UPLIFT

1
UPLIFT Understanding Potential Long-term
Impacts on Function with Tiotropium
Please be advised that some of the information
included may go beyond the existing product
labelling as this information represents
currently available medical information.
Adapted from Tashkin et al. NEJM 2008
3591543-54.
2
UPLIFT

• Objective To assess whether Tiotropium 18 ?g
  once daily is associated with a decrease in the
  rate of decline of FEV1 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
  FEV1 FVC
• SGRQ, exacerbations, mortality

Patients were allowed to continue all
previously prescribed respiratory meds except
anticholinergics
Adapted from Tashkin et al. NEJM 2008
3591543-54.
3
Major Inclusion/exclusion Criteria
Inclusion criteria Exclusion criteria
Outpatients with clinical diagnosis of COPD Post-bronchodilator FEV1 70 predicted Post-bronchodilator FEV1/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 gt12 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
3591543-54.
4
Clinic Visit Spirometry
Maximizing bronchodilation
Study drug followed by
Post dose Spirometry
Pre dose Spirometry
Salbutamol
Ipratropium
1 hour
30 min
Time
Day 30 and every 6 months during 4 year study
5
Co-Primary End Points

• Yearly rate of decline in trough
  (pre-bronchodilator) FEV1 from steady state until
  end of the treatment period.
• Yearly rate of decline in FEV1 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
3591543-54.
6
Secondary End Points

• Key Secondary Endpoints
• Time to 1st exacerbation
• Time to 1st hospitalization
• Other Secondary endpoints
• FEV1, FVC, SVC
• At each visit and rate of decline
• COPD exacerbations related hospitalizations
• HRQoL (St. Georges Respiratory Questionnaire)
• Mortality (all cause, lower respiratory)
• On-treatment
• On-treatment vital status follow-up

Adapted from Tashkin et al. NEJM 2008
3591543-54.
7
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
3591543-54.
8
Demographics
Adapted from Tashkin et al. NEJM 2008
3591543-54.
9
Baseline Characteristics
Characteristic Tiotropium (n 2986) Control (n 3006)
Male () 75.4 73.9
Age (yrs) 64.5 8.4 64.5 8.5
Body Mass Index 26.0 5.1 25.9 5.1
Smoking status
Current smoker () 29.3 29.9
Smoking history (pack-yrs) 49.0 28.0 48.4 27.9
Duration of COPD (yrs) 9.9 7.6 9.7 7.4
GOLD stage (II / III / IV) () 46 / 44 / 8 45 / 44 / 9
SGRQ total score (units) 45.7 17.0 46.0 17.2
MeanSD
Adapted from Tashkin et al. NEJM 2008
3591543-54.
10
GOLD Stage
50 lt FEV1 lt 80
30 lt FEV1 lt 50
FEV1 lt 30
Adapted from Tashkin et al. NEJM 2008
3591543-54.
11
Baseline Spirometry
Pre-Bronchodilator Pre-Bronchodilator Post-Bronchodilator Post-Bronchodilator
Tiotropium (n 2986) Control (n 3006) Tiotropium (n 2986) Control (n 3006)
FEV1 (L) 1.10 0.40 1.09 0.40 1.33 0.44 1.32 0.44
FEV1 ( predicted) 40 12 39 12 48 13 47 13
FVC (L) 2.63 0.81 2.63 0.83 3.09 0.86 3.09 0.90
FEV1/FVC 42 11 42 11 44 11 43 11
Mean SD
Adapted from Tashkin et al. NEJM 2008
3591543-54.
12
Baseline Respiratory Medications
Medication ( of patients) Tiotropium(n 2986) Tiotropium(n 2986) Control (n 3006) Control (n 3006)
Medication ( of patients) Baseline Baseline
Any respiratory medication 93.4 93.1
Short-acting anticholinergic 44.9 44.1
Short-acting beta-agonist 68.5 68.1
Long-acting beta-agonist 60.1 60.1
Inhaled steroid 61.6 61.9
Theophylline 28.4 28.5
Systemic steroids 8.4 8.3
Mucolytics 7.4 6.9
Leukotriene receptor antagonists 3.3 3.1
Supplemental O2 2.3 1.9
Used alone or in combination
Adapted from Tashkin et al. NEJM 2008
3591543-54.
13
Probability of Study Discontinuation(complete if
45 months study medication)
Tiotropium _______ Control

Probability of discontinuation
Hazard ratio 0.89 (95 CI, 0.85-0.94) Plt0.001
Tiotropium 3006 2618 2418 2249 2090 1947 1831 1723 0
Control 2986 2726 2565 2432 2293 2177 2060 1970 0
Hazard ratio 0.89 (95 CI, 0.85-0.94) Plt0.001
Adapted from Tashkin et al. NEJM 2008
3591543-54.
14
Pulmonary Function
Adapted from Tashkin et al. NEJM 2008
3591543-54.
15
Pre-bronchodilator FEV1Mean values at each time
point









(n2494)
(n2363)
0
6
42
48
0
1
12
18
24
30
36
Day 30 (steady state)
Month
Plt0.0001 vs. control.
Adapted from Tashkin et al. NEJM 2008
3591543-54.
16
Pre- and Post-bronchodilator FEV1Mean values at
each time point









(n2516)



Post-BD FEV1 ? 47 65 mL

(n2374)





(n2494)
Pre-BD FEV1 ? 87 103 mL
(n2363)
0
6
12
18
24
30
42
48
0
1
36
Month
Day 30 (steady state)
Plt0.0001 vs. control.
Adapted from Tashkin et al. NEJM 2008
3591543-54.
17
Rate of Decline in FEV1
Mean slope from day 30 until completion of
double-blind treatment treated set with 3
post-randomization measurements
Tiotropium (mL/yr) Tiotropium (mL/yr) Control (mL/yr) Control (mL/yr) ? Tio - Con 95 CI P-value
n Mean (SE) n Mean (SE) Mean (SE)
Pre-bronch 2557 30 (1) 2413 30 (1) 0 (2) -4, 4 0.95
Post-bronch 2554 40 (1) 2410 42 (1) -2 (2) -6, 2 0.20
Unadjusted P-value
Adapted from Tashkin et al. NEJM 2008
3591543-54.
18
Pre- and Post-bronchodilator FVCMean values at
each time point
Plt0.001 vs. control Plt0.05 vs. control
Post-BD FVC ? 32 to 65 mL
Pre-BD FVC ? 170 to 204 mL
Adapted from Tashkin et al. NEJM 2008
3591543-54.
19
Health-Related Quality of Life St. Georges
Respiratory Questionnaire
Adapted from Tashkin et al. NEJM 2008
3591543-54.
20
SGRQ Total ScoreMean values at each time point
Improvement








0
6
12
18
24
30
42
48
0
36
Month
Plt0.001 vs. control.
Adapted from Tashkin et al. NEJM 2008
3591543-54.
21
Percentage of Patients With ?4-Unit Improvement
in SGRQ Total Score
All P-values lt0.001 compared to Day 1
Adapted from Tashkin et al. NEJM 2008
3591543-54.
22
Exacerbations
Adapted from Tashkin et al. NEJM 2008
3591543-54.
23
Probability of COPD Exacerbation
n 3,006
n 2,986
Hazard ratio 0.86, (95 CI, 0.81-
0.91) Plt0.001 (log-rank test)
Month
Adapted from Tashkin et al. NEJM 2008
3591543-54.
24
Exacerbations
Tiotropium n 2986 Mean (SE) Control n 3006 Mean (SE) Rate Ratio 95 CI P-value
exacerbations per patient-year1 0.73 (0.02) 0.85 (0.02) 0.86 0.81, 0.91 lt0.001
exacerbation days per patient-year1 12.1 (0.32) 13.6 (0.35) 0.89 0.83, 0.95 lt0.001
1 Rate ratio from Poisson regression corrected
for treatment exposure and overdispersion Randomiz
ed patients with 1 dose of study medication were
included in the analysis.
Adapted from Tashkin et al. NEJM 2008
3591543-54.
25
Hospitalizations
Tiotropium n 2986 Mean (SE) Control n 3006 Mean (SE) Rate Ratio 95 CI P-value
exacerbation hospitalizations per patient-year1 0.15 (0.01) 0.16 (0.01) 0.94 0.82, 1.07 0.34
exacerbation hospitalization days per patient- year1 3.17 (0.17) 3.13 (0.17) 1.01 0.87, 1.18 0.86
1 Rate ratio from Poisson regression corrected
for treatment exposure and over-dispersion
Adapted from Tashkin et al. NEJM 2008
3591543-54.
26
Fatal Events
Adapted from Tashkin et al. NEJM 2008
3591543-54.
27
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
3591543-54.
28
Probability of Death from Any CauseOn-Treatment
Vital Status Day 1440
20
15
Probability of death from any cause
10
Hazard ratio 0.87 95 CI (0.76- 0.99) Plt0.05
(log-rank test)
5
Tiotropium
Control
0
0
12
24
30
36
48
18
6
42
Months
Adapted from Tashkin et al. NEJM 2008
3591543-54.
29
Probability of Death from Any CauseOn-Treatment
Vital Status Day 1470
20
15
Probability of death from any cause
10
Hazard ratio 0.89 95 CI (0.79-1.02) P0.086
(log-rank test)
5
Tiotropium
Control
0
0
12
24
30
36
48
18
6
42
Months
Adapted from Tashkin et al. NEJM 2008
3591543-54.
30
Cardiovascular Events
Composite Endpoint Used by Singh et al Applied
to UPLIFT
Placebo Placebo Tiotropium Tiotropium Rate Ratio1 (95 CI)
N Rate2 N Rate2
UPLIFT
Composite endpoint 246 2.89 208 2.25 0.78 (0.65, 0.94)
Fatal composite 124 1.42 98 1.04 0.73 (0.56, 0.95)
1 rate ratio tio vs. placebo 2per 100
person-years of time at risk to tiotropium or
placebo
System Organ Class SOC cardiac (fatal), SOC
vascular (fatal), MI (fatalnonfatal), stroke
(fatalnonfatal), sudden death, sudden cardiac
death. For Fatal Composite non-fatal MI and
non-fatal stroke excluded
31
Adverse Events
Adapted from Tashkin et al. NEJM 2008
3591543-54.
32
Adverse Event Summary
  Tiotropium Control
  n 2986 n 3006
n () n ()
Any adverse event 2764 (93) 2774 (92)
Adverse events leading to discontinuation 618 (21) 735 (25)
Serious adverse events 1540 (52) 1509 (50)
Fatal adverse events 381 (13) 411 (14)
Adverse events reported while receiving treatment
Adapted from Tashkin et al. NEJM 2008
3591543-54.\
33
Most Common Adverse Events (gt3) Incidence Rate
per 100 pt yrs tiotropiumgtcontrol
Tiotropium n2986 Control n3006 Rate Ratio (Tio/Con) 95 CI
Abdominal pain 1.22 1.12 1.09 0.83, 1.43
Arthralgia 1.36 1.10 1.24 0.95, 1.62
Benign Prostatic Hyperplasia 1.32 1.12 1.18 0.90, 1.54
Constipation 1.63 1.29 1.26 0.99, 1.61
Cough 2.64 2.57 1.03 0.86, 1.24
Depression 1.42 1.14 1.25 0.96, 1.62
Diarrhoea 1.50 1.43 1.04 0.82, 1.33
Dizziness 1.11 0.94 1.18 0.88, 1.58
Headache 1.88 1.61 1.17 0.94, 1.47
Insomnia 1.42 1.06 1.34 1.02, 1.75
Mouth dry 1.68 0.93 1.80 1.37, 2.36
Nasopharyngitis 4.33 4.06 1.07 0.92, 1.24
Oedema 1.57 1.52 1.03 0.82, 1.31
Sinusitis 2.14 1.90 1.12 0.91, 1.39
Urinary tract infections 2.08 2.00 1.04 0.85, 1.28
Appendix 8 NEJM on line
Adapted from Tashkin et al. NEJM 2008
3591543-54.
34
Relative Risk (RR) Most Common Adverse Events
(gt3)

• 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
3591543-54.
35
Relative Risk (RR) Most Common Adverse Events
(gt3)

• 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
3591543-54.
36
Serious Adverse Events
Adapted from Tashkin et al. NEJM 2008
3591543-54.
37
SAE Incidence (per 100 pt-yrs) Reported By gt1
in Any Treatment Group
Tiotropium n2986 Control n3006 Rate Ratio (Tio/Con) 95 CI
Cardiac SOC 3.56 4.21 0.84 0.73, 0.98
Angina 0.51 0.36 1.44 0.91, 2.26
Atrial fibrillation 0.74 0.77 0.95 0.68, 1.33
Cardiac failure 0.61 0.48 1.25 0.84, 1.87
Cardiac failure congestive 0.29 0.48 0.59 0.37, 0.96
Coronary artery disease 0.21 0.37 0.58 0.33, 1.01
Myocardial infarction 0.69 0.97 0.71 0.52, 0.99
Respiratory (lower) SOC 11.32 13.47 0.84 0.77, 0.92
Bronchitis 0.37 0.31 1.20 0.73, 1.98
COPD exacerbation 8.19 9.70 0.84 0.76, 0.94
Dyspnea 0.38 0.62 0.61 0.40, 0.94
Pneumonia 3.28 3.46 0.95 0.81, 1.11
Respiratory failure 0.90 1.31 0.69 0.52, 0.92
Plt0.05 excluding lung cancer (multiple
different terms)
Adapted from Tashkin et al. NEJM 2008
3591543-54.
38
UPLIFT

• Conclusions

Adapted from Tashkin et al. NEJM 2008
3591543-54.
39
Summary - Efficacy

• Primary End Point
• No effect on rate of decline of
  pre/post-bronchodilator FEV1.
• Secondary End Points
• Improvement in FEV1, 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
3591543-54.
40
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
3591543-54.
41
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
3591543-54.