A Study of LY2216684 in Healthy Participants Receiving Albuterol or Propanolol

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01263197
• Collaborator: (none)
• Enrollment: 48
• Location: 1
• Arms: 6
• Duration (Months): 3
• Patients Per Site Per Month: 16.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effect of LY2216684 on heart rate of participants receiving Albuterol and Propranolol. Information about any side effects that may occur will also be collected.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: LY2216684; Drug: albuterol; Drug: propranolol; Drug: placebo for LY2216684; Drug: placebo for albuterol; Drug: placebo for propranolol	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effect of LY2216684 on Heart Rate and Blood Pressure in Healthy Subjects Receiving Oral Doses of Albuterol or Propranolol
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY2216684, albuterol, LY2216684+albuterol LY2216684 as an 18 milligram (mg) oral dose on days 1-5 and placebo for albuterol on days 1, 3 and 5 in first intervention period, placebo for LY2216684 on days 1-5 and albuterol as a 2 mg oral dose on days 1, 3 and 5 in the second intervention period, and LY2216684 as an 18 mg oral dose on days 1-5 and albuterol as a 2 mg oral dose on days 1, 3 and 5 in the third intervention period. There is a minimum 7 day washout between each intervention period.	Drug: LY2216684; administered orally; Drug: albuterol; administered orally; Drug: placebo for LY2216684; administered orally; Drug: placebo for albuterol; administered orally
Experimental: albuterol, LY2216684+albuterol, LY2216684 Placebo for LY2216684 on days 1-5 and albuterol as a 2 mg oral dose on days 1, 3 and 5 in the first intervention period, LY2216684 as an 18 mg oral dose on days 1-5 and albuterol as a 2 mg oral dose on days 1, 3 and 5 in the second intervention period, and LY2216684 as an 18 mg oral dose on days 1-5 and placebo for albuterol on days 1, 3 and 5 in third intervention period. There is a minimum 7 day washout between each intervention period.	Drug: LY2216684; administered orally; Drug: albuterol; administered orally; Drug: placebo for LY2216684; administered orally; Drug: placebo for albuterol; administered orally
Experimental: LY2216684+albuterol, LY2216684, albuterol LY2216684 as an 18 mg oral dose on days 1-5 and albuterol as a 2 mg oral dose on days 1, 3 and 5 in the first intervention period, LY2216684 as an 18 mg oral dose on days 1-5 and placebo for albuterol on days 1, 3 and 5 in second intervention period, Placebo for LY2216684 on days 1-5 and albuterol as a 2 mg oral dose on days 1, 3 and 5 in the third intervention period. There is a minimum 7 day washout between each intervention period.	Drug: LY2216684; administered orally; Drug: albuterol; administered orally; Drug: placebo for LY2216684; administered orally; Drug: placebo for albuterol; administered orally
Experimental: LY2216684, propranolol, LY2216684+propranolol LY2216684 as an 18 mg oral dose on days 1-5 and placebo for propranolol on days 1, 3 and 5 in first intervention period, placebo for LY2216684 on days 1-5 and propranolol as a 40 mg oral dose on days 1, 3 and 5 in the second intervention period, and LY2216684 as an 18 mg oral dose on days 1-5 and propranolol as a 40 mg oral dose on days 1, 3 and 5 in the third intervention period. There is a minimum 7 day washout between each intervention period.	Drug: LY2216684; administered orally; Drug: propranolol; administered orally; Drug: placebo for LY2216684; administered orally; Drug: placebo for propranolol; administered orally
Experimental: propranolol, LY2216684+propranolol, LY2216684 Placebo for LY2216684 on days 1-5 and propranolol as a 40 mg oral dose on days 1, 3 and 5 in the first intervention period, LY2216684 as an 18 mg oral dose on days 1-5 and propranolol as a 40 mg oral dose on days 1, 3 and 5 in the second intervention period, and LY2216684 as an 18 mg oral dose on days 1-5 and placebo for propranolol on days 1, 3 and 5 in third intervention period. There is a minimum 7 day washout between each intervention period.	Drug: LY2216684; administered orally; Drug: propranolol; administered orally; Drug: placebo for LY2216684; administered orally; Drug: placebo for propranolol; administered orally
Experimental: LY2216684+propranolol, LY2216684, propranolol LY2216684 as an 18 mg oral dose on days 1-5 and propranolol as a 40 mg oral dose on days 1, 3 and 5 in the first intervention period, LY2216684 as an 18 mg oral dose on days 1-5 and placebo for propranolol on days 1, 3 and 5 in second intervention period, placebo for LY2216684 on days 1-5 and propranolol as a 40 mg oral dose on days 1, 3 and 5 in the third intervention period. There is a minimum 7 day washout between each intervention period.	Drug: LY2216684; administered orally; Drug: propranolol; administered orally; Drug: placebo for LY2216684; administered orally; Drug: placebo for propranolol; administered orally

Outcome Measures

Primary Outcome Measures

1. Maximum, Minimum and Average Changes in Heart Rate [Period 1, 2, 3: Baseline, Days 1 and 3 and 5 (postdose every 10 minutes through 24 hours postdose)]

   Using a Holter monitor, heart rate was recorded every 10 minutes through 24 hours postdose on Days 1, 3, and 5 of each period. Baseline heart rate was the average of 10-minute readings taken over 2 hours prior to dosing on Day 1 of each period. Postdose heart rate was summarized over 1-hour increments using the average of the 10-minute readings within these intervals. The postdose heart rate for a day was the average heart rate for 24 hours. The least squares (LS) mean change from baseline heart rate is reported. LS mean was calculated using a mixed effects model and adjusted for participant, sequence, period, time, treatment, and time by treatment interaction.

Secondary Outcome Measures

1. Maximum, Minimum and Average Changes in Systolic Blood Pressure [Period 1, 2, 3: Baseline, Days 1 and 3 and 5 (postdose every 15 minutes from 0600 hours through 2200 hours and every hour from 2200 hours through 0600 hours)]

   Systolic blood pressure was measured using ambulatory blood pressure monitoring (ABPM) recorded every 15 minutes during the daytime (0600 through 2200 hours) and every hour throughout the night time (2200 through 0600 hours) on Days 1, 3, and 5 of each period. Baseline systolic blood pressure was the average of 15-minute readings taken over 2 hours prior to dosing on Day 1 of each period. Postdose systolic blood pressure from ABPM was summarized over 1-hour increments using the average of the 15-minute readings within these intervals. The postdose systolic blood pressure for a day was the average systolic blood pressure for 24 hours. The least squares (LS) mean change from baseline systolic blood pressure is reported. LS mean was calculated using a mixed effects model and adjusted for participant, sequence, period, time, treatment, and time by treatment interaction.

2. Maximum, Minimum and Average Changes in Diastolic Blood Pressure [Period 1, 2, 3: Baseline, Days 1 and 3 and 5 (postdose every 15 minutes from 0600 hours through 2200 hours and every hour from 2200 hours through 0600 hours)]

   Diastolic blood pressure was measured using ambulatory blood pressure monitoring (ABPM) recorded every 15 minutes during the daytime (0600 through 2200 hours) and every hour throughout the night time (2200 through 0600 hours) on Days 1, 3, and 5 of each period. Baseline diastolic blood pressure was the average of 15-minute readings taken over 2 hours prior to dosing on Day 1 of each period. Postdose diastolic blood pressure from ABPM was summarized over 1-hour increments using the average of the 15-minute readings within these intervals. The postdose diastolic blood pressure for a day was the average diastolic blood pressure for 24 hours. The least squares (LS) mean change from baseline diastolic blood pressure is reported. LS mean was calculated using a mixed effects model and adjusted for participant, sequence, period, time, treatment, and time by treatment interaction.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Are overtly healthy, as determined by medical history and physical examination.

• Male participants - Agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug.

• Female participants - Are women of child-bearing potential who test negative for pregnancy at the time of enrollment, have used a reliable method of birth control for 6 weeks prior to administration of study drug, and agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug; or Women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause [at least 1 year without menses or 6 months without menses and a follicle stimulating hormone (FSH) >40 milli-international units per milliliter (mIU/mL)].

• Have a body weight >50 kilograms (kg).

• Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator.

• Have venous access sufficient to allow blood sampling as per the protocol.

• Have normal blood pressure and pulse rate (sitting position) as determined by the investigator.

• Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.

• Have given written informed consent approved by Lilly and the ethical review board (ERB) governing the site.

Exclusion Criteria:

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device other than the study drug, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

• Have known allergies to LY2216684, albuterol (Group 1 only), propranolol (Group 2 only), or related compounds.

• Are persons who have previously completed or withdrawn from this study or any other study investigating LY2216684 within 6 months prior to screening.

• Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study.

• Have a history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data.

• Have a history of or current asthma, including exercise induced asthma.

• Have a history or show evidence of significant active neuropsychiatric disease or have a history of suicide attempt or ideation.

• Regularly use known drugs of abuse and/or show positive findings on urinary drug screening.

• Show evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies.

• Show evidence of hepatitis C and/or positive hepatitis C antibody.

• Show evidence of hepatitis B and/or positive hepatitis B surface antigen.

• Are women with a positive pregnancy test or women who are lactating.

• Intend to use over-the-counter or prescription medication (including hormonal contraceptives) within 14 days prior to dosing unless deemed acceptable by the investigator and Sponsor's medical monitor

• Have donated blood of more than 500 milliliters (mL) within the last month.

• Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption 48 hours prior to check-in in each period and while resident at the Clinical Research Unit (CRU) [1 unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits].

• Consume 5 or more cups of coffee (or other beverages of comparable caffeine content) per day, on a habitual basis, or any participants unwilling to adhere to study caffeine restrictions.

• Have used any tobacco-containing or nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to enrollment.

• Have consumed grapefruit or grapefruit-containing products 7 days prior to enrollment and during the study.

• Have a documented or suspected history of glaucoma.

• Participants determined to be unsuitable by the investigator for any reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Evansville	Indiana	United States

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01263197
• Other Study ID Numbers: 12598; H9P-EW-LNCI
• First Posted: Dec 20, 2010
• Last Update Posted: Jan 29, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Phenylethyl Alcohol; Propranolol; Albuterol

Study Results

Participant Flow

Pre-assignment Detail	This was a 3-period, crossover study conducted in 2 groups. Participants were randomized to 1 of 3 sequences in either the albuterol group (Group 1) or 1 of 3 sequences in the propranolol group (Group 2).

Arm/Group Title	Group 1, Seq 1: LY2216684, Albuterol, LY2216684+Albuterol	Group 1, Seq 2: Albuterol, LY2216684+Albuterol, LY2216684	Group 1, Seq 3: LY2216684+Albuterol, LY2216684, Albuterol	Group 2, Seq 1: LY2216684, Propranolol, LY2216684+Propranolol	Group 2, Seq 2: Propranolol, LY2216684+Propranolol, LY2216684	Group 2, Seq 3: LY2216684+Propranolol, LY2216684, Propranolol
Arm/Group Description	Group 1, Sequence (Seq) 1 First intervention: LY2216684 administered as an 18-milligram (mg) oral dose (two 9-mg tablets) once daily (QD) on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5. Second intervention: Oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5. Third intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5. There was a minimum 7-day washout between each intervention period.	Group 1, Sequence 2 First intervention: Oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5. Second intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5. Third intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5. There was a minimum 7-day washout between each intervention period.	Group 1, Sequence 3 First intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5. Second intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5. Third intervention: Oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5. There was a minimum 7-day washout between each intervention period.	Group 2, Sequence 1 First intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5. Second intervention: Oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5. Third intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5. There was a minimum 7-day washout between each intervention period.	Group 2, Sequence 2 First intervention: Oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5. Second intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5. Third intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5. There was a minimum 7-day washout between each intervention period.	Group 2, Sequence 3 First intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5. Second intervention: LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5. Third intervention: Oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5. There was a minimum 7-day washout between each intervention period.
Period Title: First Intervention (Period 1)
STARTED	8	8	8	8	8	8
COMPLETED	8	8	8	8	8	7
NOT COMPLETED	0	0	0	0	0	1
Period Title: First Intervention (Period 1)
STARTED	8	8	8	8	8	7
COMPLETED	8	8	8	8	7	7
NOT COMPLETED	0	0	0	0	1	0
Period Title: First Intervention (Period 1)
STARTED	8	8	8	8	7	7
COMPLETED	8	8	8	8	7	7
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention (Period 1)
STARTED	8	8	8	8	7	7
COMPLETED	8	8	8	7	7	6
NOT COMPLETED	0	0	0	1	0	1
Period Title: First Intervention (Period 1)
STARTED	8	8	8	7	7	6
COMPLETED	8	7	8	7	7	6
NOT COMPLETED	0	1	0	0	0	0

Baseline Characteristics

Arm/Group Title	Group 1, Any Sequence (LY2216684, Albuterol, or Placebo)	Group 2, Any Sequence (LY2216684, Propranolol, or Placebo)	Total
Arm/Group Description	Participants were administered LY2216684, albuterol, or placebo during Periods 1, 2, and 3. LY2216684 or placebo was administered as an 18-milligram (mg) oral dose (two 9-mg tablets) once daily (QD) on Days 1 through 5 of each period. Albuterol or placebo was co-administered as a 2-mg oral dose (one 2-mg tablet) QD on Days 1, 3, and 5 of each period.	Participants were administered LY2216684, propranolol, or placebo during Periods 1, 2, and 3. LY2216684 or placebo was administered as an 18-milligram (mg) oral dose (two 9-mg tablets) QD on Days 1 through 5 of each period. Propranolol or placebo was co-administered as a 40-mg oral dose (one 40-mg tablet) QD on Days 1, 3, and 5 of each period.	Total of all reporting groups
Overall Participants	24	24	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.5 (12.0)	36.3 (10.9)	35.9 (11.4)
Sex: Female, Male (Count of Participants)
Female	7 29.2%	10 41.7%	17 35.4%
Male	17 70.8%	14 58.3%	31 64.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8.3%	1 4.2%	3 6.3%
Not Hispanic or Latino	22 91.7%	23 95.8%	45 93.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	6 25%	10 41.7%	16 33.3%
White	16 66.7%	14 58.3%	30 62.5%
More than 1 race	2 8.3%	0 0%	2 4.2%
Region of Enrollment (Count of Participants)
United States	24 100%	24 100%	48 100%
Body Mass Index (BMI) (kilograms per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per square meter (kg/m^2)]	26.10 (3.40)	28.04 (3.33)	27.07 (3.47)

Outcome Measures

1. Primary Outcome

Title	Maximum, Minimum and Average Changes in Heart Rate
Description	Using a Holter monitor, heart rate was recorded every 10 minutes through 24 hours postdose on Days 1, 3, and 5 of each period. Baseline heart rate was the average of 10-minute readings taken over 2 hours prior to dosing on Day 1 of each period. Postdose heart rate was summarized over 1-hour increments using the average of the 10-minute readings within these intervals. The postdose heart rate for a day was the average heart rate for 24 hours. The least squares (LS) mean change from baseline heart rate is reported. LS mean was calculated using a mixed effects model and adjusted for participant, sequence, period, time, treatment, and time by treatment interaction.
Time Frame	Period 1, 2, 3: Baseline, Days 1 and 3 and 5 (postdose every 10 minutes through 24 hours postdose)

Outcome Measure Data

Analysis Population Description

Randomized participants with at least 1 postdose heart rate measurement.

Arm/Group Title	LY2216684 (Group 1)	Albuterol	LY2216684+Albuterol	LY2216684 (Group 2)	Propranolol	LY2216684+Propranolol
Arm/Group Description	Participants randomized to Group 1 who received LY2216684 administered as an 18-milligram (mg) oral dose (two 9-mg tablets) once daily (QD) on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 1 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 1 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.
Measure Participants	24	24	24	22	22	22
Day 1 Maximum Change	33.4	15.7	35.7	31.1	9.41	17.2
Day 1 Minimum Change	-9.23	-15.2	-9.03	-5.81	-14.8	-10.4
Day 1 Average Change	9.33	-0.788	10.9	9.55	-3.94	1.11
Day 3 Maximum Change	36.3	19.7	37.2	37.2	15.2	27.3
Day 3 Minimum Change	-7.05	-16.3	-9.76	-5.94	-16.1	-9.40
Day 3 Average Change	12.6	0.102	14.3	14.2	-4.34	6.01
Day 5 Maximum Change	40.4	19.9	39.3	36.9	14.0	26.3
Day 5 Minimum Change	-9.47	-16.3	-7.27	-5.21	-15.4	-9.46
Day 5 Average Change	14.6	1.05	15.7	15.0	-3.65	6.25

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.27
	Confidence Interval	(2-Sided) 95%; -3.96 to 8.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.198
	Confidence Interval	(2-Sided) 95%; -3.19 to 3.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; -2.25 to 5.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	20.0
	Confidence Interval	(2-Sided) 95%; 13.7 to 26.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.19
	Confidence Interval	(2-Sided) 95%; 2.80 to 9.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	11.7
	Confidence Interval	(2-Sided) 95%; 7.87 to 15.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-13.9
	Confidence Interval	(2-Sided) 95%; -18.9 to -8.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.62
	Confidence Interval	(2-Sided) 95%; -7.67 to -1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-8.43
	Confidence Interval	(2-Sided) 95%; -11.5 to -5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.80
	Confidence Interval	(2-Sided) 95%; 2.72 to 12.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.38
	Confidence Interval	(2-Sided) 95%; 1.30 to 7.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.06
	Confidence Interval	(2-Sided) 95%; 1.93 to 8.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 3 where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.905
	Confidence Interval	(2-Sided) 95%; -5.49 to 7.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 3 where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.71
	Confidence Interval	(2-Sided) 95%; -6.96 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.66
	Confidence Interval	(2-Sided) 95%; -2.85 to 6.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 3 where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	17.5
	Confidence Interval	(2-Sided) 95%; 11.2 to 23.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.51
	Confidence Interval	(2-Sided) 95%; 2.32 to 10.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	14.2
	Confidence Interval	(2-Sided) 95%; 9.75 to 18.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.98
	Confidence Interval	(2-Sided) 95%; -14.6 to -5.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.46
	Confidence Interval	(2-Sided) 95%; -7.22 to 0.297
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-8.16
	Confidence Interval	(2-Sided) 95%; -11.6 to -4.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	12.1
	Confidence Interval	(2-Sided) 95%; 7.39 to 16.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.70
	Confidence Interval	(2-Sided) 95%; 2.91 to 10.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	10.3
	Confidence Interval	(2-Sided) 95%; 6.88 to 13.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.06
	Confidence Interval	(2-Sided) 95%; -7.41 to 5.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.20
	Confidence Interval	(2-Sided) 95%; -2.15 to 6.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; -3.23 to 5.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 5 where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	19.4
	Confidence Interval	(2-Sided) 95%; 13.2 to 25.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 5 where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	9.04
	Confidence Interval	(2-Sided) 95%; 4.78 to 13.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	14.7
	Confidence Interval	(2-Sided) 95%; 10.4 to 18.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-10.6
	Confidence Interval	(2-Sided) 95%; -15.6 to -5.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.25
	Confidence Interval	(2-Sided) 95%; -9.26 to 0.764
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-8.76
	Confidence Interval	(2-Sided) 95%; -12.6 to -4.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in heart rate on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	12.3
	Confidence Interval	(2-Sided) 95%; 7.17 to 17.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in heart rate on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.95
	Confidence Interval	(2-Sided) 95%; 0.917 to 11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in heart rate on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	9.90
	Confidence Interval	(2-Sided) 95%; 5.98 to 13.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Maximum, Minimum and Average Changes in Systolic Blood Pressure
Description	Systolic blood pressure was measured using ambulatory blood pressure monitoring (ABPM) recorded every 15 minutes during the daytime (0600 through 2200 hours) and every hour throughout the night time (2200 through 0600 hours) on Days 1, 3, and 5 of each period. Baseline systolic blood pressure was the average of 15-minute readings taken over 2 hours prior to dosing on Day 1 of each period. Postdose systolic blood pressure from ABPM was summarized over 1-hour increments using the average of the 15-minute readings within these intervals. The postdose systolic blood pressure for a day was the average systolic blood pressure for 24 hours. The least squares (LS) mean change from baseline systolic blood pressure is reported. LS mean was calculated using a mixed effects model and adjusted for participant, sequence, period, time, treatment, and time by treatment interaction.
Time Frame	Period 1, 2, 3: Baseline, Days 1 and 3 and 5 (postdose every 15 minutes from 0600 hours through 2200 hours and every hour from 2200 hours through 0600 hours)

Outcome Measure Data

Analysis Population Description

Randomized participants with at least 1 postdose systolic blood pressure measurement.

Arm/Group Title	LY2216684 (Group 1)	Albuterol	LY2216684+Albuterol	LY2216684 (Group 2)	Propranolol	LY2216684+Propranolol
Arm/Group Description	Participants randomized to Group 1 who received LY2216684 administered as an 18-milligram (mg) oral dose (two 9-mg tablets) once daily (QD) on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 1 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 1 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.
Measure Participants	24	23	24	22	22	22
Day 1 Maximum Change	14.1	15.2	15.8	17.3	9.39	10.9
Day 1 Minimum Change	-18.0	-20.5	-15.3	-17.7	-29.0	-17.5
Day 1 Average Change	-0.986	-0.912	1.69	1.73	-8.50	-1.35
Day 3 Maximum Change	13.5	15.6	13.5	15.3	7.99	11.2
Day 3 Minimum Change	-19.4	-24.9	-20.6	-18.5	-27.2	-23.3
Day 3 Average Change	-1.65	-1.87	-1.99	0.289	-8.75	-3.91
Day 5 Maximum Change	13.9	15.9	16.2	14.7	11.1	13.1
Day 5 Minimum Change	-20.8	-22.1	-18.9	-21.1	-24.9	-21.2
Day 5 Average Change	-2.07	-2.36	-0.233	-1.72	-6.83	-2.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.62
	Confidence Interval	(2-Sided) 95%; -1.81 to 5.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.73
	Confidence Interval	(2-Sided) 95%; -1.38 to 6.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.67
	Confidence Interval	(2-Sided) 95%; -0.209 to 5.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.541
	Confidence Interval	(2-Sided) 95%; -2.94 to 4.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.26
	Confidence Interval	(2-Sided) 95%; 1.09 to 9.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.60
	Confidence Interval	(2-Sided) 95%; -0.322 to 5.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.46
	Confidence Interval	(2-Sided) 95%; -11.5 to -1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.171
	Confidence Interval	(2-Sided) 95%; -5.21 to 5.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.09
	Confidence Interval	(2-Sided) 95%; -6.73 to 0.557
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; -3.61 to 6.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	11.4
	Confidence Interval	(2-Sided) 95%; 5.99 to 16.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.15
	Confidence Interval	(2-Sided) 95%; 3.49 to 10.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.0309
	Confidence Interval	(2-Sided) 95%; -5.28 to 5.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -5.93 to 3.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.333
	Confidence Interval	(2-Sided) 95%; -4.35 to 3.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.11
	Confidence Interval	(2-Sided) 95%; -7.42 to 3.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.36
	Confidence Interval	(2-Sided) 95%; -0.404 to 9.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.119
	Confidence Interval	(2-Sided) 95%; -4.14 to 3.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.16
	Confidence Interval	(2-Sided) 95%; -9.69 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.76
	Confidence Interval	(2-Sided) 95%; -10.2 to 0.718
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.20
	Confidence Interval	(2-Sided) 95%; -8.71 to 0.320
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.20
	Confidence Interval	(2-Sided) 95%; -2.34 to 8.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.95
	Confidence Interval	(2-Sided) 95%; -1.54 to 9.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.84
	Confidence Interval	(2-Sided) 95%; 0.319 to 9.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.34
	Confidence Interval	(2-Sided) 95%; -3.44 to 8.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.89
	Confidence Interval	(2-Sided) 95%; -3.22 to 7.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; -1.85 to 5.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.327
	Confidence Interval	(2-Sided) 95%; -5.45 to 6.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.18
	Confidence Interval	(2-Sided) 95%; -1.93 to 8.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.12
	Confidence Interval	(2-Sided) 95%; -1.56 to 5.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.60
	Confidence Interval	(2-Sided) 95%; -6.79 to 3.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.163
	Confidence Interval	(2-Sided) 95%; -5.00 to 4.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.829
	Confidence Interval	(2-Sided) 95%; -5.20 to 3.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in systolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.95
	Confidence Interval	(2-Sided) 95%; -3.27 to 7.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in systolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.71
	Confidence Interval	(2-Sided) 95%; -1.17 to 8.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in systolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.28
	Confidence Interval	(2-Sided) 95%; -0.103 to 8.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Maximum, Minimum and Average Changes in Diastolic Blood Pressure
Description	Diastolic blood pressure was measured using ambulatory blood pressure monitoring (ABPM) recorded every 15 minutes during the daytime (0600 through 2200 hours) and every hour throughout the night time (2200 through 0600 hours) on Days 1, 3, and 5 of each period. Baseline diastolic blood pressure was the average of 15-minute readings taken over 2 hours prior to dosing on Day 1 of each period. Postdose diastolic blood pressure from ABPM was summarized over 1-hour increments using the average of the 15-minute readings within these intervals. The postdose diastolic blood pressure for a day was the average diastolic blood pressure for 24 hours. The least squares (LS) mean change from baseline diastolic blood pressure is reported. LS mean was calculated using a mixed effects model and adjusted for participant, sequence, period, time, treatment, and time by treatment interaction.
Time Frame	Period 1, 2, 3: Baseline, Days 1 and 3 and 5 (postdose every 15 minutes from 0600 hours through 2200 hours and every hour from 2200 hours through 0600 hours)

Outcome Measure Data

Analysis Population Description

Randomized participants with at least 1 postdose diastolic blood pressure measurement.

Arm/Group Title	LY2216684 (Group 1)	Albuterol	LY2216684+Albuterol	LY2216684 (Group 2)	Propranolol	LY2216684+Propranolol
Arm/Group Description	Participants randomized to Group 1 who received LY2216684 administered as an 18-milligram (mg) oral dose (two 9-mg tablets) once daily (QD) on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 1 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 1 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.	Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.
Measure Participants	24	23	24	22	22	22
Day 1 Maximum Change	13.4	10.8	12.2	14.9	8.16	10.6
Day 1 Minimum Change	-17.3	-19.9	-16.2	-17.9	-26.7	-17.6
Day 1 Average Change	-0.674	-3.27	-0.873	0.481	-7.47	-1.44
Day 3 Maximum Change	13.6	11.8	12.7	15.4	6.87	12.5
Day 3 Minimum Change	-18.1	-21.5	-18.6	-17.8	-26.6	-18.8
Day 3 Average Change	-0.537	-3.10	-0.159	0.619	-7.80	-1.20
Day 5 Maximum Change	13.8	12.8	14.7	13.1	6.58	13.8
Day 5 Minimum Change	-17.0	-21.6	-20.5	-19.1	-26.6	-21.0
Day 5 Average	0.233	-3.17	-0.140	-0.631	-7.33	-1.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95%; -3.90 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; -1.91 to 4.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.199
	Confidence Interval	(2-Sided) 95%; -2.58 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; -1.34 to 4.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.68
	Confidence Interval	(2-Sided) 95%; 0.674 to 6.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 1, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.40
	Confidence Interval	(2-Sided) 95%; -0.0178 to 4.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.22
	Confidence Interval	(2-Sided) 95%; -7.83 to -0.619
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.335
	Confidence Interval	(2-Sided) 95%; -4.45 to 5.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.92
	Confidence Interval	(2-Sided) 95%; -4.81 to 0.969
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.47
	Confidence Interval	(2-Sided) 95%; -1.15 to 6.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	9.12
	Confidence Interval	(2-Sided) 95%; 4.30 to 13.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 1, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.03
	Confidence Interval	(2-Sided) 95%; 3.12 to 8.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.913
	Confidence Interval	(2-Sided) 95%; -4.65 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.444
	Confidence Interval	(2-Sided) 95%; -4.33 to 3.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.378
	Confidence Interval	(2-Sided) 95%; -2.20 to 2.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.878
	Confidence Interval	(2-Sided) 95%; -2.86 to 4.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.92
	Confidence Interval	(2-Sided) 95%; -0.966 to 6.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 3, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.94
	Confidence Interval	(2-Sided) 95%; 0.366 to 5.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.88
	Confidence Interval	(2-Sided) 95%; -6.84 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.975
	Confidence Interval	(2-Sided) 95%; -5.39 to 3.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.82
	Confidence Interval	(2-Sided) 95%; -5.30 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.60
	Confidence Interval	(2-Sided) 95%; 1.63 to 9.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.82
	Confidence Interval	(2-Sided) 95%; 3.39 to 12.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 3, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.60
	Confidence Interval	(2-Sided) 95%; 3.11 to 10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.847
	Confidence Interval	(2-Sided) 95%; -3.23 to 4.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.48
	Confidence Interval	(2-Sided) 95%; -8.17 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 1), LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the LY2216684 (Group 1) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.372
	Confidence Interval	(2-Sided) 95%; -2.88 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.90
	Confidence Interval	(2-Sided) 95%; -2.17 to 5.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; -3.62 to 5.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Albuterol, LY2216684+Albuterol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 5, where test is the LY2216684+albuterol treatment arm and reference is the albuterol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.03
	Confidence Interval	(2-Sided) 95%; 0.522 to 5.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.737
	Confidence Interval	(2-Sided) 95%; -3.90 to 5.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.95
	Confidence Interval	(2-Sided) 95%; -6.36 to 2.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	LY2216684 (Group 2), LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the LY2216684 (Group 2) treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -4.79 to 2.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the maximum changes in diastolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.25
	Confidence Interval	(2-Sided) 95%; 2.59 to 11.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the minimum changes in diastolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.58
	Confidence Interval	(2-Sided) 95%; 1.13 to 10.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Propranolol, LY2216684+Propranolol
	Comments	Difference of LS means (test minus reference) for the average changes in diastolic blood pressure on Day 5, where test is the LY2216684+propranolol treatment arm and reference is the propranolol treatment arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	5.53
	Confidence Interval	(2-Sided) 95%; 1.89 to 9.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	LY2216684 (Group 1)		Albuterol		LY2216684+Albuterol		LY2216684 (Group 2)		Propranolol		LY2216684+Propranolol
Arm/Group Description	Participants randomized to Group 1 who received LY2216684 administered as an 18-milligram (mg) oral dose (two 9-mg tablets) once daily (QD) on Days 1 through 5 with single oral doses of placebo (for albuterol) co-administered on Days 1, 3, and 5 in any treatment period.		Participants randomized to Group 1 who received who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.		Participants randomized to Group 1 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 2 mg albuterol (one 2-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.		Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of placebo (for propranolol) co-administered on Days 1, 3, and 5 in any treatment period.		Participants randomized to Group 2 who received oral doses of placebo (for LY2216684) administered QD on Days 1 through 5 with single oral doses of 40-mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.		Participants randomized to Group 2 who received LY2216684 administered as an 18-mg oral dose (two 9-mg tablets) QD on Days 1 through 5 with single oral doses of 40 mg propranolol (one 40-mg tablet) co-administered on Days 1, 3, and 5 in any treatment period.
All Cause Mortality
	LY2216684 (Group 1)		Albuterol		LY2216684+Albuterol		LY2216684 (Group 2)		Propranolol		LY2216684+Propranolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2216684 (Group 1)		Albuterol		LY2216684+Albuterol		LY2216684 (Group 2)		Propranolol		LY2216684+Propranolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/24 (0%)		0/22 (0%)		0/22 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	LY2216684 (Group 1)		Albuterol		LY2216684+Albuterol		LY2216684 (Group 2)		Propranolol		LY2216684+Propranolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/24 (54.2%)		2/24 (8.3%)		13/24 (54.2%)		9/22 (40.9%)		8/22 (36.4%)		13/22 (59.1%)
Cardiac disorders
Palpitations	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Tachycardia	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Ventricular tachycardia	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Eye disorders
Lacrimation increased	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Chapped lips	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Constipation	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Dry mouth	1/24 (4.2%)	1	0/24 (0%)	0	2/24 (8.3%)	2	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Nausea	5/24 (20.8%)	5	0/24 (0%)	0	3/24 (12.5%)	3	3/22 (13.6%)	3	0/22 (0%)	0	2/22 (9.1%)	2
Vomiting	2/24 (8.3%)	2	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
General disorders
Application site irritation	3/24 (12.5%)	3	1/24 (4.2%)	1	1/24 (4.2%)	1	1/22 (4.5%)	1	0/22 (0%)	0	3/22 (13.6%)	3
Chest pain	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Chills	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	2/22 (9.1%)	2	0/22 (0%)	0	1/22 (4.5%)	1
Fatigue	0/24 (0%)	0	1/24 (4.2%)	1	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Feeling hot	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	1/22 (4.5%)	1
Irritability	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Vessel puncture site pain	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Infections and infestations
Bronchitis	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Carbuncle	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Influenza	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Subcutaneous abscess	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Upper respiratory tract infection	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	1/22 (4.5%)	1
Injury, poisoning and procedural complications
Excoriation	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Groin pain	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Nervous system disorders
Dizziness	3/24 (12.5%)	3	0/24 (0%)	0	2/24 (8.3%)	2	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	2
Headache	3/24 (12.5%)	3	1/24 (4.2%)	2	4/24 (16.7%)	4	0/22 (0%)	0	3/22 (13.6%)	3	2/22 (9.1%)	2
Memory impairment	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Paraesthesia	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Presyncope	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	2/22 (9.1%)	2	0/22 (0%)	0
Somnolence	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	1/22 (4.5%)	1	0/22 (0%)	0	1/22 (4.5%)	1
Tremor	1/24 (4.2%)	1	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Psychiatric disorders
Agitation	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Anxiety	0/24 (0%)	0	0/24 (0%)	0	2/24 (8.3%)	2	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Depression	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Insomnia	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0
Renal and urinary disorders
Urinary hesitation	0/24 (0%)	0	0/24 (0%)	0	2/24 (8.3%)	2	1/22 (4.5%)	1	0/22 (0%)	0	2/22 (9.1%)	2
Reproductive system and breast disorders
Dysmenorrhoea	0/7 (0%)	0	0/7 (0%)	0	0/7 (0%)	0	0/10 (0%)	0	1/10 (10%)	1	0/9 (0%)	0
Genital pain	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Penile discharge	0/17 (0%)	0	0/17 (0%)	0	0/17 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/13 (0%)	0
Penile size reduced	0/17 (0%)	0	0/17 (0%)	0	1/17 (5.9%)	1	0/12 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1
Scrotal pain	1/17 (5.9%)	1	0/17 (0%)	0	0/17 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/13 (0%)	0
Testicular pain	0/17 (0%)	0	0/17 (0%)	0	0/17 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	1/22 (4.5%)	1	1/22 (4.5%)	1
Epistaxis	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Nasal congestion	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Oropharyngeal pain	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Sneezing	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Yawning	1/24 (4.2%)	1	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	1/24 (4.2%)	1	1/24 (4.2%)	1	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Dry skin	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	1/22 (4.5%)	1
Ecchymosis	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Hair disorder	0/24 (0%)	0	0/24 (0%)	0	1/24 (4.2%)	1	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Hyperhidrosis	4/24 (16.7%)	5	0/24 (0%)	0	2/24 (8.3%)	2	1/22 (4.5%)	1	0/22 (0%)	0	1/22 (4.5%)	1
Rash	0/24 (0%)	0	0/24 (0%)	0	0/24 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Urticaria	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0
Vascular disorders
Flushing	2/24 (8.3%)	2	0/24 (0%)	0	0/24 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0
Hot flush	2/24 (8.3%)	2	0/24 (0%)	0	2/24 (8.3%)	2	2/22 (9.1%)	2	0/22 (0%)	0	2/22 (9.1%)	2
Peripheral coldness	1/24 (4.2%)	1	0/24 (0%)	0	0/24 (0%)	0	0/22 (0%)	0	0/22 (0%)	0	0/22 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.