# Presentation: 351245

## Pulmonary-Allergy Drugs Advisory Committee

**NDA 21-395**
**Spiriva****® ****(tiotropium bromide) **
**Inhalation Powder**
**Eugene J. Sullivan, MD FCCP**
**Medical Officer**
**Division of Pulmonary and Allergy Drug Products**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Background: COPD Indication

**Proposed Indication for tiotropium: **
**“****treatment of bronchospasm **
***and dyspnea***** associated with COPD” **
**No drugs approved in the US carry an Indication for the treatment of specific symptoms of COPD, or for the “treatment of COPD” **

## Background: COPD Indication

**Currently approved drugs****: **
**“****treatment of bronchospasm associated with COPD”**
**Distinction: treatment of bronchospasm vs. treatment of the disease**
**FEV****1**** **
**direct measure of bronchospasm**
**“****surrogate” measure of the disease itself (a constellation of physical signs and symptoms, physiologic processes, and histopathologic features)**

## Background: COPD Indication

**Presumed clinical benefit of bronchodilators**
**approved based on spirometry, but clinically detectable benefit is presumed**
**“****as-needed” use of the bronchodilator albuterol reflects bronchodilator-mediated symptom benefit**

## Background: COPD Efficacy Variables

**Primary: Measure of bronchodilation**
**Usually FEV****1**
**After chronic use (for maintenance drugs)**
**Peak FEV****1****, FEV****1****-Time Curve AUC**
**Secondary (supportive)**
**Other spirometry variables**
**“****Rescue” albuterol use**
**Peak flow**
**Six-minute walk test **
**Exacerbations, Patient-Reported Outcomes, etc.**

## Background: Tiotropium P3 Primary Efficacy Variables

**All studies:**** **
**Change from baseline in “trough” (pre-dose) FEV****1**
**Two studies:**** **
**Change from baseline in “trough” (pre-dose) FEV****1**
**and**
**Transitional Dyspnea Index (TDI)**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## PK/PD Characteristics

**Bioavailability of tiotropium**
**Oral ingestion 2-3%**
**Oral inhalation 19.5%**
**Single dose PK (oral inhalation): **
**C****max****= 5 minutes**
**Detectable in blood for 2-4 hours**
**Prolonged urinary excretion **
**detectable in urine for 25 days after a dose of 108mcg**
**Volume of distribution: 32 liters/kg**

## PK/PD Characteristics

**Elimination:**
**74% eliminated in urine as parent compound**
**44% by 4 hours, 54% by 24 hours, 61% by 96 hours**
**active renal secretion (renal clearance > creatinine clearance)**
**Fate of remaining 26% not well established**
**non-enzymatic hydrolysis**
**hepatic metabolism (CYP2D6 and CYP 3A4)**

## PK/PD Characteristics

**Terminal elimination half-life = 5-6 days**
**Multiple-dose accumulation: 2-3 fold **
**suggests effective T1/2= 24-36 hours**
**PK characteristics are indicative of extensive tissue binding, with slow release back into circulation**
**large volume of distribution and long terminal elimination half-life**

## PK/PD Characteristics

**Pharmacodynamic effect increases with multiple daily dosing**
**Spirometry data from Phase 3 studies **
**Separate “sub-study” of one of the Phase 3 studies (122A, ipratropium-controlled)**
**N= 28**
**six-hour, serial spirometry on Days 1, 2, 3, 8, and 50**
**Maximum (“steady state”) effect is achieved by Day 8**

## PD Effect Increases with Multiple Dosing

**Phase 3, one-year, placebo-controlled studies:**

## PD Effect Increases with Multiple DosingOnset of Steady State “Sub-study”

**Daily AM PEFR reached maximum effect at Day 6**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Phase 3 Clinical Program

## Phase 3: Patients Studied

**Inclusion Criteria: **
**age ******** 40 years**
**smoking history > 10 pack-years**
**FEV1 ******** 60% or 65% predicted**
**FEV1 ******** 70% of FVC**
**Exclusion Criteria:**
**h/o asthma, allergic rhinitis, or atopy**
**elevated blood eosinophil count**
**significant disease other than COPD**
**symptomatic prostatic hypertrophy or bladder outlet obstruction**
**narrow angle glaucoma**
**MI (1 year), cardiac arrhythmia requiring drug treatment, or hospitalization for heart failure (3 years)**

## Phase 3: Demographic and Baseline Features

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Safety Database

**1308 patients exposed in P3**
**Phase 3 Safety Evaluations:****	**
**adverse events**
**vital signs**
**physical examination**
**clinical labs**
**ECGs (timing not specified)**

## Safety Database

**Additional Safety Data (Phase 2)**
**timed ECGs (multiple dose study, up to 44mcg QD)**
**Holter monitors (n=72 patients, pre- and on-treatment)**

## Safety Database

**Focus on one-year, placebo-controlled studies**
**Median exposure 10 days longer for  tiotropium patients (338 days) than for placebo patients (328 days).**

## Adverse Events with Tiotropium(One-year, placebo-controlled studies)

**Gastrointestinal:**
**dry mouth (16% vs. 2.7%)**
**dyspepsia (5.8% vs. 4.6%)**
**abdominal pain (4.7% vs. 3.0%)**
**constipation (3.5% vs. 1.6%)**
**vomiting (3.5% vs. 2.4%)**

## Adverse Events with Tiotropium(One-year, placebo-controlled studies)

**Respiratory System:**
**upper respiratory tract infection (41.1% vs. 37.2%)**
**epistaxis (3.6% vs. 1.9%)**
**pharyngitis (8.9% vs. 7.3%)**
**sinusitis (11.3% vs. 9.4%)**
**Chest pain (6.9% vs. 4.6%)**
**Rash (4.2% vs. 2.2%)**
**Urinary Tract Infection (7.3% vs. 5.1%)**

## Adverse Events with Tiotropium(Six-month studies)

**Fewer differences between tiotropium and placebo.**
**AEs more common in tiotropium:**
**Dry mouth (8.2% vs. 2.3%)**
**Upper Respiratory Tract Infection (19.4%vs. 16%)**
**Pharyngitis (4.5% vs. 3.0%)**
**Sinusitis (3.2% vs. 2.5%) **
**Influenza-like symptoms (6.7% vs. 4%)**

## Safety Interactions with Tiotropium(One-year, placebo-controlled studies)

**Age (********60, 61-70, ********71):**
**Dry Mouth: 11%, 16%, 21% (Pbo values: 3%, 1.9%, 3.5%)**
**Constipation: 2%, 2.8%, 6% (Pbo values: 3%, 0.6%, 1.7%)**
**Urinary Tract Infection: 3.3%, 5.2%, 12% (Pbo values: 2%, 3.9%, 6.1%)**
**Gender:**
**Dry Mouth: women 23%, men 13% (Pbo values: 2.9% and 2.6%)**

## Other Safety Observations(One-year, placebo-controlled studies)

**Urinary Retention:**
**4 patients, all treated with tiotropium**
**all required Foley catheter; three were started on medication for BPH following the event**
**“****Micturation disorder” or “micturation frequency”**
**6 (1.1%) tiotropium patients vs. 0 placebo patients**

## Other Safety Observations(One-year, placebo-controlled studies)

**Constipation:**
**one patient treated with tiotropium was hospitalized with fecal impaction**
**“****Diabetes mellitus”, “diabetes mellitus aggravated,” or “hyperglycemia”**
**14 (2.5%) tiotropium patients vs. 1 (0.3%) placebo patients**

## Other Safety Observations(One-year, placebo-controlled studies)

**Cardiovascular Effects****	**
**“****Heart Rate and Rhythm Disorders”: **
**AEs: 24 (4.4%) tiotropium patients vs.          8 (2.2%) placebo patients**
**SAEs: 1.3% tiotropium patients vs. 0.5%placebo patients**
**(signal not seen in ipratropium-controlled studies)**
**No safety signal on ECGs**

## Other Safety Observations(One-year studies)

**Deaths**
**One-year studies: **
**incidence of death similar in all groups**
**placebo-controlled: 5/7 tiotropium deaths were attributable to cardiac ischemia or arrhythmia (compared with 1/7 placebo deaths)**
**ipratropium-controlled: deaths due to MI = 3/9 tiotropium deaths, 0/3 ipratropium deaths **

## Other Safety Observations

_**Phase 2 Study:**_
**No safety signal on Holter monitors **
**N=72 patients, pre- and on-treatment**
**compared with n = 284 patients during five, 24-hour periods described in Serevent MDI label**
**One subject developed a four-fold increase in ventricular ectopy on-treatment (tiotropium). **

## Adverse Events with Tiotropium(One-year, ipratropium-controlled studies)

_**Event**__**	**__**	**__**	**__**Tiotropium**__**	**_**      **_**Ipratropium**_
**Chest Pain****	****	****     5.3%****	****	****2.2%**
**Dry Mouth****	****	****     12.1%****	****	****6.1%**
**Dyspepsia****	****	****     1.4%****	****	****0.6%**
**Moniliasis****	****	****     2.8%****	****	****1.7%**
**Pharyngitis****	****	****     6.5%****	****	****2.8%**
**Sinusitis****	****	****     3.4%****	****	****2.2%**
**URTI****	****	****	****     43%****	****	****34.6%**
**UTI****	****	****	****     3.9%****	****	****2.2%**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Bronchodilator Efficacy:Studies 114 and 115

**Trough FEV1 statistically superior on all other clinic visits (1, 7, 25, 37, and 49 weeks), with mean effect sizes of 0.11 - 0.16 liters.**
**Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 3-hour serial spirometry performed on all clinic visits.**

## Bronchodilator Efficacy:Studies 114 and 115

**Peak FEV1 Data**
**Mean Peak FEV1 response was 0.24 liters on Day 1 and 0.25 - 0.31 liters on subsequent clinic visits.**
**On Day 1, the mean peak FEV1 at each time point (0.5, 1, 2, and 3 hours) was <0.20 liters**
**This is because patients reached their personal peak FEV1 at differing time points:**

## Bronchodilator Efficacy:Studies 114 and 115

**Tiotropium was statistically superior to placebo:**
**FVC response (trough, average, and peak)**
**AM and PM PEFR, for most weeks, with mean effect sizes of    8 - 31 liters/minute (morning) and 13 to 40 liters/minute (evening)**

## Bronchodilator Efficacy:Studies 122A and 122B

**Primary Efficacy Endpoint: Trough FEV1 at 13 weeks**
**Note: Ipratropium not expected to show significant efficacy at this time point**
**Tiotropium was superior to ipratropium on this variable at all clinic visits, with mean effect sizes of 0.11 to 0.18 liters (over ipratropium)**

## Bronchodilator Efficacy:Studies 130 and 137

**Trough FEV1 was statistically superior on all other clinic visits (Day 1, and Weeks 2, 8, and 16), with mean effect sizes of 0.11 - 0.15 liters.**
**Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 12- or 3-hour serial spirometry performed on all clinic visits.**

## Bronchodilator Efficacy:Studies 130 and 137

**Tiotropium was statistically superior to placebo:**
**FVC response (trough, average, and peak)**
**AM and PM PEFR, with mean effect sizes of 14.9 - 27 liters/minute (morning) and 21 - 33 liters/minute (evening)**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Dyspnea Efficacy:Studies 130 and 137

_**TDI “responders” at 6 months **_
_**(Co-primary Endpoint)**_
_**Study**__**	**__**	**__**Tiotropium**__**	**_** **_**Placebo**__**	**__**Salmeterol**_
** ****130****	****	****   42%******	****   26%****	****	****       35%**
** ****137****	****	****   45%*****	****   33%****	****	****       48%****
***p<0.05 (placebo comparison)   **
****p<0.01 (placebo comparison)**
**[Responders defined as patients with TDI score ******** 1]**

## Exclusions from TDI Data Set

## Dyspnea Efficacy:Studies 130 and 137

_**Number Needed to Treat (NNT) Analyses***_
_**	**__**Study**__**	**__**	**__**	**__**NNT**_
**	****130****	****	****	****	****6.45**
**	****137****	****	****	****	****8.6**
**	****Combined****	****	****7.5**
***To achieve one “responder,” defined as TDI ******** 1 ****	**

## Dyspnea Efficacy:Studies 130 and 137

_**TDI “responders” at 8 and 16 weeks**_
_**(Secondary Endpoints)**_
_**8 Weeks**_
_**Study**__**	**__**	**__**Tiotropium**__**	**__**Placebo**__**	**__**Salmeterol**_
** ****130****	****	****   40%*****	****   24%****	****	****       34%**
** ****137****	****	****   44%*****	****   31%****	****	****       47%****
_**16 Weeks**_
_**Study**__**	**__**	**__**Tiotropium**__**	**__**Placebo**__**	**__**Salmeterol**_
** ****130****	****	****   43%*****	****   27%****	****	****       34%**
** ****137****	****	****   42%*****	****   30%****	****	****       47%****
*** p<0.05 (placebo comparison)****	****  **p<0.01 (placebo comparison)**

## Dyspnea Efficacy:TDI - Analyses of Mean Values

**	****	****	****	****Statistically ****	****	****Difference**
**	****	****	****	****  ****Superior****	****	****       ******** 1**
**	****	****	****	****   **_**(Weeks)**__**	**__**	**__**  (Weeks)**_
**Study 130****	**** ****	****8, 16, 24 (all)****	****	****    8, 24**
**Study 137****	****	****8, 16, 24 (all)****	****	****8, 16, 24 (all)**
**Study 114****	****	****7, 13, 25, 37, 49 (all)****	****       49**
**Study 115****	****	****7, 13, 25, 37, 49 (all)****	****    37, 49**
**Study 122A*****	****1, 26, 39, 52 (not 7, 13)****	****        -**
**Study 122B*****	****1,7,13,26,39,52 (all)****	****1, 26, 29, 52**
***comparison: ipratropium**

## Dyspnea Efficacy:Shuttle Walk Test/ Borg Dyspnea Scale

**Studies 130 and 137 included a post-dose Shuttle Walk Test on Day 1, and Weeks 8, 16, and 25.**
**Shuttle Walk Test (SWT): a standardized test in which patients walk at a steady pace on a 10-meter course until they are unable to maintain the required speed without becoming unduly***** breathless*****.**
**The Modified Borg Dyspnea Scale was administered before and after each SWT.**
**Scale: ranges from 0 (“nothing at all”) to 10 (“maximal”)**

## Dyspnea Efficacy:Shuttle Walk Test/ Borg Dyspnea Scale

**SWT (Walking Distance)**
**No difference between groups in either study**
**Placebo numerically superior in 1 study**
**Walking distance did not increase during the study in any of the groups **
**Modified Borg Dyspnea Scale**
**Study 130: No differences between tiotropium and placebo, except Week 8 (Difference: 0.24 pre-exercise, 0.32 post-exercise)**
**Study 137: No differences between tiotropium and placebo**

## Dyspnea Efficacy:“COPD Symptom Score”

**Studies 130/137 and 114/115**
**Investigator’s assessment of the prior week**
**Wheezing, Shortness of Breath, Coughing, and Tightness of Chest**
**Each scored from 0-3**
**Results: Tiotropium statistically superior to placebo for “Shortness of Breath” at most visits**
**Effect Size: 0.13 to 0.36**
**Interpretation: Uncertain significance (validation, effect size)**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Other Efficacy Findings

**Studies 114 and 115**
**Tiotropium was statistically superior to placebo:**
**Physician’s Global Evaluation (effect size of 0.25 to 0.59 on a scale of 1-8)**
**As-needed albuterol (5-6 fewer doses per week)**
**No consistent meaningful difference shown:**
**COPD exacerbations or hospitalizations**
**St. George’s Hospital Respiratory Questionnaire**
**Medical Outcomes Study SF-36**

## Other Efficacy Findings

**Studies 122A and 122B (ipratropium-controlled)**
**No consistent effect: **
**as-needed albuterol use**
**COPD exacerbations or hospitalizations**

## Other Efficacy Findings

**Studies 130 and 137**
**Tiotropium was statistically superior to placebo: **
**Physician’s Global Evaluation (all test days except one; effect size of 0.11 to 0.59 on a scale of 1-8)**
**No consistent, meaningful difference shown:**
**As-needed albuterol**
**COPD exacerbations or hospitalizations**
**St. George’s Hospital Respiratory Questionnaire**
**Patient Satisfaction Questionnaire**

## Outline

**Background**
**PK/PD characteristics**
**Overview of P3 clinical program**
**Safety findings**
**Efficacy findings**
**Bronchodilator efficacy**
**Dyspnea efficacy**
**Other efficacy findings**
**Summary**

## Summary

**PK features of tiotropium are somewhat unique among inhaled bronchodilators**
**Very large volume of distribution **
**Very long terminal elimination half-life**
**Apparent tight tissue binding with slow release back into the circulation**

## Summary

**Safety:**
**Dry mouth is common, shows an age and gender interaction, and is more frequent than with ipratropium**
**Several AEs occurred more frequently with tiotropium than placebo.   Based on the mechanism of action and the observed age interaction, constipation and urinary tract infection may be important.**
**Possible effect on heart rate/rhythm may merit further evaluation**

## Summary

**Efficacy:**
**Appears to provide clinically meaningful bronchodilation**
**Duration of action supports once-daily dosing**
**Maximum bronchodilator effect reached after multiple daily doses **
**Demonstrable effect on TDI.  However, the clinical significance of this effect is not known.**
**Issues with the instrument and its implementation in the studies**
**Effect size (NNT)**

## Summary

**Other:**
**Safety/efficacy of concurrent “as-needed” ipratropium not addressed**

## Slide 59

## Slide 60

## Questions for the Committee

**1. Is the safety database for tiotropium bromide inhalation powder for the treatment of COPD patients adequate?**
**	****A) If not, what further safety data should be obtained?**
**	****B) Which of the safety data should be obtained prior to approval?**
**2. Are there specific safety concerns regarding the use of tiotropium bromide inhalation powder in the COPD patient population that merit specific attention in the product label?**

## Questions for the Committee

**3. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful bronchodilator effect when used in the chronic treatment of patients with COPD?**

## Questions for the Committee

**4. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful effect for the symptom of dyspnea in patients with COPD?**
**5. In general, what quality and quantity of data would constitute substantial and convincing evidence of a clinically meaningful benefit for the symptom of dyspnea in patients with COPD?**

## Slide 64