Trial Outcomes & Findings for A Study of the Effect of LY2216684 on Lorazepam (NCT NCT01275144)

NCT ID: NCT01275144

Last Updated: 2019-03-11

Results Overview

The geometric least squares mean and 90% Confidence Interval are presented. Geometric least squares mean corrected for participant, treatment and random error.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 28 participants
• Primary outcome timeframe: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post lorazepam dose
• Results posted on: 2019-03-11

Participant Flow

Participant milestones

Measure	LY2216684 + Lorazepam, Then Placebo + Lorazepam Period 1, 18 milligram (mg) dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3. Period 2, dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3.	Placebo + Lorazepam, Then LY2216684 + Lorazepam Period 1, dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3.Period 2, 18 milligram (mg) dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3.
First Intervention (6 Days) STARTED	14	14
First Intervention (6 Days) Received at Least 1 Dose of Study Drug	14	14
First Intervention (6 Days) COMPLETED	14	14
First Intervention (6 Days) NOT COMPLETED	0	0
Washout (7 Days) STARTED	14	14
Washout (7 Days) COMPLETED	14	14
Washout (7 Days) NOT COMPLETED	0	0
Second Intervention (6 Days) STARTED	14	14
Second Intervention (6 Days) COMPLETED	13	14
Second Intervention (6 Days) NOT COMPLETED	1	0

Reasons for withdrawal

Measure	LY2216684 + Lorazepam, Then Placebo + Lorazepam Period 1, 18 milligram (mg) dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3. Period 2, dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3.	Placebo + Lorazepam, Then LY2216684 + Lorazepam Period 1, dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3.Period 2, 18 milligram (mg) dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3.
Second Intervention (6 Days) Withdrawal by Subject	1	0

Baseline Characteristics

A Study of the Effect of LY2216684 on Lorazepam

Baseline characteristics by cohort

Measure	Overall n=28 Participants All randomized participants
Age, Continuous	37.9 years STANDARD_DEVIATION 13.0 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	5 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	4 Participants n=5 Participants
Race/Ethnicity, Customized White	18 Participants n=5 Participants
Region of Enrollment United States	28 Participants n=5 Participants

PRIMARY outcome

Timeframe: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post lorazepam dose

Population: All enrolled participants.

The geometric least squares mean and 90% Confidence Interval are presented. Geometric least squares mean corrected for participant, treatment and random error.

Outcome measures

Measure	LY2216684 + Lorazepam n=28 Participants Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=28 Participants Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Pharmacokinetics of Lorazepam, Maximum Plasma Concentration (Cmax)	9.620 nanograms per milliliter (ng/mL) Interval 9.178 to 10.083	10.720 nanograms per milliliter (ng/mL) Interval 10.228 to 11.236

PRIMARY outcome

Timeframe: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post lorazepam dose

Population: All enrolled participants

Outcome measures

Measure	LY2216684 + Lorazepam n=28 Participants Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=28 Participants Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Pharmacokinetics of Lorazepam, Time to Maximum Plasma Concentration (Tmax)	3.00 hours Interval 1.08 to 4.02	2.00 hours Interval 1.0 to 4.0

PRIMARY outcome

Timeframe: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post lorazepam dose

Population: All enrolled participants

The geometric least squares mean and 90% Confidence Interval are presented. Geometric least squares mean corrected for participant, treatment and random error.

Outcome measures

Measure	LY2216684 + Lorazepam n=28 Participants Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=28 Participants Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Pharmacokinetics of Lorazepam, Area Under the Plasma Concentration Curve (AUC) From Time 0 to Infinity (∞)	207 nanograms*hour per milliliter (ng*h/mL) Interval 193.0 to 222.0	199 nanograms*hour per milliliter (ng*h/mL) Interval 185.0 to 213.0

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

Participants were instructed to press the 'Yes' response button as quickly as possible every time the word 'Yes' was presented on the computer screen. Fifty stimuli were presented with a varying inter-stimulus interval of between 1 and 3.5 seconds. Participant's reaction time to the stimulus was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Simple Reaction Time Day 3, 2 hours	5.0102 millisecond (msec) Standard Error 8.8823	23.9962 millisecond (msec) Standard Error 8.8823
Change From Baseline in Cognitive Function-Simple Reaction Time Day 3, 4 hours	27.9731 millisecond (msec) Standard Error 8.8823	40.0858 millisecond (msec) Standard Error 8.8823
Change From Baseline in Cognitive Function-Simple Reaction Time Day 3, 8 hours	13.1424 millisecond (msec) Standard Error 8.8823	10.0183 millisecond (msec) Standard Error 8.8823

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

A target digit was pseudo-randomly selected and constantly displayed to the right of the computer screen. A series of 450 digits was then presented in the center of the computer screen at the rate of 150 per minute. The participant was required to press the 'Yes' button as quickly as possible every time a digit in the series matched the target digit. There were 45 targets. Percentage of target digits correctly detected was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 Obsevations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 Obsevations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Digit Vigilance Targets Detected Day 3, 2 hours	-3.5852 percentage of digits correctly detected Standard Error 1.3892	-3.5577 percentage of digits correctly detected Standard Error 1.3892
Change From Baseline in Cognitive Function-Digit Vigilance Targets Detected Day 3, 4 hours	-2.4745 percentage of digits correctly detected Standard Error 1.3892	-4.1927 percentage of digits correctly detected Standard Error 1.3892
Change From Baseline in Cognitive Function-Digit Vigilance Targets Detected Day 3, 8 hours	-2.5534 percentage of digits correctly detected Standard Error 1.3892	-1.9702 percentage of digits correctly detected Standard Error 1.3892

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

A target digit was pseudo-randomly selected and constantly displayed to the right of the computer screen. A series of 450 digits was then presented in the center of the computer screen at the rate of 150 per minute. The participant was required to press the 'Yes' button as quickly as possible every time a digit in the series matched the target digit. There were 45 targets. Speed at which a participant detected target digits was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 Observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 Observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Digit Vigilance Speed Day 3, 2 hours	20.1712 millisecond (msec) Standard Error 7.0627	12.0238 millisecond (msec) Standard Error 7.0627
Change From Baseline in Cognitive Function-Digit Vigilance Speed Day 3, 4 hours	14.7702 millisecond (msec) Standard Error 7.0627	12.1391 millisecond (msec) Standard Error 7.0627
Change From Baseline in Cognitive Function-Digit Vigilance Speed Day 3, 8 hours	9.8277 millisecond (msec) Standard Error 7.0627	2.5073 millisecond (msec) Standard Error 7.0627

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

A target digit was pseudo-randomly selected and constantly displayed to the right of the computer screen. A series of digits were then presented in the center of the computer screen at the rate of 150 per minute. The participant was required to press the 'Yes' button as quickly as possible every time a digit in the series matched the target digit. There were 45 targets. The number of false alarms (incorrect 'Yes' responses) was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Digit False Alarms Day 3, 4 hours	0.1990 Number of false alarms Standard Error 0.3122	1.0510 Number of false alarms Standard Error 0.3122
Change From Baseline in Cognitive Function-Digit False Alarms Day 3, 8 hours	0.4490 Number of false alarms Standard Error 0.3122	0.7653 Number of false alarms Standard Error 0.3122
Change From Baseline in Cognitive Function-Digit False Alarms Day 3, 2 hours	1.0204 Number of false alarms Standard Error 0.3122	0.7296 Number of false alarms Standard Error 0.3122

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

Participants were required to respond to the words 'Yes' and 'No' as they appeared on the computer screen by pressing the corresponding button as quickly as possible. There were 50 trials during which each stimulus word was chosen randomly with equal probability; there was a varying inter-stimulus interval of between 1 and 3.5 seconds. The time required to respond was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Choice Reaction Time Day 3, 2 hours	28.2448 millisecond (msec) Standard Error 12.6614	8.4745 millisecond (msec) Standard Error 12.6614
Change From Baseline in Cognitive Function-Choice Reaction Time Day 3, 4 hours	8.9837 millisecond (msec) Standard Error 12.6614	10.6866 millisecond (msec) Standard Error 12.6614
Change From Baseline in Cognitive Function-Choice Reaction Time Day 3, 8 hours	9.7930 millisecond (msec) Standard Error 12.6614	-13.1780 millisecond (msec) Standard Error 12.6614

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

Participants were required to respond to the words 'Yes' and 'No' as they appeared on the computer screen by pressing the corresponding button as quickly as possible. There were 50 trials during which each stimulus word was chosen randomly with equal probability; there was a varying inter-stimulus interval of between 1 and 3.5 seconds. The percentage of correct responses was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Choice Reaction Time Accuracy Day 3, 2 hours	-1.2292 percentage of correct responses Standard Error 0.7353	-0.4851 percentage of correct responses Standard Error 0.7353
Change From Baseline in Cognitive Function-Choice Reaction Time Accuracy Day 3, 4 hours	-1.3720 percentage of correct responses Standard Error 0.7353	-1.2708 percentage of correct responses Standard Error 0.7353
Change From Baseline in Cognitive Function-Choice Reaction Time Accuracy Day 3, 8 hours	-0.5863 percentage of correct responses Standard Error 0.7353	-1.1994 percentage of correct responses Standard Error 0.7353

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

Working memory is a sum of accuracy measures from the numeric and spatial working memory tasks (sensitivity index [SI]). Working Memory SI is based on how fast the participant responds correctly and how many are correct responses. A high score reflects someone able to hold in memory for a prolonged period. A negative change from baseline reflects impairment compared to baseline.

A series of 5 digits were presented on a computer screen, one every 1.15 seconds, for the participant to hold in memory. This was followed by a series of 30 probe digits for each of which the participant had to decide whether it had appeared in the original series of digits and press the corresponding 'Yes' or 'No' response button as quickly as possible. This procedure was repeated 2 times using 2 different series and probes. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Numeric Working Memory Sensitivity Index (SI) Day 3, 2 hours	-0.00764 Sensitivity Index (SI) Standard Error 0.02639	0.003388 Sensitivity Index (SI) Standard Error 0.02639
Change From Baseline in Cognitive Function-Numeric Working Memory Sensitivity Index (SI) Day 3, 4 hours	-0.02121 Sensitivity Index (SI) Standard Error 0.02639	-0.00511 Sensitivity Index (SI) Standard Error 0.02639
Change From Baseline in Cognitive Function-Numeric Working Memory Sensitivity Index (SI) Day 3, 8 hours	0.007112 Sensitivity Index (SI) Standard Error 0.02639	-0.01865 Sensitivity Index (SI) Standard Error 0.02639

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

A series of 5 digits were presented on a computer screen, one every 1.15 seconds, for the participant to hold in memory. This was followed by a series of 30 probe digits for each of which the participant had to decide whether it had appeared in the original series of digits and press the corresponding 'Yes' or 'No' response button as quickly as possible. This procedure was repeated a further 2 times using 2 different series and probes. The time required to press the corresponding 'Yes' or 'No' response button in response to the probe digit is presented. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Numeric Working Memory Speed Day 3, 2 hours	58.2923 milliseconds (msec) Standard Error 27.7074	72.0037 milliseconds (msec) Standard Error 27.7074
Change From Baseline in Cognitive Function-Numeric Working Memory Speed Day 3, 4 hours	8.1891 milliseconds (msec) Standard Error 27.7074	25.5894 milliseconds (msec) Standard Error 27.7074
Change From Baseline in Cognitive Function-Numeric Working Memory Speed Day 3, 8 hours	-33.6927 milliseconds (msec) Standard Error 27.7074	-14.5106 milliseconds (msec) Standard Error 27.7074

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant was given a series of words to commit to memory. Immediately after the last word was presented, the participant was given 1 minute to write as many of the words as possible in any order on a sheet of paper. The percentage of words correctly recalled (present on the original list of words) was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Immediate Word Recall Accuracy Day 3, 2 hours	-2.2751 percentage of words correctly recalled Standard Error 1.8276	-3.6767 percentage of words correctly recalled Standard Error 1.8276
Change From Baseline in Cognitive Function-Immediate Word Recall Accuracy Day 3, 4 hours	-7.2744 percentage of words correctly recalled Standard Error 1.8276	-5.8195 percentage of words correctly recalled Standard Error 1.8276
Change From Baseline in Cognitive Function-Immediate Word Recall Accuracy Day 3, 8 hours	-4.4166 percentage of words correctly recalled Standard Error 1.8276	-4.1524 percentage of words correctly recalled Standard Error 1.8276

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant was given a series of words to commit to memory. Immediately after the last word was presented, the participant was given 1 minute to write as many of the words as possible in any order on a sheet of paper. The number of words incorrectly recalled (not on the original list of words) was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Immediate Word Recall Errors Day 3, 2 hours	-0.1582 number of words incorrectly recalled Standard Error 0.1494	0.1225 number of words incorrectly recalled Standard Error 0.1494
Change From Baseline in Cognitive Function-Immediate Word Recall Errors Day 3, 4 hours	0.05605 number of words incorrectly recalled Standard Error 0.1494	0.2297 number of words incorrectly recalled Standard Error 0.1494
Change From Baseline in Cognitive Function-Immediate Word Recall Errors Day 3, 8 hours	0.05605 number of words incorrectly recalled Standard Error 0.1494	0.3011 number of words incorrectly recalled Standard Error 0.1494

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant was given a series of words to commit to memory. After a delay of approximately 15-20 minutes, the participant was given 1 minute to write as many of the words as possible in any order on a sheet of paper. The percentage of words correctly recalled (present on the original list of words) was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Delayed Word Recall Accuracy Day 3, 2 hours	-2.0338 percentage of words correctly recalled Standard Error 1.8465	-6.2980 percentage of words correctly recalled Standard Error 1.8465
Change From Baseline in Cognitive Function-Delayed Word Recall Accuracy Day 3, 4 hours	-10.8423 percentage of words correctly recalled Standard Error 1.8465	-8.2034 percentage of words correctly recalled Standard Error 1.8465
Change From Baseline in Cognitive Function-Delayed Word Recall Accuracy Day 3, 8 hours	-11.5566 percentage of words correctly recalled Standard Error 1.8465	-6.0595 percentage of words correctly recalled Standard Error 1.8465

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant was given a series of words to commit to memory. After a delay, the participant was given 1 minute to write as many of the words as possible in any order on a sheet of paper. The number of incorrect words was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Delayed Word Recall Errors Day 3, 2 hours	0.1535 number of words incorrectly recalled Standard Error 0.2448	0.6323 number of words incorrectly recalled Standard Error 0.2448
Change From Baseline in Cognitive Function-Delayed Word Recall Errors Day 3, 4 hours	0.6535 number of words incorrectly recalled Standard Error 0.2448	0.8108 number of words incorrectly recalled Standard Error 0.2448
Change From Baseline in Cognitive Function-Delayed Word Recall Errors Day 3, 8 hours	0.6177 number of words incorrectly recalled Standard Error 0.2448	0.4180 number of words incorrectly recalled Standard Error 0.2448

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

Word Recognition SI is based on how fast the participant responds correctly and how many are correct responses. SI ranging from zero (chance performance) to one (perfect accuracy). Higher SI indicates better cognitive function. A negative change from baseline reflects impairment compared to baseline.

The original words from Word Presentation plus 15 distractor words were presented one at a time in a randomized order. For each word, the participant was required to indicate whether they recognized it from the original list of words by pressing the corresponding 'Yes' or 'No' button as quickly as possible. Following each response, there was a delay of 1 second before the next word was presented. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Word Recognition Sensitivity Index (SI) Day 3, 2 hours	-0.08834 Sensitivity Index (SI) Standard Error 0.04199	-0.07719 Sensitivity Index (SI) Standard Error 0.04199
Change From Baseline in Cognitive Function-Word Recognition Sensitivity Index (SI) Day 3, 4 hours	-0.06242 Sensitivity Index (SI) Standard Error 0.04199	-0.1983 Sensitivity Index (SI) Standard Error 0.04199
Change From Baseline in Cognitive Function-Word Recognition Sensitivity Index (SI) Day 3, 8 hours	-0.1523 Sensitivity Index (SI) Standard Error 0.04199	-0.1524 Sensitivity Index (SI) Standard Error 0.04199

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The original words from Word Presentation plus 15 distractor words were presented one at a time in a randomized order. For each word, the participant was required to indicate whether they recognized it from the original list of words by pressing the corresponding 'Yes' or 'No' button as quickly as possible. Following each response, there was a delay of 1 second before the next word was presented. The time required to press the corresponding 'Yes' or 'No' response button in response to the word was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Word Recognition Speed Day 3, 2 hours	-13.7645 milliseconds (msec) Standard Error 36.5329	-6.3483 milliseconds (msec) Standard Error 36.5329
Change From Baseline in Cognitive Function-Word Recognition Speed Day 3, 4 hours	-39.5052 milliseconds (msec) Standard Error 36.5329	-25.9919 milliseconds (msec) Standard Error 36.5329
Change From Baseline in Cognitive Function-Word Recognition Speed Day 3, 8 hours	-40.9574 milliseconds (msec) Standard Error 36.5329	-133.24 milliseconds (msec) Standard Error 36.5329

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

Picture Recognition SI is based on how fast the participant responds correctly and how many are correct responses. SI ranging from zero (chance performance) to one (perfect accuracy). Higher SI indicates better cognitive function. A negative change from baseline reflects impairment compared to baseline.

The original pictures from Picture Presentation plus 20 distractor pictures were presented one at a time. For each picture, the participant was required to indicate whether they recognized it from the original series of pictures by pressing the corresponding 'Yes' or 'No' button as quickly as possible. Following the response, there was a delay of 1 second before the next pictures was presented. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Picture Recognition Sensitivity Index (SI) Day 3, 2 hours	0.02080 Sensitivity Index Standard Error 0.04778	-0.03440 Sensitivity Index Standard Error 0.04778
Change From Baseline in Cognitive Function-Picture Recognition Sensitivity Index (SI) Day 3, 4 hours	-0.04431 Sensitivity Index Standard Error 0.04778	-0.06015 Sensitivity Index Standard Error 0.04778
Change From Baseline in Cognitive Function-Picture Recognition Sensitivity Index (SI) Day 3, 8 hours	-0.1054 Sensitivity Index Standard Error 0.04778	-0.09855 Sensitivity Index Standard Error 0.04778

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The original pictures from Picture Presentation plus 20 distractor pictures were presented one at a time. For each picture, the participant was required to indicate whether they recognized it from the original series of pictures by pressing the corresponding 'Yes' or 'No' button as quickly as possible. Following the response, there was a delay of 1 second before the next pictures was presented. The time required to press the corresponding 'Yes' or 'No' response button in response to the picture was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Picture Recognition Speed Day 3, 2 hours	57.2341 milliseconds (msec) Standard Error 37.5217	144.67 milliseconds (msec) Standard Error 37.5217
Change From Baseline in Cognitive Function-Picture Recognition Speed Day 3, 4 hours	51.7809 milliseconds (msec) Standard Error 37.5217	62.2059 milliseconds (msec) Standard Error 37.5217
Change From Baseline in Cognitive Function-Picture Recognition Speed Day 3, 8 hours	-59.9669 milliseconds (msec) Standard Error 37.5217	-23.2941 milliseconds (msec) Standard Error 37.5217

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant used a joystick to track a randomly moving target on the computer screen. The distance from the target was measured. Participant's response was measured twice. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Tracking Average Distance From Target Day 3, 2 hours	0.3850 millimeters (mm) Standard Error 2.4910	-0.3614 millimeters (mm) Standard Error 2.4910
Change From Baseline in Cognitive Function-Tracking Average Distance From Target Day 3, 4 hours	6.1672 millimeters (mm) Standard Error 2.4910	-0.1104 millimeters (mm) Standard Error 2.4910
Change From Baseline in Cognitive Function-Tracking Average Distance From Target Day 3, 8 hours	0.3743 millimeters (mm) Standard Error 2.4910	-0.6036 millimeters (mm) Standard Error 2.4910

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The ability to stand upright without moving was assessed using equipment modeled on the Wright Ataxia-meter. To measure movements, a cord was attached to the participant who was required to stand for one minute, as still as possible, with feet apart and eyes closed. The amount of sway is expressed as the total angular movement calibrated in units of one-third degree of angle of sway.

The amount of sway is expressed as the total angular movement in the antero-posterior plane and calibrated in units of one-third degree of angle of sway. Higher result indicates better postural stability. A negative change from baseline reflects impairment compared to baseline. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Postural Stability Day 3, 2 hours	-1.5464 1/3 degree of angle of sway Standard Error 2.0012	9.1392 1/3 degree of angle of sway Standard Error 2.0012
Change From Baseline in Cognitive Function-Postural Stability Day 3, 4 hours	0.1965 1/3 degree of angle of sway Standard Error 2.0012	2.1857 1/3 degree of angle of sway Standard Error 2.0012
Change From Baseline in Cognitive Function-Postural Stability Day 3, 8 hours	-0.9571 1/3 degree of angle of sway Standard Error 2.0012	-1.6429 1/3 degree of angle of sway Standard Error 2.0012

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant was required to rate how they felt "at this moment" on sixteen 10 centimeter visual analogue scales. The scale endpoints were anchored using polar word pairs such as 'drowsy-alert', 'clumsy-well coordinated', 'mentally slow-quick witted' and 'incompetent-proficient'. Responses from the 16 scales were scored to yield 3 main factors: Self-rated Alertness, Self-rated Contentment, and Self-rated Calmness. The possible range of scores are 0 to 100 for each factor and are represented in millimeters on the 10 centimeter line with higher numbers indicating greater alertness. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Self-rated Alertness Day 3, 2 hours	5.1411 millimeters (mm) Standard Error 2.4896	3.2597 millimeters (mm) Standard Error 2.4896
Change From Baseline in Cognitive Function-Self-rated Alertness Day 3, 4 hours	3.6887 millimeters (mm) Standard Error 2.4896	4.0018 millimeters (mm) Standard Error 2.4896
Change From Baseline in Cognitive Function-Self-rated Alertness Day 3, 8 hours	3.7205 millimeters (mm) Standard Error 2.4896	3.1287 millimeters (mm) Standard Error 2.4896

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

The participant was required to rate how they felt "at this moment" on sixteen 10 centimeter visual analogue scales. The scale endpoints were anchored using polar word pairs such as 'drowsy-alert', 'clumsy-well coordinated', 'mentally slow-quick witted' and 'incompetent-proficient'. Responses from the 16 scales were scored to yield 3 main factors: Self-rated Alertness, Self-rated Contentment, and Self-rated Calmness. The possible range of scores are 0 to 100 for each factor and are represented in millimeters on the 10 centimeter line with higher numbers indicating greater contentment. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Self-rated Contentment Day 3, 2 hours	3.1100 millimeters (mm) Standard Error 1.9527	1.3686 millimeters (mm) Standard Error 1.9527
Change From Baseline in Cognitive Function-Self-rated Contentment Day 3, 4 hours	3.0171 millimeters (mm) Standard Error 1.9527	3.3829 millimeters (mm) Standard Error 1.9527
Change From Baseline in Cognitive Function-Self-rated Contentment Day 3, 8 hours	3.3743 millimeters (mm) Standard Error 1.9527	0.01857 millimeters (mm) Standard Error 1.9527

SECONDARY outcome

Timeframe: Baseline, 2, 4, 8 hours on Day 3

Population: All enrolled participants

The participant was required to rate how they felt "at this moment" on sixteen 10 centimeter visual analogue scales. The scale endpoints were anchored using polar word pairs such as 'drowsy-alert', 'clumsy-well coordinated', 'mentally slow-quick witted' and 'incompetent-proficient'. Responses from the 16 scales were scored to yield 3 main factors: Self-rated Alertness, Self-rated Contentment, and Self-rated Calmness. The possible range of scores are 0 to 100 for each factor and are represented in millimeters on the 10 centimeter line with higher numbers indicating greater calmness. Least squares means were adjusted for baseline, period, sequence, time, treatment and treatment*time.

Outcome measures

Measure	LY2216684 + Lorazepam n=56 observations Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3	Placebo + Lorazepam n=56 observations Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3
Change From Baseline in Cognitive Function-Self-rated Calmness Day 3, 2 hours	-0.9651 millimeters (mm) Standard Error 1.9110	0.3401 millimeters (mm) Standard Error 1.9110
Change From Baseline in Cognitive Function-Self-rated Calmness Day 3, 4 hours	1.4099 millimeters (mm) Standard Error 1.9110	-1.3564 millimeters (mm) Standard Error 1.9110
Change From Baseline in Cognitive Function-Self-rated Calmness Day 3, 8 hours	3.4635 millimeters (mm) Standard Error 1.9110	0.3936 millimeters (mm) Standard Error 1.9110

Adverse Events

LY2216684

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

LY2216684 + Lorazepam

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Placebo + Lorazepam

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	LY2216684 n=28 participants at risk Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3; Serious and Other Adverse Events assessed on Days 1 and 2	Placebo n=28 participants at risk Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3; Serious and Other Adverse Events assessed on Days 1 and 2	LY2216684 + Lorazepam n=28 participants at risk Oral 18 mg dose of LY2216684 on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3; Serious and Other Adverse Events assessed on Days 3-6	Placebo + Lorazepam n=28 participants at risk Oral dose of Placebo on Days 1-6 with a single oral 1 mg dose of lorazepam on Day 3; Serious and Other Adverse Events assessed on Days 3-6
Cardiac disorders Palpitations	7.1% 2/28 • Number of events 2	0.00% 0/28	0.00% 0/28	0.00% 0/28
Ear and labyrinth disorders Tinnitus	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28
Gastrointestinal disorders Constipation	3.6% 1/28 • Number of events 1	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28
Gastrointestinal disorders Diarrhoea	0.00% 0/28	0.00% 0/28	0.00% 0/28	7.1% 2/28 • Number of events 2
Gastrointestinal disorders Dyspepsia	3.6% 1/28 • Number of events 1	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28
Gastrointestinal disorders Nausea	14.3% 4/28 • Number of events 4	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1
General disorders Chills	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/28
General disorders Suprapubic pain	3.6% 1/28 • Number of events 1	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28
Infections and infestations Conjunctivitis viral	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28
Infections and infestations Upper respiratory tract infection	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	3.6% 1/28 • Number of events 1
Metabolism and nutrition disorders Decreased appetite	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/28
Musculoskeletal and connective tissue disorders Groin pain	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/28
Nervous system disorders Dizziness	14.3% 4/28 • Number of events 4	0.00% 0/28	0.00% 0/28	0.00% 0/28
Nervous system disorders Dizziness postural	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28
Nervous system disorders Headache	10.7% 3/28 • Number of events 3	0.00% 0/28	3.6% 1/28 • Number of events 1	3.6% 1/28 • Number of events 1
Nervous system disorders Lethargy	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/28
Nervous system disorders Somnolence	7.1% 2/28 • Number of events 2	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28
Psychiatric disorders Abnormal dreams	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28
Renal and urinary disorders Chromaturia	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28
Renal and urinary disorders Dysuria	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/28
Renal and urinary disorders Semenuria	0.00% 0/23	0.00% 0/23	4.3% 1/23 • Number of events 1	0.00% 0/23
Renal and urinary disorders Urinary hesitation	25.0% 7/28 • Number of events 7	0.00% 0/28	0.00% 0/28	0.00% 0/28
Reproductive system and breast disorders Erection increased	0.00% 0/23	0.00% 0/23	4.3% 1/23 • Number of events 1	0.00% 0/23
Reproductive system and breast disorders Penis disorder	0.00% 0/23	0.00% 0/23	4.3% 1/23 • Number of events 1	0.00% 0/23
Reproductive system and breast disorders Scrotal pain	0.00% 0/23	0.00% 0/23	4.3% 1/23 • Number of events 1	0.00% 0/23
Reproductive system and breast disorders Testicular pain	0.00% 0/23	0.00% 0/23	4.3% 1/23 • Number of events 1	0.00% 0/23
Reproductive system and breast disorders Testicular retraction	4.3% 1/23 • Number of events 1	0.00% 0/23	0.00% 0/23	0.00% 0/23
Respiratory, thoracic and mediastinal disorders Nasal congestion	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/28
Vascular disorders Hot flush	7.1% 2/28 • Number of events 2	0.00% 0/28	0.00% 0/28	0.00% 0/28

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: GT60