Drug Trials Snapshots: STIOLTO RESPIMAT

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The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race, and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

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Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the STIOLTO RESPIMAT Prescribing Information for complete information.

STIOLTO RESPIMAT (tiotropium bromide and olodaterol)
(sti-OL-to– RES peh mat)
Boehringer Ingelheim
Approval date: May 21, 2015

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

STIOLTO RESPIMAT is a long-term treatment for adults with a lung disease called COPD (chronic obstructive pulmonary disease). It is a combination of two drugs already used for COPD.

STIOLTO RESPIMAT should only be used to treat COPD and not for other breathing problems.

How is this drug used?

STIOLTO RESPIMAT is a spray inhaled through the mouth. Patients should use 2 puffs once a day at the same time each day.

What are the benefits of this drug?

STIOLTO RESPIMAT relaxes the muscles in the airways. This allows air to move easier in the lungs which helps prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath.

What are the benefits of this drug (results of trials used to assess efficacy)?

Table 2 below summarizes the co-primary efficacy endpoints for each trial separately. These were based on the FEV₁ response for STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg after 24 weeks.

Table 2. FEV₁ AUC_0-3hr and Trough FEV₁ response for STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg

	Trial 1			Trial 2
	n	Mean (L)	Difference (L) (95%CI)	n	Mean (L)	Difference (L) (95%CI)
FEV1 AUC0-3h response
STIOLTO RESPIMAT	522	0.256	_	502	0.268	_
Tiotropium 5 mcg	526	0.139	0.117 (0.094,0.140	500	0.165	0.103 (0.078,0.127)
Olodaterol 5 mcg	525	0.133	0.123 (0.100,0.146)	507	0.136	0.132 (0.108, 0.157)
Trough FEV1 response
STIOLTO RESPIMAT	521	0.136	_	497	0.145	_
Tiotropium 5 mcg	520	0.065	0.071 (0.047, 0.094)	498	0.096	0.050 (0.024, 0.075)
Olodaterol 5 mcg	519	0.054	0.082 (0.059, 0.106)	503	0.057	0.088 (0.063, 0.113)

L=liters; Pre-treatment baseline FEV₁: Trial 1=1.16 L; Trial 2=1.15 L
p≤0.0001 for all comparisons between STIOLTO RESPIMAT and the monotherapies
Source: STIOLTO RESPIMAT Prescribing Information, Section 14, Table 2

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

• Sex: The majority of patients in the trials were men. STIOLTO RESPIMAT appeared to be similarly effective in men and women.
• Race: The majority of patients in the trials were white or Asian. STIOLTO RESPIMAT appears to be similarly effective in these races. Differences in response to STIOLTO RESPIMAT in other races could not be determined.
• Age: All patients in the trial were 40 years of age and above. STIOLTO RESPIMAT was similarly effective in all age groups studied.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The tables below summarize the responses to STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol for the populations in each trial.

Table 3. Subgroup Analysis of Primary Endpoint (FEV₁ AUC_0-3h response) STIOLTO RESPIMAT v. Tiotropium

Subgroup	Trial 1			Trial 2
	SR v. Tio (L)	95% CI		SR v. Tio (L)	95% CI
		LL	UL		LL	UL
Sex
Male	0.118	0.09	0.145	0.097	0.066	0.127
Female	0.114	0.076	0.152	0.118	0.078	0.158
Age Group
>=17 - 65>	0.142	0.106	0.177	0.099	0.062	0.135
>=65 years	0.091	0.057	0.125	0.123	0.087	0.159
>=75 years	0.12	0.066	0.174	0.024	-0.036	0.084
Race
White	0.115	0.087	0.143	0.112	0.082	0.142
Black or African American	NE	NE	NE	NE	NE	NE
Asian	0.123	0.079	0.166	0.089	0.046	0.132
American Indian or Alaska Native	NE	NE	NE	NE	NE	NE
Unknown	NE	NE	NE	NE	NE	NE
Region
United States	0.086	0.03	0.141	0.126	0.068	0.183
Rest of the World	0.123	0.098	0.147	0.097	0.07	0.125

SR= STIOLTO RESPIMAT
Tio= Tiotropium 5mcg
NE=Not evaluable (too few patients to perform subgroup analysis)
L= liters
Source: Company Clinical Trial Data

Table 4. Subgroup Analysis of Primary Endpoint (trough FEV₁ response) STIOLTO RESPIMAT v. Tiotropium

Subgroup	Trial 1			Trial 2
	SR v. Tio (L)	95% CI		SR v. Tio (L)	95% CI
		LL	UL		LL	UL
Sex
Male	0.071	0.043	0.1	0.05	0.019	0.081
Female	0.066	0.028	0.105	0.05	0.009	0.091
Age Group
>=17 - 65>	0.088	0.051	0.124	0.053	0.016	0.091
>=65 years	0.059	0.026	0.093	0.06	0.023	0.097
>=75 years	0.04	-0.017	0.098	-0.019	-0.082	0.044
Race
White	0.064	0.036	0.093	0.057	0.026	0.087
Black or African  American	NE	NE	NE	NE	NE	NE
Asian	0.088	0.044	0.131	0.036	-0.01	0.082
American Indian or Alaska Native	NE	NE	NE	NE	NE	NE
Unknown	NE	NE	NE	NE	NE	NE
Region
United States	0.021	-0.035	0.076	0.083	0.024	0.143
Rest of the World	0.08	0.054	0.106	0.042	0.014	0.07

SR= STIOLTO RESPIMAT
Tio= Tiotropium 5mcg
NE=Not evaluable (too few patients to perform subgroup analysis)
L=liters
Source: Company Clinical Trial Data

Table 5. Subgroup Analysis of Primary Endpoint (FEV₁ AUC_0-3h response) STIOLTO RESPIMAT v. Olodaterol

Subgroup	Trial 1			Trial 2
	SR v. Olo (L)	95% CI		SR v. Olo (L)	95% CI
		LL	UL		LL	UL
Sex
Male	0.122	0.093	0.15	0.127	0.097	0.157
Female	0.125	0.087	0.163	0.147	0.106	0.187
Age Group
>=17 - 65>	0.154	0.119	0.189	0.148	0.111	0.186
>=65 years	0.085	0.051	0.119	0.111	0.076	0.147
>=75 years	0.147	0.089	0.206	0.088	0.03	0.146
Race
White	0.111	0.082	0.139	0.13	0.1	0.159
Black or African American	NE	NE	NE	NE	NE	NE
Asian	0.155	0.112	0.198	0.144	0.1	0.188
American Indian or Alaska Native	NE	NE	NE	NE	NE	NE
Unknown	NE	NE	NE	NE	NE	NE
Region
United States	0.108	0.051	0.165	0.151	0.094	0.208
Rest of the World	0.125	0.1	0.15	0.128	0.101	0.155

SR= STIOLTO RESPIMAT
Olo=Olodaterol 5 mcg
NE=Not evaluable (too few patients to perform subgroup analysis)
L=liters
Source: Company Clinical Trial Data

Table 6. Subgroup Analysis of Primary Endpoint (trough FEV₁ response) STIOLTO RESPIMAT v. Olodaterol

Subgroup	Trial 1			Trial 2
	SR v. Olo (L)	95% CI		SR v. Olo (L)	95% CI
		LL	UL		LL	UL
Sex
Male	0.088	0.059	0.117	0.09	0.059	0.121
Female	0.067	0.029	0.106	0.083	0.041	0.125
Age Group
>=17 - 65>	0.096	0.06	0.133	0.105	0.066	0.144
>=65 years	0.062	0.028	0.096	0.065	0.028	0.102
>=75 years	0.106	0.043	0.167	0.073	0.012	0.134
Race
White	0.062	0.033	0.091	0.087	0.057	0.118
Black or African American	NE	NE	NE	NE	NE	NE
Asian	0.127	0.084	0.17	0.098	0.051	0.144
American Indian or Alaska Native	NE	NE	NE	NE	NE	NE
Unknown	NE	NE	NE	NE	NE	NE
Region
United States	0.064	0.007	0.12	0.107	0.048	0.166
Rest of the World	0.085	0.059	0.111	0.083	0.055	0.111

SR= STIOLTO RESPIMAT; Olo=Olodaterol 5 mcg
NE=Not evaluable (too few patients to perform subgroup analysis)
L=liters
Source: Company Clinical Trial Data

What are the possible side effects?

The most common side effects of STIOLTO RESPIMAT include common cold, cough, and back pain.

STIOLTO RESPIMAT should never be used to treat asthma. Using STIOLTO RESPIMAT in someone with asthma can worsen the asthma and lead to death.

STIOLTO RESPIMAT can cause serious side effects, including:

• Severe allergic reactions, including rash, itchy and raised patches of skin, breathing problems, and swelling of the mouth, face, and tongue
• Sudden shortness of breath that may be life-threatening
• Heart problems including fast or irregular heartbeat, chest pain, and an increase in blood pressure
• New or worsening eye problem called narrow-angle glaucoma: symptoms can include eye pain, blurry vision, red eyes and seeing halos or colored images around lights
• New or worsening problems with urination: symptoms can include difficulty passing urine or painful urination
• Low blood potassium
• High blood sugar

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions for the two pooled trials. The population represented is the Safety population, which includes any patient who received at least one dose of trial drug.

Table 7. Number and Frequency of Adverse Drug Reactions in STIOLTO RESPIMAT arm Greater than 3% and Higher than Tiotropium and/or Olodaterol (Pooled data from the trials)

Adverse Drug Reaction	STIOLTO RESPIMAT (once daily) n=1029 n (%)	Tiotropium (5 mcg once daily) n=1033 n (%)	Olodaterol (5 mcg once daily) n=1038 n (%)
Nasopharyngitis	128 (12.4)	121 (11.7)	131 (12.6)
Cough	40 (3.9)	45 (4.4)	31 (3.0)
Back Pain	37 (3.6)	19 (1.8)	35 (3.4)

Source: STIOLTO RESPIMAT Prescribing Information, Section 6, Table 1

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race, and age.

• Sex: The majority of patients in the trials were men. The risk of overall side effects appeared to be similar in men and women.
• Race: The majority of patients in the trials were white or Asian. The risk of overall side effects appeared to be similar in these races. Differences in side effects in other races could not be determined.
• Age: All patients in the trial were 40 years of age and above. The risk of overall side effects was similar in all age groups studied.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes adverse events in the two trials by subgroups.

Table 8. Adverse Events During Treatment in the Pooled Trials

Subgroup	STIOLTO RESPIMAT		Tiotropium 5 mcg		Olodaterol 5 mcg
	x (%)*	Total, n	x (%)*	Total, n	x (%)*	Total, n
Any TEAEs**	761 (74.0)	1029	757 (73.3)	1033	795 (76.6)	1038
Sex
Male	524 (71.5)	733	534 (70.7)	755	573 (75.0)	764
Female	237 (80.1)	296	223 (80.2)	278	222 (81.0)	274
Age Group
>=17 - 65>	379 (72.2)	525	376 (69.6)	540	389 (74.8)	520
>=65 years	305 (74.9)	407	290 (75.7)	383	319 (78.2)	408
>=75 years	77 (79.4)	97	91 (82.7)	110	87 (79.1)	110
Race
White	555 (75.8)	732	537 (75.2)	714	564 (77.4)	729
Black or African American	14 (87.5)	16	7 (58.3)	12	10 (83.3)	12
Asian	169 (67.6)	250	190 (68.3)	278	210 (75.3)	279
American Indian or Alaska Native	6 (85.7)	7	11 (91.7)	12	1 (100.0)	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Unknown	17 (70.8)	24	12 (70.6)	17	10 (58.8)	17
Region
United States	132 (80.0)	165	130 (78.3)	166	130 (79.3)	164
Rest of the World	629 (72.8)	864	627 (72.3)	867	665 (76.1)	874

* Percentages are calculated based on the number of subjects in the subgroup per arm
**Treatment Emergent Adverse Events
Source: Company Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved STIOLTO RESPIMAT based on evidence from two clinical trials which included 3100 adult patients with COPD who received STIOLTO RESPIMAT or one of its individual components (tiotropium or olodaterol). The trials were conducted in North America, Western Europe, East Asia, Eastern Europe, Latin America, India, Australia, New Zealand, and South Africa.

Figure 1 summarizes how many men and women were enrolled in the clinical trials.

Figure 1. Baseline Demographics by Sex

Source: Company Clinical Trial Data

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trials.

Figure 2. Baseline Demographics by Race

Source: Company Clinical Trial Data

Table 1. Demographics of Efficacy Trials by Race

Race	Number of Patients	Percentage
White	2175	70.2%
Black or African American	40	1.3%
Asian	807	26.0%
American Indian or Alaska Native	20	0.6%
Unknown	58	1.9%

Source: Company Clinical Trial Data

The figure below summarizes the age of patients in the clinical trial. Because COPD is rarely seen in younger adults, the trials only included patients 40 years of age and above.

Figure 3. Baseline Demographics by Age

Source: Company Clinical Trial Data

Who participated in trials?

Table 9. Baseline Demographics for the Trials

Demographic Parameters	Trial #1			Trial #2				Total                (N=3100)   n(%)
	STIOLTO RESPIMAT (N=522) n(%)*	Tiotropium (N=527) n(%)	Olodaterol (N=528) n(%)	STIOLTO RESPIMAT (N=507) n(%)	Tiotropium (N=506) n(%)	Olodaterol (N=510) n(%)
Sex
Male	384 (73.6)	383 (72.7)	386(73.1)	349 (68.8)	372 (73.5)	378 (74.1)		2252 (72.6)
Female	138 (26.4)	144 (27.3)	142(26.9)	158 (31.2)	134 (26.5)	132 (25.9)		848 (27.4)
Age
Mean years (SD)	64.8 (8.2)	64.2 (8.5)	63.7 (8.0)	62.7 (8.4)	63.5 (8.7)	64.7 (8.3)		64.0 (8.4)
Median (years)	65	64	64	64	64	65		64
Min, Max (years)	42, 85	40, 89	40, 86	40, 82	40, 97	43, 87		40, 97
Age Group
>=17 - 65>	240 (46.0)	268 (50.9)	278(52.7)	285 (56.2)	272 (53.8)	242 (47.5)	1585 (51.1)
>=65 - 75>	223 (42.7)	199 (37.8)	205(38.8)	184 (36.3)	184 (36.4)	203 (39.8)	1198 (38.6)
>=75 years	59 (11.3)	60 (11.4)	45 (8.5)	38 (7.5)	50 (9.9)	65 (12.7)	317 (10.2)
Race
White	357 (68.4)	356 (67.6)	358(67.8)	375 (74.0)	358 (70.8)	371 (72.7)	2175 (70.2)
Black or African American	5 (1.0)	5 (0.9)	4 (0.8)	11 (2.2)	7 (1.4)	8 (1.6)	40 (1.3)
Asian	132 (25.3)	141 (26.8)	150(28.4)	118 (23.3)	137 (27.1)	129 (25.3)	807 (26)
American Indian or Alaska Native	6 (1.1)	9 (1.7)	0 (0.0)	1 (0.2)	3 (0.6)	1 (0.2)	20 (0.6)
Native Hawaiian or Other Pacific Islander	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0
Unknown	22 (4.2)	16 (3.0)	16 (3.0)	2 (0.4)	1 (0.2)	1 (0.2)	58 (1.9)
Region
United States	73 (14.0)	86 (16.3)	78 (14.8)	92 (18.1)	80 (15.8)	86 (16.9)	495 (16)
Rest of the World	449 (86.0)	441 (83.7)	450 (85.2)	415 (81.9)	426 (84.2)	424 (83.1)	2605 (84)

* Percentages are calculated based on the number of subjects in the subgroup per arm
Source: Company Clinical Trial Data

How were the trials designed?

There were two trials that evaluated the benefit and side effects of STIOLTO RESPIMAT. In each trial, patients were randomly assigned to receive either STIOLTO RESPIMAT or one of its individual components (tiotropium or olodaterol) once daily for 52 weeks. The benefit of STIOLTO RESPIMAT was measured at 24 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.

The trials measured how well air flows through the lungs and compared STIOLTO RESPIMAT to each of the other two drugs.

How were the trials designed?

Two randomized, multicenter, double-blind, active controlled, trials were conducted to assess the efficacy and safety of 24 weeks of once daily treatment of orally inhaled tiotropium and olodaterol fixed dose combination (5mcg/5mcg) (delivered by the Respimat® Inhaler) in comparison to the individual components (5 mcg tiotropium, 5 mcg olodaterol delivered by the Respimat® Inhaler) in patients with chronic obstructive pulmonary disease. The trials enrolled patients with a diagnosis of moderate to severe COPD, with the following pertinent entry criteria: a) 40 years of age and older; b) FEV₁

The co-primary endpoints for the trials were FEV₁ AUC_0-3h and trough FEV₁response at week 24. Safety assessments continued until Week 52.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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