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Introduction and Overview
Burkhard Blank, M.D.
Senior Vice President
Medical and Regulatory Affairs
COPD
• Increasing prevalence worldwide
• Fourth leading cause of death in the US
• Further increase in prevalence and mortality predicted
COPD
• Progressive limitation of airflow
• Most patients seek medical attention because of dyspnea
• Typically dyspnea progresses and eventually limits everyday activities
COPD
• Smoking cessation has been shown to change the progression of the disease
• In the US bronchodilators are the only approved pharmacologic principle
Spiriva® Clinical Development Program
• 4,124 subjects
• Phase 3 included 2,663 patients in six pivotal studies - three replicate pairs
• One-year vs. placebo
• One-year vs. ipratropium
• Six-month vs. placebo and salmeterol
Spiriva® Phase 3
• Primary endpoints for efficacy
• Bronchodilation: trough FEV1 in all studies
• Dyspnea relief: as co-primary in six-month studies
• Safety
Major Topics for Today
• 24-hour bronchodilation
• Relief of dyspnea• Use of validated instrument
• Clinically meaningful response
• Safety profile• Cardiovascular adverse events
24-hour Bronchodilation
• Trough FEV1 as primary endpoint
• Consistency of findings across pivotal studies
• Supported by secondary spirometric data
Relief of Dyspnea
• BDI/TDI chosen as an appropriate instrument
• Improvement over placebo shown in both pivotal studies
• Supportive evidence from the other four Phase 3 studies
Safety Profile
• Large patient numbers and patient exposure
• Adverse events reflect anticholinergic pharmacology
• No association with life threatening events
Proposed Indication
SPIRIVA® (tiotropium) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm and dyspnea associated with Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema.
Presentation Overview
24-Hour BronchodilationBernd Disse, M.D., Ph.D.Therapeutic Area HeadRespiratory Diseases
Measurement of DyspneaP. Jones, M.D., Ph.D.Professor of Respiratory MedicineDepartment of PhysiologySt. George’s Hospital Medical Center
Relief of DyspneaT. Witek, Dr. P.H.Vice President and HeadRespiratory Development & Operations
Safety S. Kesten, M.D. Medical Director International SPIRIVA® Program
Clinical Perspective J. Donohue, M.D.
Professor of Medicine and Director Clinical Group Pulmonary Division University of North Carolina
Conclusions B. Blank, M.D.
Senior Vice PresidentMedical and Regulatory Affairs
Consultants
J. Donohue, M.D.
Professor of Medicine and Director, Clinical Group Pulmonary Division University of North Carolina
P. Jones, M.D., Ph.D.
Professor of Respiratory Medicine Department of PhysiologySt. George’s Hospital Medical School
D. Mahler, M.D.
Chief of PulmonaryCritical Care Medicine SchoolDartmouth Hitchcock Medical Center
E. Prystowsky, M.D.
Director, Clinical ElectrophysiologySt. Vincent Hospital, Indianapolis, INConsulting Professor of MedicineDuke University Medical Center, Durham, NC
Bernd Disse, M.D., Ph.D.
Therapeutic Area Head Respiratory Diseases
Bronchodilator Efficacy in COPD
SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD
• Preclinical and clinical pharmacology
• Long-term Phase 3 studies
• Patients
• Spirometry (primary endpoint)
• Subgroup analysis
• Secondary endpoints, supportive information
• Summary and conclusion
Anticholinergics: From Ipratropium to Tiotropium
• Ipratropium
• Standard anticholinergic bronchodilator with established safety record, q.i.d administration
• Tiotropium
• KD at M3: 10 pM vs. 200 pM for ipratropium
• Long duration of action
• Most likely due to slow dissociation from M3-receptors
Tiotropium Phase 2
• Single-dose study in COPD patients (10-160 µg) established
pharmacodynamic duration of action exceeding 24 hours
• Multiple-dose (4-week treatment, 4.5 - 36 µg, placebo)
allowed to select 18 µg for Phase 3
• Approaching pharmacodynamic plateau for FEV1
• Increasing tendency for dry mouth with 36 µg
Delivered Dose: 10 µg
Dose Deposited in the Lungs
3.6 µg
Fine Particles(20% of nominal
dose)OropharyngealDeposited Dose
6.4 µg
Coarse Particles
Mucociliary Clearance
AbsorptionFrom Lungs:
90-100%
Systemic Dose3.5 µg
0.15 µg=3.65 µg
Oral Bioavailability:2-3 %
Topical (Inhalative) Selectivity ofN-quaternary Anticholinergics
HandiHaler®:18 µg
Nominal Dose
Clinical Pharmacokinetics
Metabolism: 25 % (CYP 2D6, 3A4), including ester cleavage
Urine : 75 % (parent compound)
Bioavailability: 19.5 % by dry powder inhalationPlasma conc.: trough: 3-4 pg/mL, C max,ss: 15-20 pg/mL
CLR(i.v.) : 669 mL/min
ClCR: 50-80 30-50 < 30 [mL/min]
and AUC0-4h: +39% +81% +94% = AUC increase plateauing
t½ : 5-6 days
SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD
• Preclinical and clinical pharmacology
• Long-term Phase 3 studies
• Patients
• Spirometry (primary endpoint)
• Subgroup analysis
• Secondary endpoints, supportive information
• Summary and conclusion
Proposed Indication
SPIRIVA® (tiotropium) is indicated for the
long-term, once-daily, maintenance treatment
of bronchospasm and dyspnea associated with
Chronic Obstructive Pulmonary Disease (COPD)
including chronic bronchitis and emphysema
Long-term Phase 3 Studies
Randomized, double-blind, double-dummy (if applicable), parallel groupTreatment: 18g tiotropium DPI once-a-day
114/115 122A/122B 130/137
N per study 470/451 288/247 623/584
Duration One-Year One-Year Six-Month
Placebo PlaceboComparator
Ipratropium 40µg MDIfour-times-daily
Salmeterol 50µg MDItwice-daily
Clinical Program: Patient Selection
• Clinical diagnosis of COPD and exclusion of patients with history of asthma, allergic rhinitis, atopy (eosinophils 600/mm3)
• FEV1 65% of predicted normal, FEV1 70% of FVC
• Age 40 years and smoker >10 pack-years
Clinical Program: Exclusion Criteria
• Not able to participate in long-term trial as judged by investigator (significant other disease),
• Recent respiratory tract infection within six weeks prior to study
• Daytime oxygen, pulmonary rehab, thoracotomy
• Recent history of MI, cardiac arrhythmia requiring treatment, hospitalization for heart failure
• Significant abnormal laboratory finding
• Known prostatic hypertrophy, bladder neck obstruction, narrow-angle glaucoma
Selected Co-Morbidities of Phase 3 Study Population
• Cardiovascular diseases, total 42 - 67%• Hypertension 14 - 35%
• Arrhythmias 5.0 - 12%
• Coronary artery disease 2.2 - 12%
• Myocardial infarction in history 6.2 - 7.1%
• Neurologic and psychiatric disease 21 - 57%• Depression 1.7 – 21%
• Renal/urinary tract disease 13 - 33%• Prostatic hypertrophy + micturition disturbance 1.7 - 11%
• Metabolic/endocrine disease 10 - 28%• Diabetes 3.9 - 7.3%
• Hyperlipidemia 3.0 – 16%
One-YearPlacebo
Controlled
One-YearIpratropiumControlled
Six-MonthPlacebo & Salmeterol
Controlled
N = 921 N = 535 N = 1207
% Males 65 85 76
Race: % Caucasian 94 100 99
Age: Mean
(range)
65
(39-87)
64
(41-82)
64
(39-87)
Smoking History(pack years)
61 34 44
Duration of COPD:Mean
8 11 10
FEV1 (L): Mean
(Range)
1.02
(0.29 - 2.63)
1.23
(0.29 - 2.45)
1.09
(0.26 - 2.51)
FEV1 % Pred: Mean 39 43 41
FEV1/FVC (%): Mean 46 46 42
Demographics and Baseline Characteristics
Long-term Studies: Endpoints
One-Year Studies Six-Month Studies
Trough FEV1* At 13 weeks At 24 weeks
Dyspnea At 24 weeks
* Mean of PFTs at 1 hour and at 5 min before morning administration Reflects drug activity at the end-of-dosing-interval
Secondary Endpoints:• Time course FEV1 and FVC, PEFR (at home)
• Shuttle Walking Test (Six-month studies)• Symptom Scores, albuterol use• Exacerbations of COPD, patient reported outcomes
Primary Endpoint:
SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD
• Preclinical and clinical pharmacology
• Long-term Phase 3 studies
• Patients
• Spirometry (primary endpoint)
• Subgroup analysis
• Secondary endpoints, supportive information
• Summary and conclusion
30min 1 h 2 h 3 hTime After Administration
-1 h -5min0.95
1.00
1.05
1.10
1.15
1.20
1.25
FE
V1
(Lit
ers)
Day 344
Day 344
Day 8
Day 8Day 1
Day 1
Day 92
Day 92
Study 114: FEV1 -Time Profile vs. Placebo
dose
TioPbo
1.2
1.25
1.3
1.35
1.4
1.45
1.5
1.55
-1h -5min 30min 1h 2h 3h 4h 5h 6h
Time After Administration
FE
V1
(Lit
er)
1.15
Day 1
Day 1Day 8
Day 8Day 364
Day 364
Study 122A: FEV1 -Time Profile vs. Ipratropium
dose
TioIb
1.00
1.05
1.10
1.15
1.20
1.25
1.30
1.35
-1h -10min 30min 1h 2h 3h 4h 6h 8h 10h 12hTime After Administration
FE
V1
(Lit
er)
Study 130: FEV1 -Time Profile vs. Placebo and Salmeterol
dose
Day 1
Day 1
Day 15
Day 15
Day 169
Day 169
TioPbo
Day 1Day 15
Day 169
Sal
-1h -10min 30min 1h 2h 3hTime after administration
1.05
1.10
1.15
1.20
1.25
1.30
1.35
1.40
FE
V1
(Lit
er)
Study 137: FEV1 -Time Profile vs. Placebo and Salmeterol
dose
Day 15
Day 15
Day 169
Day 169
Day 1
Day 1
Day 15
Day 169
Day 1
TioPboSal
Magnitude of Spirometric Improvements
Study #Tiotropium
114 115 130 137Salmeterol
130 137
Peak* [L] 0.22 0.21 0.25 0.19 0.16 0.13
Trough* [L]%Baseline
0.1616%
0.1515%
0.1413%
0.109%
0.088%
0.087%
* FEV1-response from baseline compared to placebo at end of study
%Baseline 22% 21% 24% 17% 15% 12%
Efficacy in Subgroups
• Age 40-64 / 65 to 74 / 75 years• Gender male / female• Smoking status ex-smoker /current-smoker• Severity of disease FEV1< 35 / 35 to 49 / 50 %• Previous Atrovent use user / non-user
• Concomitant medication:• Inhaled steroids user / non-user• Theophylline user / non-user
• Tiotropium was similarly effective in all subgroups based on subgroup analysis in combined replicate studies
SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD
• Preclinical and clinical pharmacology
• Long-term Phase 3 studies
• Patients
• Spirometry (primary endpoint)
• Subgroup analysis
• Secondary endpoints, supportive information
• Summary and conclusion
Combined data of studies 114/115nominal p<0.0001 for each time point in individual studies
Peak and Trough FVC Response Over One-Year vs. Placebo
Trough
Day
Peak
Day
00.10.20.30.40.50.60.70.8
1 8 50 92 176 260 344
F
VC
(L
ite
r)
290mL
440mL
00.10.20.30.40.50.60.70.8
1 8 50 92 176 260 344
F
VC
(L
ite
r)Tio (n=518)
Pbo (n=328)
Mean Morning and Evening Peak Flow Rate (L/Min) for the One-Year Placebo-Controlled Studies
Morning Peak Flow
PPPP
TTTTTTT
TTTTTT
TTTTTTTTTTTTT
TTTTTTTTTTTTTTTTTTTTTTT
PPPPPPPPPPPPPP
PPPPPPPPPPPPP
PPPPPPPPPPPPPPPPPPP
T
250
240
230
220
210
200
190
0
PEFR(L/m)
0 8 16 24 32 40 48 56Week
Combined Studies 114/115
Evening Peak Flow
PT
TTTTTTT
TTTTTTTTTTTTTTTTT
TTTTTTTTTTTTTTTTTTTTTTTTT
PPPPPPPPPPPP
PPPPPPPPPPPPPPPPPPPPPPPPPPPPPP
PPPPPPP
Week
T T TP P P
Tio (N=507)Pbo (N=332)
T T TP P P
Tio (N=479)Pbo (N=311)
250
240
230
220
210
200
190
0
PEFR(L/m)
0 8 16 24 32 40 48 56
Exacerbations of COPD
• Evaluation retrospective and of exploratory nature in combined replicate one-year studies
• Prespecified secondary endpoint for combined analysis of replicate studies in six-month studies
Definition:Physician defined COPD exacerbation, or a complex of COPD related symptoms (i.e. cough, wheeze, dyspnea or sputum production), lasting at least three days and reported as adverse event
0
0.5
0.6
0.7
0.8
0.9
1.0
0 50 100 150 200 250 300 350
Tiotropium (n = 550)
Placebo (n = 371)
Days on Treatment
Pro
bab
ility
of
No
Exa
cerb
atio
n
Time to first COPD exacerbation, nominal p=0.011 (log rank test) n.s. in individual studies 114/115
COPD Exacerbation Combined Replicate Studies vs. Placebo, 114/115
0
0.5
0.6
0.7
0.8
0.9
1.0
0 50 100 150 200 250 300 350
Tiotropium (n = 356)
Ipratropium (n = 179)
Days on Treatment
Pro
bab
ility
of
No
Exa
cerb
atio
n
Vincken W et al. Eur Respir J (2002)
Time to first COPD exacerbation, nominal p=0.008 (log rank test) n.s. in study 122A alone
COPD Exacerbation Combined Replicate Studies vs. Ipratropium, 122A/122B
Time to first COPD exacerbation, nominal p=0.005, tiotropium vs. pbo (log rank test)
0
0.5
0.6
0.7
0.8
0.9
1
0 30 60 90 120 150 180
Tio (n = 402)
Sal (n = 405)
Pbo (n = 400)
Days
Pro
bab
ility
of
No
Exa
cerb
atio
n
COPD Exacerbation Combined Replicate Studies vs. Placebo/Salmeterol 130/137
Symptoms – distress due to respiratory symptomsActivity – disturbance of physical activities and
mobility caused by dyspneaImpacts – psycho-social effects of the disease Total score – overall health status
Decreasing scores indicate improvement Score change of 4 clinically meaningful
Health Status:St. George’s Respiratory Questionnaire (SGRQ)
Domains:
Disease-specific instrument
SGRQ Total Score in One-Year Placebo-Controlled Studies
114 115Score
P P P
PP
PT
T TT T T
50
49
48
47
46
45
44
43
4241
40
1 50 92 176 260 344Test Day
PP P P
PP
T
50
49
48
47
46
45
44
43
4241
40
1 50 92 176 260 344Test Day
TT T
TT
Score
TioPbo
3.4
4.1
* ** **
*****
*****
* p < 0.05, ** p < 0.01, *** p < 0.001 (nominal p values)
Summary and Conclusion
• Secondary endpoints and exploratory analyses show improvements of
• related lung-function measures (FVC, PEFR)
• exacerbations
• health status (approaching predefined clinical significance)
• Tiotropium once-daily provides sustained improvement of spirometric measures for 24 hours
• Improvements were maintained over one year, with no evidenceof tachyphylaxis
Quantification of Dyspnea
Paul Jones M.D., Ph.D.
Professor of Respiratory MedicineSt. George’s Hospital Medical School
London
This Presentation
• Measurement of breathlessness
• Validation of BDI & TDI
• Identification of clinically significant threshold
Dyspnea
• Principal symptom of COPD
• Multiple causes of dyspnea in COPD
– Expiratory airflow limitation
– Static lung volume
– Dynamic hyperinflation
• Dyspnea should be measured directly
Dyspnea (a Sensation) Must Be Related to a Known Level of Stimulus
In laboratory tests:
• Work Rate
• Minute Ventilation
• Oxygen Consumption
Reference Points for Dyspnea in Daily Life
1. Strenuous exercise
2. Walking up hills
3. Normal pace on level
4. Slow pace on level
5. Washing & dressing
Reference Points for Dyspnea in Daily Life
1. Strenuous exercise
2. Walking up hills
3. Normal pace on level
4. Slow pace on level
5. Washing & dressing
MRC/ATS grading system for dyspnea
Reference Points for Dyspnea in Daily Life
1. Strenuous exercise
2. Walking up hills
3. Normal pace on level
4. Slow pace on level
5. Washing & dressing
MRC/ATS grading system for dyspnea
DecreasingMetabolicDemand
Multifactorial Relationship between Dyspnea and Activity
• Activities causing dyspnea
• Activities more difficult because of dyspnea
• Activities prevented by dyspnea
BDI & TDI: Construction
• Functional Impairment– Activities limited by dyspnea
• Magnitude of Task– Level of activity causing dyspnea
• Magnitude of effort– Level of effort causing dyspnea
• Baseline Dyspnea Index (BDI)• Cross-sectional • Between patients• Discriminative
• Transitional Dyspnea Index (TDI)• Grounded on BDI• Longitudinal• Within patients• Evaluative
Characteristics of BDI & TDI
Testing Validity of BDI - Psychometrics
Internal consistency (Cronbach alpha) 1 0.80
Inter-rater reliability (Weighted Kappa) 1,2 0.72 - 0.88
Test-retest reliability consistency (r value) 1 0.76
1 Eakin et al Int J Behavioral Med 1995; 2: 118-342 Mahler et al Chest 1988; 93: 580-6
Do BDI & TDI Measure Dyspnea ?
Test whether they relate to:
– Physiological impairment
– Other measures of dyspnea
– Health status
r - values
FEV1 1-2 0.40 - 0.41
1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-34
BDI: Correlation With Measures of COPD Severity
r - values
FEV1 1-2 0.40 - 0.41
6-minute walk 1-3 0.48 - 0.75
1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-24
BDI: Correlation With Measures of COPD Severity
r - values
FEV1 1-2 0.40 - 0.41
6-minute walk 1-3 0.48 - 0.75
ATS Dyspnea, OCD, SOBQ 1-2 0.52 - 0.74
1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-24
BDI: Correlation With Measures of COPD Severity
r - values
FEV1 1-2 0.40 - 0.41
6-minute walk 1-3 0.48 - 0.75
ATS Dyspnea, OCD, SOBQ 1-2 0.52 - 0.74
CRQ, SGRQ 4 0.58 - 0.73
1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-244 Hajiro et al Am J Respir Crit Care Med 1998; 157: 785-90
BDI: Correlation With Measures of COPD Severity
r - values
FEV1 1-2 0.40 - 0.41
6-minute walk 1-3 0.48 - 0.75
ATS Dyspnea, OCD, SOBQ 1-2 0.52 - 0.74
CRQ, SGRQ 4 0.58 - 0.73
SF-36, QWB 2 0.50 - 0.91
1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-244 Hajiro et al Am J Respir Crit Care Med 1998; 157: 785-90
BDI: Correlation With Measures of COPD Severity
TDI: Inter-Rater Reliability
Weighted Kappa = 0.83
Eakin et al Int J Behavioral Med 1995; 2: 118-34
TDI: Correlates of Change
TDI Focal vs ∆ CRQ Dyspnea r = 0.59
1 Guyatt, et al. J Clin Epidemiol 1999; 52: 187-192
Changes following pulmonary rehabilitation 1
TDI: Correlates of Change
TDI Focal vs ∆ CRQ Dyspnea r = 0.59
1 Guyatt, et al. J Clin Epidemiol 1999; 52: 187-192
2 Aaron, et al. Chest 2002; 121: 688-696
Changes following pulmonary rehabilitation 1
Recovery from a COPD exacerbation 2
TDI Focal vs. CRQ Dyspnea r = 0.78TDI Focal vs. FEV1 r = 0.46
Clinical Significance
“The smallest difference in score which patients perceive as beneficial and would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient’s management”
Jaeschke and Guyatt. Measurement of health status: ascertaining the minimal clinically important difference. Controlled Clinical Trials 1989; 10:407-415
Clinical Significance - Humanistic Approach
-3Major Deterioration. Has deteriorated two grades or greater from baseline status.
-2Moderate Deterioration. Has deteriorated at least one grade but fewer than two grades from baseline status.
-1Minor Deterioration. Has deteriorated less than one grade from baseline. Patient with distinct deterioration within grade, but has not changed grades.
0No Change. No change from baseline.
+1 Minor Improvement. Has improved less than one grade from baseline. Patient with distinct improvement within grade, but has not changed grades.
+2 Moderate Improvement. Has improved at least one grade but fewer than two grades from baseline.
+3 Major Improvement. Has improved two grades or greater from baseline
ZFurther Impairment for Reasons Other than Shortness of Breath. Patient has reduced exertional capacity, but not related to shortness of breath. For example, musculoskeletal problem or chest pain.
Clinically Meaningful Change:Magnitude of Task
+1 unit change
A patient who was dyspneic Walking on the level or even when washing
Now only becomes dyspneicWalking up a gradual hill or carrying light load on the level
1. Strenuous Exercise
2. On hills
3. Normal pace on level
4. Slow pace on level
5. Wash/dress
ATS Dyspnea Grading (Abbreviated)
1. Strenuous Exercise
2. On hills
3. Normal pace on level
4. Slow pace on level
5. Wash/dress
ATS Dyspnea Grading (Abbreviated)
1. Strenuous Exercise
2. On hills
3. Normal pace on level
4. Slow pace on level
5. Wash/dress
ATS Dyspnea Grading (Abbreviated)
Dyspnea - As Measured by BDI & TDI
• Reliable measurement properties
• Scores are valid estimates of dyspnea
• Clinical significance can be attached to scores
Dyspnea and Related Measures
Theodore J. Witek Jr., Dr.P.H.
Vice President and Head Respiratory Development & Operations
Dyspnea
SPIRIVA® (tiotropium) is indicated for the long-term,
once-daily, maintenance treatment of bronchospasm
and dyspnea associated with Chronic Obstructive Pulmonary
Disease (COPD) including chronic bronchitis and emphysema.
• Assessing dyspnea in clinical trials
• Application of BDI/TDI in our program
• Response of TDI and related measures to Tiotropium
Dyspnea Assessments in Clinical Trials
• Long-term assessments particularly important in chronic disease maintenance treatment
• Instrument needs to be practical for multi-center and multi-national programs
• Dyspnea assessment needs to be in context of clinic visit
• Supportive assessments should be included to assist in determining validity and consistency
Key Protocol Elements
• TDI evaluations performed at clinic visit (e.g. Days 57, 113, and 169)
• TDI assessments reference the BDI scores measured at baseline visit
• TDI completed after SGRQ and prior to post-dose PFTs
BDI TDI
Grade Axis Grade
0 to +4 Functional impairment -3 to +3
0 to +4 Magnitude of task -3 to +3
0 to +4 Magnitude of effort -3 to +3
0 to +12 Focal Score -9 to +9
Domains of BDI and TDI
• Performance of daily activities and occupation
• Severity or difficulty of physical activities
• Degree of exertional effort
Frequency Distribution of BDI Focal Score
BDI Focal Score
% o
f P
atie
nts
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8 9 10 11 12
0.44 0.55
2.76
8.069.05
11.59
2.431.10
6.62
27.04
20.20
8.72
1.43
Source: Studies 114 and 115
BDI=6 May describe a patient who…
• Abandoned at least one activity due to shortness of breath• Becomes short of breath with an average task such as walking
up a gradual hill• Becomes short of breath with moderate effort, tasks performed
with occasional pauses and requiring longer to complete thanan average person
Improvements in Dyspnea with Tiotropium
• Two studies: TDI primary endpoint (responder analysis)
• Four studies: TDI secondary endpoint (means)
• TDI improvements
• Supportive endpoints
• Consistency - across time and across studies
TDI: Responder Analysis vs. Population Mean
• Responder analysis:• Proportion of patients achieving meaningful response
• One unit change: meaningful effect inherent in the instrument
• Responder analysis reflects individual patient benefit from baseline
• Analysis of means:• Reflects overall population change
• A positive and statistically significant delta vs. placebo indicates overall benefit
Study 130
Pbo (n=148)Tio (n=184)
TDI Responders
* p < 0.05 vs. placeboco-primary endpoint
0
10
20
30
40
50
60
70
57 113 169
Test Day
Pe
rce
nt
of
Pa
tien
ts (
%)
** *
TDI Responders
0
10
20
30
40
50
60
70
57 113 169
Test Day
Pe
rce
nt
of
Pa
tien
ts (
%)
** *
* p < 0.05 vs. placeboco-primary endpoint
Study 130Tio (n=184)
Sal (n=179)Pbo (n=148)
TDI RespondersStudy 137
Tio (n=164)
Pbo (n=161)
0
10
20
30
40
50
60
70
57 113 169
Test Day
Per
cen
t o
f P
atie
nts
(%
)
* * *
* p < 0.05 vs. placebo
TDI Responders
Study 137Tio (n=164)
Sal (n=161)
Pbo (n=161)
* p < 0.05 vs. placebo
0
10
20
30
40
50
60
70
57 113 169
Test Day
Per
cen
t o
f P
atie
nts
(%
)
* * ** * *
T
T
PP
Mean TDI Focal Score Over Six-Months
-1.2
-0.9
-0.6
-0.3
0.0
0.3
0.6
0.9
1.2
57 113 169
* * *
P
P
T
=
1.0
2p
< 0
.05
T
*nominal p<0.05 vs placebo
Me
an
TD
I F
oc
al
Sc
ore
Imp
rov
em
en
t
57 113 169
* **
PP
TT
=
1.2
1p
< 0
.05
Study 130 Study 137
Tio (n=164)
P
T
Sal (n=161) S
SS S
SS
S
* **
Pbo (n=161)
Percent of TDI Responders(Placebo-Controlled, Supportive Studies)
Tio (n=258)
Pbo (n=171)
Tio (n=249)
Pbo (n=154)
*nominal p 0.05 vs. placebo
**
010203040506070
50 92 176 260 344Day
Per
cen
t o
f P
ati
en
ts (
%)
010
203040506070
50 92 176 260 344Day
Per
cen
t o
f P
ati
en
ts (
%)
** * *
* * * **
Study 114
Study 115
Percent of TDI Responders(Ipratropium-Controlled, Supportive Studies)
0
10
20
30
40
50
60
70
8 50 92 182 273 364
Pe
rce
nt
of
Pa
tie
nts
(%
)
Tio (n=172)
IB (n=85)
Day
0
10
20
30
40
50
60
70
8 50 92 182 273 364Day
Pe
rce
nt
of
Pa
tie
nts
(%
)
Tio (n=148)
IB (n=67)
*nominal p 0.05 vs. ipratropium
*
* **
Study 122A
Study 122B
50 92 176 260 344
Score
-0.4-0.20.00.20.4
0.60.81.01.21.41.6
Test Day
TT
TT T
P P
P PP
Tio (n=248)Pbo (n=154)
50 92 176 260 344
Score
-0.4-0.20.00.20.40.60.81.01.21.41.6
Test Day
P
P PP P
Tio (n=258)Pbo (n=171)
Mean TDI Focal Score (One-Year Placebo-Controlled Studies)
TT
TT
T
Study 114 Study 115
nominal p<0.05 vs. placebo (all days) nominal p<0.001 vs. placebo (all days)
PT
PT
8 50 92 182 273 364
Score
-0.8-0.6-0.4-0.20.00.20.40.60.81.01.21.41.6
Test Day8 50 92 182 273 364
Score
-0.8-0.6-0.4-0.20.00.20.40.60.81.01.21.41.6
Test Day
Tio (n=148)IB (n=67)
Tio (n=172)IB (n=85)
Mean TDI Focal Score (One-Year Ipratropium-Controlled Studies)
Study 122A Study 122B
nominal p<0.05 vs. ipratropium (days 8, 182, 273, 364) nominal p<0.05 vs. ipratropium (all days)
Dyspnea Score
S
1 57 113 1690.8
1.0
1.2
1.4
1.6
1.8
Test Day
Tio (N=203) Pbo (N=180)Sal (N=204)
T
TT
T
TT T
T
S
S S SS S
P
P
PP P P P
Shortnessof BreathScore
Study 130 Study 137
S S S
SP
1 57 113 1690.8
1.0
1.2
1.4
1.6
1.8
Test Day
T
T TT
TS S SS
PP P
PP P
P
Shortnessof BreathScore
TT
T
TIO vs. PBO nominal p<0.001 (all days) TIO vs. PBO nominal p<0.05 (days 1, 57)
PT
S
Tio (N=185)
Pbo (N=186)Sal (N=187)
PT
S
P
Dyspnea Score
PP
1 50 92 176 260 3441.0
1.2
1.4
1.6
1.8
2.0
Test Day
T
T T TT T T
TT T T T
T T TT T TP
PP P P
P P
P
PP P
PP P P
P
Tio (N=258)
Pbo (N=160)
Shortnessof BreathScore
Shortnessof BreathScoreTio (N=275)
Pbo (N=184)
P
1 50 92 176 260 3441.0
1.2
1.4
1.6
1.8
2.0
Test Day
T
T T T T TT
TT T T
T TT
TT T TP P P P
PP
P
P
PP P
PP
PP
P
Study 114 Study 115
TIO vs. PBO nominal p<0.05 (all days) TIO vs. PBO nominal p<0.05 (except days 113, 134)
PT
P
T
S
SS
SP
S
SP
1 57 113 169 1 57 113 169
Score
4.14.24.34.44.54.64.74.84.95.05.1
Test Day
T
TT
T
T TT
S SS S S
P
P PP
PP
P
Tio (N=203)Sal (N=204)Pbo (N=180)
T T TS S SP P P
Tio (N=185)Sal (N=187)Pbo (N=186)
T T TS S SP P P
Score
4.14.24.34.44.54.64.74.84.95.05.1
Test Day
T
TT
T TT
S TS S S
S
PP P
P P PP
Study 130 Study 137
Mean Score; Physician’s Global Evaluation (Six-Month Studies)
T
T
TIO vs. PBO nominal p<0.001 (all days) TIO vs. PBO nominal p<0.05 (days 1, 57, 113)
P
1 50 92 176 260 344
Score
4.0
4.4
4.8
5.2
5.6
6.0
Test Day
T
T TT T T
T TT T T T
P P P P PP P P
P P P
Tio (N=275)Pbo (N=184)
T T TP P P
Study 114
P
1 50 92 176 260 344
Score
4.0
4.4
4.8
5.2
5.6
6.0
Test Day
T
TT T T T T T
T T T T
PP P P P P
P P P P P
Tio (N=259)Pbo (N=161)
T T TP P P
Study 115
Mean Score; Physician’s Global Evaluation (One-Year Placebo-Controlled Studies)
TIO vs. PBO nominal p<0.001 (all days) TIO vs. PBO nominal p<0.05 (all days)
PPPPP PP
SSSS
SSSS
SSSSSSS
SSSSSSS
S
SP
SP
SSSSSSSSSS
SSSS
SSS
SSSSS
SS
Week
Puffs
2.02.22.42.62.83.03.23.43.63.84.04.24.44.6
0 4 8 12 16 20 24
T
TT T
T TT T TT T T T TT T TT TT T T T T T
PPP
PPPPPPPPPPPP
PPP
PPPPPP
T T TS S SP P P
Tio (N=181)Sal (N=184)Pbo (N=187)
Week
Puffs
2.02.22.42.62.83.03.23.43.63.84.04.24.44.6
0 4 8 12 16 20 24
T
TT T
TT T T
T T T T T T TTT T
T TT TTT
T
PPPPPPP PPPPPPP
PP P
Study 130 Study 137
Mean Number of Daily Doses of Albuterol -(Six-Month Studies)
P
Tio (N=203)Sal (N=208)Pbo (N=176)
T T TS S SP P P
TIO vs. PBO nominal p<0.01 (all weeks) TIO vs. PBO nominal p<0.05 (week 1 only)
Tio (N=276)Pbo (N=186)
T T TP P P
P
Doses
2.42.62.83.03.23.43.63.84.04.24.4
Week0 8 16 24 32 40 48 56
T
TTTT
TTTTTTTTTT
TTTTTTTTTTT
TTTTTT
TTTTTTTTTTTTT
TTTTTPPPPPPP
PPPPPPPPPP
PPPPPPPP
PPPPPPPPPP
PPPPPPPPPPPPPP
Study 114Tio (N=267)Pbo (N=166)
T T TP P P
P
Doses
2.42.62.83.03.23.43.63.84.04.24.4
Week0 8 16 24 32 40 48 56
T
TTTTTTTT
TTTTTTTTTTTTT
TTTTT
TTTTTT
TTTTTTTTTTTTTTTTTP
P
PPPPPPPPPPP
PPPPPP
PPPP
PPPPPPPPP
PPPPPPP
PPPPPPPPPP
Study 115
Mean Number of Daily Doses of Albuterol -(One-Year Studies)
TIO vs. PBO nominal p<0.002 (all weeks) TIO vs. PBO nominal p<0.01 (all weeks)
Consistency of Tiotropium Benefit
Dyspnea Symptom Score
SGRQ Total Score
Physician Global
Albuterol Use
Endpoint
FEV1 Trough
TDI % Responders
TDI Mean vs. Placebo
114 115 130 137
0.0001 0.0001 0.0001 0.0001
0.0024 0.0001
0.0001 0.0001
0.0049 0.0232
0.0134 0.0021
0.0002 0.0003 0.0001
0.0021 0.0006 0.0374 0.0388
0.0001 0.0264 0.0001
0.0010 0.0010 0.0001
0.6937
0.9683
0.3480
nominal p-value vs. placebo at end of study
p-value vs. placebo at end of study
The Effect of Tiotropium on Dyspnea
Summary
• Utilization of a validated instrument
• Prespecification of primary endpoint
• Statistical significance observed in two independent studies
• Proportion with meaningful change supported by mean responses
• Dyspnea response reflected in related measures
Proposed Indication
Given the importance of dyspnea as a
COPD symptom and given our demonstration
of dyspnea relief, we believe that dyspnea
should be included as an indication for use.
SPIRIVA® (tiotropium)
Clinical Safety Evaluation
Steven Kesten, M.D.
Medical DirectorInternational SPIRIVA® Program
Tiotropium: Safety
• Extensive clinical safety evaluation
• Large patient experience
• Long-term exposure
• Clinical safety profile similar to ipratropium
• Fifteen years experience in the US
Experience With Ipratropium
Cardiovascular: palpitations, tachycardia, SVT, atrial fibrillation
Gastrointestinal: dry mouth, constipation
Genitourinary: urinary retention, urinary difficulty
Opthalmologic: blurred vision, worsening of narrow-angle glaucoma, acute eye pain, mydriasis
Healthy Volunteers
Single Dosing Inhaled Tiotropium• 160 g (n=6)
• no effect on vital signs, ECG, pupillometry, salivary secretions• 282 g (n=6)
• no effect on vital signs, ECG, pupillometry, salivary secretions
Multiple Dosing Inhaled Tiotropium• 70.4 g (n=11), 140.8 g (n=12), 7 days treatment• decreased salivary secretions, dry mouth [7/11 for 70.4 g,
12/12 for 140.8 g]• no effect on vital signs, ECG, pupillometry
COPD Experience
Tiotropium Patients
1,723*
Short-Term Studies Long-Term Studies414 1,308
61 353Single-Dose Multiple-Dose
906 402One-Year Six-Month
*one patient discontinued after placebo, before tiotropium
COPD: Clinical Safety Evaluation
Clinical Adverse Event Reporting
Supporting Measures
• Physical examination and vital signs
• Lung function
• Laboratory evaluations
• Characterization studies
• Electrocardiograms
COPD: Electrocardiographic Evaluation
ECG Profiling:• 12 lead ECGs + 2 minute rhythm strips: multi-dose, dose-ranging• 134 patients, 4 weeks (2,198 ECGs on tiotropium)
Holter monitoring:• 72 patients, 6 weeks
Long-Term Studies:• 12 lead ECGs: long-term studies• placebo-controlled: 550 patients (1,809 ECGs on tiotropium)• ipratropium-controlled: 371 patients (1,225 ECGs on tiotropium)• six-month studies: 402 patients (390 ECGs on tiotropium)
Total ECGs on Tiotropium: 5,622
Placebo 4.5 g 9 g 18 g 36 g
Total Patients Treated 35 34 33 33 34
Total with Changes 20 24 22 23 16
Borderline PR Interval 1 0 1 0 0First Degree A-V Block 1 1 0 1 0
Atrial Fibrillation 0 0 1 0 0
Sinus Arrhythmia 0 0 0 0 1
Sinus Tachycardia 1 0 0 1 0
Consistent with Ventricular Tachycardia 0 1 0 0 0
Repetitive Premature Systoles 1 2 0 2 0
Multiforme Premature Systoles 0 4 2 1 2
Premature Systoles, Ventricular 9 11 7 10 8
Premature Systoles, Atrial 10 10 10 10 6Sinus Arrest or Sino-atrial Block 0 2 2 0 0
Ectopic Atrial Rhythm 2 0 2 1 0
Borderline QT Interval 1 0 0 1 0
ECG Profiling: Changes in ECG During Multi-dose Dose-Ranging Study
ECG Results: One-Year Placebo-Controlled Studies
Maximum HR (bpm)
101-105 106-110 111-120 121-130Tiotropium 6 2 3 1Placebo 2 2 1 1
Tiotropium Placebo
Number of Patients 518 343
Number of ECGs 1,758 1,108
Abnormal Rhythm 9.0% 10.1%
Heart Rate
Mean change (bpm) 0 0Mean maximum change (bpm) 7 6Percent with bradycardia events 0.2% 0.3%Percent with tachycardia events 2.3% 1.7% Number of patients with single event 10/12 6/6
Short-Term Studies (< 6 weeks)
• Eight studies in COPD patients receiving capsules (n=414)
4.5 g 9 g 18 g 36 g 72 g
Number of patients 34 93 312 93 34
• Adverse events
• Overall, similar frequency to placebo
• Dry mouth - evidence of dose-response
• No relevant imbalances with other adverse events
• Serious adverse events: tiotropium - 5, placebo - 6
• Deaths: 3 (lymphoma 15 weeks post-study, MI 11 weeks post-study, respiratory failure)
Long-Term Studies
Four One-Year Studies
TIO
356
IB
179
TIO
550
PBO
371
Two Six-Month Studies
TIO
402
PBO
400
SAL
405
906
1,308
Tiotropium Patients
Adverse Event Profile: One-Year Studies
Total adverse events 495 90 338 91 318 89 162 91
Leading to disc. 53 10 50 14 35 10 22 12
Serious 99 18 78 21 57 16 46 26
Fatal 7 1 7 2 9 3 3 2
Total treated 550 100 371 100 356 100 179 100
Tio N %
PboN %
TioN %
IbN %
Chest Pain 7 5 5 2Edema 5 4 3 5
GASTROINTESTINAL Abdominal Pain 5 3 6 6Constipation 4 2 1 1Dry Mouth 16 3 12 6Dyspepsia 6 5 1 1
RESISTANCEMECHANISM
Infection 4 3 1 3Moniliasis 4 2 3 2
BODY AS A WHOLE Accidents 13 11 5 8% % % %
Vomiting 1 24 2
MUSCULOSKELETAL Myalgia 4 3 4 3
Most Common Adverse Events: One-Year Studies
TioN=550
PboN=371
TioN=356
Ib N=179
TioN=550
PboN=371
TioN=356
Ib N=179
RESPIRATORY SYSTEM - UPPER
Epistaxis 4 2 1 1Pharyngitis 9 7 7 3Rhinitis 6 5 3 2Sinusitis 11 9 3 2Upper RespiratoryTract Infection
41 37 43 35
URINARY SYSTEM Urinary Tract Infection 7 5 4 2
SKIN & APPENDAGE Rash 4 2 2 2
RESPIRATORY SYSTEM - LOWER
COPD Exacerbation 36% 40% 35% 48%Pneumonia 4 7 5 6
Most Common Adverse Events: One-Year Studies
Tio Pbo Tio Ib
Total with serious adverse events 18.0% 21.0% 16.0% 25.7%
BODY AS A WHOLE Accidents 0.4 0.0 0.8 0.0
CARDIOVASCULAR Cardiac Failure 0.5 0.8 0.0 0.6Syncope 0.5 0.0 0.6 0.6
HEART RATE ANDRHYTHM
Atrial Fibrillation 0.4 0.3 0.0 1.1
Chest Pain 1.5 1.1 0.3 0.0Fall 0.0 0.5 0.0 0.0
GASTROINTESTINAL Abdominal Pain 0.0 0.5 0.3 0.0Diverticulitis 0.0 0.5 0.0 0.0GI Hemorrhage 0.4 0.5 0.0 0.0Pancreatitis 0.2 0.5 0.0 0.0
METABOLIC ANDNUTRITIONAL
Dehydration 0.9 0.0 0.0 0.0Diabetes MellitusAggravated
0.4 0.0 0.3 0.0
Hyperglycemia 0.4 0.0 0.0 0.0
N=550 N=371 N=356 N=179
Serious Adverse Events: One-Year Studies
MYO, ENDOAND PERICARDIAL
Angina Pectoris 0.4 0.3 0.8 1.7Coronary ArteryDisorder
0.7 0.8 0.0 0.0
Myocardial Infarction 0.5 0.3 0.8 0.0
PLATELET BLEEDINGAND CLOTTING
Embolism Pulmonary 0.0 0.0 0.6 0.0
PSYCHIATRIC Manic Reaction 0.4 0.0 0.0 0.0
NEOPLASM Basal Cell Carcinoma 0.5 1.3 0.0 0.0Neoplasm Malignant 0.7 0.0 0.0 0.6Oral NeoplasmMalignant
0.0 0.5 0.0 0.0
Pulmonary Carcinoma 0.4 0.5 1.1 0.6Skin NeoplasmMalignant
0.2 0.8 0.0 0.0
REPRODUCTIVE, MALE
Prostatic Disorder 0.4 0.0 0.0 0.6
Tio Pbo Tio IbN=550 N=371 N=356 N=179
Serious Adverse Events: One-Year Studies (continued)
RESPIRATORYSYSTEM - LOWER
COPD Exacerbation 5.8 8.1 6.5 11.7Dyspnea 0.0 0.3 0.0 1.1Pneumonia 2.4 3.8 1.7 2.2
RESISTANCEMECHANISM
Infection 0.4 0.0 0.0 0.0
Tio Pbo Tio IbN=550 N=371 N=356 N=179
VASCULAR CerebrovascularDisorder
0.7 0.3 0.3 0.6
Serious Adverse Events: One-Year Studies (continued)
BODY AS A WHOLE 0.2 0.3 0.0 0.6CARDIOVASCULAR 0.2 0.3 0.0 0.0HEART RATE AND RHYTHM 0.4 0.0 0.0 0.0MYO, ENDO AND PERICARDIAL 0.5 0.3 0.8 0.6NEOPLASM 0.0 1.1 0.8 0.0PSYCHIATRIC 0.2 0.0 0.0 0.0PLATELET, BLEEDING AND CLOTTING 0.0 0.0 0.3 0.0RESISTANCE MECHANISM 0.0 0.0 0.3 0.0RESPIRATORY SYSTEM - LOWER 0.0 0.3 0.3 0.6URINARY SYSTEM 0.0 0.0 0.3 0.0VASCULAR EXTRACARDIAC 0.0 0.0 0.3 0.0WHITE CELL AND RESISTANCE 0.0 0.0 0.0 0.6
Fatal Adverse Events: One-Year Studies
Total with fatal adverse events 1.3% 1.9% 2.5% 1.7%
Tio Pbo Tio IbN=550 N=371 N=356 N=179
Fatal Cardiovascular EventsOne-year Six-Month
Tio550
Pbo371
Tio356
Ib179
Tio402
Pbo400
Salm405
DEATHS TOTAL 7 7 9 3 1 5 6
CV DEATHS TOTAL 6 1 3 1 1 3 2body as a whole death 0 0 0 0 0 1 0
sudden death 1 0 0 0 0 0 1CV, general cardiac failure 1* 1t 0 0 0 0 1
cor pulmonale 0 1t 0 0 0 0 0heart rate & rhythm arrhythmia 1 0 0 0 0 0 0
cardiac arrest 1 0 0 0 0 2 0myo,endo,peric. aneurysm 0 0 0 1 1 0 0
cardiomyopathy 1* 0 0 0 0 0 0CAD 1 1 0 0 0 0 0MI 1 0 3 0 0 0 0
* t same patient
Rationale• Reduce random error
Justification• Similar protocols and populations
• Similar patterns of response
Variables • Incidence rates (IR) per 100 person-years
• Rate differences (RD)
• RD = IR (tiotropium) - IR (placebo)
• P-values to assess statistical reliability
Adverse Events: Pooled Placebo-Controlled Studies
Pooled Placebo-Controlled Studies
Four One-Year Studies
TIO
356
IB
179
TIO
550
PBO
371
Two Six-Month Studies
TIO
402
PBO
400
SAL
405
TIO
952
PBO
771
Pooled Placebo-Controlled Studies
906
1,308Tiotropium Patients
679 pyrsTio
P-valueN Rate483 pyrs
Pbo
N Rate RD
Adverse Events: Pooled Placebo-Controlled Studies
HEART RATE AND RHYTHM
Tachycardia 8 2 0.77
Supraventricular Tachycardia 3 1 0.23
Arrhythmia 4 1 0.38 Atrial Fibrillation 7 3 0.41
Cardiac Arrest 1 2 -0.27 Palpitation 5 6 -0.51
0.181.19 0.41
0.44 0.21
0.59 0.201.03 0.62
0.15 0.410.74 1.25
0.57
0.380.49
0.450.40
MYO, ENDO AND PERICARDIAL
Angina Pectoris 9 3 0.71
Angina Pectoris Aggravated 2 0 0.29 CAD 4 4 -0.24
1.33 0.62
0.30 0.000.59 0.83
0.26
0.340.64
Myocardial Infarction 5 5 -0.300.74 1.04 0.60 Thrombosis Coronary 1 0 0.150.15 0 0.58
Selected Adverse Events: Pooled Placebo-Controlled Studies
Tachycardia/SVT/Atrial fibrillation 18 6 1.432.68 1.25 0.10
679 pyrsTiotropium
RD P-valueN Rate483 pyrsPlacebo
N Rate
Angina/CAD/thrombosis coronary 16 7 0.932.38 1.45 0.28
Myocardial infarction 5 5 -0.300.74 1.04 0.60
Ischemic deaths 2 1 0.090.29 0.21 0.82
Arrhythmic deaths 3 3 -0.180.44 0.62 0.69
Cardiovascular deaths 7 5 0.001.03 1.03 0.98
Total deaths 8 12 -1.311.18 2.48 0.11
679 pyrsTio
P-valueN Rate483 pyrs
Pbo
N Rate RD
RESPIRATORY SYSTEM - UPPER
Epistaxis 23 11 1.16 Laryngitis 7 1 0.83
Pharyngitis 67 39 1.99
Sinusitis 75 45 2.02
Upper Resp Tract Infection 304 202 6.18
0.273.46 2.300.101.03 0.21
0.2910.33 8.35
0.3211.70 9.69
0.2156.92 50.73
RESPIRATORY SYSTEM - LOWER
COPD Exacerbation 331 311 -23.44
Dyspnea 51 56 -4.31
<0.0161.06 84.51
0.027.68 11.99
GASTROINTESTINAL
Dry Mouth 121 19 16.22 <0.01 Constipation 23 8 1.78 0.07
20.23
3.444.02
1.67
Selected Adverse Events: Pooled Placebo-Controlled Studies
679 pyrsTio
P-valueN Rate483 pyrs
Pbo
N Rate RD
URINARY SYSTEM
Micturition Disorders 4 0 0.59
Urinary Retention 5 0 0.74
Urinary Tract Infection 41 17 2.63
Cystitis 6 7 -0.57
0.120.59 0.00
0.070.74 0.00
0.056.21 3.57
0.380.89 1.46
VISUAL
Glaucoma 3 3 -0.18 0.690.44 0.62
Selected Adverse Events: Pooled Placebo-Controlled Studies
Summary
• Safety data includes long-term studies of 1,308 tiotropium treated patients
• Events consistent with anticholinergic pharmacology• SVT, dry mouth, constipation, urinary tract disorders
• No associations of treatment with life-threatening events
• Tiotropium safety profile consistent with established inhaled anticholinergic therapy
Clinical Perspective
Dr. James Donohue, M.D.
Professor & Chairman of Pulmonary Critical Care
UNC Pulmonary DivisionSchool of Medicine
Chapel Hill, NC
Overview of COPD
• 32 million with COPD
• 17 million diagnosed
• 6 million on therapy
• Older patients with comorbidities
• Limited therapeutic options
Based on Fletcher and Peto. Br Med J. 1977;1:1645-1648.*Average and range of FEV1 decline
FE
V1 (
% o
f va
lue
at a
ge
25)
Smokedregularly andsusceptible toits effects
Death
Never smoked or not susceptible to smoke*
Stoppedat 45
Stoppedat 65
25 50 75
Age (years)
0
25
50
75
100
Disability
Disease Progression
Bronchodilation
• Clinical relevance of tiotropium bronchodilator effect
• Once-daily dosing
• Magnitude of effect: Trough, Peak, and Average
• Peak-to-trough differences in FEV1
• Consistent, sustained bronchodilation
• No evidence of tachyphylaxis on long-term treatment
Dyspnea
• Challenges in demonstrating dyspnea relief in clinical studies
• Dyspnea is a highly complex subjective symptom
• Patients alter activity to avoid this unpleasant sensation
• Individual patients vary considerably in their evaluation
• Substantial placebo response
• Comorbidities complicate assessment of treatment benefit
• Drug effect must be robust to be consistently detected
Dyspnea
• Clinical relevance of one-unit improvement in TDI focal score
• Clinical relevance of responder rate comparison to placebo
Safety
• Substantial long-term exposure
• Representative COPD population with stable comorbidities
• Low incidence of adverse events consistent with inhaled anticholinergic side effects
Conclusion
• Tiotropium represents a significant addition to the medical armamentarium
Conclusions
Burkhard Blank, M.D.
Senior Vice PresidentMedical and Regulatory Affairs
Major Topics for Today
• Safety profile• Cardiovascular adverse events
• 24-hour bronchodilation
• Relief of dyspnea• Use of validated instrument
• Clinically meaningful response
Proposed Indication
SPIRIVA® (tiotropium) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm and dyspnea associated with Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema.