A Study of LY2216684 and Theophylline in Healthy Subjects

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01263106
• Collaborator: (none)
• Enrollment: 21
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 20.6

Study Details

Study Description

Brief Summary

The primary objective of this study is to confirm that LY2216684 is not an inhibitor of cytochrome P450 1A2 (CYP1A2) in healthy participants using theophylline as a probe substrate for the enzyme. Because LY2216684 has been observed to increase heart rate in some healthy participants, this study will also assess heart rate when coadministered with theophylline.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: LY2216684; Drug: Theophylline	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of LY2216684 on the Pharmacokinetics of Theophylline in Healthy Subjects
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Theophylline, LY2216684 + Theophylline Period 1: single 200-milligram (mg) theophylline oral dose on Day 1; Washout period of at least 7 days; Period 2: 18 mg LY2216684 orally, once daily on Days 1-5 with single 200-mg theophylline oral dose coadministered on Day 3	Drug: LY2216684; 18-mg LY2216684 oral dose; Drug: Theophylline; 200-mg theophylline oral dose
Experimental: LY2216684 + Theophylline, Theophylline Period 1: 18 mg LY2216684 orally, once daily on Days 1-5 with single 200-mg theophylline oral dose coadministered on Day 3; Washout period of at least 7 days; Period 2: single 200-mg theophylline oral dose on Day 1	Drug: LY2216684; 18-mg LY2216684 oral dose; Drug: Theophylline; 200-mg theophylline oral dose

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of Theophylline [Predose 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-administration of theophylline on Days 1 and 3]

   The Least Squares (LS) geometric mean was based on AUC0-∞. The AUC for theophylline was calculated on Day 1 of a given period when theophylline was administered alone and on Day 3 of another period when theophylline was coadministered with LY2216684.

2. Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Theophylline [Predose 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-administration of theophylline on Days 1 and 3]

   The Least Squares (LS) geometric mean was based on Cmax for theophylline on Day 1 of a given period when theophylline was administered alone and on Day 3 of another period when theophylline was coadministered with LY2216684.

3. Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Theophylline [Predose 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-administration of theophylline on Days 1 and 3]

   This outcome was measured based on Tmax for theophylline on Day 1 of a given period when theophylline was administered alone and on Day 3 of another period when theophylline was coadministered with LY2216684.

Secondary Outcome Measures

1. Mean Change From Baseline in Heart Rate: 200 mg Theophylline [Baseline, Day 1]

2. Mean Change From Baseline in Heart Rate: 18 mg LY221684 + 200 mg Theophylline [Baseline, Day 1, Day 3]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Are overtly healthy males or females, 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 both during the study and for 1 month following the last dose of study drug; or are 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 mass International Units per milliliter [mIU/mL]).

• Have 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 sitting blood pressure and pulse rate as determined by the investigator.

• Are reliable and willing to be 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 investigator site personnel directly affiliated with this study and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.

• 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, theophylline, 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 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 within 14 days prior to dosing unless deemed acceptable by the investigator and Sponsor's medical monitor.

• Use of any drugs or substances that are known to be substrates, inducers, or inhibitors of cytochrome P450 1A2 (CYP1A2) within 30 days prior to dosing.

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

• Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption for 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 and chocolate 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.	Dallas	Texas	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: NCT01263106
• Other Study ID Numbers: 12594; H9P-EW-LNCE
• First Posted: Dec 20, 2010
• Last Update Posted: Jul 8, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Theophylline

Study Results

Participant Flow

Arm/Group Title	Theophylline Alone, Then LY2216684 + Theophylline	LY2216684 + Theophylline, Then Theophylline Alone
Arm/Group Description	Period 1: single 200 mg theophylline oral dose on Day 1; Washout period of at least 7 days; Period 2: 18 mg LY2216684 orally once daily on Days 1-5. Single dose of 200 mg theophylline coadministered on Day 3.	Period 1: 18 mg LY2216684 orally once daily on Days 1-5. Single dose of 200 mg theophylline coadministered on Day 3.Washout period of at least 7 days; Period 2: single 200 mg theophylline oral dose on Day 1
Period Title: Period 1 (7 Days)
STARTED	11	10
COMPLETED	11	10
NOT COMPLETED	0	0
Period Title: Period 1 (7 Days)
STARTED	11	10
COMPLETED	10	9
NOT COMPLETED	1	1
Period Title: Period 1 (7 Days)
STARTED	10	9
COMPLETED	10	9
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All started participants.
Overall Participants	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.2 (6.9)
Sex: Female, Male (Count of Participants)
Female	9 42.9%
Male	12 57.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 57.1%
Not Hispanic or Latino	9 42.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 33.3%
White	14 66.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of Theophylline
Description	The Least Squares (LS) geometric mean was based on AUC0-∞. The AUC for theophylline was calculated on Day 1 of a given period when theophylline was administered alone and on Day 3 of another period when theophylline was coadministered with LY2216684.
Time Frame	Predose 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-administration of theophylline on Days 1 and 3

Outcome Measure Data

Analysis Population Description

The safety population included participants who were randomized, received study drug, and had at least 1 post-dose safety assessment.

Arm/Group Title	Theophylline Alone	LY2216684 + Theophylline
Arm/Group Description	Single 200 mg theophylline oral dose on Day 1.	Oral dose of 18 mg LY2216684, once daily on Days 1-5 with single 200 mg theophylline dose coadministered on Day 3.
Measure Participants	20	20
Geometric Mean (90% Confidence Interval) [nanogram*hour per milliliter (ng*h/mL)]	70200	78700

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline Alone, LY2216684 + Theophylline
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LS Means
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 90%; 1.05 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Theophylline
Description	The Least Squares (LS) geometric mean was based on Cmax for theophylline on Day 1 of a given period when theophylline was administered alone and on Day 3 of another period when theophylline was coadministered with LY2216684.
Time Frame	Predose 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-administration of theophylline on Days 1 and 3

Outcome Measure Data

Analysis Population Description

The safety population included participants who were randomized, received study drug, and had at least 1 post-dose safety assessment.

Arm/Group Title	Theophylline	LY2216684 + Theophylline
Arm/Group Description	Single 200 mg theophylline oral dose on Day 1.	Oral dose of 18 mg LY2216684, once daily on Days 1-5 with single 200 mg theophylline dose coadministered on Day 3.
Measure Participants	20	20
Geometric Mean (90% Confidence Interval) [nanogram per milliliter (ng/mL)]	3174.35	3054.84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline Alone, LY2216684 + Theophylline
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LS Means
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.92 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Theophylline
Description	This outcome was measured based on Tmax for theophylline on Day 1 of a given period when theophylline was administered alone and on Day 3 of another period when theophylline was coadministered with LY2216684.
Time Frame	Predose 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-administration of theophylline on Days 1 and 3

Outcome Measure Data

Analysis Population Description

The safety population included participants who were randomized, received study drug, and had at least 1 post-dose safety assessment.

Arm/Group Title	Theophylline	LY2216684 + Theophylline
Arm/Group Description	Single 200 mg theophylline oral dose on Day 1.	Oral dose of 18 mg LY2216684, once daily on Days 1-5 with single 200 mg theophylline dose coadministered on Day 3.
Measure Participants	19	19
Median (Full Range) [hour (h)]	12.00	12.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Theophylline Alone, LY2216684 + Theophylline
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -3.00 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline in Heart Rate: 200 mg Theophylline
Time Frame	Baseline, Day 1

Outcome Measure Data

Analysis Population Description

The safety population included participants who were randomized, received study drug, and had at least 1 post-dose safety assessment.

Arm/Group Title	Theophylline
Arm/Group Description	Single 200 mg theophylline oral dose on Day 1.
Measure Participants	20
Day 1 (-2 to 0 hours)	74.1 (8.9)
Day 1 (23 to 24 hours)	82.7 (9.5)

5. Secondary Outcome

Title	Mean Change From Baseline in Heart Rate: 18 mg LY221684 + 200 mg Theophylline
Time Frame	Baseline, Day 1, Day 3

Outcome Measure Data

Analysis Population Description

The safety population included participants who were randomized, received study drug, and had at least 1 post-dose safety assessment.

Arm/Group Title	18 mg LY2216684 + 200 mg Theophylline
Arm/Group Description	Oral dose of 18 mg LY2216684, once daily on Days 1-5 with single 200 mg theophylline dose coadministered on Day 3.
Measure Participants	20
Day 1 (-2 to 0 hr)	70.1 (7.2)
Day 1 (23 to 24 hr)	89.6 (9.1)
Day 3 (-2 to 0 hr)	74.1 (8.9)
Day 3 (23 to 24 hr)	95.7 (10.7)

Adverse Events

Adverse Event Reporting Description	During Period 1: 1 participant took theophylline alone but was not given LY + theophylline and 1 participant took LY + theophylline but was not given theophylline alone.
Arm/Group Title	LY2216684		Theophylline		LY2216684 + Theophylline
Arm/Group Description	18 mg LY2216684 orally		single 200-mg theophylline oral dose		18 mg LY2216684 orally with single 200-mg theophylline oral dose coadministered
All Cause Mortality
	LY2216684		Theophylline		LY2216684 + Theophylline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2216684		Theophylline		LY2216684 + Theophylline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	LY2216684		Theophylline		LY2216684 + Theophylline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/20 (20%)		6/20 (30%)		7/20 (35%)
Cardiac disorders
Palpitations	2/20 (10%)	2	0/20 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Constipation	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
Gastrooesophageal reflux disease	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
Nausea	3/20 (15%)	3	0/20 (0%)	0	0/20 (0%)	0
Vomiting	3/20 (15%)	3	0/20 (0%)	0	0/20 (0%)	0
General disorders
Chills	1/20 (5%)	1	0/20 (0%)	0	1/20 (5%)	1
Feeling jittery	1/20 (5%)	1	0/20 (0%)	0	1/20 (5%)	1
Thirst	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Vessel puncture site pain	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Infections and infestations
Pharyngitis	0/20 (0%)	0	2/20 (10%)	2	0/20 (0%)	0
Nervous system disorders
Dizziness	3/20 (15%)	3	0/20 (0%)	0	2/20 (10%)	2
Headache	1/20 (5%)	1	1/20 (5%)	1	2/20 (10%)	2
Paraesthesia	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
Somnolence	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
Psychiatric disorders
Anxiety	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Reproductive system and breast disorders
Dysmenorrhoea	0/20 (0%)	0	1/20 (5%)	1	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Epistaxis	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
Rhinorrhoea	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Rash papular	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Vascular disorders
Flushing	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1

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.