. Yearly rate of decline in FEV 1 measured 90 minutes after inhalation of study drug and ipratropium (30 minutes after inhalation of salbutamol) from steady state until end of the treatment period. Adapted from Tashkin et al. NEJM 2008: 359:

Secondary End Points Key Secondary Endpoints Time to 1st exacerbation Time to 1st hospitalization Other Secondary endpoints FEV 1, FVC, SVC At each visit and rate of decline COPD exacerbations & related hospitalizations HRQoL (St. George’s Respiratory Questionnaire) Mortality (all cause, lower respiratory) On-treatment On-treatment + vital status follow-up Adapted from Tashkin et al. NEJM 2008: 359:

Treatments Patients randomized to receive: Tiotropium (18 mcg) or placebo once daily via HandiHaler ® inhalation device. Permitted: ALL respiratory medications except inhaled anticholinergics throughout the trial. Patients received open-label ipratropium for use during the 30 day follow-up period. Adapted from Tashkin et al. NEJM 2008: 359:

Demographics Adapted from Tashkin et al. NEJM 2008: 359:

Baseline Characteristics Characteristic Tiotropium (n = 2986) Control (n = 3006) Male (%) Age (yrs)*64.5 ± ± 8.5 Body Mass Index*26.0 ± ± 5.1 Smoking status Current smoker (%) Smoking history (pack- yrs)* 49.0 ± ± 27.9 Duration of COPD (yrs)*9.9 ± ± 7.4 GOLD stage (II / III / IV) (%)46 / 44 / 845 / 44 / 9 SGRQ total score (units)*45.7 ± ± 17.2 *Mean±SD Adapted from Tashkin et al. NEJM 2008: 359:

GOLD Stage 50% < FEV1 < 80% 30% < FEV1 < 50%FEV1 < 30% Adapted from Tashkin et al. NEJM 2008: 359:

Baseline Spirometry Pre-BronchodilatorPost-Bronchodilator Tiotropium (n = 2986) Control (n = 3006) Tiotropium (n = 2986) Control (n = 3006) FEV 1 (L)1.10 ± ± ± ± 0.44 FEV 1 (% predicted)40 ± 1239 ± 1248 ± 1347 ± 13 FVC (L)2.63 ± ± ± ± 0.90 FEV 1 /FVC42 ± ± 1143 ± 11 Mean ± SD Adapted from Tashkin et al. NEJM 2008: 359:

Baseline Respiratory Medications Medication (% of patients) Tiotropium (n = 2986) Control (n = 3006) Baseline Any respiratory medication Short-acting anticholinergic* Short-acting beta-agonist* Long-acting beta-agonist*60.1 Inhaled steroid* Theophylline Systemic steroids Mucolytics Leukotriene receptor antagonists Supplemental O *Used alone or in combination Adapted from Tashkin et al. NEJM 2008: 359:

Probability of Study Discontinuation (complete if ≥45 months study medication) Tiotropium _______ Control ¨¨¨¨¨¨¨¨¨¨¨¨¨ Probability of discontinuation [%] Tiotropium: Control: Hazard ratio = 0.89 (95% CI, ) P<0.001 Adapted from Tashkin et al. NEJM 2008: 359:

Pulmonary Function Adapted from Tashkin et al. NEJM 2008: 359:

Pre-bronchodilator FEV 1 Mean values at each time point Day 30 (steady state) Month * * * * * * * * * (n=2494) (n=2363) *P< vs. control. Adapted from Tashkin et al. NEJM 2008: 359:

Pre- and Post-bronchodilator FEV 1 Mean values at each time point * Day 30 (steady state ) * * * * * * * * Month * * * * * * * * * (n=2516) (n=2374) (n=2494) (n=2363) *P< vs. control. Pre-BD FEV1  = 87 – 103 mL Post-BD FEV1  = 47 – 65 mL Adapted from Tashkin et al. NEJM 2008: 359:

Rate of Decline in FEV 1 *Unadjusted P-value Mean slope from day 30 until completion of double-blind treatment treated set with ≥3 post-randomization measurements Tiotropium (mL/yr) Control (mL/yr) ∆ Tio - Con95% CIP-value* nMean (SE)n Pre-bronch (1) (1)0 (2)-4, Post-bronch (1) (1)-2 (2)-6, Adapted from Tashkin et al. NEJM 2008: 359:

* P<0.001 vs. control † P<0.05 vs. control ** * * * ** * * Day 30 (steady state) Month * * * * * * † † * n=2516 n=2374 n=2494 n=2363 Pre- and Post-bronchodilator FVC Mean values at each time point Pre-BD FVC  = 170 to 204 mL Post-BD FVC  = 32 to 65 mL Adapted from Tashkin et al. NEJM 2008: 359:

Health-Related Quality of Life St. George’s Respiratory Questionnaire Adapted from Tashkin et al. NEJM 2008: 359:

SGRQ Total Score Mean values at each time point *P<0.001 vs. control. Adapted from Tashkin et al. NEJM 2008: 359: Month * * * * ** * * Improvement

Percentage of Patients With  4-Unit Improvement in SGRQ Total Score* All P-values <0.001; *compared to Day 1 Adapted from Tashkin et al. NEJM 2008: 359:

Exacerbations Adapted from Tashkin et al. NEJM 2008: 359:

Probability of COPD Exacerbation Hazard ratio = 0.86, (95% CI, ) P<0.001 (log-rank test) Month n = 3,006 n = 2,986 Adapted from Tashkin et al. NEJM 2008: 359:

Exacerbations Tiotropium n = 2986 Mean (SE) Control n = 3006 Mean (SE) Rate Ratio 95% CIP-value # exacerbations per patient-year (0.02)0.85 (0.02) , 0.91<0.001 # exacerbation days per patient-year (0.32)13.6 (0.35) , 0.95< Rate ratio from Poisson regression corrected for treatment exposure and overdispersion Randomized patients with ≥1 dose of study medication were included in the analysis. Adapted from Tashkin et al. NEJM 2008: 359:

Hospitalizations Tiotropium n = 2986 Mean (SE) Control n = 3006 Mean (SE) Rate Ratio 95% CIP-value # exacerbation hospitalizations per patient-year (0.01)0.16 (0.01) , # exacerbation hospitalization days per patient- year (0.17)3.13 (0.17) , Rate ratio from Poisson regression corrected for treatment exposure and over-dispersion Adapted from Tashkin et al. NEJM 2008: 359:

Fatal Events Adapted from Tashkin et al. NEJM 2008: 359:

Fatal Events: Definitions Vital status 4 years + 30 days follow-up (day 1470) 4 years follow-up (day 1440) Cause of death investigator assessed mortality adjudication committee Adapted from Tashkin et al. NEJM 2008: 359:

Tiotropium Control Hazard ratio = % CI: ( ) P<0.05 (log-rank test) Probability of death from any cause [%] Months Probability of Death from Any Cause On-Treatment + Vital Status – Day 1440 Adapted from Tashkin et al. NEJM 2008: 359:

Tiotropium Control Hazard ratio = % CI: ( ) P=0.086 (log-rank test) Probability of death from any cause [%] Months Probability of Death from Any Cause On-Treatment + Vital Status – Day 1470 Adapted from Tashkin et al. NEJM 2008: 359:

Cardiovascular Events PlaceboTiotropiumRate Ratio 1 (95 % CI) NRate 2 N UPLIFT Composite endpoint (0.65, 0.94) Fatal composite (0.56, 0.95) 1 rate ratio tio vs. placebo; 2 per 100 person-years of time at risk to tiotropium or placebo *System Organ Class SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death. For Fatal Composite: non-fatal MI and non-fatal stroke excluded Composite Endpoint* Used by Singh et al Applied to UPLIFT

Adverse Events Adapted from Tashkin et al. NEJM 2008: 359:

Adverse Event Summary TiotropiumControl n =2986n = 3006 n (%) Any adverse event2764 (93)2774 (92) Adverse events leading to discontinuation 618 (21)735 (25) Serious adverse events1540 (52)1509 (50) Fatal adverse events381 (13)411 (14) Adverse events reported while receiving treatment Adapted from Tashkin et al. NEJM 2008: 359: \

Most Common Adverse Events (>3%) Incidence Rate per 100 pt yrs: tiotropium>control Tiotropium n=2986 Control n=3006 Rate Ratio (Tio/Con) 95 % CI Abdominal pain , 1.43 Arthralgia , 1.62 Benign Prostatic Hyperplasia , 1.54 Constipation , 1.61 Cough , 1.24 Depression , 1.62 Diarrhoea , 1.33 Dizziness , 1.58 Headache , 1.47 Insomnia , 1.75 Mouth dry , 2.36 Nasopharyngitis , 1.24 Oedema , 1.31 Sinusitis , 1.39 Urinary tract infections , 1.28 Appendix 8 NEJM on line Adapted from Tashkin et al. NEJM 2008: 359:

Relative Risk (RR) Most Common Adverse Events (>3%) Most common adverse events were due to lower respiratory causes (tiotropium group & controls); COPD exacerbations (64.8% and 66.1%; RR, 0.84; 95% CI, 0.79 to 0.89), Dyspnea (12.2% and 14.7%; RR, 0.75; 95% CI, 0.65 to 0.86). Pneumonia (14.5% and 13.9%; RR, 0.96; 95% CI, 0.84 to 1.10) Respiratory failure developed in 88 patients in the tiotropium group and in 120 in the control group (RR, 0.67; 95% CI, 0.51 to 0.89). Adapted from Tashkin et al. NEJM 2008: 359:

Relative Risk (RR) Most Common Adverse Events (>3%) Myocardial infarction developed in 67 patients in the tiotropium group and 85 in the control group (relative risk, 0.73; 95% CI, 0.53 to 1.00) Stroke developed in 82 in the tiotropium group and 80 in the control group (relative risk, 0.95; 95% CI, 0.70 to 1.29). Adverse events consistent with the known safety profile of tiotropium, such as dry mouth and constipation, were observed. Adapted from Tashkin et al. NEJM 2008: 359:

Serious Adverse Events Adapted from Tashkin et al. NEJM 2008: 359:

SAE Incidence (per 100 pt-yrs) Reported By >1% in Any Treatment Group** Tiotropium n=2986 Control n=3006 Rate Ratio (Tio/Con) 95% CI Cardiac SOC , 0.98 * Angina , 2.26 Atrial fibrillation , 1.33 Cardiac failure , 1.87 Cardiac failure congestive , 0.96 * Coronary artery disease , 1.01 Myocardial infarction , 0.99 * Respiratory (lower) SOC , 0.92 * Bronchitis , 1.98 COPD exacerbation , 0.94 * Dyspnea , 0.94 * Pneumonia , 1.11 Respiratory failure , 0.92 * *P<0.05; **excluding lung cancer (multiple different terms) Adapted from Tashkin et al. NEJM 2008: 359:

UPLIFT Conclusions Adapted from Tashkin et al. NEJM 2008: 359:

Summary - Efficacy Primary End Point No effect on rate of decline of pre/post-bronchodilator FEV 1. Secondary End Points Improvement in FEV 1, FVC and SVC maintained throughout study; Improvement in SGRQ maintained throughout study; Tiotropium group similar to baseline after 4 years treatment. Reduction in risk for exacerbation and hospitalization for exacerbations; Reduction in number of exacerbations, not significant for number of hospitalizations for exacerbations. Adapted from Tashkin et al. NEJM 2008: 359:

Summary - Safety Reduced mortality Evidence for reduced cardiac morbidity No increased risk for stroke or myocardial infarction Reduced lower respiratory morbidity Decreased risk for respiratory failure Adapted from Tashkin et al. NEJM 2008: 359:

Overall Conclusions Although UPLIFT did not demonstrate changes in the rate of decline in lung function over 4 years with tiotropium in the setting of concomitant respiratory medications, it did reveal other benefits of tiotropium: maintenance of improved lung function and HRQoL over 4 years reduced risk of exacerbations & exacerbation-related hospitalizations reduced respiratory morbidity and cardiac morbidity and improved overall survival Adapted from Tashkin et al. NEJM 2008: 359: